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Normal Cardiac Structure
and Function
1
Ja cob E. Lemieux
Ela zer R. Edelma n
Ga ry R. Stricha rtz
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Cardiac Anatomy and Histology
Pericardium
Sur ace Anatomy o the Heart
Internal Structure o the Heart
Impulse-Conducting System
Cardiac Innervation
Cardiac Vessels
Histology o Ventricular
Myocardial Cells
Basic Electrophysiology
Ion Movement and Channels
Resting Potential
Action Potential
Re ractory Periods
Impulse Conduction
Normal Sequence o Cardiac
Depolarization
Excitation–Contraction Coupling
Contractile Proteins in the
Myocyte
Calcium-Induced Calcium
Release and the Contractile
Cycle
Introduction to Cardiac Signaling
Systems
β-Adrenergic and Cholinergic
Signaling
K
nowledge o normal structure and unction o the heart is
crucial to understanding diseases that a f ict the cardiovascular system. The purpose o this chapter is to describe the heart’s
basic anatomy, its electrical system, and the cellular and molecular
mechanisms o contraction that allow the heart to serve its critical
unctions.
CARDIAC ANATOMY AND HISTOLOGY
Although the study o cardiac anatomy dates back to ancient
times, interest in this eld has recently gained momentum.
The application o sophisticated cardiac imaging techniques such as coronary angiography, echocardiography,
computed tomography, and magnetic resonance imaging
requires an intimate knowledge o the spatial relationships
o cardiac structures. Such in ormation also proves helpul in understanding the pathophysiology o heart disease.
This section emphasizes the aspects o cardiac anatomy
that are important to the clinician—that is, the “ unctional”
anatomy.
Pericardium
The heart and roots o the great vessels are enclosed by a
broserous sac called the pericardium (Fig. 1-1). This structure consists o two layers: a strong outer brous layer and
an inner serosal layer. The inner serosal layer adheres to the
external wall o the heart and is called the visceral pericardium. The visceral pericardium ref ects back on itsel and
lines the outer brous layer, orming the parietal pericardium. The space between the visceral and parietal layers
contains a thin lm o pericardial f uid that allows the heart
to beat in a minimal- riction environment.
1
2
Chapter 1
The pericardium is attached to the sternum and the mediastinal portions o the
right and le t pleurae. Its many connections
to the surrounding structures keep the pericardial sac rmly anchored within the thorax and thereby help to maintain the heart in
its normal position.
Emanating rom the pericardium in a
superior direction are the aorta, the pulmonary artery, and the superior vena cava (see
Fig. 1-1). The in erior vena cava projects
through the pericardium in eriorly.
S upe rior
ve na cava
Aorta
Pulmona ry
a rte ry
He a rt within
pe rica rdium
Infe rior
ve na cava
Dia phra gm
FIGURE 1-1. The position of the heart in the chest.
The superior vena cava, aorta, and pulmonary artery
exit superiorly, whereas the inferior vena cava projects
inferiorly.
Surface Anatomy of the Heart
The heart is shaped roughly like a cone and
consists o our muscular chambers. The
right and le t ventricles are the main pumping chambers. The less muscular right and le t
atria deliver blood to their respective ventricles.
Several terms are used to describe the heart’s sur aces and borders (Fig. 1-2). The apex is
ormed by the tip o the le t ventricle, which points in eriorly, anteriorly, and to the le t. The
base or posterior sur ace o the heart is ormed by the atria, mainly the le t, and lies between
the lung hila. The anterior sur ace o the heart is shaped by the right atrium and ventricle.
Because the le t atrium and ventricle lie more posteriorly, they orm only a small strip o this
anterior sur ace. The inferior sur ace o the heart is ormed by both ventricles, primarily the
le t. This sur ace o the heart lies along the diaphragm; hence, it is also re erred to as the
diaphragmatic sur ace.
Observing the chest rom an anteroposterior view (as on a chest radiograph; see
Chapter 3), our recognized borders o the heart are apparent. The right border is established by the right atrium and is almost in line with the superior and in erior venae cavae.
The in erior border is nearly horizontal and is ormed mainly by the right ventricle, with
a slight contribution rom the le t ventricle near the apex. The le t ventricle and a portion
o the le t atrium make up the le t border o the heart, whereas the superior border is
shaped by both atria. From this description o the sur ace o the heart emerges two basic
“rules” o normal cardiac anatomy: (1) right-sided structures lie mostly anterior to their
le t-sided counterparts and (2) atrial chambers are located mostly to the right o their corresponding ventricles.
Internal Structure of the Heart
Four major valves in the normal heart direct blood f ow in a orward direction and prevent
backward leakage. The atrioventricular (AV) valves (tricuspid and mitral) separate the atria
and ventricles, whereas the semilunar valves (pulmonic and aortic) separate the ventricles
rom the great arteries (Fig. 1-3). All our heart valves are attached to the brous cardiac
skeleton, which is composed o dense connective tissue. The cardiac skeleton also serves as
a site o attachment or the ventricular and atrial muscles.
The sur ace o the heart valves and the interior sur ace o the chambers are lined by
a single layer o endothelial cells, termed the endocardium. The subendocardial tissue
contains broblasts, elastic and collagenous bers, veins, nerves, and branches o the conducting system and is continuous with the connective tissue o the heart muscle layer, the
myocardium. The myocardium is the thickest layer o the heart and consists o bundles o
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Normal Cardiac Structure and Function
Bra chioce pha lic a rte ry
Le ft common
ca rotid a rte ry
S upe rior ve na cava
Le ft s ubclavia n
a rte ry
As ce nding a orta
Le ft pulmona ry
a rte ry
Right s upe rior
pulmona ry a rte ry
Right infe rior
pulmona ry a rte ry
Le ft pulmona ry
ve ins
Right
pulmona ry ve ins
Pulmona ry trunk
Le ft a tria l a ppe nda ge
Right a tria l
a ppe nda ge
Le ft ve ntricle
Right a trium
Infe rior ve na cava
Right ve ntricle
A
Apex of he a rt
Infe rior he a rt borde r
Le ft common
ca rotid a rte ry
Bra chioce pha lic
a rte ry
Le ft s ubclavia n
a rte ry
Arch of a orta
Le ft pulmona ry
a rte ry
S upe rior ve na cava
Le ft s upe rior
pulmona ry ve in
Right pulmona ry
a rte ry
Le ft infe rior
pulmona ry ve in
Right s upe rior
pulmona ry ve in
Le ft a trium
Right infe rior
pulmona ry ve in
Right a trium
Corona ry
s ulcus
Infe rior ve na
cava
Le ft
ve ntricle
Corona ry
s inus
B
Right ve ntricle
Infe rior he a rt borde r
FIGURE 1-2. The heart and great vessels. A. The anterior view. B. The posterior aspect (or base), as viewed
from the back. (From Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy, 7th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2014:137–138.)
3
4
Chapter 1
Ante rio r
Pulmonic
va lve
Aortic
va lve
Tricus pid
va lve
Mitra l
va lve
Annulus
fibros us
Annulus
fibros us
Po s te rio r
FIGURE 1-3. The four heart valves
viewed from above with atria removed.
The f gure depicts the period o
ventricular f lling (diastole) during which
the tricuspid and mitral valves are open
and the semilunar valves (pulmonic and
aortic) are closed. Each annulus f brosus
surrounding the mitral and tricuspid
valves is thicker than those surrounding
the pulmonic and aortic valves; all our
contribute to the heart’s f brous skeleton,
which is composed o dense connective
tissue.
cardiac muscle cells, the histology o which is described later in the chapter. External to the
myocardium is a layer o connective tissue and adipose tissue through which pass the larger
blood vessels and nerves that supply the heart muscle. The epicardium is the outermost
layer o the heart and is identical to, and just another term or, the visceral pericardium
previously described.
Right Atrium and Ventricle
Opening into the right atrium are the superior and in erior venae cavae and the coronary
sinus (Fig. 1-4). The venae cavae return deoxygenated blood rom the systemic veins into the
right atrium, whereas the coronary sinus carries venous return rom the coronary arteries.
The interatrial septum orms the posteromedial wall o the right atrium and separates it rom
the le t atrium. The tricuspid valve is located in the f oor o the atrium and opens into the
right ventricle.
The right ventricle (see Fig. 1-4) is roughly triangular in shape, and its superior aspect
orms a cone-shaped outf ow tract, which leads to the pulmonary artery. Although the inner
wall o the outf ow tract is smooth, the rest o the ventricle is covered by a number o irregular
bridges (termed trabeculae carneae) that give the right ventricular wall a spongelike appearance. A large trabecula that crosses the ventricular cavity is called the moderator band. It
carries a component o the right bundle branch o the conducting system to the ventricular
muscle.
The right ventricle contains three papillary muscles, which project into the chamber and
via their thin, stringlike chordae tendineae attach to the edges o the tricuspid valve leaf ets.
The leaf ets, in turn, are attached to the brous ring that supports the valve between the right
atrium and ventricle. Contraction o the papillary muscles prior to other regions o the ventricle tightens the chordae tendineae, helping to align and restrain the leaf ets o the tricuspid
valve as they are orced closed. This action prevents blood rom regurgitating into the right
atrium during ventricular contraction.
At the apex o the right ventricular outf ow tract is the pulmonic valve, which leads to the
pulmonary artery. This valve consists o three cusps attached to a brous ring. During relaxation o the ventricle, elastic recoil o the pulmonary arteries orces blood back toward the
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Normal Cardiac Structure and Function
5
Pulmona ry a rte ry
Aorta
Pulmonic va lve
S upe rior ve na cava
Inte rve ntricula r s e ptum
Right a trium
Mode ra tor
ba nd
Tra be cula e
ca rne a e
Infe rior ve na cava
Corona ry s inus
Tricus pid va lve
Right ve ntricle
Pa pilla ry mus cle s
FIGURE 1-4. Interior structures of the right atrium and right ventricle. (Modif ed rom Goss CM. Gray’s
Anatomy. 29th ed. Philadelphia, PA: Lea & Febiger; 1973:547.)
heart, distending the valve cusps toward one another. This action closes the pulmonic valve
and prevents regurgitation o blood back into the right ventricle.
Left Atrium and Ventricle
Entering the posterior hal o the left atrium are the our pulmonary veins (Fig. 1-5). The
wall o the le t atrium is about 2 mm thick, being slightly greater than that o the right
atrium. The mitral valve opens into the le t ventricle through the in erior wall o the le t
atrium.
The cavity o the left ventricle is approximately cone shaped and longer than that o the
right ventricle. In a healthy adult heart, the wall thickness is 9 to 11 mm, roughly three times
that o the right ventricle. The aortic vestibule is a smooth-walled part o the le t ventricular
cavity located just in erior to the aortic valve. In erior to this region, most o the ventricle is
covered by trabeculae carneae, which are ner and more numerous than those in the right
ventricle.
The le t ventricular chamber (see Fig. 1-5B) contains two large papillary muscles. These
are larger than their counterparts in the right ventricle, and their chordae tendineae are thicker
but less numerous. The chordae tendineae o each papillary muscle distribute to both leaf ets
o the mitral valve. Similar to the case in the right ventricle, tensing o the chordae tendineae
during le t ventricular contraction helps restrain and align the mitral leaf ets, enabling them
to close properly and preventing the backward leakage o blood.
The aortic valve separates the le t ventricle rom the aorta. Surrounding the aortic valve
opening is a brous ring to which is attached the three cusps o the valve. Just above the
right and le t aortic valve cusps in the aortic wall are the origins o the right and le t coronary
arteries (see Fig. 1-5B).
Interventricular Septum
The interventricular septum is the thick wall between the le t and right ventricles. It is composed o a muscular and a membranous part (see Fig. 1-5B). The margins o this septum
can be traced on the sur ace o the heart by ollowing the anterior and posterior interventricular grooves. Owing to the greater hydrostatic pressure within the le t ventricle, the large
6
Chapter 1
Pulmona ry ve ins
Le ft a trium
Le ft a tria l
a ppe nda ge
Fibrous ring of
le ft AV orifice
Chorda e te ndine a e
Le ft ve ntricle
Pa pilla ry mus cle s
Ante rior cus p of mitra l va lve
To a ortic ve s tibule
A
Orifice of right corona ry a rte ry
As ce nding a orta
Pos te rior cus p of a ortic va lve
Orifice of le ft
corona ry a rte ry
Le ft cus p of
a ortic va lve
Pulmona ry a rte ry
Right a ortic s inus
Right cus p of a ortic va lve
Inte rve ntricula r s e ptum,
me mbra nous pa rt
Chorda e te ndine a e
Inte rve ntricula r
s e ptum, mus cula r pa rt
Ante rior cus p of mitra l va lve
Ante rior pa pilla ry mus cle
Right ve ntricle
Pos te rior
pa pilla ry mus cle
Tra be cula e ca rne a e
B
FIGURE 1-5. Interior structures of the left atrium and left ventricle. A. The le t atrium and le t ventricular (LV) in ow
region. B. Interior structures o the LV cavity. (Modif ed rom Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy,
7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:142–143.)
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Normal Cardiac Structure and Function
7
muscular portion o the septum bulges toward the right ventricle. The small, oval-shaped
membranous part o the septum is thin and located just in erior to the cusps o the aortic
valve.
To summarize the unctional anatomic points presented in this section, the ollowing is a
review o the path o blood f ow: deoxygenated blood is delivered to the heart through the
in erior and superior venae cavae, which enter into the right atrium. Flow continues through
the tricuspid valve ori ce into the right ventricle. Contraction o the right ventricle propels the
blood across the pulmonic valve to the pulmonary artery and lungs, where carbon dioxide is
released and oxygen is absorbed. The oxygen-rich blood returns to the heart through the pulmonary veins to the le t atrium and then passes across the mitral valve into the le t ventricle.
Contraction o the le t ventricle pumps the oxygenated blood across the aortic valve into the
aorta, rom which it is distributed to all other tissues o the body.
Impulse-Conducting System
The impulse-conducting system (Fig. 1-6) consists o specialized cells that initiate the heartbeat and electrically coordinate contractions o the heart chambers. The sinoatrial (SA) node
is a small mass o specialized cardiac muscle bers in the wall o the right atrium. It is located
to the right o the superior vena cava entrance and normally initiates the electrical impulse
or contraction. The atrioventricular (AV) node lies beneath the endocardium in the in eroposterior part o the interatrial septum.
Distal to the AV node is the bundle of His, which per orates the interventricular septum
posteriorly. Within the septum, the bundle o His bi urcates into a compact, cablelike structure on the right side, known as the right bundle branch, and a broad sheet o bers that
continues over the le t side o the septum, the left bundle branch.
The right bundle branch is thick and deeply buried in the muscle o the interventricular
septum and continues toward the apex. Near the junction o the interventricular septum
and the anterior wall o the right ventricle, the right bundle branch becomes subendocardial
S inoa tria l node
Mitra l va lve
Corona ry s inus
Me mbra nous pa rt of
IV s e ptum
Bifurca tion of bundle
of His
Atriove ntricula r node
Bundle of His
Right bundle bra nch
Mus cula r pa rt of
IV s e ptum
Le ft bundle bra nch
Purkinje fibe rs unde r
e ndoca rdium of pa pilla ry
mus cle
Mode ra tor ba nd
FIGURE 1-6. Main components of the cardiac conduction system. This system includes the sinoatrial node,
atrioventricular node, bundle o His, right and le t bundle branches, and the Purkinje f bers. The moderator
band carries a large portion o the right bundle. (IV, interventricular).
8
Chapter 1
and bi urcates. One branch travels across the right ventricular cavity in the moderator band,
whereas the other continues toward the tip o the ventricle. These branches eventually arborize into a nely divided anastomosing plexus that travels throughout the right ventricle.
Functionally, the le t bundle branch is divided into an anterior and a posterior ascicle and
a small branch to the septum. The anterior ascicle runs anteriorly toward the apex, orming a
subendocardial plexus in the area o the anterior papillary muscle. The posterior ascicle travels to the area o the posterior papillary muscle; it then divides into a subendocardial plexus
and spreads to the rest o the le t ventricle.
The subendocardial plexuses o both ventricles send distributing Purkinje bers to the
ventricular muscle. Impulses within the His–Purkinje system are transmitted rst to the papillary muscles and then throughout the walls o the ventricles, allowing papillary muscle contraction to precede that o the ventricles. This coordination prevents regurgitation o blood
f ow through the AV valves, as discussed earlier.
Cardiac Innervation
The heart is innervated by both parasympathetic and sympathetic a erent and e erent
nerves. Preganglionic sympathetic neurons, with cell bodies located within the upper ve
to six thoracic levels o the spinal cord, synapse with second-order neurons in the cervical
sympathetic ganglia. Traveling within the cardiac nerves, these bers terminate in the heart
and great vessels. Preganglionic parasympathetic bers originate in the dorsal motor nucleus
o the medulla and pass as branches o the vagus nerve to the heart and great vessels. Here,
the bers synapse with second-order neurons located in ganglia within these structures. A
rich supply o vagal a erents rom the in erior and posterior aspects o the ventricles mediates
important cardiac ref exes, whereas the abundant vagal e erent bers to the SA and AV nodes
are active in modulating electrical impulse initiation and conduction.
Cardiac Vessels
The cardiac vessels consist o the coronary arteries and veins and the lymphatics. The largest
components o these structures lie within the loose connective tissue in the epicardial at.
Coronary Arteries
The heart muscle is supplied with oxygen and nutrients by the right and le t coronary arteries, which arise rom the root o the aorta just above the aortic valve cusps (Fig. 1-7; see also
Fig. 1-5B). A ter their origin, these vessels pass anteriorly, one on each side o the pulmonary
artery (see Fig. 1-7).
The large le t main coronary artery passes between the le t atrium and the pulmonary
trunk to reach the AV groove. There it divides into the le t anterior descending (LAD) coronary artery and the circumf ex artery. The LAD travels within the anterior interventricular
groove toward the cardiac apex. During its descent on the anterior sur ace, the LAD gives o
septal branches that supply the anterior two thirds o the interventricular septum and the
apical portion o the anterior papillary muscle. The LAD also gives o diagonal branches that
supply the anterior sur ace o the le t ventricle. The circumf ex artery continues within the
le t AV groove and passes around the le t border o the heart to reach the posterior sur ace. It
gives o large obtuse marginal branches that supply the lateral and posterior wall o the le t
ventricle.
The right coronary artery (RCA) travels in the right AV groove, passing posteriorly
between the right atrium and ventricle. It supplies blood to the right ventricle via acute
marginal branches. In most people, the distal RCA gives rise to a large branch, the posterior
descending artery (see Fig. 1-7C). This vessel travels rom the in eroposterior aspect o the
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Normal Cardiac Structure and Function
9
Pulmona ry a rte ry
Le ft ma in
corona ry a rte ry
Aorta
Le ft circumflex
corona ry a rte ry
Le ft a nte rior
de s ce nding
corona ry a rte ry
Right corona ry
a rte ry
A
Le ft circumflex
corona ry a rte ry
Le ft a nte rior
de s ce nding
corona ry a rte ry
Right
corona ry
a rte ry
Dia gona l
bra nch
Le ft circumflex
corona ry a rte ry
Obtus e
ma rgina l
bra nche s
Acute
ma rgina l bra nch
B
C
Right
corona ry
a rte ry
Pos te rior de s ce nding
corona ry a rte ry
FIGURE 1-7. Coronary artery anatomy. A. Schematic representation o the right and le t coronary arteries demonstrates
their orientation to one another. The le t main artery bi urcates into the circumf ex artery, which per uses the lateral and
posterior regions o the le t ventricle (LV), and the anterior descending artery, which per uses the LV anterior wall, the
anterior portion o the intraventricular septum, and a portion o the anterior right ventricular (RV) wall. The right coronary
artery (RCA) per uses the right ventricle and variable portions o the posterior le t ventricle through its terminal branches.
The posterior descending artery most o ten arises rom the RCA. B. Anterior view o the heart demonstrating the coronary
arteries and their major branches. C. Posterior view o the heart demonstrating the terminal portions o the right and
circumf ex coronary arteries and their branches.
heart to the apex and supplies blood to the in erior and posterior walls o the ventricles and
the posterior one third o the interventricular septum. Just be ore giving o the posterior
descending branch, the RCA usually gives o the AV nodal artery.
The posterior descending and AV nodal arteries arise rom the RCA in 85% o the population,
and in such people, the coronary circulation is termed right dominant. In approximately 8% ,
the posterior descending artery arises rom the circumf ex artery instead, resulting in a left dominant circulation. In the remaining population, the heart’s posterior blood supply is contributed
to rom branches o both the RCA and the circumf ex, orming a codominant circulation.
10
Chapter 1
The blood supply to the SA node is also most o ten (70% o the time) derived rom the
RCA. However, in 25% o normal hearts, the SA nodal artery arises rom the circumf ex
artery, and in 5% o cases, both the RCA and the circumf ex artery contribute to this vessel.
From their epicardial locations, the coronary arteries send per orating branches into the
ventricular muscle, which orm a richly branching and anastomosing vasculature in the walls
o all the cardiac chambers. From this plexus arise a massive number o capillaries that orm
an elaborate network surrounding each cardiac muscle ber. The muscle bers located just
beneath the endocardium, particularly those o the papillary muscles and the thick le t ventricle, are supplied either by the terminal branches o the coronary arteries or directly rom the
ventricular cavity through tiny vascular channels, known as thebesian veins.
Collateral connections, usually less than 200 µm in diameter, exist at the subarteriolar level
between the coronary arteries. In the normal heart, ew o these collateral vessels are visible.
However, they may become larger and unctional when atherosclerotic disease obstructs a
coronary artery, thereby providing blood f ow to distal portions o the vessel rom a nonobstructed neighbor.
Coronary Veins
The coronary veins ollow a distribution similar to that o the major coronary arteries. These
vessels return blood rom the myocardial capillaries to the right atrium predominantly via the
coronary sinus. The major veins lie in the epicardial at, usually super cial to their arterial
counterparts. The thebesian veins, described earlier, provide an additional potential route or
a small amount o direct blood return to the cardiac chambers.
Lymphatic Vessels
The heart lymph is drained by an extensive plexus o valved vessels located in the subendocardial connective tissue o all our chambers. This lymph drains into an epicardial plexus
rom which are derived several larger lymphatic vessels that ollow the distribution o the
coronary arteries and veins. Each o these larger vessels then combines in the AV groove to
orm a single lymphatic conduit, which exits the heart to reach the mediastinal lymphatic
plexus and ultimately the thoracic duct.
Histology of Ventricular Myocardial Cells
The mature myocardial cell (also termed the myocyte) measures up to 25 µm in diameter and
100 µm in length. The cell shows a cross-striated banding pattern similar to that o the skeletal
muscle. However, unlike the multinucleated skeletal myo bers, myocardial cells contain only
one or two centrally located nuclei. Surrounding each myocardial cell is connective tissue
with a rich capillary network.
Each myocardial cell contains numerous myof brils, which are long chains o individual
sarcomeres, the undamental contractile units o the cell (Fig. 1-8). Each sarcomere is made
up o two groups o overlapping laments o contractile proteins. Biochemical and biophysical interactions occurring between these myo laments produce muscle contraction. Their
structure and unction are described later in the chapter.
Within each myocardial cell, the neighboring sarcomeres are all in register, producing
the characteristic cross-striated banding pattern seen by light microscopy. The relative densities o the cross bands identi y the location o the contractile proteins. Under physiologic
conditions, the overall sarcomere length (Z-to-Z distance) varies between 2.2 and 1.5 µm
during the cardiac cycle. The larger dimension ref ects the ber stretch during ventricular
lling, whereas the smaller dimension represents the extent o ber shortening during
contraction.
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Normal Cardiac Structure and Function
Myofibril
Sa rcopla s mic
re ticulum
Sa rcole mma
11
T tubule
Mitochondrion
FIGURE 1-8. Myocardial cell. Top. Schematic
representation o the ultrastructure o
the myocardial cell. The cell consists o
multiple parallel myof brils surrounded by
mitochondria. The T tubules are invaginations
o the cell membrane (the sarcolemma) that
increase the sur ace area or ion transport
and transmission o electrical impulses. The
intracellular sarcoplasmic reticulum houses
most o the intracellular calcium and abuts
the T tubules. (Modif ed rom Katz AM.
Physiology of the Heart. 2nd ed. New York, NY:
Raven Press; 1992:21). Bottom. Expanded
view o a sarcomere, the basic unit o
contraction. Each myof bril consists o serially
connected sarcomeres that extend rom one Z
line to the next. The sarcomere is composed
o alternating thin (actin) and thick (myosin)
myof laments. Titin is a protein that tethers
myosin to the Z line and provides elasticity.
Z
Actin
Myos in
Titin Z
Sa rcome re
The myocardial cell membrane is named the sarcolemma. A specialized region o the membrane is the intercalated disk, a distinct characteristic o cardiac muscle tissue. Intercalated disks
are seen on light microscopic study as darkly staining transverse lines that cross chains o cardiac
cells at irregular intervals. They represent the gap junction complexes at the inter ace o adjacent
cardiac f bers and establish structural and electrical continuity between the myocardial cells.
Another unctional eature o the cell membrane is the transverse tubular system (or
T tubules). This complex system is characterized by deep, f ngerlike invaginations o the
sarcolemma (Fig. 1-9; see also Fig. 1-8). Similar to the intercalated disks, transverse tubular
membranes establish pathways or rapid transmission o the excitatory electrical impulses
that initiate contraction. The T tubule system increases the sur ace area o the sarcolemma
T tubule
Sa rcole mma
Ca ++
Ca ++
Ca ++
FIGURE 1-9. Schematic view
of the tubular systems of the
myocardial cell. The T tubules,
invaginations o the sarcolemma,
abut the sarcoplasmic reticulum
at right angles at the terminal
cisternae sacs. This relationship
is important in linking membrane
excitation with intracellular
release o calcium rom the
sarcoplasmic reticulum.
Ca ++
Ca ++
Ca ++
Sa rcopla s mic
re ticulum
ATPa s e
Ca ++
Ca ++
Ca ++
Ca ++
Te rmina l cis te rna e
Ca ++
12
Chapter 1
in contact with the extracellular environment, allowing the transmembrane ion transport
accompanying excitation and relaxation to occur quickly and synchronously.
The sarcoplasmic reticulum (SR, the myocyte analog o the endoplasmic reticulum) is
an extensive intracellular tubular membrane network that complements the T tubule system
both structurally and unctionally. The SR abuts the T tubules at right angles in lateral sacs,
called the terminal cisternae (see Fig. 1-9). These sacs house most o intracellular calcium
stores; the release o these stores is important in linking membrane excitation with activation
o the contractile apparatus. Lateral sacs also abut the intercalated disks and the sarcolemma,
providing each with a complete system or excitation–contraction coupling.
To serve the tremendous metabolic demand placed on the heart and the need or a constant supply o high-energy phosphates, the myocardial cell has an abundant concentration o
mitochondria. These organelles are located between the individual myo brils and constitute
approximately 35% o cell volume (see Fig. 1-8).
BASIC ELECTROPHYSIOLOGY
Rhythmic contraction o the heart relies on the organized propagation o electrical impulses
along its conduction pathway. The marker o electrical stimulation, the action potential, is created by a sequence o ion f uxes through speci c channels in the sarcolemma. To provide a basis
or understanding how electrical impulses lead to cardiac contraction, the process o cellular
depolarization and repolarization is reviewed here. This material serves as an important oundation or topics addressed later in the book, including electrocardiography (see Chapter 4), cardiac
arrhythmias (see Chapters 11 and 12), and the actions o antiarrhythmic drugs (see Chapter 17).
Cardiac cells capable o electrical excitation are o three electrophysiologic types, the properties o which have been studied by intracellular microelectrode and patch-clamp recordings:
1. Pacemaker cells (e.g., SA node, AV node)
2. Specialized rapidly conducting tissues (e.g., Purkinje bers)
3. Ventricular and atrial muscle cells
The sarcolemma o each o these cardiac cell types is a phospholipid bilayer that, by itsel , is
largely impermeable to ions. There are specialized proteins interspersed throughout the membrane that serve as ion channels, passive cotransporters, and active transporters (Fig. 1-10).
These help to maintain ionic concentration gradients and charge di erentials between the
inside and the outside o the cardiac cells. Note that normally the Na + and Ca + + concentrations
are much higher outside the cell, and the K+ concentration is much higher inside.
Ion Movement and Channels
The movement o speci c ions across the cell membrane serves as the basis o the action
potential. Passive ion movement depends on two major actors: (1) the energetic avorability
and (2) the permeability o the membrane or the ion.
Energetics
The two major orces that drive the direction o passive ion f ux are the concentration gradient
and the transmembrane potential (voltage). Molecules di use rom areas o high concentration to areas o lower concentration, and the gradient between these values is a determinant
o the rate o ion f ow. For example, the extracellular Na + concentration is normally 145 mM,
while the concentration inside the myocyte is 15 mM. As a result, a strong di usive orce
tends to drive Na + into the cell, down its concentration gradient.
The transmembrane potential o cells exerts an electrical orce on ions (i.e., like charges
repel one another, and opposite charges attract). The transmembrane potential o a myocyte
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Normal Cardiac Structure and Function
Na +
13
Ca ++
A
B
C
K+
Ca ++
GAP
J UNCTION
G
Inte rna l
[Na +]
[K+]
[Cl– ]
[Ca ++]
ATP
Ca ++
Na +
D
Na +
E
15 mM
150 mM
5 mM
10 –7 M
Ca ++
ATP
Ca ++
F
ATP
Exte rna l
K+
[Na +]
[K+]
[Cl– ]
[Ca ++]
145
5
120
2
mM
mM
mM
mM
FIGURE 1-10. Ion channels, cotransporters, and active transporters of the myocyte. A. Sodium entry
through the ast sodium channel is responsible or the rapid upstroke (phase 0) o the action potential (AP)
in nonpacemaker cells. B. Calcium enters the cell through calcium channel during phase 2 o the Purkinje f ber
and muscle cell AP and is the main channel responsible or depolarization o pacemaker cells. C. Potassium
exits through a number o di erent potassium channels to repolarize the cell, and open potassium channels
contribute to the resting potential (phase 4) o nonpacemaker cells. D. Sodium–calcium exchanger helps
maintain the low intracellular calcium concentration. E. Sodium–potassium ATPase maintains concentration
gradients or these ions. F, G. Active calcium transporters aid removal o calcium to the external environment
and into the sarcoplasmic reticulum, respectively.
at rest is about − 90 mV (the inside o the cell is negative relative to the outside). Extracellular
Na + , a positively charged ion, is there ore attracted to the relatively negatively charged interior o the cell. Thus, there is a strong tendency or Na + to enter the cell and remain there,
because o the steep concentration gradient and the electrical attraction.
Permeability
I there is such a strong orce driving Na + into the cell, what keeps this ion rom actually moving inside? The membrane o the cell at its resting potential is not permeable to sodium. The
phospholipid bilayer o the cell membrane is composed o a hydrophobic core that does not
allow simple passage o charged, hydrophilic particles. Instead, permeability o the membrane
is dependent on the opening o specif c ion channels, specialized proteins that span the cell
membrane and contain hydrophilic pores through which certain charged atoms can pass under
specif c circumstances. Typically, one cell’s sarcolemma contains a million or more such channels. Each type o channel is normally selective or a specif c ion, which is a mani estation o the
size and structure o its pore. For example, in cardiac cells, some channels permit the passage o
sodium ions, some are specif c or potassium, and others allow only calcium to transit through.
Ions can pass through their specif c channels only at certain times. That is, ion channels
are gated—at any given moment, a channel is either open or closed. The more time a channel is in its open state, the larger the number o ions that can pass through it and there ore,
the greater the transmembrane current. The voltage across the membrane determines what
Chapter 1
raction o channels is open at a given time. There ore, the gating o channels is said to be
voltage sensitive. As the membrane voltage changes during depolarization and repolarization o the cell, speci c channels open and close, with corresponding alterations in the ion
f uxes across the sarcolemma.
An example o voltage-sensitive gating is apparent in the cardiac channel known as the fast
sodium channel. The transmembrane protein that orms this channel assumes various conormations depending on the cell’s membrane potential (Fig. 1-11). At a voltage o − 90 mV
CHANNEL CLOS ED
(RESTING)
Ac tiva tion
ga te
Ra p id d e p ola riza tion
Na +
III
IV
Outs ide
CHANNEL OP EN
++++
II
++++
––––
––––
––––
––––
++++
++++
Ce ll
me mbra ne
Ins ide
Ina c tiva tion ga te
A
B
Na +
R
e
p
s
o
p
o
n
n
o
ti
ta
n
e
za
ri
o
u
la
S
14
CHANNEL CLOS ED
(INACTIVE)
Na +
––––
––––
++++
++++
C
FIGURE 1-11. Schematic representation of gating of fast sodium channels. A. Four covalently linked
transmembrane domains (I, II, III, and IV) form the sodium channel, which is guarded by activation and
inactivation gates. (Here, domain I is cut away to show the transmembrane pore.) In the resting membrane,
most channels are in a closed state. Even though the inactivation gate is open, Na+ ions cannot easily pass
through because the activation gate is closed. B. A rapid depolarization changes the cell membrane voltage
and forces the activation gate to open, presumably mediated by translocation of the charged portions of a
segment in each domain. With the channel in this conformation (in which both the activation and inactivation
gates are open), Na+ ions permeate into the cell. C. As the inactivation gate spontaneously closes, the sodium
current ceases. The inactivation gating function is thought to be achieved by a peptide loop that connects
domains III and IV, which translocates into the intracellular opening of the channel pore (black arrow). The
channel cannot reopen directly from this closed, inactive state. Cellular repolarization returns the channel
to the resting condition ( A) . During repolarization, as high negative membrane voltages are reachieved, the
activation gate closes and the inactivation gate reopens.
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Normal Cardiac Structure and Function
15
(the typical resting voltage o a ventricular muscle cell), the channels are predominantly in a
closed, resting state, such that Na + ions cannot pass through (Fig. 1-11A). In this resting state,
the channels are available or conversion to the open con guration.
A rapid wave o depolarization renders the membrane potential less negative, and this activates the resting channels to change con ormation to the open state (see Fig. 1-11B). Na + ions
readily permeate through the open channels, constituting an inward Na + current that urther
depolarizes the cell. However, the activated channels remain open or only a brie time, a ew
thousandths o a second, and then spontaneously close to an inactive state (see Fig. 1-11C).
Channels in the inactivated con ormation cannot be directly converted back to the open state.
The inactivated state persists until the membrane voltage has been repolarized nearly
back to its original resting level. Until then, the inactivated channel con ormation maintains
a closed pore that prevents any f ow o sodium ions. Thus, during normal cellular depolarization, the voltage-dependent ast sodium channels conduct or a short period and then inactivate, unable to conduct current again until the cell membrane has nearly ully repolarized,
and the channels recover rom the inactivated to the closed resting state.
Another important attribute o cardiac ast sodium channels should be noted. I the transmembrane voltage o a cardiac cell is slowly depolarized and maintained chronically at levels
less negative than the usual resting potential, inactivation o channels occurs without initial opening and current f ow. Furthermore, as long as this partial depolarization exists, the
closed, inactive channels cannot recover to the resting state. Thus, the ast sodium channels
in such a cell are persistently unable to conduct Na + ions. This is the typical case in cardiac
pacemaker cells (e.g., the SA and AV nodes) in which the membrane voltage is generally less
negative than − 70 mV throughout the cardiac cycle. As a result, the ast sodium channels in
pacemaker cells are persistently inactivated and do not play a role in the generation o the
action potential in these cells.
Calcium and potassium channels in cardiac cells also act in voltage-dependent ashions,
but they behave di erently than the sodium channels, as described later.
Resting Potential
In nonpacemaker cardiac cells at rest, prior to excitation, the electrical charge di erential
between the inside and outside o a cell corresponds to the resting potential. The magnitude
o the resting potential o a cell depends on two main properties: (1) the concentration gradients or all the di erent ions between the inside and outside o the cell and (2) the relative
permeabilities o ion channels that are open at rest.
As in other tissues such as nerve cells and skeletal muscle, the potassium concentration is much greater inside cardiac cells compared with outside. This is attributed mainly to
the cell membrane transporter Na + K+ -ATPase (see Fig. 1-10). This protein “pump” actively
extrudes 3 Na + ions out o the cell in exchange or the inward movement o 2 K+ ions in an
ATP-dependent process. This acts to maintain intracellular Na + at low levels and intracellular
K+ at high levels.
Cardiac myocytes contain a set o potassium channels (termed inward rectif er potassium
channels) that are open in the resting state, at a time when other ionic channels (e.g., sodium
and calcium) are closed. There ore, the resting cell membrane is much more permeable
to potassium than to other ions. As a result, K+ f ows in an outward direction down its
concentration gradient, removing positive charges rom the cell. As potassium ions exit the
cell, negatively charged anions that are impermeant to passage are le t behind, causing the
interior o the cell to become electrically negative with respect to the outside.
As the interior o the cell becomes more negatively charged by the outward f ux o potassium, the positively charged K+ ions are attracted back by the electrical potential toward the
cellular interior, slowing their net exit rom the cell. Thus, the K+ concentration gradient
and the electrostatic orce oppose each other (Fig. 1-12). At equilibrium, these orces are
16
Chapter 1
Ope n
pota s s ium
cha nne ls
Ins ide ce ll
CONCENTRATION [K+] out
(5 mM)
GRADIENT
ELECTRICAL
FORCE
K+
[K+] in
(150 mM)
+ –
+ –
+ –
+ –
Equilibrium (Ne rns t) pote ntia l = –26.7 ln ([K+] in /[K+] out) = –91mV
FIGURE 1-12. The resting potential of a
cardiac muscle cell is determined by the
balance between the concentration gradient
and electrostatic forces for potassium, because
only potassium channels are open at rest. The
concentration gradient avors outward movement
o K+ , whereas the electrical orce attracts the
positively charged K+ ions inward. The resting
potential is approximated by the Nernst equation
or potassium, as shown here.
balanced, and there is zero net movement o K+ across the membrane. The electrical potential at which that occurs is known as the potassium equilibrium potential and in ventricular
myocytes is − 91 mV, as calculated by the Nernst equation, shown in Figure 1-12. Since at rest
the membrane is almost exclusively permeable to potassium ions alone, this value closely
approximates the cell’s resting potential.
The permeability o the cardiac myocyte cellular membrane or sodium is minimal in the
resting state because the channels that conduct that ion are essentially closed. However, there
is a slight leak o sodium ions into the cell at rest. This small inward current o positively
charged ions explains why the actual resting potential is slightly less negative (− 90 mV) than
would be predicted i the cell membrane were truly only permeable to potassium. The sodium
ions that slowly leak into the myocyte at rest (and the much larger amount that enters during
the action potential) are continuously removed rom the cell and returned to the extracellular
environment by Na + K+ -ATPase, as previously described.
Action Potential
When the cell membrane’s voltage is altered, its permeability to specif c ions changes because
o the voltage-gating characteristics o the ion channels. Each type o channel has a characteristic pattern o activation and inactivation that determines the progression o the electrical
signal. The ionic currents that pass through the channels discussed in this chapter are listed
in Table 1-1. This description begins by ollowing the development o the action potential in
a typical cardiac muscle cell (Fig. 1-13). The unique characteristics o action potentials in
cardiac pacemaker cells are described therea ter.
TABLE 1-1
Transmembrane Cardiac Ionic Currents Described in
This Chapter
Current
Description
I
I Na
ICa.L
Pacemaker current; responsible or phase 4 depolarization in pacemaker cells
Na+ + current; responsible or phase 0 rapid depolarization in nonpacemaker cells
Slow, long-lasting Ca+ + current; responsible or phase 0 depolarization in pacemaker cells,
and major contributor to inward current during phase 2 o nonpacemaker cells
Maintains resting potential; current o the inward recti ying potassium channel
Transient outward potassium current; responsible or phase 1 o action potential
Delayed rectif er potassium currents o slow (I Ks) and rapid (I Kr) types; repolarizing
currents that are active during phases 2 and 3 o action potential
I K1
Ito
I Ks, I Kr
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Normal Cardiac Structure and Function
Cardiac Muscle Cell
Ca ++ inwa rd a nd
K+ outwa rd
1
l
Until stimulated, the resting potential o
a cardiac muscle cell remains stable, at
approximately − 90 mV. This resting state
be ore depolarization is known as phase 4
o the action potential. Following phase 4,
our additional phases characterize depolarization and repolarization o the cell (see
Fig. 1-13).
i
a
0
t
17
)
p
o
t
e
n
2
3
–50
Na +
inwa rd
M
e
m
b
r
a
(
n
m
e
V
0
K+
outwa rd
4
–100
0
C
u
r
r
e
INa
I
n
w
a
r
d
0
ICa.L
s
IK1
+
Ito
r
d
K
C
u
r
r
e
n
t
0
t
w
a
0
u
O
At the resting membrane voltage, sodium
and calcium channels are closed. Any process that makes the membrane potential
less negative than the resting value causes
some sodium channels to open. As these
channels open, sodium ions rapidly enter
the cell, f owing down their concentration
gradient toward the negatively charged cellular interior. The entry o Na + ions into
the cell causes the transmembrane potential to become progressively less negative,
which in turn causes more sodium channels to open and promotes urther sodium
entry into the cell. When the membrane
voltage approaches the threshold potential
(approximately − 70 mV in cardiac muscle
cells), enough o these ast Na + channels
have opened to generate a sel -sustaining
inward Na + current (termed INa ). The entry
o positively charged Na + ions at and beyond
threshold exceeds the exit o K+ ions through
the open inward recti er channels, such that
the cell continues to depolarize, transiently
to a net positive potential.
The prominent inf ux o sodium ions is
responsible or the rapid upstroke, or phase
0, o the action potential. However, the Na +
channels remain open or only a ew thousandths o a second and are then quickly
inactivated, preventing urther inf ux (see
Fig. 1-13). Thus, while activation o these ast
Na + channels causes the rapid early depolarization o the cell, the rapid inactivation makes
tial short lived.
n
t
s
Phase 0
IKr
IKs
IKr
IKs
0
FIGURE 1-13. Schematic representation of a
myocyte action potential ( AP) and major ionic
currents. The resting potential is represented
by phase 4 o the AP. During depolarization, Na+
in ux (I Na) results in the rapid upstroke o phase
0; a transient outward potassium current (Ito) is
responsible or partial repolarization during phase
1; slow Ca+ + in ux (ICa.L) balanced by K+ e ux (I Ks
and I Kr) results in the plateau o phase 2; and f nal
rapid repolarization results largely rom urther K+
e ux during phase 3. The resting potential o phase
4 is maintained primarily by the current IK1 through
inward rectif er potassium channels.
their major contribution to the action poten-
Phase 1
Following rapid phase 0 depolarization into the positive voltage range, a brie current o
repolarization during phase 1 returns the membrane potential to approximately 0 mV.
18
Chapter 1
The responsible current (termed Ito) is carried by the outward f ow o K+ ions through a type
o transiently activated potassium channel.
Phase 2
This relatively long “plateau” phase o the action potential is mediated by the balance o
outward K+ currents (known as IKs and IKr) carried through voltage-gated delayed rectif er K+
channels, in competition with an inward Ca + + current, which f ows through speci c L-type
calcium channels. The latter channels begin to open during phase 0, when the membrane
voltage reaches approximately − 40 mV, allowing Ca + + ions to f ow down their concentration gradient into the cell (this current is termed Ica.L). Ca + + entry proceeds in a more gradual
ashion than the initial inf ux o sodium, because with calcium channels, activation is slower
and the channels remain open much longer compared with sodium channels (see Fig. 1-13).
During this phase, the near equality o current rom inward Ca + + inf ux and outward K+ e f ux
results in nearly zero net current, and the membrane voltage does not change or a prolonged
period, which accounts or the f at plateau portion o the action potential curve. Calcium ions
that enter the cell during this phase play a critical role in triggering additional internal calcium
release rom the SR, which is important in initiating myocyte contraction, as discussed later
in this chapter. As the Ca + + channels gradually inactivate and the charge e f ux o K+ begins
to exceed the charge inf ux o calcium, phase 3 begins.
Phase 3
This is the nal phase o repolarization that returns the transmembrane voltage back to the
resting potential o approximately − 90 mV. A continued outward potassium current exceeds
the low inward current o other cations and is thus responsible or this period o rapid repolarization. Phase 3 completes the action potential cycle, with a return to resting phase 4,
preparing the cell or the next stimulus or depolarization.
To preserve normal transmembrane ionic concentration gradients, sodium and calcium
ions that enter the cell during depolarization must be returned to the extracellular environment, and potassium ions must return to the cell interior. As shown in Figure 1-10, Ca + +
ions are removed by the sarcolemmal Na + –Ca + + exchanger and to a lesser extent by the ATPenergized calcium pump (sarcolemmal Ca + + -ATPase). The corrective exchange o Na + and K+
across the cell membrane is mediated by Na + K+ -ATPase, as described earlier.
Specialized Conduction System
The process described in the previous sections applies to the action potential o cardiac muscle cells. The cells o the specialized conduction system (e.g., Purkinje bers) behave similarly, although the resting potential is slightly more negative and the upstroke o phase 0 is
even more rapid, due to a greater presence o Na + channels in these tissues.
Pacemaker Cells
The upstroke o the action potential o cardiac muscle cells does not normally occur spontaneously. Rather, when a wave o depolarization reaches the myocyte through the electrical
junctions with neighboring cells, its membrane potential becomes less negative and an action
potential is triggered.
Conversely, certain heart cells do not require external provocation to initiate their action
potential. Rather, they are capable o sel -initiated depolarization in a rhythmic ashion and
are known as pacemaker cells. They are endowed with the property o automaticity, by
which the cells undergo spontaneous depolarization during phase 4. When the threshold voltage is reached in such cells, an action potential upstroke is triggered (Fig. 1-14).
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0
m
V
19
n
t
i
a
l
(
Ca ++ influx
(ICa .L)
–40
4
lf
e
m
b
r
a
n
e
p
o
t
e
0
K+ e fflux
(IKs a nd IKr)
M
Cells that display pacemaker behavior include
the SA node (the “natural pacemaker” o the
heart) and the AV node. Although atrial and
ventricular muscle cells do not normally display
automaticity, they may do so under disease conditions such as ischemia.
The shape o the action potential o a pacemaker cell is di erent rom that o a ventricular
muscle cell in three ways:
)
Normal Cardiac Structure and Function
–80
1. The maximum negative voltage o pacemaker
Time
cells is approximately − 60 mV, substantially
less negative than the resting potential o ven- FIGURE 1-14. Action potential of a
tricular muscle cells (− 90 mV). The persistently pacemaker cell. Phase 4 is characterized by
less negative membrane voltage of pacemaker gradual, spontaneous depolarization owing to
cells causes the fast sodium channels within the pacemaker current (I ). When the threshold
potential is reached, at about − 40 mV, the
these cells to remain inactivated.
upstroke o the action potential ollows.
2. Unlike that o cardiac muscle cells, phase 4 o
The upstroke o phase 0 is less rapid than
the pacemaker cell action potential is not f at in nonpacemaker cells because the current
but has an upward slope, representing sponta- represents Ca+ + inf ux through the relatively
neous gradual depolarization. This spontane- slow calcium channels (Ica.L). Repolarization
ous depolarization is the result o an ionic f ux occurs with inactivation o the calcium channels
+
known as the pacemaker current (denoted by and K e f ux rom the cell through potassium
channels (I Ks and I Kr).
If; see Table 1-1). The pacemaker current is carried predominantly by Na + ions. The ion channel through which the pacemaker current passes is di erent rom the ast sodium channel
responsible or phase 0 o the action potential. Importantly, this pacemaker channel opens
in the very negative voltage ranges reached during repolarization o the cell. The inf ux o
positively charged Na + ions through the pacemaker channel causes the membrane potential
to become progressively less negative during phase 4, ultimately depolarizing the cell to its
threshold voltage (see Fig. 1-14).
3. The phase 0 upstroke o the pacemaker cell action potential is less rapid and reaches a
lower amplitude than that o a cardiac muscle cell. These characteristics result rom the
ast sodium channels o the pacemaker cells being inactivated and the upstroke o the
action potential relying solely on Ca + + inf ux through the relatively slow calcium channels.
Repolarization o pacemaker cells occurs in a ashion similar to that o ventricular muscle
cells and relies on inactivation o the calcium channels and increased activation o potassium
channels with enhanced K+ e f ux rom the cell.
Refractory Periods
Compared with electrical impulses in nerves and skeletal muscle, the cardiac action potential
is much longer in duration, supporting prolonged Ca + + entry and muscle contraction during
systole. This results in a prolonged period o channel inactivation during which the muscle
is re ractory (unresponsive) to restimulation. Such a long period is physiologically necessary
because it allows the ventricles su cient time to relax and re ll be ore the next contraction.
There are di erent levels o re ractoriness during the action potential o a myocyte, as
illustrated in Figure 1-15. The degree o re ractoriness primarily ref ects the percentage o ast
Na + channels that have recovered rom their inactive state and are capable o reopening. As
phase 3 o the action potential progresses, an increasing number o Na + channels recover rom
inactivated to resting states and can then open in response to the next depolarization. This, in
turn, corresponds to an increasing probability that a stimulus will trigger an action potential
and result in a propagated impulse.
Chapter 1
0
1
n
t
i
a
l
(
m
V
)
20
–50
Abs olute
RP
3
M
e
m
b
r
a
n
e
p
o
t
e
2
–100
Effe ctive
RP
Re la tive
RP
S upra norma l
pe riod
FIGURE 1-15. Refractory periods
( RPs) of the myocyte. During the
absolute refractory period (ARP), the
cell is unexcitable to stimulation. The
effective refractory period includes
a brief time beyond the ARP during
which stimulation produces a localized
depolarization that does not propagate
(curve 1). During the relative refractory
period, stimulation produces a weak
action potential (AP) that propagates,
but more slowly than usual (curve
2). During the supranormal period,
a weaker-than-normal stimulus can
trigger an AP (curve 3).
The absolute re ractory period re ers to the time during which the cell is completely unexcitable to any new stimulation. The effective re ractory period includes the absolute re ractory period
but extends beyond it to include a short interval o phase 3, during which stimulation produces
a localized action potential that is not strong enough to propagate urther. The relative re ractory
period is the interval during which stimulation triggers an action potential that is conducted, but
the rate o rise o the action potential is lower during this period because some o the Na + channels are inactivated and some o the delayed recti er K+ channels remain activated, thus reducing
the available net inward current. Following the relative re ractory period, a short “supranormal”
period is present in which a less-than-normal stimulus can trigger an action potential.
The re ractory period o atrial cells is shorter than that o ventricular muscle cells, such that
atrial rates can generally exceed ventricular rates during rapid arrhythmias (see Chapter 11).
Impulse Conduction
During depolarization, the electrical impulse spreads along each cardiac cell, and rapidly rom
cell to cell because each myocyte is connected to its neighbors through low-resistance gap junctions. Gap junctions are a special type o ion channel that provide electrical and biochemical
coupling between cardiac myocytes, allowing the action potential to spread rapidly through the
myocardium. The speed o tissue depolarization (phase 0) and the conduction velocity along
the cell depend on the net inward current (which is largely dependent on the number o sodium
channels), on the value o the resting potential (which sets the degree o Na+ channel inactivation), and on the resistance to current f ow between cells though the gap junctions. Tissues with
a high concentration o Na + channels, such as Purkinje bers, have a large, ast inward current,
which spreads quickly within and between cells to support rapid conduction. However, the less
negative the resting potential, the greater the raction o ast sodium channels that are in the
inactivated state and the less rapid the upstroke velocity (Fig. 1-16). Thus, alterations in the resting potential signi cantly impact the upstroke and conduction velocity o the action potential.
Normal Sequence of Cardiac Depolarization
Electrical activation o the heartbeat is normally initiated at the SA node (see Fig. 1-6). The
impulse spreads to the surrounding atrial muscle through the intercellular gap junctions, providing electrical continuity between the cells. Ordinary atrial muscle bers participate in the
propagation o the impulse rom the SA to the AV node, although in certain regions the bers
are more densely arranged, lowering intercellular resistance and thus acilitating conduction.
Fibrous tissue surrounds the tricuspid and mitral valves, such that there is no direct electrical connection between the atrial and ventricular chambers other than through the AV
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21
0
a
l
(
m
V
)
Normal Cardiac Structure and Function
e
t
o
p
e
n
r
a
–50
m
b
B
e
A
M
FIGURE 1-16. Dependence of speed of
depolarization on resting potential.
A. Normal resting potential (RP) and
rapid rise of phase 0. B. Less negative
RP results in slower rise of phase 0 and
lower maximum amplitude of the action
potential.
n
t
i
P ha s e
0
–100
node. As the electrical impulse reaches the AV node, a delay in conduction (approximately
0.1 seconds) is encountered. This delay occurs because the small-diameter f bers in this
region conduct slowly, and the action potential is o the “slow” pacemaker type (recall that
the ast sodium channels are permanently inactivated in pacemaker tissues, such that the
upstroke velocity relies on the slower calcium channels). The pause in conduction at the AV
node is actually benef cial because it allows the atria time to contract and ully empty their
contents be ore ventricular stimulation. In addition, the delay allows the AV node to serve as
a “gatekeeper” o conduction rom atria to ventricles, which is critical or limiting the rate o
ventricular stimulation during abnormally rapid atrial rhythms.
A ter traversing the AV node, the cardiac action potential spreads into the rapidly conducting bundle o His and Purkinje f bers, which distribute the electrical impulses to the bulk o
the ventricular muscle cells, in a spatially synchronized manner. This allows or precisely
timed stimulation and organized contraction o the ventricular myocytes, optimizing the volume o blood ejected by the heart.
EXCITATION–CONTRACTION COUPLING
This section reviews how the electrical action potential leads to physical contraction o cardiac
muscle cells, a process known as excitation–contraction coupling. During this process, chemical energy in the orm o high-energy phosphate compounds is translated into the mechanical
energy o myocyte contraction.
Contractile Proteins in the Myocyte
Several distinct proteins are responsible or cardiac muscle cell contraction (Fig. 1-17). O
the major proteins, actin and myosin are the chie contractile elements. Two other proteins,
tropomyosin and troponin, serve regulatory unctions.
Myosin is arranged in thick f laments, each composed o lengthwise stacks o approximately 300 molecules. The myosin f lament exhibits globular heads that are evenly spaced
TnC
Actin
TnI
TnT
Tropomyos in
Myos in he a ds
FIGURE 1-17. Schematic diagram of the main
contractile proteins of the myocyte, actin, and myosin.
Tropomyosin and troponin (components TnI, TnC, and
TnT) are regulatory proteins.
Myos in thick fila me nt
22
Chapter 1
along its length and contain myosin ATPase, an enzyme that is necessary or contraction to
occur. Actin, a smaller molecule, is arranged in thin laments as an α-helix consisting o two
strands that interdigitate between the thick myosin laments (see Fig. 1-8). Titin (also termed
connectin) is a very large protein that helps tether myosin to the Z line o the sarcomere and
provides elasticity to the contractile process.
Tropomyosin is a double helix that lies in the grooves between the actin laments and,
in the resting state, inhibits the interaction between myosin heads and actin, thus preventing contraction. Troponin sits at regular intervals along the actin strands and is composed
o three subunits. The troponin T (TnT) subunit links the troponin complex to the actin and
tropomyosin molecules. The troponin I (TnI) subunit inhibits the ATPase activity o the actin–
myosin interaction. The troponin C (TnC) subunit is responsible or binding calcium ions that
regulate the contractile process.
Calcium-Induced Calcium Release and the Contractile Cycle
The sensitivity o TnC to calcium establishes a crucial role or intracellular Ca + + ions in cellular contraction. The cycling o calcium in and out o the cytosol during each action potential
e ectively couples electrical excitation to physical contraction.
Recall that during phase 2 o the action potential, activation o L-type Ca + + channels results
in an inf ux o Ca + + ions into the myocyte. The small amount o calcium that enters the cell
in this ashion is not su cient to cause contraction o the myo brils, but it triggers a much
greater Ca + + release rom the SR, as ollows: The T tubule invaginations o the sarcolemmal membrane bring the L-type channels into close apposition with specialized Ca + + release
receptors in the SR, known as ryanodine receptors (Fig. 1-18). When calcium enters the cell
and binds to the ryanodine receptor, the receptor changes to an open con ormation, which
results in a much greater release o Ca + + into the cytosol rom the abundant stores in the
terminal cisternae o the SR. Thus, the initial L-type Ca + + channel inf ux is ampli ed by this
mechanism, known as calcium-induced calcium release (CICR), and the cytosolic calcium
concentration dramatically increases.
Na +
Ca ++
Outs ide ce ll
ATP
Ins ide ce ll
Rya nodine
re ce ptor
Sa rcopla s mic
re ticulum
Ca ++
Ca ++
Ca ++
+
Binds to TnC
Ca ++
Contra ction
PL
Ca ++
ATP
S ERCA
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FIGURE 1-18. Calcium ion
movements during excitation and
contraction in cardiac muscle cells.
Ca+ + enters the cell through calcium
channels during phase 2 of the action
potential, triggering a much larger
calcium release from the sarcoplasmic
reticulum (SR) via the ryanodine
receptor complex. The binding of
cytosolic Ca+ + to troponin C (TnC)
allows contraction to ensue. Relaxation
occurs as Ca+ + is returned to the SR by
sarco(endo)plasmic reticulum calcium
ATPase (SERCA). Phospholamban
(PL) is a major regulator of this
pump, inhibiting Ca+ + uptake in
its dephosphorylated state. Excess
intracellular calcium is returned to the
extracellular environment by sodium–
calcium exchange and to a smaller
degree by the sarcolemmal Ca+ + -ATPase.
Normal Cardiac Structure and Function
23
As calcium ions bind to TnC, the activity o TnI is inhibited, which induces a con ormational change in tropomyosin. The latter event exposes the active site between actin and
myosin, enabling contraction to proceed.
Contraction ensues as myosin heads bind to actin laments and “f ex,” thus causing the
interdigitating thick and thin laments to move past each other in an ATP-dependent reaction
(Fig. 1-19). The rst step in this process is activation o the myosin head by hydrolysis o ATP,
ollowing which the myosin head binds to actin and orms a cross bridge. The interaction
between the myosin head and actin results in a con ormational change in the head, causing
it to pull the actin lament inward.
Next, while the myosin head and actin are still attached, ADP is released, and a new
molecule o ATP then binds to the myosin head, causing it to release the actin lament. The
cycle can then repeat. Progressive coupling and uncoupling o actin and myosin cause the
muscle ber to shorten by increasing the overlap between the myo laments within each
sarcomere. In the presence o ATP, this process continues or as long as the cytosolic calcium
concentration remains su ciently high to inhibit the troponin–tropomyosin blocking action.
Myocyte relaxation, like contraction, is synchronized with the electrical activity o the
cell. Toward the end o phase 2 o the action potential, L-type channels inactivate, arresting
the inf ux o Ca + + into the cell and abolishing the trigger or CICR. Concurrently, calcium is
pumped back into the SR and out o the cell. Calcium is sequestered back into the SR primarily by sarco(endo)plasmic reticulum Ca+ + ATPase (SERCA), as shown in Figure 1-18. The
small amount o Ca + + that entered the cell through L-type calcium channels is removed via
Actin
ATP
Myos in
ADP
-ATP
A. Activa tion of myos in he a d
by ATP hydrolys is
D. ADP re le a s e, ATP binding,
a ctin fila me nt re le a s e
-ADP
C. P hos pha te re le a s e
-ADP-P i
B. Cros s -bridge forma tion
be twe e n myos in he a d
a nd a ctin fila me nt
a nd powe r s troke
Pi
-ADP-P i
FIGURE 1-19. The contractile process. A. Myosin head is activated by hydrolysis o ATP. B. During cellular
depolarization, cytoplasmic calcium concentration increases and removes the troponin–tropomyosin inhibition,
such that a cross bridge is ormed between actin and myosin. C. Inorganic phosphate (Pi) is released and a
con ormational change in the myosin head draws the actin f lament inward. D. ADP is released and replaced by
ATP, causing the myosin head to dissociate rom the actin f lament. As the process repeats, the muscle f ber
shortens. The cycle continues until cytosolic calcium concentration decreases at the end o phase 2 o the
action potential.
24
Chapter 1
the sarcolemmal Na + –Ca + + exchanger and to a lesser extent by the ATP-consuming calcium
pump, sarcolemmal Ca + + -ATPase (see Fig. 1-10).
As cytosolic Ca + + concentrations all and calcium ions dissociate rom TnC, tropomyosin
once again inhibits the actin–myosin interaction, leading to relaxation o the contracted cell.
The contraction–relaxation cycle can then repeat with the next action potential.
INTRODUCTION TO CARDIAC SIGNALING SYSTEMS
β-Adrenergic and Cholinergic Signaling
There is substantial evidence that the concentration o Ca + + within the cytosol is the major
determinant o the orce o cardiac contraction with each heartbeat. Mechanisms that raise
intracellular Ca + + concentration enhance orce development, whereas actors that lower Ca + +
concentration reduce the contractile orce.
β-Adrenergic stimulation is one mechanism that enhances calcium f uxes in the myocyte
and thereby strengthens the orce o ventricular contraction (Fig. 1-20). Catecholamines (e.g.,
norepinephrine) bind to the myocyte β1-adrenergic receptor, which is coupled to and activates
the G protein system (Gs) attached to the inner sur ace o the cell membrane. Gs in turn stimulates membrane-bound adenylate cyclase to produce cyclic AMP (cAMP) rom ATP. cAMP
then activates speci c intracellular protein kinases (PKAs), which phosphorylate cellular
Nore pine phrine
Ace tylcholine
β 1 -a dre ne rgic
re ce ptor
Mus ca rinic
Ca ++
re ce ptor
Ade nyla te
cycla s e
+
–
+
G s prote in
G i prote in
ATP
cAMP
Ina ctive
prote in
kina s e s
Ca ++
Active
prote in
kina s e s
PL
Ca ++
+
ATP
Sa rcopla s mic
re ticulum
FIGURE 1-20. Effects of β-adrenergic and cholinergic stimulation on cardiac cellular signaling and calcium
ion movement. The binding of a ligand (e.g., norepinephrine) to the β1-adrenergic receptor induces G protein–
mediated stimulation of adenylate cyclase and formation of cyclic AMP (cAMP). The latter activates protein
kinases, which phosphorylate cellular proteins, including ion channels. Phosphorylation of the slow Ca+ + channel
enhances calcium movement into the cell and therefore strengthens the force of contraction. Protein kinases also
phosphorylate phospholamban (PL), reducing the latter’s inhibition of Ca+ + uptake by the sarcoplasmic reticulum.
The enhanced removal of Ca+ + from the cytosol facilitates relaxation of the myocyte. Cholinergic signaling,
triggered by acetylcholine binding to the muscarinic receptor, activates inhibitory G proteins that reduce
adenylate cyclase activity and cAMP production, thus antagonizing the effects of β-adrenergic stimulation.
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Normal Cardiac Structure and Function
25
proteins, including the L-type calcium channels within the cell membrane. Phosphorylation
o the calcium channel augments Ca + + inf ux, which triggers a corresponding increase in Ca + +
release rom the SR, thereby enhancing the orce o contraction.
β-Adrenergic stimulation o the myocyte also enhances myocyte relaxation. The return o
Ca + + rom the cytosol to the SR is regulated by phospholamban (PL), a low molecular weight
protein in the SR membrane. In its dephosphorylated state, PL inhibits Ca + + uptake by SERCA
(see Fig. 1-18). However, β-adrenergic activation o PKAs causes PL to become phosphorylated, an action that blunts PL’s inhibitory e ect (see Fig. 1-20). The subsequently greater
uptake o calcium ions by the SR hastens Ca + + removal rom the cytosol, promoting myocyte
relaxation. The increased cAMP activity also results in phosphorylation o TnI, an action that
inhibits actin–myosin interactions and there ore urther enhances relaxation o the cell.
Cholinergic signaling via parasympathetic inputs (mainly rom the vagus nerve) opposes the
e ects o β-adrenergic stimulation (see Fig. 1-20). Acetylcholine released rom parasympathetic
nerve terminals binds to the muscarinic M2 receptor on cardiac cells. This receptor also activates
G proteins, but in distinction to the β-adrenergic receptor, it is coupled to Gi, an inhibitory G
protein system. Gi associated with cholinergic stimulation inhibits adenylate cyclase activity and
reduces cAMP ormation. At the sinus node, these actions o cholinergic stimulation serve to
reduce heart rate. In the myocardium, the e ect is to counteract the orce o contraction induced
by β-adrenergic stimulation. It should be noted that ventricular cells are much less sensitive to
this cholinergic e ect than atrial cells, likely ref ecting di erent degrees o G protein coupling.
Thus, physiologic or pharmacologic catecholamine stimulation o the myocyte β1-adrenergic
receptor enhances contraction o the cell, while cholinergic stimulation opposes that enhancement. We will return to these important properties in later chapters.
SUMMARY
• This chapter has reviewed basic cardiac anatomy and cellular composition, the cardiac
conduction system, excitation–contraction coupling, and cardiac signaling systems. The
physiology o myocyte contraction will be described in Chapter 9. Each o these complex
pieces integrate together to orm an organ system that unctions in a organized ashion,
is robust to errors, and operates reliably over many years. As a result, the heart is capable
o purpose ul stimulation billions o times during the li e span o a normal person. With
each contraction cycle, the heart receives and propagates blood through the circulation to
provide nutrients to and remove waste products rom the body’s tissues.
• The ollowing chapters explore what can go wrong with this remarkable system.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Ken Young Lin, MD; Vivek Iyer, MD;
Kirsten Greineder, MD; Stephanie Harper, MD; Scott Hyver, MD; Paul Kim, MD; Rajeev
Malhotra, MD; Laurence Rhines, MD; and James D. Marsh, MD.
Ad d i t i o n a l Rea d i n g
Bers DM. Calcium cycling and signaling in cardiac myocytes.
Annu Rev Physiol. 2008;70:23–49.
Christo els VM, Smits GJ, Kispert A, Moorman AFM.
Development o pacemaker tissues o the heart. Circ Res.
2010;106:240–254.
Courneya C, Parker MJ. Cardiovascular Physiology. A Clinical
Approach. Baltimore, MD: Lippincott Williams & Wilkins; 2011.
Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol.
2009;2:185–194.
Katz AM. Physiology of the Heart. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2010.
Saucerman JJ, McCulloch AD. Cardiac beta-adrenergic signaling: rom subcellular microdomains to heart ailure. Ann
N Y Acad Sci. 2006;1080:348–361.
Smyth JW, Shaw RM. Forward tra cking o ion channels: What the clinician needs to know. Heart Rhythm.
2010;7:1135–1140.
Wilcox BR, Cook AC, Anderson RH. Surgical Anatomy of the
Heart. 4th ed. Cambridge, MA: Cambridge University Press;
2013.
Zipes DP, Jali e J, eds. Cardiac Electrophysiology: From Cell to
Bedside. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013.
The Cardiac Cycle:
Mechanisms of Heart
Sounds and Murmurs
2
Da vid B. Fischer
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Cardiac Cycle
Heart Sounds
First Heart Sound (S1)
Second Heart Sound (S2)
Extra Systolic Heart Sounds
Extra Diastolic Heart Sounds
Murmurs
Systolic Murmurs
Diastolic Murmurs
Continuous Murmurs
C
ardiac diseases o ten cause abnormal ndings on physical examination, including pathologic heart sounds and
murmurs. These ndings are clues to the underlying pathophysiology, and proper interpretation is essential or success ul diagnosis and disease management. This chapter rst describes heart
sounds in the context o normal cardiac physiology and then
ocuses on the origins o pathologic heart sounds and murmurs.
Many cardiac diseases are mentioned brief y in this chapter as
examples o abnormal heart sounds and murmurs. Each o these
conditions is described in greater detail later in the book, so it
is not necessary or desirable to memorize all o the examples
presented here. Rather, the goal o this chapter is to explain the
mechanisms by which the abnormal sounds are produced, so that
their descriptions will make sense in later chapters.
CARDIAC CYCLE
The cardiac cycle consists o precisely timed electrical and
mechanical events that are responsible or rhythmic atrial and
ventricular contractions. Figure 2-1 displays the pressure relationships between the le t-sided cardiac chambers during the
normal cardiac cycle and serves as a plat orm or describing
key events. Mechanical systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ventricular
relaxation and f lling. Throughout the cardiac cycle, the right
and le t atria accept blood returning to the heart rom the
systemic veins and rom the pulmonary veins, respectively.
During diastole, blood passes rom the atria into the ventricles
across the open tricuspid and mitral valves, causing a gradual
increase in ventricular diastolic pressures. In late diastole,
atrial contraction propels a f nal bolus o blood into each ventricle, an action that produces a brie urther rise in atrial and
ventricle pressures, termed the a wave (see Fig. 2-1).
26
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
27
Contraction o the ventricles ollows, signaling the
onset o mechanical systole. As the ventricles start to
contract, the pressures within them rapidly exceed
AV c los e s
atrial pressures. This results in the orced closure o
AV op e ns
the tricuspid and mitral valves, which produces the
100
rst heart sound, termed S1. This sound has two nearly
Ao rta
superimposed components: the mitral component
slightly precedes that o the tricuspid valve because o
the earlier electrical activation o the le t ventricle (as
LV
described in Chapter 4).
50
As the right and le t ventricular pressures rapidly
MV op e ns
rise urther, they soon exceed the diastolic pressures
MV c los e s
within the pulmonary artery and aorta, orcing the
pulmonic and aortic valves to open, and blood is
LA
v
c
a
ejected into the pulmonary and systemic circulations.
Time
The ventricular pressures continue to increase during
the initial portion o this ejection phase, and then
decline as ventricular relaxation commences. Since
the pulmonic and aortic valves are open during this
S1
S2
phase, the aortic and pulmonary artery pressures
DIASTOLE
SYSTOLE
DIASTOLE
rise and all in parallel to those o the corresponding
ventricles.
FIGURE 2-1. The normal cardiac cycle, showing
At the conclusion o ventricular ejection, the venpressure relationships between the left-sided heart
chambers. During diastole, the mitral valve (MV) is
tricular pressures decline below those o the pulmoopen, so that the le t atrial (LA) and le t ventricular
nary artery and aorta (the pulmonary artery and aorta
(LV) pressures are equal. In late diastole, LA
are elastic structures that dissipate pressure more
contraction causes a small rise in pressure in both the
gradually than do the ventricles), such that the pulLA and LV (the a wave). During systolic contraction,
monic and aortic valves are orced to close, producthe LV pressure rises; when it exceeds the LA pressure,
ing the second heart sound, S2. Like the rst heart
the MV closes, contributing to the rst heart sound
sound (S1), this sound consists o two parts: the aortic
(S1). As LV pressure rises above the aortic pressure,
the aortic valve (AV) opens, which is a silent event.
(A2) component normally precedes the pulmonic (P2)
As the ventricle begins to relax and its pressure alls
because the diastolic pressure gradient between the
below that o the aorta, the AV closes, contributing
aorta and le t ventricle is greater than that between
to the second heart sound (S2). As LV pressure alls
the pulmonary artery and the right ventricle, orcing
urther, below that o the LA, the MV opens, which is
the aortic valve to shut more readily. The ventricular
silent in the normal heart. In addition to the a wave,
pressures all rapidly during the subsequent relaxation
the LA pressure curve displays two other positive
phase. As they drop below the pressures in the right
def ections: the c wave represents a small rise in LA
pressure as the MV closes and bulges into the atrium,
and le t atria, the tricuspid and mitral valves open,
and the v wave is the result o passive lling o the
ollowed by diastolic ventricular lling and then repLA rom the pulmonary veins during systole, when the
etition o this cycle.
MV is closed.
Notice in Figure 2-1 that in addition to the a wave,
the atrial pressure curve (in red color) displays two
other positive def ections during the cardiac cycle: the c wave represents a small rise in atrial
pressure as the tricuspid and mitral valves close and bulge into their respective atria. The
v wave is the result o passive lling o the atria rom the systemic and pulmonary veins during systole, a period during which blood accumulates in the atria because the tricuspid and
mitral valves are closed.
At the bedside, systole can be approximated as the period rom S1 to S2, and diastole rom S2
to the next S1. Although the duration o systole remains constant rom beat to beat, the length
o diastole varies with the heart rate: the aster the heart rate, the shorter the diastolic phase.
P
r
e
s
s
u
r
e
(
m
m
H
g
)
ECG
28
Chapter 2
The main sounds, S1 and S2, provide a framework from which all other heart sounds and
murmurs can be timed.
The pressure relationships and events depicted in Figure 2-1 are those that occur in the left
side of the heart. Equivalent events occur simultaneously in the right side of the heart in the
right atrium, right ventricle, and pulmonary artery. At the bedside, clues to right heart function can be ascertained by examining the jugular venous pulse, which is representative of the
right atrial pressure (see Box 2-1).
BOX 2-1
Jugular Venous Pulsations and Assessment of Right Heart
Function
Bedside observation o jugular venous pulsations in the neck is a vital part o the cardiovascular
examination. With no structures impeding blood f ow between the internal jugular (IJ) veins and
the superior vena cava and right atrium
a
(RA), the height o the IJ venous column
(termed the “jugular venous pressure” or
v
JVP) is an accurate representation o the
c
RA pressure. Thus, the JVP provides an
y
easily obtainable measure o right heart
x
unction.
Typical f uctuations in the jugular
venous pulse during the cardiac cycle, mani ested by oscillations in the overlying skin, are shown
in the gure (notice the similarity to the atrial pressure tracing in Fig. 2-1). There are two major
upward components, the a and v waves, ollowed by two descents, termed x and y. The x descent,
which represents the pressure decline ollowing the a wave, may be interrupted by a small upward
def ection (the c wave) at the time o tricuspid valve closure, but that is o ten not distinguishable
in the JVP. The a wave represents transient venous distension caused by back pressure rom RA
contraction. The v wave corresponds to passive lling o the RA rom the systemic veins during
systole, when the tricuspid valve is closed. Opening o the tricuspid valve in early diastole allows
blood to rapidly empty rom the RA into the right ventricle; that all in RA pressure corresponds to
the y descent.
Conditions that abnormally raise right-sided cardiac pressures (e.g., heart ailure, tricuspid
valve disease, pulmonic stenosis, pericardial diseases) elevate the JVP, while reduced intravascular
volume (e.g., dehydration) decreases it. In addition, speci c disease states can inf uence the
individual components o the JVP, examples o which are listed here or re erence and explained in
subsequent chapters:
Prominent a: right ventricular hypertrophy, tricuspid stenosis
Prominent v: tricuspid regurgitation
Prominent y: constrictive pericarditis
Technique of Measurement
The JVP is measured as the maximum vertical height o the internal jugular vein (in cm) above the
center o the right atrium, and in a normal person is ≤ 9 cm. Because the sternal angle is located
approximately 5 cm above the center o the RA, the JVP is calculated at the bedside by adding
5 cm to the vertical height o the top o the IJ venous column above the sternal angle.
The right-sided IJ vein is usually the easiest to evaluate because it extends directly upward
rom the RA and superior vena cava. First, observe the pulsations in the skin overlying the IJ with
the patient supine and the head o the bed at about a 45-degree angle. Shining a light obliquely
across the neck helps to visualize the pulsations. Be sure to examine the IJ, not the external
jugular vein. The ormer is medial to, or behind, the sternocleidomastoid muscle, whereas the
external jugular is usually more lateral. Although the external jugular is typically easier to see,
it does not always accurately ref ect RA pressure because it contains valves that inter ere with
venous return to the heart.
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
BOX 2-1
29
Jugular Venous Pulsations and Assessment of Right Heart
Function ( continued)
I the top o the IJ column is not visible at 45 degrees, the column o blood is either too
low (below the clavicle) or too high (above the jaw) to be measured in that position. In such
situations, the head o the bed must be lowered or raised, respectively, so that the top o the
column becomes visible. As long as the top can be ascertained, the vertical height o the JVP
above or below the sternal angle will accurately ref ect RA pressure, no matter the angle o the
head o the bed.
Sometimes it can be di cult to distinguish the jugular venous pulsations rom the neighboring
carotid artery. Unlike the carotid, the JVP is usually not pulsatile to palpation, it has a double (or
triple) upstroke rather than a single one, and it declines in most patients by assuming the seated
position or during inspiration.
HEART SOUNDS
Commonly used stethoscopes contain two chest pieces or auscultation o the heart.
The concave “bell” chest piece, meant to be applied lightly to the skin, accentuates lowrequency sounds. Conversely, the f at “diaphragm” chest piece is designed to be pressed
rmly against the skin to eliminate low requencies and there ore accentuate high- requency
sounds and murmurs. Some modern stethoscopes incorporate both the bell and diaphragm
unctions into a single chest piece; in these models, placing the piece lightly on the skin
brings out the low- requency sounds, while rm pressure accentuates the high- requency
ones. The sections below describe when, and where on the chest, to listen or high- versus
low- requency sounds.
First Heart Sound ( S1 )
S1 is produced by the closu re o the m itral an d tricuspid valves in early systole an d is
lou dest near the apex o the heart (Fig. 2-2). It is a high- requency sound, best heard with
the diaphragm o the stethoscope. Although mitral closure usually precedes tricuspid closure, they are separated by only about 0.01 seconds, such that the human ear appreciates
only a single sound. An exception occurs in patients
Pulmo nic are a
Ao rtic are a
with right bundle branch block (see Chapter 4),
(2nd–3rd le ft
(2nd–3rd right
in whom these components ma y be audibly split
inte rs pa ce )
inte rs pa ce )
because o delayed right ventricular contraction and
late closure o the tricuspid valve.
Three actors determine the intensity o S1: (1) the
distance separating the leaf ets o the open valves at the
onset o ventricular contraction, (2) the mobility o the
mitral and tricuspid leaf ets (normal, or rigid because o
stenosis), and (3) the rate o rise o ventricular pressure
Tric us pid are a
(Table 2-1).
(le ft lowe r
Mitral are a
s te rna l borde r)
The distance between the open valve leaf ets at
(a pe x)
the onset o ventricular contraction relates to the
electrocardiographic PR interval (see Chapter 4), the
period between the onset o atrial and ventricular
FIGURE 2-2. Standard positions of stethoscope
activation. Atrial contraction at the end o diastole
placement for cardiac auscultation. The mitral area
orces the tricuspid and mitral valve leaf ets apart.
localizes to the cardiac apex while the aortic and
pulmonic regions represent the cardiac base.
They start to passively dri t back together, but once
30
Chapter 2
TABLE 2-1 Causes o Altered Intensity o the First Heart Sound ( S1 )
Accent uat ed S1
1. Shortened PR interval
2. Mild mitral stenosis
3. High cardiac output states or tachycardia ( e.g., exercise)
Diminished S1
1. Lengthened PR interval: f rst-degree AV nodal block
2. Mitral regurgitation
3. Severe mitral stenosis
4. “Sti ” le t ventricle ( e.g., le t ventricular hypertrophy due to systemic hypertension)
ventricular contraction causes the ventricular pressure to exceed that in the atrium, the
leaf ets are orced to close rom whatever positions they occupy at that moment. An a ccen tua ted S1 results when the PR interval is shorter than normal, because the valve leaf ets
have less time to dri t back together and are there ore orced shut rom a relatively wide
distance.
Similarly, in mild mitral stenosis (see Chapter 8), impeded f ow through the mitral valve
causes a prolonged diastolic pressure gradient between the le t atrium and ventricle, which
keeps the mobile portions o the mitral leaf ets arther apart than normal during late diastole.
Because the leaf ets are relatively wide apart at the onset o systole, they are orced shut
loudly when the le t ventricle contracts.
S1 may also be accentuated when the heart rate is more rapid than normal (i.e., tachycardia) because diastole is shortened and the leaf ets have less time to dri t back together be ore
the ventricles contract.
Conditions that reduce the intensity o S1 are also listed in Table 2-1. In rst-degree
atrioventricular (AV) block (see Chapter 12), a diminished S1 results rom an abnormally
prolonged PR interval, which delays the onset o ventricular contraction. Consequently,
ollowing atrial contraction, the mitral and tricuspid valves have a ddition al time to f oat
back together so that the leaf ets are orced closed rom only a small distance apart and the
sound is so tened.
In patients with mitral regurgitation (see Chapter 8), S1 is o ten diminished in intensity
because the mitral leaf ets may not come into ull contact with one another as they close. In
severe mitral stenosis, the leaf ets are nearly xed in position throughout the cardiac cycle,
and that reduced movement lessens the intensity o S1.
In patients with a “sti ened” le t ventricle (e.g., a hypertrophied chamber), atrial contraction generates a higher-than-normal ventricular pressure at the end o diastole. This greater
pressure causes the mitral leaf ets to dri t together more rapidly, so that they are orced closed
rom a smaller-than-normal distance when ventricular contraction begins, thus reducing the
intensity o S1.
Second Heart Sound ( S2 )
The second heart sound results rom the closure o the aortic and pulmonic valves and thereore has aortic (A2) and pulmonic (P2) components. Unlike S1, which is usually heard only as
a single sound, the components o S2 vary with the respiratory cycle: they are normally used
as one sound during expiration but become audibly separated during inspiration, a situation
termed normal or physiologic splitting (Fig. 2-3).
One explanation or normal splitting o S2 is as ollows. Expansion o the chest during
inspiration causes the intrathoracic pressure to become more negative. The negative pressure
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
31
Expira tion
P hys iologic (norma l)
s plitting
S1
A2 P 2
In expira tion, A2 a nd P 2
fus e a s one s ound
Ins pira tion
Co mmo n c aus e s
Expira tion
Wide ne d s plitting
S1
A2 P 2
• Right bundle bra nch block
• Pulmona ry s te nos is
S1
A2 P 2
• Atria l s e pta l de fe ct
S1
P 2 A2
Ins pira tion
Expira tion
Fixe d s plitting
Ins pira tion
Expira tion
Pa ra doxica l s plitting
(Note reve rs e d pos ition
of A2 a nd P 2 )
• Le ft bundle bra nch block
• Adva nce d a ortic s te nos is
Ins pira tion
FIGURE 2-3. Splitting patterns of the second heart sound ( S2). A2, aortic component; P2, pulmonic component
o S2; S1, f rst heart sound.
transiently increases the capacitance (and reduces the impedance) of the intrathoracic pulmonary vessels. As a result, there is a temporary delay in the diastolic “back pressure” in the
pulmonary artery responsible for the closure of the pulmonic valve. Thus, P 2 is delayed; that
is, it occurs later during inspiration than during expiration.
Inspiration has the opposite effect on aortic valve closure. Because the capacitance of the
intrathoracic pulmonary veins is increased by the negative pressure generated by inspiration,
32
Chapter 2
the venous return to the le t atrium and ventricle temporarily decreases. Reduced lling o the
LV diminishes the stroke volume during the next systolic contraction and there ore shortens
the time required or LV emptying. There ore, aortic valve closure (A2) occurs slightly earlier
in inspiration than during expiration. The combination o an earlier A2 and delayed P2 during
inspiration causes audible separation o the two components. Since these components are
high- requency sounds, they are best heard with the diaphragm o the stethoscope, and splitting o S2 is usually most easily appreciated near the second le t intercostal space next to the
sternum (see the pulmonic area in Fig. 2-2).
Abnormalities o S2 include alterations in its intensity and changes in the pattern o splitting. The intensity o S2 depends on the velocity o blood coursing back toward the valves
rom the aorta and pulmonary artery a ter the completion o ventricular contraction, and the
suddenness with which that motion is arrested by the closing valves. In systemic hypertension or pulmonary arterial hypertension, the diastolic pressure in the respective great artery is
higher than normal, such that the velocity o the blood surging toward the valve is augmented
and S2 is accentuated. Conversely, in severe aortic or pulmonic valve stenosis, the valve commissures are nearly xed in position, such that the contribution o the stenotic valve to S2 is
diminished.
There are three types o abnormal splitting patterns o S2: widened, xed, and paradoxical.
Widened splitting o S2 re ers to an increase in the time interval between A2 and P2, such that
the two components are audibly separated even during expiration and become more widely
separated in inspiration (see Fig. 2-3). This pattern is usually the result o delayed closure o
the pulmonic valve, which occurs in right bundle branch block (described in Chapter 4) and
sometimes in pulmonic valve stenosis (see Chapter 16).
Fixed splitting o S2 is an abnormally widened interval between A2 and P 2 that persists
unchanged through the respiratory cycle (see Fig. 2-3). The most common abnormality
that causes xed splitting o S2 is an atrial septal de ect (see Chapter 16). In that condition, chronic volume overload o the right-sided circulation results in a high-capacitance,
low-resistance pulmonary vascular system. This alteration in pulmonary artery hemodynamics delays the back pressure responsible or the closure o the pulmonic valve. Thus,
P 2 occurs later than normal, even during expiration, such that there is wider-than-normal
separation o A2 and P 2. The pattern o splitting does not change (i.e., it is xed) during
the respiratory cycle because (1) inspiration does not substantially increase urther the
already elevated pulmonary vascular capacitance and (2) augmented lling o the right
atrium rom the systemic veins during inspiration is counterbalanced by a reciprocal
decrease in the le t-to-right transatrial shunt, eliminating respiratory variations in right
ventricular lling.
Paradoxical splitting (also termed “reversed” splitting) re ers to audible separation o A2
and P2 during expiration that uses into a single sound on inspiration, the opposite o the
normal situation. It ref ects an abnormal delay in the closure o the aortic valve such that P2
precedes A2. In adults, the most common cause is le t bundle branch block (LBBB). In LBBB,
described in Chapter 4, the spread o electrical activity through the le t ventricle is impaired,
resulting in delayed ventricular contraction and late closure o the aortic valve, causing A2 to
abnormally ollow P2 with wide separation between them. Then, during inspiration, as in the
normal case, the pulmonic valve closure sound becomes delayed and the aortic valve closure
sound moves earlier. This results in narrowing, and o ten superimposition, o the two sounds;
thus, there is no apparent split at the height o inspiration (see Fig. 2-3). In addition to LBBB,
paradoxical splitting may be observed under circumstances in which le t ventricular ejection
is greatly prolonged, such as aortic stenosis.
Extra Systolic Heart Sounds
Extra systolic heart sounds may occur in early-, mid-, or late systole.
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
Early Extra Systolic Heart Sounds
Abnormal early systolic sounds, or ejection clicks,
occur shortly a ter S1 and coincide with the opening o
the aortic or pulmonic valves (Fig. 2-4). These sounds
have a sharp, high-pitched quality, so they are heard
best with the diaphragm o the stethoscope placed
over the aortic and pulmonic areas (see Fig. 2-2).
Ejection clicks indicate the presence o aortic or pulmonic valve stenosis or dilatation o the pulmonary
artery or aorta. In stenosis o the aortic or pulmonic
valve, the sound occurs as the de ormed valve lea lets reach their maximal level o ascent into the great
artery, just prior to blood ejection. At that moment,
the rapidly ascending valve reaches its elastic limit
and decelerates abruptly, an action thought to result
in the sound generation. In dilatation o the root o
the aorta or pulmonary artery, the sound is associated
with sudden tensing o the aortic or pulmonic root
with the onset o blood f ow into the vessel. The a ortic
ejection click is heard at both the base (represented by
the aortic and pulmonary regions in Fig. 2-2) and the
apex o the heart and does not vary with respiration.
In contrast, the pulmon ic ejection click is heard only at
the base, and its intensity diminishes during inspiration (see Chapter 16).
Mid- or Late Extra Systolic Heart Sounds
Clicks occurring in mid- or late systole are usually the
result o systolic prolapse o the mitral or tricuspid
valves, in which the leaf ets bulge abnormally rom the
ventricular side o the AV junction into the atrium during ventricular contraction, o ten accompanied by valvular regurgitation (described in Chapter 8). They are
loudest over the mitral or tricuspid auscultatory regions,
respectively.
33
ECG
Ao rta
LV
MV op e ns
LA
S4 S1
Eje ction
click
S2
OS
S3
FIGURE 2-4. Timing of extra
systolic and diastolic heart sounds.
S4 is produced by atrial contraction
into a “sti ” le t ventricle (LV). An
ejection click ollows the opening o
the aortic or pulmonic valve in cases
o valve stenosis or dilatation o the
corresponding great artery. S3 occurs
during the period o rapid ventricular
f lling; it is normal in young people,
but its presence in adults implies LV
contractile dys unction. The timing
o an opening snap (OS) in a patient
with mitral stenosis is placed or
comparison. It is not likely that more
than one or two o these extra sounds
would appear in the same person.
LA, le t atrium; MV, mitral valve.
Extra Diastolic Heart Sounds
Extra heart sounds in diastole include the opening snap (OS), the third heart sound (S3), the
ourth heart sound (S4), and the pericardial knock.
Opening Snap
Opening o the mitral and tricuspid valves is normally silent, but mitral or tricuspid valvular
stenosis (usually the result o rheumatic heart disease; see Chapter 8) produces a sound,
termed as sn ap, when the a ected valve opens. It is a sharp, high-pitched sound, and its
timing does not vary signi cantly with respiration. In mitral stenosis (which is much more
common than is tricuspid valve stenosis), the OS is heard best between the apex and the le t
sternal border, just a ter the aortic closure sound (A2), when the le t ventricular pressure alls
below that o the le t atrium (see Fig. 2-4).
34
Chapter 2
Expira tion
OS
S1
S2
OS
Ins pira tion
P
A2 2
FIGURE 2-5. Timing of the opening
snap ( OS) in mitral stenosis does
not change with respiration. On
inspiration, normal splitting o the
second heart sound (S2) is observed so
that three sounds are heard. A2, aortic
component; P2, pulmonic component
o S2; S1, f rst heart sound.
Because o its proximity to A2, the A2–OS sequence can be
con used with a widely split second heart sound. However, careul auscultation at the pulmonic area during inspiration reveals
three sounds occurring in rapid succession (Fig. 2-5), which correspond to aortic closure (A2), pulmonic closure (P 2), and then
the OS. The three sounds become two on expiration when A2 and
P 2 normally use.
The severity o mitral stenosis can be approximated by the time
interval between A2 and the OS: the more advanced the stenosis,
the shorter the interval. This occurs because the degree o le t atrial
pressure elevation corresponds to the severity o mitral stenosis.
When the ventricle relaxes in diastole, the greater the le t atrial pressure, the earlier the mitral valve opens. Compared with severe stenosis, mild disease is marked by a less elevated le t atrial pressure,
lengthening the time it takes or the le t ventricular pressure to all
below that o the atrium. There ore, in mild mitral stenosis, the OS
is widely separated rom A2, whereas in more severe stenosis, the
A2–OS interval is narrower.
Third Heart Sound ( S3 )
When present, an S3 occurs in early diastole, ollowing the opening o the AV valves, during
the ventricular rapid lling phase (see Fig. 2-4). It is a dull, low-pitched sound best heard with
the bell o the stethoscope. A le t-sided S3 is typically loudest over the cardiac apex while the
patient lies in the le t lateral decubitus position. A right-sided S3 is better appreciated at the
lower le t sternal border. Production o the S3 appears to result rom tensing o the chordae
tendineae during rapid lling and expansion o the ventricle.
An S3 is a normal nding in children and young adults. In these groups, an S3 implies the
presence o a supple ventricle capable o normal rapid expansion in early diastole. Conversely,
when heard in middle-aged or older adults, an S3 is a sign o disease resulting rom a dilated
ventricle (e.g., a patient with heart ailure due to impaired systolic contraction, as described
in Chapter 9) or rom the increased transvalvular f ow that accompanies advanced mitral or
tricuspid regurgitation (described in Chapter 8). A pathologic S3 is sometimes re erred to as
a ventricular gallop.
Fourth Heart Sound ( S4 )
When an S4 is present, it occurs in late diastole and coincides with contraction o the atria
(see Fig. 2-4). This sound is generated by the le t (or right) atrium ejecting blood into a
sti ened ventricle. Thus, an S4 usually indicates the presence o cardiac disease—speci cally,
a decrease in ventricular compliance typically resulting rom ventricular hypertrophy or myocardial ischemia. Like an S3, the S4 is a dull, low-pitched sound and is best heard with the bell
o the stethoscope. In the case o the more common le t-sided S4, the sound is loudest at the
apex, with the patient lying in the le t lateral decubitus position. S4 is sometimes re erred to
as an atrial gallop.
Quadruple Rhythm or Summation Gallop
In a patient with both an S3 and S4, those sounds, in conjunction with S1 and S2, produce a
quadruple beat. I a patient with a quadruple rhythm develops tachycardia, diastole becomes
shorter in duration, the S3 and S4 coalesce, and a summation gallop results. The summation
o S3 and S4 is heard as a long middiastolic, low-pitched sound, o ten louder than S1 and S2.
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The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs
35
Pericardial Knock
A pericardial knock is an uncommon, high-pitched sound that occurs in patients with
severe constrictive pericarditis (see Chapter 14). It appears early in diastole soon a ter S2
and can be con used with an OS or an S3. However, the knock appears slightly later in diastole than the timing o an OS and is louder and occurs earlier than does a ventricular gallop.
It results rom the abrupt cessation o ventricular lling that occurs when the expanding
ventricle meets a rigid pericardium in early diastole, which is the hallmark o constrictive
pericarditis.
MURMURS
A murmur is the sound generated by turbulent blood f ow. Under normal conditions, the
movement o blood through the vascular bed is laminar, smooth, and silent. However, as a
result o hemodynamic and/ or structural changes, laminar f ow can become disturbed and
produce an audible noise. Murmurs result rom any o the ollowing mechanisms:
1. Flow across a partial obstruction (e.g., aortic stenosis)
2. Increased f ow through normal structures (e.g., aortic systolic murmur associated with a
high-output state, such as anemia)
3. Ejection into a dilated chamber (e.g., aortic systolic murmur associated with aneurysmal
dilatation o the aorta)
4. Regurgitant f ow across an incompetent valve (e.g., mitral regurgitation)
5. Abnormal shunting o blood rom one vascular chamber to a lower-pressure chamber (e.g.,
ventricular septal de ect [VSD])
Murmurs are described by their timing, intensity, pitch, shape, location, radiation, and
response to maneuvers. Timing re ers to whether the murmur occurs during systole or diastole, or is continuous (i.e., begins in systole and continues into diastole). The intensity o the
murmur is typically quanti ed by a grading system. In the case o systolic murmurs:
Grade
Grade
Grade
Grade
Grade
Grade
1/ 6
2/ 6
3/ 6
4/ 6
5/ 6
6/ 6
(or I/ VI):
(or II/ VI):
(or III/ VI):
(or IV/ VI):
(or V/ VI):
(or VI/ VI):
Barely audible (i.e., medical students may not hear it!)
Faint but immediately audible
Easily heard
Easily heard and associated with a palpable thrill
Very loud; heard with the stethoscope lightly on the chest
Audible without the stethoscope directly on the chest wall
And in the case o diastolic murmurs:
Grade
Grade
Grade
Grade
1/ 4
2/ 4
3/ 4
4/ 4
(or I/ IV):
(or II/ IV):
(or III/ IV):
(or IV/ IV):
Barely audible
Faint but immediately audible
Easily heard
Very loud
Pitch re ers to the requency o the murmur, ranging rom high to low. High- requency murmurs are caused by large pressure gradients between chambers (e.g., aortic stenosis) and are
best appreciated using the diaphragm chest piece o the stethoscope. Low- requency murmurs
imply less o a pressure gradient between chambers (e.g., mitral stenosis) and are best heard
using the stethoscope’s bell piece.
36
Chapter 2
Shape describes how the murmur changes in intensity rom its onset to its completion.
For example, a crescen do–decrescen do (or “diamond-shaped”) murmur rst rises and then
alls o in intensity. Other shapes include decrescen do (i.e., the murmur begins at its maximum intensity then becomes so ter) and uniform (the intensity o the murmur does not
change).
Location re ers to the murmur’s region o maximum intensity and is usually described in
terms o speci c auscultatory areas (see Fig. 2-2):
Aortic area:
Pulmonic area:
Tricuspid area:
Mitral area:
Second to third right intercostal spaces, next to the sternum
Second to third le t intercostal spaces, next to the sternum
Lower le t sternal border
Cardiac apex
From their primary locations, murmurs are o ten heard to radiate to other areas o the
chest, and such patterns o transmission relate to the direction o the turbulent f ow. Finally,
similar types o murmurs can be distinguished rom one another by simple bedside maneuvers, such as standing upright, Valsalva ( orce ul expiration against a closed airway), or
clenching o the sts, each o which alters the heart’s loading conditions and can a ect the
intensity o many murmurs. Examples o the e ects o maneuvers on speci c murmurs are
presented in Chapter 8.
When reporting a murmur, some or all o these descriptors are mentioned. For example,
you might describe a particular patient’s murmur o aortic stenosis as “A grade III/ VI highpitched, crescendo–decrescendo systolic murmur, loudest at the upper right sternal border,
with radiation toward the neck.”
Systolic Murmurs
Systolic murmurs are subdivided into systolic ejection murmurs, pansystolic murmurs, and
late systolic murmurs (Fig. 2-6). A systolic ejection murmur is typical o aortic or pulmonic valve stenosis. It begins a ter the rst heart sound and terminates be ore or during
S2, depending on its severity and whether the obstruction is o the aortic or pulmonic valve.
The shape o the murmur is o the crescendo–decrescendo type (i.e., its intensity rises and
then alls).
Example s
A. Eje ction type
• Aortic s te nos is
• P ulmona ry s te nos is
S1
S2
• Mitra l re gurgita tion
• Tricus pid re gurgita tion
• Ve ntricula r s e pta l de fe ct
B. P a ns ys tolic
(holos ys tolic)
S1
S2
C. La te s ys tolic
• Mitra l va lve prola ps e
S 1 Click S 2
FIGURE 2-6. Classif cation o systolic
murmurs. Ejection murmurs are crescendo–
decrescendo in conf guration (A), whereas
pansystolic murmurs are uni orm throughout
systole (B). A late systolic murmur o ten ollows
a midsystolic click and suggests mitral (or
tricuspid) valve prolapse (C).
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
37
The ejection murmur o aortic stenosis begins in
systole a ter S1, rom which it is separated by a short
audible gap (Fig. 2-7). This gap corresponds to the
period o isovolumetric contraction o the le t ventricle
Ao rta
(the period a ter the mitral valve has closed but be ore
the aortic valve has opened). The murmur becomes
more intense as f ow increases across the aortic valve
during the rise in le t ventricular pressure (crescendo).
Then, as the ventricle relaxes, orward f ow decreases
and the murmur lessens in intensity (decrescendo) and
LV
nally ends prior to the aortic component o S2. The
murmur may be immediately preceded by an ejection
click, especially in mild orms o aortic stenosis.
Although the intensity o the murmur does not correlate well with the severity o aortic stenosis, other
eatures do. For example, the more severe the stenosis, the longer it takes to orce blood across the valve,
and the later the murmur peaks in systole (Fig. 2-8).
Also, as shown in Figure 2-8, as the severity o stenosis
S1
S2
increases, the aortic component o S2 so tens because
the leaf ets become more rigidly xed in place.
Aortic stenosis causes a high- requency murmur,
FIGURE 2-7. Systolic ejection murmur of aortic
ref ecting the sizable pressure gradient across the
stenosis. There is a short delay between the f rst
valve. It is best heard in the “aortic area” at the second
heart sound (S1) and the onset o the murmur (f rst
and third right intercostal spaces close to the sternum
dashed line). LV, le t ventricle; S2, second heart sound.
(see Fig. 2-2). The murmur typically radiates toward
the neck (the direction o turbulent blood f ow) but o ten can be heard in a wide distribution,
including the cardiac apex.
The murmur o pulmonic stenosis also begins a ter S1. It may be preceded by an ejection
click, but unlike aortic stenosis, it may extend beyond the A2 sound. That is, i the stenosis
is severe, it will result in a very prolonged right ventricular ejection time, elongating the
murmur, which will continue beyond the closure o the aortic valve and end just be ore the
closure o the pulmonic valve (P2). Pulmonic stenosis is usually loudest at the second to third
le t intercostal spaces close to the sternum. It does not radiate as widely as aortic stenosis, but
sometimes it is transmitted to the neck or le t shoulder.
Young adults o ten have benign systolic ejection murmurs (also termed “innocent murmurs”) resulting rom increased systolic f ow across normal aortic and pulmonic valves. This
type o murmur o ten becomes so ter or disappears when the patient sits upright.
Pansystolic (also termed holosystolic) murmurs are caused by regurgitation o blood
across an incompetent mitral or tricuspid valve or through a ventricular septal de ect (see
Chapter 16). These murmurs are characterized by a uni orm intensity throughout systole
(Fig. 2-6). In mitral and tricuspid valve regurgitation, as soon as ventricular systolic pressure exceeds atrial pressure (i.e., when S1 occurs), there is immediate retrograde f ow across
the regurgitant valve. Thus, there is no gap between S1 and the onset o these pansystolic
murmurs, in contrast to the systolic ejection murmurs discussed earlier. Similarly, there is no
signi cant gap between S1 and the onset o the systolic murmur o a VSD, because le t ventricular systolic pressure exceeds right ventricular systolic pressure (and f ow occurs) quickly
a ter the onset o contraction.
The pansystolic murmur o advanced mitral regurgitation continues through the aortic closure sound because le t ventricular pressure remains greater than that in the le t atrium at the
time o aortic closure. The murmur is heard best at the apex, is high pitched and “blowing” in
quality, and o ten radiates toward the le t axilla; its intensity does not change with respiration.
Aortic
valve
ope ns
38
Chapter 2
Tricuspid valve regurgitation is best heard along
the le t lower sternal border. It generally radiates to
the right o the sternum and is high pitched and blowing in quality. The intensity o the murmur increases
with inspiration because the negative intrathoracic pressure induced during inspiration enhances
venous return to the heart. The latter augments right
ventricular stroke volume, thereby increasing the
amount o regurgitated blood.
The murmur o a VSD is heard best at the ourth to
sixth le t intercostal spaces, is high pitched, and may
be associated with a palpable thrill. The intensity o
the murmur does not increase with inspiration, nor
does it radiate to the axilla, which helps distinguish it
rom tricuspid and mitral regurgitation, respectively. O
note, the smaller the VSD, the greater the turbulence
o blood f ow between the le t and right ventricles and
the louder the murmur. Some o the loudest murmurs
ever heard are those associated with small VSDs.
Late systolic murmurs begin in mid-to-late systole and continue to the end o systole (see Fig. 2-6).
The most common example is mitral regurgitation
caused by mitral valve prolapse—bowing o abnormally redundant and elongated valve leaf ets into the
le t atrium during ventricular contraction. This murmur is usually preceded by a midsystolic click and is
described in Chapter 8.
Diastolic Murmurs
A. Mild
A2 P 2
S1
EJ
B. Mode ra te
S1
A2 P
2
C. S eve re
S1
P2
FIGURE 2-8. The severity of aortic
stenosis affects the shape of the systolic
murmur and the heart sounds. A. In mild
stenosis, an ejection click (EJ) is o ten
present, ollowed by an early peaking
crescendo–decrescendo murmur and a
normal aortic component o S2 (A2). B. As
stenosis becomes more severe, the peak
o the murmur becomes more delayed in
systole and the intensity o A2 lessens.
The prolonged ventricular ejection time
delays A2 so that it merges with or occurs
a ter the pulmonic component o S2 (P2);
the ejection click may not be heard. C. In
severe stenosis, the murmur peaks very late
in systole, and A2 is usually absent because
o immobility o the valve leaf ets. S1, rst
heart sound; S2, second heart sound.
Diastolic murmurs are divided into early decrescendo murmurs and mid-to-late rumbling murmurs (Fig. 2-9). Early diastolic murmurs result
rom regurgitant f ow through either the aortic or
pulmonic valve, with the ormer being much more
common in adults. I produced by a ortic valve regurgitation , the murmur begins at A2, has a decrescendo
shape, and terminates be ore the next S1. Because
diastolic relaxation o the le t ventricle is rapid, a
pressure gradient develops immediately between
the aorta and lower-pressured le t ventricle in patients with aortic regurgitation, and the
murmur there ore displays its maximum intensity at its onset. Therea ter in diastole, as the
aortic pressure alls and the LV pressure increases (as blood regurgitates into the ventricle),
the gradient between the two chambers diminishes and the murmur decreases in intensity.
Aortic regurgitation is a high-pitched murmur, best heard using the diaphragm o the stethoscope along the le t sternal border with the patient sitting, leaning orward, and exhaling.
Pulmonic regurgitation in adults is usually due to pulmonary arterial hypertension. It is an
early diastolic decrescendo murmur similar to that o aortic regurgitation, but it is best heard
in the pulmonic area (Fig. 2-2), and its intensity may increase with inspiration.
Mid-to-late diastolic murmurs result rom either turbulent f ow across a stenotic mitral
or tricuspid valve or less commonly rom abnormally increased f ow across a normal mitral
or tricuspid valve (see Fig. 2-9). I resulting rom stenosis, the murmur begins a ter S2 and is
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The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
39
• Aortic re gurgita tion
• Pulmonic re gurgita tion
A. Ea rly de cre s ce ndo
S1
S2
S1
B. Mid-to-la te
• Mild mitra l or tricus pid s te nos is
S1
S2
S1
OS
C. P rolonge d mid-to-la te
• S eve re mitra l or tricus pid s te nos is
S1
S2
OS
S1
FIGURE 2-9. Classif cation o diastolic murmurs. A. An early diastolic decrescendo murmur is typical o
aortic or pulmonic valve regurgitation. B. Mid-to-late low- requency rumbling murmurs are usually the result
o mitral or tricuspid valve stenosis and ollow a sharp opening snap (OS). Presystolic accentuation o the
murmur occurs in patients in normal sinus rhythm because o the transient rise in atrial pressure during atrial
contraction. C. In more severe mitral or tricuspid valve stenosis, the opening snap and diastolic murmur
commence earlier, and the murmur is prolonged. S1, f rst heart sound; S2, second heart sound.
preceded by an opening snap. The shape o this murmur is unique. Following valvular opening (and the OS), the murmur is at its loudest because the pressure gradient between the
atrium and ventricle is at its maximum. The murmur then decrescendos or disappears totally
during diastole as the transvalvular gradient decreases. The degree to which the murmur ades
depends on the severity o the stenosis. I the stenosis is severe, the murmur is prolonged; i the
stenosis is mild, the murmur disappears in mid-to-late diastole. Whether the stenosis is mild
or severe, the murmur intensi es at the end o diastole in patients in normal sinus rhythm,
when atrial contraction augments f ow (and turbulence) across the valve (see Fig. 2-9). Since
the pressure gradient across a stenotic mitral valve tends to be airly low, the murmur o mitral
stenosis is low pitched and is heard best with the bell o the stethoscope at the apex, while the
patient lies in the le t lateral decubitus position. The much less common murmur o tricuspid
stenosis is better auscultated at the lower sternum, near the xiphoid process.
Hyperdynamic states such as ever, anemia, hyperthyroidism, and exercise cause increased
f ow across the normal tricuspid and mitral valves and can there ore result in a diastolic murmur. Similarly, in patients with advanced mitral regurgitation, the expected systolic murmur
can be accompanied by an additional diastolic murmur owing to the increased volume o
blood that must return across the valve to the le t ventricle in diastole. Likewise, patients with
either tricuspid regurgitation or an atrial septal de ect (see Chapter 16) have increased f ow
across the tricuspid valve, and may there ore display a diastolic f ow murmur rom that site.
Continuous Murmurs
Continuous murmurs are heard throughout the cardiac cycle. Such murmurs result rom conditions in which there is a persistent pressure gradient between two structures during both systole
and diastole. An example is the murmur o patent ductus arteriosus, in which there is an abnormal congenital communication between the aorta and the pulmonary artery (see Chapter 16).
During systole, blood f ows rom the high-pressure ascending aorta through the ductus into the
40
Chapter 2
• Pa te nt ductus a rte rios us
Continuous
S1
S2
S1
• Aortic s te nos is a nd re gurgita tion
• Pulmonic s te nos is a nd re gurgita tion
To-a nd-fro
S1
S2
S1
FIGURE 2-10. A continuous murmur peaks at, and extends through, the second heart sound ( S2 ) . A
to-and- ro murmur is not continuous; rather, there is a systolic component and a distinct diastolic component,
separated by S2. S1, f rst heart sound.
lower-pressure pulmonary artery. During diastole, the aortic pressure remains greater than that
in the pulmonary artery and the f ow continues across the ductus. This murmur begins in early
systole, crescendos to its maximum at S2, then decrescendos until the next S1 (Fig. 2-10).
The “to-and- ro” combined murmur in a patient with both aortic stenosis and aortic regurgitation could be mistaken or a continuous murmur (see Fig. 2-10). During systole, there is a
diamond-shaped ejection murmur, and during diastole, a decrescendo murmur. However, in
the case o a to-and- ro murmur, the sound does not extend through S2 because it has discrete
systolic and diastolic components.
SUMMARY
• Cardiac diseases o ten result in abnormal heart sounds and murmurs, which are clues to
the underlying pathophysiology.
• Systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ventricular relaxation and lling.
• The normal cardiac cycle proceeds as ollows: (1) during diastole, the mitral valve (MV)
is open, so that the le t atrial (LA) and le t ventricular (LV) pressures are equal; (2) in late
diastole, LA contraction causes a small rise in pressure in both the LA and LV; (3) a ter a
short delay, ventricular contraction causes the LV pressure to rise, and when the LV pressure exceeds the LA pressure, the MV closes, contributing to the rst heart sound (S1);
(4) as LV pressure rises above the aortic pressure, the aortic valve (AV) opens, a silent
event in a normal heart; (5) a ter contraction, as the ventricle relaxes and its pressure
alls below that o the aorta, the AV closes, contributing to the second heart sound (S2);
(6) when the LV pressure declines below that o the le t atrium, the mitral valve opens,
and the cycle repeats.
• Extra systolic sounds include ejection clicks, indicating aortic or pulmonic stenosis or
dilatation o the aortic root or pulmonary artery, and mid-to-late clicks, indicating mitral or
tricuspid valve prolapse.
• Extra diastolic sounds include the opening snap (signi ying mitral stenosis), the S3 sound
(indicating heart ailure or a volume overload state in older adults; an S3 is a normal
sound in children and young adults), and the S4 sound (indicating reduced ventricular
compliance).
• Common murmurs include systolic ejection murmurs rom aortic or pulmonic stenosis,
pansystolic murmurs rom mitral or tricuspid regurgitation, late systolic murmurs rom mitral
valve prolapse, early diastolic murmurs rom aortic or pulmonic regurgitation, and mid-tolate diastolic murmurs rom mitral stenosis.
• Tables 2-2 and 2-3 and Figure 2-11 summarize eatures o the heart sounds and murmurs
described in this chapter.
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TABLE 2-2 Common Heart Sounds
Sound
Location
Pitch
Signif cance
S1
S2
Apex
Base
High
High
Normal closure of mitral and tricuspid valves
Normal closure of aortic (A2) and pulmonic
(P2) valves
Extra systolic sounds
Ejection clicks
Aortic: apex and base
Pulmonic: base
Mid-to-late click
Mitral: apex
Tricuspid: LLSB
Extra diastolic sounds
Opening snap
Apex
S3
Left-sided: apex
High
High
High
High
Aortic or pulmonic stenosis, or dilatation of
aortic root or pulmonary artery
High
Low
S4
Low
Mitral stenosis
Normal in children
Abnormal in adults: indicates heart failure
or volume overload state
Reduced ventricular compliance
Left-sided: apex
Mitral or tricuspid valve prolapse
LLSB, lower left sternal border.
TABLE 2-3 Common Murmurs
Murmur Type
Example
Location and Radiation
Systolic ejection
Aortic stenosis
Second right intercostal space → neck (but may
radiate widely)
Second to third left intercostal spaces
Pulmonic stenosis
S1
S2
Pansystolic
S1
Apex → axilla
Aortic regurgitation
Pulmonic regurgitation
Along left side of the sternum
Upper left side of the sternum
Mitral stenosis
Apex
S1
Mid-to-late diastolic
S2
Mitral valve prolapse
S2
Early diastolic
S2
Apex → axilla
Left lower sternal border → right lower sternal
border
S2
Late systolic
S2
Mitral regurgitation
Tricuspid regurgitation
S1
42
Chapter 2
Pulmo nic are a
Eje c tion-typ e murmur
• P ulmonic s te nos is
• Flow murmur
Ao rtic are a
Eje c tion-typ e murmur
• Aortic s te nos is
• Flow murmur
Le ft s te rnal bo rde r
Ea rly d ia s tolic murmur
• Aortic re gurgita tion
• P ulmonic re gurgita tion
Tric us pid are a
P a ns ys tolic murmur
• Tricus pid re gurgita tion
• Ve ntricula r s e pta l de fe ct
Mitral are a
P a ns ys tolic murmur
• Mitra l re gurgita tion
Mid -to-la te d ia s tolic
murmur
• Tricus pid s te nos is
• Atria l s e pta l de fe ct
FIGURE 2-11.
Mid -to-la te d ia s tolic murmur
• Mitra l s te nos is
Locations of maximum intensity of common murmurs.
Ack n ow le d gm en t s
Contributors to previous editions of this chapter were Henry Jung, MD; Nicole Martin, MD;
Oscar Benavidez, MD; Bradley S. Marino, MD; and Allan Goldblatt, MD.
Ad d i t i o n a l Rea d i n g
Bickley LS. Bates’ Guide to Physical Examination and History
Taking. 11th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2013.
Constant J. Essentials of Bedside Cardiology. 2nd ed. Totowa,
NJ: Humana Press; 2003.
LeBlond RF, DeGowin RL, Brown DD. DeGowin’s Diagnostic
Examination. 9th ed. New York, NY: McGraw-Hill; 2008.
Orient JM. Sapira’s Art and Science of Bedside Diagnosis.
4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2010.
Simel DL, Rennie D. The Rational Clinical Examination:
Evidence-Based Clinical Diagnosis. New York, NY: McGrawHill; 2009.
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Cardiac Imaging and
Catheterization
3
Dia na M. López
Pa tricia Cha llender Come
Ch a p t e r O u t l i n e
Cardiac Radiography
Cardiac Silhouette
Pulmonary Mani estations o
Heart Disease
Echocardiography
Ventricular Assessment
Valvular Lesions
Coronary Artery Disease
Cardiomyopathy
Pericardial Disease
Cardiac Catheterization
Measurement o Pressure
Measurement o Blood Flow
Calculation o Vascular
Resistance
Contrast Angiography
Nuclear Imaging
Assessment o Myocardial
Per usion
Radionuclide Ventriculography
Assessment o Myocardial
Metabolism
Computed Tomography
Magnetic Resonance Imaging
Integration
I
maging plays a central role in the assessment o cardiac
unction and pathology. Traditional modalities such as
chest radiography, echocardiography (echo), cardiac catheterization with angiography, and nuclear imaging are undamental
in the diagnosis and management o cardiovascular diseases.
These procedures are increasingly supplemented by newer techniques, including computed tomography (CT) and magnetic
resonance imaging (MRI).
This chapter presents an overview o imaging studies as
they are used to assess the cardiovascular disorders described
later in this book. On f rst reading, it would be benef cial to
amiliarize yoursel with the in ormation but not to memorize
the details. This chapter is meant as a re erence or diagnosis
o conditions that will be explained in more detail in subsequent chapters.
CARDIAC RADIOGRAPHY
The extent o penetration o x-rays through the body is
inversely proportional to tissue density. Air-f lled tissues,
such as the lung, absorb ew x-rays and expose the underlying f lm (or electronic recording sensor), causing it to
appear black. In contrast, dense materials, such as bone,
absorb more radiation and appear white or radiopaque. For
a boundary to show between two structures, they must di er in density. Myocardium, valves, and other intracardiac
structures have densities similar to that o adjacent blood;
consequently, radiography cannot delineate these structures unless they happen to be calcif ed. Conversely, heart
borders adjacent to a lung are depicted clearly because the
heart and an air-f lled lung have di erent densities.
43
44
Chapter 3
Frontal and lateral radiographs are routinely used to assess the heart and lungs
(Fig. 3-1). The frontal view is usually a
posterior–anterior image in which the
x-rays are transmitted rom behind (i.e.,
posterior to) the patient, pass through the
body, and are then captured by the lm
(or electronic sensor) placed against the
anterior chest. This positioning places
the heart close to the x-ray recording lm
plate so that its image is only minimally
distorted, allowing or an accurate assessment o size. In the standard lateral view,
the patient’s le t side is placed against the
lm plate and the x-rays pass through the
body rom right to le t. The rontal radiograph is use ul or assessing the size o the
le t ventricle, le t atrial appendage, pulmonary artery, aorta, and superior vena cava;
the lateral view evaluates right ventricular
size, posterior borders o the le t atrium
and ventricle, and the anteroposterior
diameter o the thorax.
AV
AO
LAA
LA
RA
RV
TV
LV
IVC
B
A
MPA
RPA
LPA
AO
AA
LA
RA
MV
RV
TV
LV
IVC
C
Cardiac Silhouette
MPA
SVC
D
FIGURE 3-1. Posteroanterior ( A and B) and lateral
( C and D) chest radiographs of a person without
cardiopulmonary disease, illustrating cardiac
chambers and valves. AO, aorta; AV, azygos vein;
IVC, inferior vena cava; LA, left atrium; LAA, left
atrial appendage; LPA, left pulmonary artery; LV, left
ventricle; MPA, main pulmonary artery; MV, mitral valve;
RA, right atrium; RPA, right pulmonary artery; RV, right
ventricle; SVC, superior vena cava; TV, tricuspid valve.
(Reprinted from Come PC, ed. Diagnostic Cardiology:
Noninvasive Imaging Techniques. Philadelphia, PA: J.B.
Lippincott; 1985, with permission.)
Chest radiograph s are use u l to evalu ate
th e size o h eart ch am bers an d th e pu lm onary con sequen ces o cardiac disease.
Alteration s in ch am ber size are re lected
by ch an ges in th e cardiac silh ou ette. In
th e ron tal view o adu lts, an en larged
h eart is iden ti ied by a cardiothoracic
ratio (th e m axim u m w idth o the h eart
divided by th e m axim u m in tern al diam eter o th e th oracic cage) o greater
th an 50% .
In certain situations, the cardiac silhouette inaccurately ref ects heart size. For example, an
elevated diaphragm, or narrow chest anteroposterior diameter, may cause the silhouette to
expand transversely such that the heart appears larger than its actual dimensions. There ore,
the chest anteroposterior diameter should be assessed on the lateral view be ore concluding
the heart is truly enlarged. The presence o a pericardial e usion around the heart can also
widen the cardiac silhouette because f uid and myocardial tissue a ect x-ray penetration
similarly.
Radiographs can depict dilatation o individual cardiac chambers. O note, concentric ventricular hypertrophy alone (i.e., without dilatation) may not result in radiographic abnormalities, because it generally occurs at the expense o the cavity’s internal volume and
produces little or no change in overall cardiac size. Major causes o chamber and great vessel dilatation include heart ailure, valvular lesions, abnormal intracardiac and extracardiac
communications (shunts), and certain pulmonary disorders. Because dilatation takes time to
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Cardiac Imaging and Catheterization
45
FIGURE 3-2. Posteroanterior chest
radiograph of a patient with severe
mitral stenosis and secondary pulmonary
vascular congestion. The radiograph shows a
prominent left atrial appendage (arrowheads)
with consequent straightening of the left
heart border and suggestion of a double
density right cardiac border (arrows) produced
by the enlarged left atrium. The aortic
silhouette is small, which suggests chronic
low cardiac output. Radiographic signs
of pulmonary vascular congestion include
increased caliber of upper-zone pulmonary
vessel markings and decreased caliber of
lower-zone vessels.
develop, recent lesions, such as acute mitral valve insu ciency, may present without apparent cardiac enlargement.
The pattern o chamber enlargement may suggest speci c disease entities. For example,
dilatation o the le t atrium and right ventricle, accompanied by signs o pulmonary hypertension, suggests mitral stenosis (Fig. 3-2). In contrast, dilatation o the pulmonary artery and
right heart chambers, but without enlargement o the le t-sided heart dimensions, can be seen
in patients with pulmonary vascular obstruction, in those with increased pulmonary artery
blood f ow (e.g., due to an atrial septal de ect), or in those with pulmonary hypertension o
diverse causes (Fig. 3-3).
Chest radiographs can also detect dilatation o the aorta. Causes o aortic enlargement
include aneurysm, dissection, and aortic valve disease (Fig. 3-4). Normal aging and atherosclerosis may also cause the aorta to become dilated and tortuous.
Pulmonary Manifestations of Heart Disease
The appearance o the pulmonary vasculature ref ects abnormalities o pulmonary arterial
and venous pressures and pulmonary blood f ow. Increased pulmonary venous pressure,
as occurs in le t heart ailure, causes increased vascular markings, redistribution o blood
f ow rom the bases to the apices o the lungs (termed cepha liza tion o vessels), interstitial edema, and alveolar edema (Fig. 3-5). Cephalization appears as an increase in the
number or width o vascular markings at the apex (Fig. 3-5A). Interstitial edema occurs
as pulmonary congestion progresses, and the connective tissue spaces become thickened
with f uid (Fig. 3-5B). Kerley B lines (short horizontal parallel lines at the periphery o
the lungs adjacent to the pleura, most o ten at the lung bases) depict f uid in interlobular
spaces that results rom interstitial edema (Fig. 3-5C). When f uid accumulates in the
air spaces, alveolar orms o pulmonary edema produce opacity radiating rom the hilar
46
Chapter 3
FIGURE 3-3. Posteroanterior chest
radiograph o a patient with pulmonary
hypertension secondary to an atrial septal
de ect. Radiographic signs of pulmonary
hypertension include pulmonary artery
dilatation (black arrows; compare with the
appearance of left atrial appendage dilatation
in Fig. 3-2) and large central pulmonary
arteries (white arrows) associated with
small peripheral vessels (a pattern known as
peripheral pruning).
region bilaterally (known as a “butterf y” pattern) and air bronchograms may be seen
(Fig. 3-5D). Fluid accumulation in the pleural spaces in heart ailure (i.e., pleural e usions) is mani est by blunting o the costophrenic angles (the angle between the ribs and
the diaphragm).
FIGURE 3-4. Posteroanterior chest radiograph
o a patient with aortic stenosis and
insu f ciency secondary to a bicuspid aortic
valve. In addition to poststenotic dilatation of
the ascending aorta (black arrows), the transverse
aorta (white arrow) is prominent.
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Cardiac Imaging and Catheterization
A
B
C
D
47
FIGURE 3-5. Posteroanterior radiographs of patients with heart failure ( HF) . A. Early mani estations o HF
include upper zone redistribution (cephalization) o vessels (green arrows); cardiomegaly is present. B. More
pronounced mani estations o HF include interstitial edema with pulmonary vascular markings throughout the
lung f elds owing to edematous interlobular septae. Fluid-associated thickening o bronchial walls is visualized
as peribronchiolar cu f ng (red arrow). C. Enlarged view o Kerley B lines (yellow arrows) at the periphery o the
lower le t lung f eld. D. Severe HF mani est by di use alveolar edema. Air bronchograms (blue arrows) occur
when the radiolucent bronchial tree is contrasted with opaque edematous tissue. Patients with HF o ten have
a combination o interstitial and alveolar edema. (Courtesy o Gillian Lieberman, MD, Beth Israel Deaconess
Medical Center, Boston, MA.)
Changes in pulmonary blood f ow may also alter the appearance o the pulmonary vessels.
For example, ocal oligemia (reduction in the size o blood vessels due to decreased blood
f ow) is occasionally observed distal to a pulmonary embolism (termed the Westermark sign).
The nding o enlarged central pulmonary arteries, but small peripheral vessels (termed
peripheral pruning), suggests pulmonary hypertension (see Fig. 3-3).
Table 3-1 summarizes the major radiographic ndings in common orms o cardiac
disease.
48
Chapter 3
TABLE 3-1 Chest Radiography of Common Cardiac Disorders
Disorder
Findings
Congestive heart failure
•
•
•
•
•
•
•
•
•
•
•
•
•
Pulmonic valve stenosis
Aortic valve stenosis
Aortic regurgitation
Mitral stenosis
Mitral regurgitation
Cephalization o vessels
Interstitial edema (peribronchial cu f ng, Kerley B lines)
Alveolar edema (air bronchograms)
Pleural e usions
Poststenotic dilatation o pulmonary artery
Poststenotic dilatation o ascending aorta
Le t ventricular dilatation
Dilated aorta
Le t atrial dilatation
Signs o pulmonary venous congestion
Le t atrial dilatation
Le t ventricular dilatation
Signs o pulmonary venous congestion in acute MR (see Chapter 8)
ECHOCARDIOGRAPHY
Echocardiography plays an essential role in the diagnosis and serial evaluation o many cardiac disorders. It is sa e, noninvasive, and relatively inexpensive. High- requency (ultrasonic)
waves generated by a piezoelectric element travel through the body and are ref ected at interaces where there are di erences in the acoustic impedance o adjacent tissues. The ref ected
waves return to the transducer and are recorded. The machine measures the time elapsed
between the initiation and reception o the sound waves, allowing it to calculate the distance
between the transducer and each anatomic ref ecting sur ace. Images are then constructed
rom these calculations.
Three types o imaging are routinely per ormed during an echocardiographic examination: M-mode, two-dimensional (2D), and Doppler. Each type o imaging can be per ormed
rom various body locations. Most commonly, transthoracic studies are per ormed, in which
images are obtained by placing the transducer on the sur ace o the chest. When greater structural detail is required, transesophageal imaging is per ormed.
M-mode echocardiography, the oldest orm o cardiac ultrasonography, provides data rom
only one ultrasonic beam and is now rarely used by itsel . It supplements the other modalities
to provide accurate measurements o wall thicknesses and timing o valve movements.
In 2D echocardiography, multiple ultrasonic beams are transmitted rom the transducer
through a wide arc. The returning signals are integrated to produce 2D images o the heart
on a video monitor. As a result, this technique depicts anatomic relationships and de nes
the movement o cardiac structures relative to one another. Wall and valve motion abnormalities, and many types o intracardiac masses (e.g., vegetations, thrombi, tumors), can be
depicted.
Each 2D plane (Fig. 3-6) delineates only part o a given cardiac structure. Optimal evaluation o the entire heart is achieved by using combinations o views. In transthoracic echocardiography (TTE), in which the transducer is placed against the patient’s skin, these include
the parasternal long axis, parasternal short axis, apical views, and subcostal views. The parasternal long-axis view is recorded with the transducer in the third or ourth intercostal space
to the le t o the sternum. This view is particularly use ul or evaluation o the le t atrium,
mitral valve, le t ventricle, and le t ventricular outf ow tract (LVOT), which includes the aortic
valve and adjacent interventricular septum. To obtain parasternal short-axis views, the transducer is rotated 90 degrees rom its position or the long-axis view. The short-axis images
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Cardiac Imaging and Catheterization
49
Inte rve ntricula r s e ptum
RV
Ao
Aortic
va lve
LV
LA
Mitra l
va lve
A
LV pos te rior wa ll
RV
LV
FIGURE 3-6. Transthoracic twodimensional echocardiographic views.
A. Parasternal long-axis view. B. Parasternal
short-axis view. Notice that the le t
ventricle appears circular in this view, while
the right ventricle is crescent shaped. C.
Apical our-chamber view. Ao, aorta; LA,
le t atrium; LV, le t ventricle; RA, right
atrium; RV, right ventricle. (Modif ed rom
Sahn DJ, Anderson F. Two-Dimensional
Anatomy of the Heart. New York, NY: John
Wiley & Sons; 1982.)
B
RV
LV
Mitra l
va lve
Tricus pid
va lve
RA
LA
C
depict transverse planes o the heart. Several di erent levels are imaged to assess the aortic
valve, mitral valve, and le t ventricular wall motion.
Apical TTE views are produced when the transducer is placed at the point o maximal apical impulse. The apical four-chamber view evaluates the mitral and tricuspid valves as well
as the atrial and ventricular chambers, including the motion o the lateral, septal, and apical
le t ventricular walls. The apical two-chamber view shows only the le t side o the heart, and
it depicts movement o the anterior, in erior, and apical walls.
In some patients, such as those with obstructive airways disease, the parasternal and apical views do not adequately show cardiac structures because the excessive underlying air
attenuates the acoustic signal. In such patients, the subcostal view, in which the transducer is
placed in erior to the rib cage, may provide a better ultrasonic window.
Doppler imaging depicts blood f ow direction and velocity and identi es regions o vascular turbulence. Additionally, it permits estimation o pressure gradients within the heart and
great vessels. Doppler studies are based on the physical principle that waves ref ected rom
a moving object undergo a requency shi t according to the moving object’s velocity relative
to the source o the waves. Color f ow mapping converts the Doppler signals to a scale o
colors that represent direction, velocity, and turbulence o blood f ow in a semiquantitative
way. The colors are superimposed on 2D images and show the location o stenotic and regurgitant valvular lesions and o abnormal communications within the heart and great vessels.
For example, Doppler echocardiography in a patient with mitral regurgitation shows a jet o
retrograde f ow into the le t atrium during systole (Fig. 3-7).
50
Chapter 3
Sound requency shi ts are converted by the echo machine into
blood f ow velocity measurements by the ollowing relationship:
v=
LV
fs c
2fO (cos θ )
RV
in which v equals the blood f ow velocity (m/ sec); fs, the Doppler requency shi t (kHz); c, the velocity o sound in body tissue (m/ sec); fO,
the requency o the sound pulse emitted rom the transducer (MHz);
RA
and θ, the angle between the transmitted sound pulse and the mean
LA
axis o the blood f ow being assessed.
Transesophageal echocardiography (TEE) uses a miniaturized
transducer mounted at the end o a modi ed endoscope to transmit and receive ultrasound waves rom within the esophagus, thus
producing very clear images o the neighboring cardiac structures
FIGURE 3-7. Doppler color f ow
(Fig. 3-8) and much o the thoracic aorta. Modern probes permit
mapping o mitral regurgitation
multiplanar imaging and Doppler interrogation. TEE is particularly
( MR) . The color Doppler
help ul in the assessment o aortic and atrial abnormalities, conimage, recorded in systole, is
ditions that are less well visualized by conventional transthoracic
superimposed on an apical ourchamber view. The color Doppler
echo imaging. For example, TEE is more sensitive than transthoracic
signal lling the le t atrium (LA)
echo or the detection o thrombus within the le t atrial appendindicates retrograde f ow o MR
age (Fig. 3-9). The proximity o the esophagus to the heart makes
rom the le t ventricle (LV) across
TEE imaging particularly advantageous in patients or whom transthe mitral valve (arrow). RA, right
thoracic echo images are unsatis actory (e.g., those with chronic
atrium; RV, right ventricle.
obstructive lung disease).
TEE is also advantageous in the evaluation o patients with prosthetic heart valves. During standard transthoracic imaging, arti cial mechanical valves ref ect
a large portion o ultrasound waves, thus inter ering with visualization o more posterior structures (termed acoustic shadowing). TEE aids visualization in such patients and is there ore
the most sensitive noninvasive technique or evaluating perivalvular leaks. In addition, TEE is
A. Cros s -s e ctiona l
view of a ortic
va lve
LA
Es opha gus
RA
N L
R
RV
A
C. S hort a xis view
of le ft ve nticle
B
LV
RV
RA
LA
C
B. Long a xis view
of ca rdia c
cha mbe rs
LV
RV
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FIGURE 3-8. Transesophageal
echocardiographic views. LA,
le t atrium; LV, le t ventricle; RA,
right atrium; RV, right ventricle; N,
noncoronary cusp o aortic valve; L, le t
coronary cusp o aortic valve; R, right
coronary cusp o aortic valve.
Cardiac Imaging and Catheterization
51
LA
LAA
Thrombus
A
B
FIGURE 3-9. Echocardiographic imaging of an intracardiac thrombus. A. Transesophageal echocardiographic
image demonstrates thrombus within the left atrial appendage. (Courtesy of Scott Streckenbach, MD,
Massachusetts General Hospital, Boston, MA.) B. Schematic drawing of same image. LA, left atrium; LAA, left
atrial appendage.
more sensitive than TTE or detecting eatures o endocarditis, such as vegetations and myocardial abscesses.
TEE is commonly used to evaluate patients with cerebral ischemic events (i.e., strokes) o
unexplained etiology, because it can identi y cardiovascular sources o embolism with high
sensitivity. These etiologies include intracardiac thrombi or tumors, atherosclerotic debris
within the aorta, and valvular vegetations. TEE is also highly sensitive and speci c or the
detection o aortic dissection.
In the operating room, TEE permits immediate evaluation a ter surgical repair o cardiac
lesions. In addition, imaging o ventricular wall motion can identi y periods o myocardial
ischemia during surgery.
New ultrasound modalities include 3D echocardiography and intracardiac echocardiography. The spatial reconstructions a orded by 3D echo are o particular bene t in the assessment o valvular de ects, intracardiac masses, and congenital mal ormations. Intracardiac
echo utilizes a transducer mounted on a catheter to provide imaging during interventional
procedures in the cardiac catheterization laboratory.
Contrast echocardiography is sometimes used to supplement standard imaging to evaluate or abnormal intracardiac shunts. In this technique, o ten called a “bubble study,” an
echocardiographic contrast agent (e.g., agitated saline) is rapidly injected into a peripheral
vein. Using standard imaging, the contrast can be visualized passing through the cardiac
chambers. Normally, there is rapid opaci cation o the right-sided chambers, but because
the contrast is ltered out (harmlessly) in the lungs, it does not reach the le t-sided chambers. However, in the presence o an intracardiac shunt with abnormal right-to-le t heart
blood f ow, or in the presence o an intrapulmonary shunt, bubbles o contrast will appear
in the le t-sided chambers as well. Newer perf uorocarbon-based contrast agents have been
developed with su ciently small particle size to intentionally pass through the pulmonary
circulation. These agents are used to opaci y the le t ventricular cavity and, via the coronary
arteries, the myocardium, enabling superior assessment o LV contraction and myocardial
per usion.
Echocardiographic techniques can identi y valvular lesions, complications o coronary artery disease (CAD), septal de ects, intracardiac masses, cardiomyopathy, ventricular hypertrophy, pericardial disease, aortic disease, and congenital heart disease.
52
Chapter 3
S
LV
LV
LVOT
LA
LA
P
P
A
B
FIGURE 3-10. Le t ventricular outf ow tract ( LVOT) obstruction in hypertrophic cardiomyopathy—
parasternal long-axis view. Notice that the interventricular septum (S) is thicker and more echogenic than the
posterior wall (P). A. Be ore ventricular contraction, the LVOT is only slightly narrowed. B. During contraction,
the rapidly f owing blood through the LVOT incites a Venturi e ect and abnormally draws the mitral valve
anteriorly toward the hypertrophied septum (arrow), creating a unctional obstruction. LA, le t atrium; LV, le t
ventricle.
Typical evaluation includes assessment o cardiac chamber sizes, wall thicknesses, wall
motion, valvular unction, blood f ow, and intracardiac hemodynamics. A ew o these
topics are highlighted here.
Ventricular Assessment
Echocardiography allows measurement o ventricular wall thickness and mass (Fig. 3-10)
and calculation o the ejection fraction, a measure o contractile unction (see Chapter 9).
Furthermore, 2D echocardiography depicts regional ventricular wall motion abnormalities, a
sign o CAD, and displays right ventricular unction qualitatively.
Diastolic dys unction (e.g., caused by ischemic disease, ventricular hypertrophy, or restrictive cardiomyopathy; see Chapter 9) can be evaluated by Doppler techniques. For example,
Doppler tissue imaging is a modality that can readily record the maximum velocity o mitral
annular movement in early diastole, an indicator o the le t ventricle’s ability to relax normally. Doppler measurement o f ow velocity across the mitral valve in early, compared with
late, diastole also provides in ormation about diastolic unction.
Valvular Lesions
Echocardiography can determine underlying causes o valvular abnormalities, and Doppler
imaging quantitates the degree o valvular stenosis and regurgitation. The pressure gradient
across a stenotic valve can be calculated rom the maximum blood f ow velocity (v) measured
distal to the valve, using the simpli ed Bernoulli equation:
Pressure gradient = 4 × v 2
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Cardiac Imaging and Catheterization
1
2
V2
V1
A1
A2
A1 x V1 = A2 x V2
FIGURE 3-11. The continuity equation. Within
a closed f ow stream, the volume rate o f ow at
any point (calculated as the cross-sectional area
at that site multiplied by the f ow velocity at the
same location) is equal to the volume rate o f ow
at sequential points. Thus, cross-sectional area and
velocity at any location are inversely proportional
to one another. Here, location 2 is narrower than
location 1. There ore, the velocity at location 2 must
be greater or the same volume to pass per unit
time.
53
As an example, i the peak velocity recorded distal to a stenotic aortic valve is 5 m/ sec, then the
calculated peak pressure gradient across the valve =
4 × 5 2 = 100 mm Hg.
Other calculations permit noninvasive determination o the cross-sectional area o stenotic valves. The
continuity equation is o ten used to calculate aortic
valve area. This equation assumes that blood f ow (F,
expressed in cc/ sec) is the same at the aortic valve
ori ce (AV) as at a neighboring position along the
f ow stream (e.g., in the LVOT):
FLVOT = FAV
As shown in Figure 3-11, blood f ow at any position along a f ow stream can also be expressed as the
product o the Doppler velocity (V, in cm/ sec) and
cross-sectional area (A, in cm 2) at that level. I location 1 in Figure 3-11 represents a position in the LVOT
and location 2 represents the aortic valve, then
ALVOT × VLVOT = AAV × VAV
The cross-sectional area o the LVOT (ALVOT) is calculated simply as π(d/ 2) 2, where d represents the LVOT diameter, measured rom the parasternal long-axis view. The velocities (VLVOT
and VAV) are measured by Doppler interrogation, rom the apical our-chamber view. The
equation can then be solved or the aortic valve area (AAV):
AAV =
ALVOT × VLVOT
VAV
Color Doppler analysis provides a qualitative assessment o the severity o regurgitant valve
lesions. In mitral regurgitation (see Fig. 3-7), or example, the ratio o the regurgitant jet color
Doppler area to the entire le t atrial area has traditionally been used to classi y the regurgitation as mild, moderate, or severe. More quantitative evaluation o mitral regurgitation can now
be per ormed by what is known as the proximal isovelocity sur ace area (PISA) method. This
technique uses advanced color Doppler techniques to calculate the regurgitant volume and
e ective regurgitant ori ce area, two values that predict clinical outcomes in patients with
chronic mitral regurgitation.
Coronary Artery Disease
Echocardiography demonstrates ventricular wall motion abnormalities associated with
in arcted or ischemic myocardium. The location and degree o abnormal systolic contraction and decreased systolic wall thickening indicate the extent o an in arction and implicate
the responsible coronary artery. Echocardiography also detects complications o in arction
including thrombus ormation, papillary muscle rupture, ventricular septal rupture, and
aneurysm.
Although echocardiography can depict those consequences o CAD, transthoracic echo
resolution in adults is insu cient to satis actorily image the coronary arteries themselves.
However, stress echocardiography is a technique that aids in the diagnosis o CAD. This
technique visualizes le t ventricular regional wall motion abnormalities that are induced by
exercise, or the in usion o speci c pharmacologic agents (e.g., dobutamine), as a sign o
myocardial ischemia (see Chapter 6).
54
Chapter 3
Cardiomyopathy
Cardiomyopathies are heart muscle disorders that include dilated, hypertrophic, and restrictive orms (see Chapter 10). Echocardiography can distinguish these and permits assessment
o the severity o systolic and diastolic dys unction. For example, Figure 3-10 depicts asymmetrically thickened ventricular walls in a patient with hypertrophic cardiomyopathy.
Pericardial Disease
Two-dimensional echocardiography can identi y abnormalities in the pericardial cavity
(e.g., excessive pericardial f uid and tumor). Tamponade and constrictive pericarditis, the
main complications o pericardial disease (see Chapter 14), are associated with particular
echocardiographic abnormalities. In tamponade, the increased intrapericardial pressure compresses the cardiac chambers and results in diastolic “collapse” o the right atrium and right
ventricle (Fig. 3-12). Constrictive pericarditis is associated with increased thickness o the
pericardial echo, abnormal patterns o diastolic le t ventricular wall motion, alterations in
pulmonary and hepatic venous f ow patterns, and exaggerated changes in mitral and tricuspid
valve inf ow velocities during respiration.
Table 3-2 summarizes the echocardiographic eatures o common cardiac diseases.
A
B
C
D
FIGURE 3-12. Echocardiogram of a patient with a pericardial effusion causing cardiac tamponade.
A. Parasternal long-axis image showing a large pericardial effusion (PE) surrounding the heart. This frame
was obtained in systole and shows normal appearance of the left (LV) and right (RV) ventricles during that
phase. B. Same image as ( A) , but this frame was obtained in early diastole and shows collapse of the RV free
wall (arrow) due to compression by the effusion. C. Subcostal view, obtained in systole, demonstrating the
PE surrounding the right atrium (RA), RV, left atrium (LA), and LV. D. Same image as ( C) , obtained during
diastole, showing inward collapse of the RA (arrow).
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55
TABLE 3-2 Echocardiography in Common Cardiac Disorders
Disorder
Findings
Valvular lesions
Mitral stenosis
Mitral regurgitation
Aortic stenosis
Aortic regurgitation
Left ventricular function
Myocardial in arction and complications
Cardiomyopathies
Dilated
Hypertrophic
Restrictive
•
•
•
•
•
•
•
•
•
•
•
•
Enlarged le t atrium
Thickened mitral valve leaf ets
Decreased movement and separation o mitral valve leaf ets
Decreased mitral valve ori ce
Enlarged le t atrium (i chronic)
Enlarged le t ventricle (i chronic)
Systolic f ow rom le t ventricle into le t atrium by Doppler
Thickened aortic valve cusps
Decreased valve ori ce
Increased le t ventricular wall thickness
Enlarged le t ventricle
Abnormalities o aortic valve or aortic root
•
•
•
•
•
Abnormal regional ventricular wall motion
Thrombus within le t ventricle
Aneurysm o ventricular wall
Septal rupture (abnormal Doppler f ow)
Papillary muscle rupture
•
•
•
•
•
•
•
•
•
•
Enlarged ventricular chamber sizes
Decreased systolic contraction
Normal or decreased ventricular chamber sizes
Increased ventricular wall thickness
Diastolic dys unction (assessed by Doppler)
Normal or decreased ventricular chamber sizes
Increased ventricular wall thickness
Ventricular contractile unction may be abnormal
Diastolic dys unction (assessed by Doppler)
Enlarged atria (o ten markedly so)
CARDIAC CATHETERIZATION
To diagnose many cardiovascular abnormalities, intravascular catheters are inserted to measure pressures in the heart chambers, to determine cardiac output and vascular resistances,
and to inject radiopaque material to examine heart structures and blood f ow. In 1929, Werner
Forssmann per ormed the rst cardiac catheterization, on himself, thus ushering in the era o
invasive cardiology. Much o what is known about the pathophysiology o valvular heart disease and congestive heart ailure comes rom decades o subsequent hemodynamic research
in the cardiac catheterization laboratory.
Measurement of Pressure
Be ore catheterization o an artery or vein, the patient is mildly sedated, and a local anesthetic is used to numb the skin site o catheter entry. The catheter, attached to a pressure transducer outside the body, is then introduced into the appropriate blood vessel. To
measure pressures in the right atrium, right ventricle, and pulmonary artery, a catheter is
Chapter 3
Ao rta
PCW
2–10
100–140
60–90
LA
2–10
PA
RA
15–30
4–12
LV
2–8
100–140
3–12
RV
15–30
2–8
PA
15–30
4–12
Lung s
LA
PCW
2–10
2–10
LV
100–140
3–12
Ao rta
100–140
60–90
FIGURE 3-13. Diagrams indicating
normal pressures in the cardiac
chambers and great vessels. The top
f gure shows the normal anatomic
relationship o the cardiac chambers
and great vessels, whereas the f gure
on the bottom shows a simplif ed
schematic to clari y the pressure
relationships. Numbers indicate
pressures in mm Hg. LA, le t atrial
mean pressure; LV, le t ventricular
pressure; PA, pulmonary artery
pressure; PCW, pulmonary capillary
wedge mean pressure; RA, right atrial
mean pressure; RV, right ventricular
pressure.
inserted into a emoral, brachial, or jugular vein. Pressures in the aorta and le t ventricle
are measured via catheters inserted into a radial, brachial, or emoral artery. Once in the
blood vessel, the catheter is guided by f uoroscopy (continuous x-ray images) to the area o
study, where pressure measurements are made. Figure 3-13 depicts normal intracardiac and
intravascular pressures.
The measurement o right heart pressures is per ormed with a specialized balloon-tipped
catheter (a common version o which is known as the Swan–Ganz catheter) that is advanced
through the right side o the heart with the aid o normal blood f ow, and into the pulmonary
artery. As it travels through the right side o the heart, recorded pressure measurements identi y the catheter tip’s position (see Box 3-1).
BOX 3-1
Intracardiac Pressure Tracings
When a catheter is inserted into a systemic vein and advanced into the right side o the heart,
each cardiac chamber produces a characteristic pressure curve. It is important to distinguish these
recordings rom one another to localize the position o the catheter tip and to derive appropriate
physiologic in ormation.
ECG
P ulmona ry a rte ry
20
P ulmona ry ca pilla ry we dge
a v
m
m
H
g
)
Right ve ntricle
(
e
r
u
s
s
e
2–8
RV
15–30
2–8
r
RA
P
56
10
Right a trium
a c v
x y
Time
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Cardiac Imaging and Catheterization
BOX 3-1
Intracardiac Pressure Tracings
57
( continued)
The normal right atrial (RA) pressure demonstrates three positive def ections (see the gure
in Box 2.1 or an enlarged view): the a wave ref ects RA contraction at the end o diastole, the
c wave results rom bulging o the tricuspid valve toward the right atrium as it closes in early
systole, and the v wave represents passive lling o the right atrium rom the systemic veins
during systole, when the tricuspid valve is closed. The downward def ection that ollows the c wave
is known as the x descent, and the downward def ection a ter the v wave is called the y descent.
O ten the a and c waves merge so that only two major positive def ections are seen. In patients
with atrial brillation, the a wave is absent because there is no organized le t atrial contraction.
As the catheter is advanced into the right ventricle (RV), a dramatic increase in systolic
pressure is seen. The RV systolic wave orm is characterized by a rapid upstroke and downstroke. In
diastole, there is a gradual continuous increase in RV pressure as the chamber lls with blood.
As the catheter is moved orward into the pulmonary artery (PA), the systolic pressure remains
the same as that in the RV (as long as there is no obstruction to RV outf ow, such as pulmonic
valve stenosis). However, three characteristics o the recording indicate entry into the pulmonary
artery: (1) the PA diastolic pressure is higher than that o the RV; (2) the descending systolic
portion o the PA tracing inscribes a dicrotic wave, a small transient pressure increase that occurs
a ter the systolic peak and is related to pulmonic valve closure; and (3) the diastolic portion o
the PA tracing is downsloping compared with the upsloping RV diastolic pressure.
Further advancement o the catheter into a branch o the pulmonary artery results in the
pulmonary capillary wedge (PCW) tracing, which ref ects the le t atrial pressure (Fig. 3-14). Its
characteristic shape is similar to the RA tracing, but the pressure values are usually higher, and
the tracing is o ten less clear (with the c wave not observed) because o damped transmission
through the capillary vessels.
Right Atrial Pressure
Right atrial pressure is equal to the central venous pressure (estimated by the jugular venous
pressure on physical examination) because no obstructing valves impede blood return rom
the central veins into the right atrium. Similarly, right atrial pressure normally equals right
ventricular pressure during diastole because the right heart unctions as a “common chamber” when the tricuspid valve is open. The mean right atrial pressure is reduced when there is
intravascular volume depletion. It is elevated in right ventricular ailure, right-sided valvular
disease, and cardiac tamponade (in which the cardiac chambers are surrounded by highpressure pericardial f uid; see Chapter 14).
Certain abnormalities cause characteristic changes in individual components o the right
atrial (and there ore jugular venous) pressure (Table 3-3). For example, a prominent a wave
is seen in tricuspid stenosis and right ventricular hypertrophy. In these conditions, the right
atrium contracts vigorously against the obstructing tricuspid valve or sti ened right ventricle,
respectively, generating a prominent pressure wave. Similarly, ampli ed “cannon” a waves
may be produced by conditions o atrioventricular dissociation (see Chapter 12), when the
right atrium contracts against a closed tricuspid valve. A prominent v wave is observed in
tricuspid regurgitation because normal right atrial lling is augmented by the regurgitated
blood in systole.
Right Ventricular Pressure
Right ventricular systolic pressure is increased by pulmonic valve stenosis or pulmonary
hypertension. Right ventricular diastolic pressure increases when the right ventricle is subjected to pressure or volume overload and may be a sign o right heart ailure.
58
Chapter 3
TABLE 3-3 Causes of Increased Intracardiac Pressures
Chamber and Measurement
Causes
Right atrial pressure
•
•
•
•
•
•
Right ventricular ailure
Cardiac tamponade
Tricuspid stenosis
Right ventricular hypertrophy
Atrioventricular dissociation
Tricuspid regurgitation
•
•
•
•
•
Pulmonic stenosis
Pulmonary hypertension
Right ventricular ailure
Cardiac tamponade
Right ventricular hypertrophy
a wave
v wave
Right ventricular pressure
Systolic
Diastolic
Pulmonary artery pressure
Systolic and diastolic
Systolic only
Pulmonary artery wedge pressure
a wave
v wave
• Pulmonary hypertension
• Le t-sided heart ailure
• Chronic lung disease
• Pulmonary vascular disease
• Increased f ow (le t-to-right shunt)
• Le t-sided heart ailure
• Mitral stenosis or regurgitation
• Cardiac tamponade
• Le t ventricular hypertrophy
• Mitral regurgitation
• Ventricular septal de ect
Pulmonary Artery Pressure
Elevation o systolic and diastolic pulmonary artery pressures occurs in three conditions: (1) leftsided heart ailure, (2) parenchymal lung disease (e.g., chronic bronchitis or end-stage emphysema), and (3) pulmonary vascular disease (e.g., pulmonary embolism, primary pulmonary
hypertension, or acute respiratory distress syndrome). Normally, the pulmonary artery diastolic
pressure is equivalent to the le t atrial pressure because o the low resistance o the pulmonary
vasculature that separates them. I the le t atrial pressure rises because o le t-sided heart ailure,
both systolic and diastolic pulmonary artery pressures increase in an obligatory manner to maintain orward f ow through the lungs. This situation leads to “passive” pulmonary hypertension.
In certain conditions, however, pulmonary vascular resistance becomes abnormally high,
causing pulmonary artery diastolic pressure to be elevated compared with le t atrial pressure.
For example, pulmonary vascular obstructive disease may develop as a complication o a chronic
le t-to-right cardiac shunt, such as an atrial or ventricular septal de ect (see Chapter 16).
Pulmonary Artery Wedge Pressure
I a catheter is advanced into the right or le t pulmonary artery, its tip will ultimately reach one
o the small pulmonary artery branches and temporarily occlude orward blood f ow beyond it.
During that time, a column o stagnant blood stands between the catheter tip and the portions
o the pulmonary capillary and pulmonary venous segments distal to it (Fig. 3-14). That column
o blood acts as an extension o the catheter, and the pressure recorded through the catheter
ref ects that o the downstream chamber—namely, the le t atrium. Such a pressure measurement is termed the pulmonary artery wedge pressure or pulmonary capillary wedge pressure
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59
PA
LA
Pulmona ry
a rte ry ca the te r
A pulmona ry
ve in
Ca the te r tip
occlude s bra nch
of pulmona ry a rte ry
This a re a re pre s e nts
“column of blood” be twe e n
ca the te r tip a nd LA
Pulmona ry
ca pilla rie s
FIGURE 3-14. Diagram of a pulmonary artery catheter inserted into a branch of the pulmonary artery
( PA) . Flow is occluded in the arterial, arteriolar, and capillary vessels beyond the catheter; thus, these vessels
act as a conduit that transmits the left atrial (LA) pressure to the catheter tip.
(PCW) and closely matches the le t atrial pressure in most individuals. Furthermore, while the
mitral valve is open during diastole, the pulmonary venous bed, le t atrium, and le t ventricle
normally share the same pressures. Thus, the PCW can be used to estimate the le t ventricular
diastolic pressure, a measurement o ventricular preload (see Chapter 9). As a result, measurement o PCW may be use ul in managing certain critically ill patients in the intensive care unit.
Elevation o the mean PCW is seen in le t-sided heart ailure and in mitral stenosis or regurgitation. The individual components o the PCW tracing can also become abnormally high.
The a wave may be increased in conditions o decreased le t ventricular compliance, such as
le t ventricular hypertrophy or acute myocardial ischemia, and in mitral stenosis. The v wave
is greater than normal when there is increased le t atrial lling during ventricular contraction,
as in mitral regurgitation.
Measurement of Blood Flow
Cardiac output is measured by either the thermodilution method or the Fick technique. In the
thermodilution method, saline o a known temperature is injected rapidly through a catheter
side port into the right side o the heart, at a speci c distance rom the distal tip o the catheter. The catheter tip, positioned in the pulmonary artery, contains a thermistor that registers
the change in temperature induced by the injected saline. The cardiac output is proportional
to the rate o the temperature change and is automatically calculated by the equipment.
The Fick method relies on the principle that the quantity o oxygen consumed by tissues
is related to the amount o O2 content removed rom blood as it f ows through the tissue
capillary bed:
O2 consumption = O2 content removed
mL O2
min
mL O2
mL blood
×
Flow
mL blood
min
Or, in more applicable terms:
O2 consumption = AVO2 di erence × Cardiac output
where the arteriovenous O2 (AVO2) di erence equals the di erence in oxygen content between
the arterial and venous compartments. Total body oxygen consumption can be determined by
analyzing expired air rom the lungs, and arterial and venous O2 content is measured in blood
samples. By rearranging the terms, the cardiac output can be calculated:
Cardiac output =
O2 consumption
AVO2 di erence
60
Chapter 3
For example, i the arterial blood in a normal adult contains 190 mL o O2 per liter and the
venous blood contains 150 mL o O2 per liter, the arteriovenous di erence is 40 mL o O2 per
liter. I this patient has a measured O2 consumption o 200 mL/ min, the calculated cardiac
output is 5 L/ min.
In many orms o heart disease, the cardiac output is lower than normal. In that situation, the total body oxygen consumption does not change signi cantly; however, a greater
percentage o O2 is extracted per volume o circulating blood by the metabolizing tissues.
The result is a lower-than-normal venous O2 content and there ore an increased AVO2 di erence. In our example, i the patient’s venous blood O2 content ell to 100 mL/ L, the AVO2
di erence would increase to 90 mL/ L and the calculated cardiac output would be reduced
to 2.2 L/ min.
Because the normal range o cardiac output varies with a patient’s size, it is common to
report the cardiac index, which is equal to the cardiac output divided by the patient’s body
sur ace area (normal range o cardiac index = 2.6 – 4.2 L/ min/ m 2).
Calculation of Vascular Resistance
Once pressures and cardiac output have been determined, pulmonary and systemic vascular resistances can be calculated, based on the principle that the pressure di erence
across a vascular bed is proportional to the product o f ow and resistance. The calculations are:
PVR =
MPAP − LAP
× 80
CO
PVR, pulmonary vascular resistance (dynes-sec-cm − 5)
MPAP, mean pulmonary artery pressure (mm Hg)
LAP, mean le t atrial pressure (mm Hg)
CO, cardiac output (L/ min)
SVR =
MAP − RAP
× 80
CO
SVR, systemic vascular resistance (dynes-sec-cm − 5)
MAP, mean arterial pressure (mm Hg)
RAP, mean right atrial pressure (mm Hg)
CO, cardiac output (L/ min)
The normal PVR ranges rom 20 to 130 dynes-sec-cm − 5. The normal SVR is 700 to 1,600
dynes-sec-cm − 5.
Contrast Angiography
This technique uses radiopaque contrast to visualize regions o the cardiovascular system.
A catheter is introduced into an appropriate vessel and guided under f uoroscopy to the site
o injection. Following administration o the contrast agent, x-rays are transmitted through
the area o interest. A continuous series o x-ray exposures is recorded to produce a motion
picture cineangiogram (o ten simply called a “cine” or “angiogram”).
Selective injection o contrast into speci c heart chambers can be used to identi y valvular
insu ciency, intracardiac shunts, thrombi within the heart, congenital mal ormations, and
to measure ventricular contractile unction (Fig. 3-15). However, the noninvasive techniques
described in this chapter (e.g., echocardiography) have largely supplanted the need or invasive contrast angiography or these purposes.
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A
61
B
FIGURE 3-15. Left ventriculogram, in diastole ( A) and systole ( B) in the right anterior oblique projection,
from a patient with normal ventricular contractility. A catheter (black arrow) is used to inject contrast into
the le t ventricle (LV). The catheter can also be seen in the descending aorta (white arrowhead). AO, aortic root.
An important and widespread application of contrast injection is coronary artery angiography, to examine the location and severity of coronary atherosclerotic lesions. To maximize
the test’s sensitivity and reproducibility, each patient is imaged in several standard views.
When necessary, angioplasty and stent placement can be performed (Figs. 3-16 and 3-17;
see Chapter 6).
LCX
LM
LM
LAD
LAD
Diag o nal
branc h
S e ptal
pe rfo rato rs
A
B
FIGURE 3-16. Cardiac catheterization and stenting of a proximal left anterior descending artery ( LAD)
stenosis, shown in an anteroposterior cranial projection. A. When contrast agent is injected into the le t main
coronary artery (LM), the le t circumf ex artery (LCX) lls normally, but the LAD is almost completely occluded at
its origin (white arrow). B. A ter the stenosis is success ully stented, the LAD and its branches ll robustly.
62
Chapter 3
A
B
FIGURE 3-17. Cardiac catheterization and stenting o right coronary artery ( RCA) stenoses. Both
images are obtained in the le t anterior oblique (LAO) projection. A. The stenotic segment is located between
the white arrows. B. A ter stenting, the caliber o the vessel and f ow have improved.
A small risk is associated with catheterization and contrast angiography. Complications are
uncommon but include myocardial per oration by the catheter, precipitation o arrhythmias
and conduction blocks, damage to vessel walls, hemorrhage, dislodgement o atherosclerotic
plaques, pericardial tamponade (see Chapter 14), and in ection. The contrast medium itsel
can cause anaphylaxis and renal toxicity.
Table 3-4 summarizes the catheterization ndings in common cardiac abnormalities.
Therapeutic interventional catheterization techniques are described in Chapter 6.
NUCLEAR IMAGING
Heart unction can be evaluated using injected, radioactively labeled tracers and γ-camera
detectors. The resulting images ref ect the distribution o the tracers within the cardiovascular
system. Nuclear techniques are used to assess myocardial per usion, to image blood passing
through the heart and great vessels, to localize and quanti y myocardial ischemia and in arction, and to assess myocardial metabolism.
TABLE 3-4 Cardiac Catheterization and Angiography in Cardiac Disorders
Disorder
Finding
Coronary artery disease
Mitral regurgitation
Mitral stenosis
• Identi cation o atherosclerotic lesions
• Large systolic v wave in le t atrial pressure tracing
• Abnormally high pressure gradient between the le t atrium and le t
ventricle in diastole
• Large systolic v wave in the right atrial pressure tracing
• Systolic pressure gradient between the le t ventricle and aorta
• Reduced ejection raction (see Chapter 9) i systolic dys unction
• Elevated diastolic pressure with normal ejection raction i diastolic
dys unction
Tricuspid insu f ciency
Aortic stenosis
Heart ailure
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63
Assessment of Myocardial Perfusion
Ischemia and infarction resulting from CAD can be detected by myocardial perfusion imaging using various radioisotopes, including compounds labeled with thallium-201 ( 201Tl) and
technetium-99m ( 99m Tc). Of the latter, currently, 99m Tc-sestamibi and 99m Tc-tetrofosmin are
used. Both 201Tl- and 99m Tc-labeled compounds are sensitive for the detection of ischemic or
scarred myocardium, but each has distinct advantages. For example, the 99m Tc-labeled agents
provide better image quality and are superior for detailed single photon emission computed
tomography (SPECT, as in Fig. 3-18). Conversely, enhanced detection of myocardial cellular
viability is possible with 201Tl imaging.
In the case of 201Tl imaging, the radioisotope is injected intravenously while the patient
exercises on a treadmill or stationary bicycle. Because thallium is a potassium analogue, it
enters normal myocytes, a process thought to be partially governed by sodium–potassium
ATPase. The intracellular concentration of thallium, estimated by the density of the image,
depends on vascular supply (perfusion) and membrane function (tissue viability). In the
normal heart, the radionuclide scan shows a homogenous distribution of thallium in the
S HORT AXIS
Ante rior
STRES S
Sep
La t
Infe rior
REST
B
STRES S
HORIZONTAL
LONG AXIS
Sep
A
REST
C
FIGURE 3-18. Stress and rest myocardial perfusion single photon emission computed tomography
images ( using 99mTc-tetrofosmin) of a patient with a high-grade stenosis within the proximal
left anterior descending coronary artery. A. Miniaturized reproduction of the complete scan showing
tomographic images in each of the three views (from top to bottom: short axis, vertical long axis, and
horizontal long axis). The f rst, third, and f th rows demonstrate images during stress, and the second, ourth,
and sixth rows are matching images acquired at rest. B, C. Enlarged selected panels from ( A) showing stress
and rest images in the short-axis and horizontal long-axis views. The arrows indicate regions of decreased
perfusion during stress but normal perfusion on the matching resting scans, consistent with inducible
ischemia. Lat, lateral wall of the LV; Sep, septal wall. (Courtesy of Marcelo Di Carli, MD, Brigham and Women’s
Hospital, Boston, MA.)
La t
64
Chapter 3
myocardial tissue. Conversely, myocardial regions that are scarred (by previous in arction) or
have reduced per usion during exercise (i.e., transient myocardial ischemia) do not accumulate as much thallium as normal heart muscle. Consequently, these areas will appear on the
thallium scan as light or “cold” spots.
When evaluating or myocardial ischemia, an initial set o images is taken right a ter exercise and 201Tl injection. Well-per used myocardium will take up more tracer than ischemic or
in arcted myocardium at this time. Delayed images are acquired several hours later, because
201
Tl accumulation does not remain xed in myocytes. Rather, continuous redistribution o the
isotope occurs across the cell membrane. A ter 3 to 4 hours o redistribution, when additional
images are obtained, all viable myocytes will have equal concentrations o 201Tl. Consequently,
any uptake abnormalities on the initial exercise scan that were caused by myocardial ischemia
will have resolved (i.e., lled in) on the delayed scan (and are there ore termed “reversible”
de ects), and those representing infarcted or scarred myocardium will persist as cold spots
(“ xed” de ects).
O note, some myocardial segments that demonstrate persistent 201Tl de ects on both
stress and redistribution imaging are alsely characterized as nonviable, scarred tissue.
Sometimes, these areas represent ischemic, noncontractile, but metabolically, active areas
that have the potential to regain unction i an adequate blood supply is restored. For
example, such areas may represent hibernating myocardium, segments that demonstrate
diminished contractile unction owing to chronic reduction o coronary blood f ow (see
Chapter 6). This viable state (in which the a ected cells can be predicted to regain unction
ollowing coronary revascularization) can o ten be di erentiated rom irreversibly scarred
myocardium by repeat imaging at rest a ter the injection o additional 201Tl to enhance
uptake by viable cells.
99m
Tc-sestamibi (commonly re erred to as MIBI) is an example o a widely used 99m Tclabeled compound. This agent is a large lipophilic molecule that, like thallium, is taken up in
the myocardium in proportion to blood f ow. The uptake mechanism di ers in that the compound crosses the myocyte membrane passively, driven by the negative membrane potential.
Once inside the cell, it urther accumulates in mitochondria, driven by that organelle’s even
more negative membrane potential. The myocardial distribution o MIBI ref ects per usion at
the moment o injection, and in contrast to thallium, it remains xed intracellularly, that is,
it redistributes only minimally over time. Consequently, per orming a MIBI procedure is more
f exible, as images can be obtained up to 4 to 6 hours a ter injection and repeated as necessary. A MIBI study is usually per ormed as a 1-day protocol in which an initial injection o a
small tracer dose and imaging are per ormed at rest. Later, a larger tracer dose is given a ter
exercise, and imaging is repeated.
Stress nuclear imaging studies with either 201Tl- or 99m Tc-labeled compounds have
greater sensitivity and speci city than standard exercise electrocardiography or the detection o ischemia but are more expensive and should be ordered judiciously. Nuclear imaging is particularly appropriate or patients with certain baseline electrocardiogram (ECG)
abnormalities o the ST segment that preclude accurate interpretation o a standard exercise test. Examples include patients with electronic pacemaker rhythms, those with le t
bundle branch block, those with ST abnormalities due to le t ventricular hypertrophy, and
those who take certain medications that alter the ST segment, such as digoxin. Nuclear
scans also provide more accurate anatomic localization o the ischemic segment(s) and
quanti cation o the extent o ischemia compared with standard exercise testing. In addition, electronic synchronizing (gating) o nuclear images to the ECG cycle permits wall
motion analysis.
Patients with orthopedic or neurologic conditions, as well as those with severe physical
deconditioning or chronic lung disease, may be unable to per orm an adequate exercise test
on a treadmill or bicycle. In such patients, stress images can be obtained instead by administering pharmacologic agents, such as adenosine or dipyridamole. These agents induce di use
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Cardiac Imaging and Catheterization
65
coronary vasodilation, augmenting blood f ow to myocardium per used by healthy coronary
arteries. Since ischemic regions are already maximally dilated (because o local metabolite
accumulation), the drug-induced vasodilation causes a “steal” phenomenon, reducing isotope
uptake in regions distal to signi cant coronary stenoses (see Chapter 6). Alternatively, dobutamine (see Chapter 17) can be in used intravenously to increase myocardial oxygen demand
as a means to assess or ischemia.
Radionuclide Ventriculography
Radionuclide ventriculography (RVG, also known as blood pool imaging) is occasionally used
to analyze right and le t ventricular unction. A radioisotope (usually 99m Tc) is bound to red
blood cells or to human serum albumin and then injected as a bolus. Nuclear images are
obtained at xed time intervals as the labeled material passes through the heart and great
vessels. Multiple images are displayed sequentially to produce a dynamic picture o blood
f ow. Calculations, such as determination o the ejection raction, are based on the di erence
between radioactive counts present in the ventricle at the end o diastole and at the end o
systole. There ore, measurements are largely independent o any assumptions o ventricular
geometry and are highly reproducible. Studies suggest that RVG and echocardiography provide similar le t ventricular ejection raction values.
RVG has been used historically to assess baseline cardiac unction in patients scheduled to
undergo potentially cardiotoxic chemotherapy (e.g., doxorubicin) and to ollow cardiac unction over time in such patients. However, echocardiography is usually easier to per orm, does
not expose the patient to ionizing radiation, and now commonly serves this role.
Assessment of Myocardial Metabolism
Positron emission tomography (PET) is a specialized nuclear imaging technique used to assess
myocardial per usion and viability. PET imaging employs positron-emitting isotopes (e.g.,
rubidium-82, nitrogen-13, and f uorine-18) attached to metabolic or f ow tracers. Sensitive
detectors measure positron emission rom the tracer molecules.
Myocardial perfusion is commonly assessed using nitrogen-13–labeled ammonia or rubidium-82. Both are taken up by myocytes in proportion to blood f ow. Myocardial viability
can be determined by PET by studying glucose utilization in myocardial tissue. In normal
myocardium under asting conditions, glucose is used or approximately 20% o energy production, with ree atty acids providing the remaining 80% . In ischemic conditions, however,
metabolism shi ts toward glucose use, and the more ischemic the myocardial tissue, the
stronger the reliance on glucose. Fluoro-18 deoxyglucose ( 18FDG), created by substituting
f uorine-18 or hydrogen in 2-deoxyglucose, is used to study glucose uptake. This substance
competes with glucose both or transport into myocytes and or subsequent phosphorylation. Unlike glucose, however, 18FDG is not metabolized and becomes trapped within the
myocyte.
Combined evaluation o per usion and 18FDG metabolism allows assessment o both
regional blood f ow and glucose uptake, respectively. PET scanning thus helps determine
whether areas o ventricular contractile dys unction with decreased f ow represent irreversibly damaged scar tissue or whether the region is still viable (e.g., hibernating myocardium).
In scar tissue, both blood f ow to the a ected area and 18FDG uptake are decreased. Because
the myocytes in this region are permanently damaged, such tissue is not likely to bene t
rom revascularization. Hibernating myocardium, in contrast, shows decreased blood f ow
but normal or elevated 18FDG uptake. Such tissue may bene t rom revascularization procedures (see Chapter 6).
Table 3-5 summarizes the radionuclide imaging abnormalities associated with common
cardiac conditions.
66
Chapter 3
TABLE 3-5 Nuclear Imaging in Cardiac Disorders
Disorder
Findings
Myocardial ischemia
Stress-delayed reinjection
201
Tl
Rest–stress 99mTc-labeled compounds
PET (N-13 ammonia/ 18FDG)
Myocardial infarction
Stress-delayed reinjection 201Tl
Rest–stress 99mTc-labeled compounds
PET (N-13 ammonia/ 18FDG)
Hibernating myocardium
Rest-delayed 201Tl
PET (N-13 ammonia/ 18FDG)
18
• Low uptake during stress with complete or partial ll-in with
delayed or reinjection images
• Normal uptake at rest with decreased uptake during stress
• Decreased f ow with normal or increased 18FDG uptake during stress
• Low uptake during stress and low uptake a ter reinjection
• Low uptake in rest and stress images
• Decreased f ow and decreased 18FDG uptake at rest
• Complete or partial ll-in o de ects a ter reinjection
• Decreased f ow and normal or increased 18FDG uptake at rest
FDG, f uoro-18 deoxyglucose; N-13, nitrogen-13; PET, positron emission tomography;
99m
Tc, technetium-99m;
201
Tl, thallium-201.
COMPUTED TOMOGRAPHY
CT uses thin x-ray beams to obtain a large series o axial plane images. An x-ray tube is programmed to rotate around the body, and the generated beams are partially absorbed by body
tissues. The remaining beams emerge and are captured by electronic detectors, which relay
in ormation to a computer or image composition. CT scanning typically requires administration o an intravenous contrast agent to distinguish intravascular contents (i.e., blood) rom
neighboring so t tissue structures (e.g., myocardium).
Applications o CT in cardiac imaging include assessment o the great vessels, pericardium, myocardium, and coronary arteries. CT is used to diagnose aortic dissections
and aneurysms (Fig. 3-19). It can identi y abnormal pericardial f uid, thickening, and
calci cation. Myocardial abnormalities, such as regional hypertrophy or ventricular aneurysms, and intracardiac thrombus ormation can be distinctly visualized by CT. A limitation
o conventional CT techniques is the arti act generated by patient motion (i.e., breathing)
during image acquisition. Modern spiral CT (also called helical CT) imaging allows more
rapid image acquisition, o ten during a single breath-hold, at relatively lower radiation
doses than conventional CT. Spiral CT is particularly important in the diagnosis o pulmonary embolism. When an intravenous iodine-based contrast agent is administered, emboli
create the appearance o “ lling de ects” in otherwise contrast-enhanced pulmonary vessels
(Fig. 3-20).
Electron beam computed tomography (EBCT) uses a direct electron beam to acquire
images in a matter o milliseconds. Rapid succession o images depicts cardiac structures at
multiple times during a single cardiac cycle. Displaying these images in a cine ormat can
provide estimates o le t ventricular volumes and ejection raction. Capable o detecting coronary artery calci cation, EBCT has been used primarily to screen or CAD. Because calci ed
coronary artery plaques have a radiodensity similar to that o bone, they appear attenuated
(white) on CT. The Agatston score, a measure o total coronary artery calcium, correlates well
with atherosclerotic plaque burden and predicts the risk o coronary events, independently o
other cardiac risk actors.
Newer CT technology can characterize atherosclerotic stenoses in great detail. Current
multidetector row CT scanners acquire as many as 320 anatomic sections with each rotation, providing excellent spatial resolution. Administration o intravenous contrast and
computer re ormatting allows visualization o the arterial lumen and regions o coronary
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AA
PA
AA
AA
A
RK
Live r
RK
LK
LK
RCl
LCl
LCl
LEI
B
C
D
FIGURE 3-19. Computed tomography ( CT) imaging of aortic dissection. A,B. Axial images demonstrate an
intimal f ap (blue arrowheads) separating the true and alse lumens o the descending thoracic and abdominal
aorta. C. CT angiography (CTA) with three-dimensional reconstructions. In this le t anterior oblique view, the
origin o the dissection (blue arrowhead) is apparent in the distal portion o the aortic arch. The dissection
continues to the level o the renal arteries (white arrowhead) and beyond. D. In this CTA le t posterior oblique
view, the dissection extends to the in rarenal aorta (white arrowhead) and involves the le t common and
external iliac arteries (blue arrowhead). AA, ascending aorta; LCI, le t common iliac artery; LEI, le t external
iliac artery; LK, le t kidney; PA, main pulmonary artery; RCI, right common iliac artery; RK, right kidney.
(Courtesy o Suhny Abbara, MD, Massachusetts General Hospital, Boston, MA.)
FIGURE 3-20. Spiral ( helical)
computed tomography image
demonstrating a massive
pulmonary embolism. The white
arrows point to a large thrombus
within the right pulmonary artery.
It appears as a lling de ect within
the otherwise contrast-enhanced
pulmonary vasculature. AA,
ascending aorta; DA, descending
aorta; LPA, le t pulmonary artery;
PA, main pulmonary artery; RPA,
right pulmonary artery; SVC,
superior vena cava.
68
Chapter 3
Ao
Ao
RCA
Ao
RA
LA
PA
LCX
LM
LM
RCA
LA
LAD
RV
PA
LAD
LCX
LAD
RV
LV
A
LV
B
C
FIGURE 3-21. Computed tomography ( CT) coronary angiography. A ter a patient is imaged in a highresolution axial CT scanner, three-dimensional reconstructions (termed volume renderings) are generated
by a computer. A. Volume rendering o a normal CT angiogram. B. Volume rendering o a CT angiogram that
demonstrates di use coronary artery disease. Notice that the caliber o each vessel is irregular along its
length. C. This curved re ormat o the le t anterior descending artery (LAD) depicts the entire course o the
vessel in a single, f at image, making it easier to detect stenoses. None are present here. Ao, aorta; LA, le t
atrium; LCX, le t circumf ex artery; LM, le t main coronary artery; LV, le t ventricle; PA, pulmonary artery; RA,
right atrium; RCA, right coronary artery; RV, right ventricle. (Courtesy o Suhny Abbara, MD, Massachusetts
General Hospital, Boston, MA.)
narrowings (Fig. 3-21). Because image acquisition is timed with the cardiac cycle, a relatively
low heart rate is desirable, such that a β-blocker is o ten administered prior to scanning.
CT is not as sensitive as conventional angiography or the detection o coronary lesions,
and it cannot adequately evaluate stenosis within coronary artery stents. In addition, this
technique results in signi cant radiation exposure. However, CT is rapid, relatively inexpensive, and signi cantly less invasive than conventional angiography. Its role in assessing
patients with symptoms suggestive o CAD and or ollowing the progression o known coronary disease is under active evaluation.
MAGNETIC RESONANCE IMAGING
MRI uses a power ul magnetic eld to obtain detailed images o internal structures. This
technique is based on the magnetic polarity o hydrogen nuclei, which align themselves
with an applied magnetic eld. Radio requency excitation causes the nuclei to move out o
alignment momentarily. As they return to their resting states, the nuclei emit the absorbed
energy into signals that are translated into computer-generated images. There ore, unlike CT
imaging, MRI requires no ionized radiation. Among all the imaging modalities, MRI is best at
di erentiating tissue contrasts (blood, f uid, at, and myocardium) and can o ten do so even
without the use o contrast agents. The addition o gadolinium-based contrast allows urther
characterization o cardiac structures and tissues.
The detail o so t tissue structures is o ten exquisitely demonstrated in magnetic resonance images (Fig. 3-22). Cardiac MRI (CMR) has an established role in evaluating congenital
anomalies, such as shunts, and diseases o the aorta, including aneurysm and dissection. It
is also used to assess le t and right ventricular mass and volume, intravascular thrombus,
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Cardiac Imaging and Catheterization
69
A
B
FIGURE 3-22. Cardiac magnetic resonance images of a normal person. A. Three-chamber long-axis view
of the heart in diastole and systole showing the left ventricle (LV), right ventricle (RV), and left atrium (LA).
The mitral valve (MV), aortic valve (AV), ascending aorta (AAO), and descending aorta (DA) are also imaged.
B. Midventricular short-axis view demonstrating the LV, RV, and left ventricular papillary muscles (PMs). PW,
posterior wall; S, septum. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.)
cardiomyopathies, and neoplastic disease (Fig. 3-23). ECG-gated and cine MRI techniques
capture images at discrete times in the cardiac cycle, allowing or the evaluation o valvular
and ventricular unction.
Two applications o CMR deserve special mention. Coronary magnetic resonance angiography (coronary MRA) is a noninvasive, contrast- ree angiographic imaging modality.
Laminar blood f ow appears as bright signal intensity, whereas turbulent blood f ow, at the
site o stenosis, results in less bright or absent signal intensity. This technique has shown high
sensitivity and accuracy or the detection o important CAD in the le t main coronary artery
and in the proximal and midportions o the three major coronary vessels. Coronary MRA is
also use ul in delineating coronary artery congenital anomalies.
In contrast-enhanced MRI, a gadolinium-based agent is administered intravenously to
identi y in arcted (irreversibly damaged) myocardium and to di erentiate it rom impaired
(but viable) muscle segments. This technique is based on the act that gadolinium is excluded
rom viable cells with intact cell membranes but can permeate and concentrate in in arcted
zones, producing “hyperenhancement” on the image (Fig. 3-24). Owing to the high spatial
resolution o this technique, the transmural extent o myocardial scar can be depicted, and the
pattern o in arcting tissue can be di erentiated rom that o acute myocarditis, a condition
that may present with similar clinical eatures. The use o late-enhancing gadolinium imaging
also allows or the identi cation o poorly contractile “hibernating” myocardium (described
in Chapter 6), tissue that is chronically ischemic, but would be expected to recover unction
i adequate blood per usion is restored.
70
Chapter 3
LV
LV
RV
RV
RA
RA
LA
LA
A
B
FIGURE 3-23. Magnetic resonance imaging of an intracardiac mass. Both images are apical four-chamber
views. A. Before a gadolinium-based contrast agent is administered, an abnormal left atrial mass (indicated
by the oval) demonstrates diminished signal relative to the surrounding tissue. In this respect, it resembles
a nonvascular thrombus. B. After contrast injection, the mass enhances similar to the surrounding tissue,
indicating that it is vascularized. Biopsy revealed a spindle cell carcinoma. LA, left atrium; LV, left ventricle;
RA, right atrium; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital,
Boston, MA.)
RV
A
LV
RV
LV
B
FIGURE 3-24. Gadolinium-enhanced magnetic resonance images demonstrating a region of nonviable
myocardium. Both images are short-axis views. A. Imaging before administration of gadolinium demonstrates
thinning of the anterior and anteroseptal myocardium (blue arrow) suggestive of infarcted tissue (compare
to short-axis view of healthy myocardial wall in Fig. 3.22-B). B. After contrast injection, the subendocardial
regions of the anterior and anteroseptal segments of the left ventricle selectively enhance (white arrows),
indicating that scar tissue is present. Because more than half the thickness of the ventricular wall is scarred,
coronary revascularization would have a low likelihood of improving contractile function of these myocardial
segments. LV, left ventricle; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s
Hospital, Boston, MA.)
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Cardiac Imaging and Catheterization
71
INTEGRATION
This chapter has presented an overview o imaging and catheterization techniques available to assess cardiac structure and unction. Many o these tools are expensive and yield
similar in ormation. For example, estimates o ventricular contractile unction can be made
by echocardiography, nuclear imaging, contrast angiography, gated CT, or MRI. Myocardial
viability can be assessed using nuclear imaging studies, gadolinium MRI, or dobutamine
echocardiography.
Determining the single best test or any given patient depends on a number o actors. One is the ease by which images may be obtained. In a critically ill patient, bedside echocardiography provides a readily acquired measure o le t ventricular systolic
unction. Conversely, obtaining similar in ormation rom a nuclear or magnetic resonance study would require a trip to the respective scanner. Other actors to consider
include the magnitude o radiation exposure and the invasiveness o a given imaging
technique. Expense, available equipment, and institutional expertise also play roles in
selecting an imaging approach. When used appropriately, each o these tools can provide important in ormation to guide the diagnosis and management o cardiovascular
disorders.
SUMMARY
• Imaging and catheterization techniques provide important in ormation to guide the diagnosis and management o cardiovascular disorders; key uses are summarized here and in
Table 3-6.
• Chest radiography can detect chamber dilatation and visualize pulmonary signs o heart
ailure.
• Transthoracic echocardiography can assess ventricular systolic and diastolic dys unction, identi y valvular abnormalities and vegetations, diagnose consequences o myocardial in arction, and demonstrate pericardial and congenital abnormalities.
• Transesophageal echocardiography is used to visualize intracardiac thrombus, evaluate prosthetic valve dys unction, identi y valvular vegetations and myocardial abscess in endocarditis, and diagnose aortic dissection.
• Diagnostic cardiac catheterization is the “gold standard” to assess intracardiac pressures and
to identi y and grade coronary artery stenoses.
• Nuclear imaging can diagnose myocardial ischemia and distinguish viable myocardium rom
scar tissue.
• Positron emission tomography is used to assess or ischemia and can distinguish viable myocardium rom scar tissue.
• Computed tomography is sensitive or the diagnosis o aortic dissection and pulmonary
embolism, can assess pericardial conditions and detect coronary artery calcif cation and
stenoses.
• Magnetic resonance imaging demonstrates great detail o so t tissue structures and is used
to def ne the specif c conditions listed in Table 3-6.
Ack n ow le d gm en t s
The authors are grate ul to Marcelo Di Carli, MD; Raymond Y. Kwong, MD; and Gillian
Lieberman, MD or their help ul suggestions. Contributors to previous editions o this chapter
were Henry Jung, MD; Ken Young Lin, MD; Nicole Martin, MD; Deborah Bucino, MD; Sharon
Horesh, MD; Shona Pendse, MD; Albert S. Tu, MD; and Patrick Yachimski, MD.
72
Chapter 3
TABLE 3-6 Summary of Cardiac Imaging Techniques
Imaging Technique
Findings
Examples of Clinical Uses
Chest radiography
• Cardiac and mediastinal
contours
• Pulmonary vascular
markings
• Wall thickness, chamber
dimensions
• Anatomic relationships
and motion o cardiac
structures
• Flow direction, turbulence, and velocity
measurements
• Echo contrast studies
• Stress echocardiography
• Similar to TTE but higher
resolution
• Detect chamber dilatation
• Identi y consequences o stenotic and regurgitant valve lesions and intracardiac shunts
• Visualize pulmonary signs o heart ailure
• Assess global and segmental ventricular
contraction
• Identi y valvular abnormalities and vegetations
• Diagnose consequences o myocardial
in arction (e.g., ventricular aneurysm, papillary muscle rupture, intraventricular thrombus)
• Identi y myocardial, pericardial, and congenital abnormalities
Transthoracic
echocardiography
(TTE)
Transesophageal
echocardiography
(TEE)
Cardiac
catheterization
• Pressure measurement
• Contrast angiography
Nuclear SPECT imaging (using 99mTclabeled compounds
or 201Tl)
• Regional myocardial
per usion
• Myocardial viability
Radionuclide
ventriculography
Positron emission
tomography (PET)
Computed tomography (CT)
• Ventricular contractile
unction
• Myocardial per usion and
metabolism
• Anatomy and structural
relationships
Magnetic resonance
imaging (MRI)
• Detailed so t tissue
anatomy
• Visualize intracardiac thrombus
• Evaluate prosthetic valves and perivalvular
leaks
• Identi y valvular vegetations and myocardial
abscess in endocarditis
• Diagnose aortic dissection
• Evaluate intracardiac pressures (e.g., in valvular disease, heart ailure, pericardial disease)
• Visualize ventricular contractile unction,
regurgitant valve lesions
• Identi y coronary anatomy and severity o
stenoses
• Detect, quanti y, and localize myocardial
ischemia
• Per orm stress testing in patients with baseline
ECG abnormalities
• Distinguish viable myocardium rom scar tissue
• Calculate ventricular ejection raction and
quantitate intracardiac shunts
• Evaluate contractile unction
• Distinguish viable myocardium rom scar tissue
• Diagnose disease o the great vessels (aortic
dissection, pulmonary embolism)
• Assess pericardial disease and myocardial
abnormalities
• Detect coronary artery calcif cation and
stenoses
• Assess myocardial structure and unction (e.g.,
ventricular mass and volume, neoplastic disease, intracardiac thrombus, cardiomyopathies)
• Diagnose aortic and pericardial disease
• Detect areas o ischemic vs. in arcted
myocardium
ECG, electrocardiogram; SPECT, single photon emission computed tomography;
99m
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Tc, technetium-99m;
201
Tl, thallium-201.
Cardiac Imaging and Catheterization
73
Ad d i t i o n a l Rea d i n g
Bengel FM, Higuchi T, Javadi MS, et al. Cardiac positron
emission tomography. J Am Coll Cardiol. 2009;54:1–15.
Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ ASE/
AHA/ ASNC/ HFSA/ HRS/ SCAI/ SCCM/ SCCT/ SCMR 2011
appropriate use criteria for echocardiography. J Am Coll
Cardiol. 2011;57:1126–1166.
Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ AHA/ ACP/
AATS/ PCNA/ SCAI/ STS Guideline for the diagnosis and
management of patients with stable ischemic heart disease.
J Am Coll Cardiol. 2012;60:e44–e164.
Kern MJ, Samady H. Current concepts of integrated coronary
physiology in the catheterization laboratory. J Am Coll
Cardiol. 2010;55:173–185.
Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic
resonance in patients with myocardial infarction: current
and emerging applications. J Am Coll Cardiol. 2010;55:1–16.
Maganti K, Rigolin VH, Sarano EM, et al. Valvular heart
disease: diagnosis and management. Mayo Clin Proc.
2010;85:483–500.
Min JK, Shaw LJ, Berman DS. The present state of coronary
computed tomographic angiography. J Am Coll Cardiol.
2010;55:957–965.
Moscucci M, Grossman W. Grossman’s Cardiac Catheterization,
Angiography and Intervention. 8th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2013.
Otto CM. Textbook of Clinical Echocardiography. 5th ed.
Philadelphia, PA: Elsevier Saunders; 2013.
Pennell DJ. Cardiovascular magnetic resonance. Circulation.
2010;121:692–705.
Perrino AC, Reeves ST. A Practical Approach to
Transesophageal Echocardiography. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2013.
The Electrocardiogram
Da vid B. Fischer
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Electrical Measurement—SingleCell Model
Electrocardiographic Lead
Reference System
Sequence of Normal Cardiac
Activation
Interpretation of the
Electrocardiogram
Calibration
Heart Rhythm
Heart Rate
Intervals (PR, QRS, QT)
Mean QRS Axis
Abnormalities o the P Wave
Abnormalities o the QRS
Complex
ST-Segment and T-Wave
Abnormalities
4
C
ardiac contraction relies on the organized f ow o electrical impulses through the heart. The electrocardiogram
(ECG) is an easily obtained recording o that activity and provides a wealth o in ormation about cardiac structure and unction. This chapter presents the electrical basis o the ECG in
health and disease and leads the reader through the basics o
interpretation. To practice using these principles and to become
skill ul at interpreting ECG tracings o your patients, you should
also consult one o the complete electrocardiographic manuals
listed at the end o this chapter.
ELECTRICAL MEASUREMENT—SINGLECELL MODEL
This section begins by observing the propagation of an
electrical impulse along a single cardiac muscle cell, illustrated in Figure 4-1. On the right side of the diagram, a
voltmeter records the electrical potential at the cell’s surface on graph paper. In the resting state, the cell is polarized; that is, the entire outside of the cell is electrically
positive with respect to the inside, because of the ionic
distribution across the cell membrane, as described in
Chapter 1. In this resting state, the voltmeter electrodes,
which are placed on opposite outside surfaces of the cell,
do not record any electrical activity, because there is no
electrical potential difference between them (the myocyte
surface is homogeneously charged).
This equilibrium is disturbed, however, when the cell is
stimulated (see Fig. 4-1B). During the action potential, cations rush across the sarcolemma into the cell and the polarity at the stimulated region transiently reverses such that
the outside becomes negatively charged with respect to the
inside; that is, the region depolarizes. At that moment, an
electrical potential is created on the cell surface between the
74
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The Electrocardiogram 75
+
–
+
–
+
–
Voltme te r
–
–
+
+
–
–
+
–
+
–
+
–
+
–
+
–
–
–
+
A
–
+
De p ola riza tion Curre nt
+
–
+
–
+
–
+
–
+
–
–
–
–
+
+
–
+
+
(+)
B
+
–
–
+
–
+
–
+
–
+
–
+
–
+
–
+
–
+
+
–
+
–
+
–
–
–
–
+
+
–
+
+
(+)
+
–
+
–
–
+
–
+
–
+
–
+
–
+
–
+
–
+
–
+
–
+
–
–
+
–
+
–
+
–
+
–
–
+
–
+
–
+
–
+
–
+
–
+
–
–
E
(–)
+
–
+
+
–
–
(+)
+
–
+
D
(+)
+
–
+
–
+
+
–
+
C
+
FIGURE 4-1. Depolarization of a single cardiac
muscle cell. A. In the resting state, the sur ace o
the cell is positively charged relative to the inside.
Because the sur ace is homogeneously charged,
the voltmeter electrodes outside the cell do not
record any electrical potential di erence (“f at
line” recording). B. Stimulation o the cell initiates
depolarization (blue shaded area); the outside o
the depolarized region becomes negatively charged
relative to the inside. Because the current o
depolarization is directed toward the (+ ) electrode
o the voltmeter, an upward def ection is recorded.
C. Depolarization spreads, creating a greater
upward def ection by the recording electrode.
D. The cell has become ully depolarized. The
sur ace o the cell is now completely negatively
charged compared with the inside. Because the
sur ace is again homogeneously charged, a f at
line is recorded by the voltmeter. E. Notice that i
the position o the voltmeter electrodes had been
reversed, the electrical current would have been
directed away rom the (+ ) electrode, causing the
def ection to be downward.
(+)
+
CARDIAC MUS CLE CELL
+
(–)
+
–
+
+
–
+
–
+
–
+
–
+
–
+
–
+
–
depolarized area (negatively charged sur ace) and the still-polarized (positively charged sur ace)
portions o the cell. As a result, an electrical current begins to f ow between these two regions.
By convention, the direction o an electrical current is said to f ow rom areas that are negatively charged to those that are positively charged. When a depolarization current is directed
toward the (+ ) electrode o the voltmeter, an upward def ection is recorded. Conversely, i
it is directed away rom the (+ ) electrode, a downward def ection is recorded. Because the
depolarization current in this example proceeds rom le t to right—that is, toward the (+ )
electrode—an upward def ection is recorded by the voltmeter. As the wave o depolarization
propagates rightward along the cell, additional electrical orces directed toward the (+ ) electrode record an even greater upward def ection (see Fig. 4-1C). Once the cell has become ully
depolarized (see Fig. 4-1D), its outside is completely negatively charged with respect to the
inside, the opposite o the initial resting condition. However, because the sur ace charge is
homogeneous once again, the external electrodes measure a potential di erence o zero and
the voltmeter records a neutral “f at line” at this time.
Note that in Figure 4-1E, i the voltmeter electrode positions had been reversed, such that
the (+ ) pole was placed to the left o the cell, then as the wave o depolarization proceeds
toward the right, the current would be directed away rom the (+ ) electrode and the recorded
def ection would be downward. This relationship should be kept in mind when the polarity
o ECG leads is described below.
Depolarization initiates myocyte contraction and is then ollowed by repolarization, the
process by which the cellular charges return to the resting state. In Figure 4-2, as the le t side
76
Chapter 4
–
–
+
+
–
–
+
–
+
A
(+)
+
+
–
– Dire–c tion– of Curre
– nt–
+
+
+
+
+
+
–
+
–
+
–
+
–
+
–
De pola rize d portion
Re pola rize d portion
+
–
+
–
–
+
–
+
–
+
+
–
+
–
+
–
–
–
+
+
–
+
–
+
–
+
–
+
–
+
–
C
D
–
–
+
–
+
–
+
–
+
–
+
–
–
+
+
–
+
–
+
–
+
+
–
–
+
–
+
–
+
+
B
(+)
+
+
–
(+)
FIGURE 4-2. Sequence of repolarization of a
single cardiac muscle cell. A. As repolarization
commences, the sur ace o the cell at that site
becomes positively charged and a current is generated
rom the still negatively charged sur ace areas to
the repolarized region (blue arrows). Because the
current is directed away rom the (+ ) electrode o
the voltmeter, a downward de ection is recorded.
B. Repolarization progresses. C. Repolarization has
completed, and the outside sur ace o the cell is
once again homogeneously charged, so that no
urther electrical potential is detected ( at line once
again). D. Sequence o cardiac depolarization and
repolarization as measured by an ECG machine at the
skin sur ace. As described in the text, repolarization
actually proceeds in the direction opposite to that
o depolarization in the intact heart, such that the
de ections o repolarization are inverted compared
to the schematics presented in parts A–C o this
f gure. There ore, the def ections o depolarization and
repolarization o the normal heart are oriented in the
same direction. Note that the wave o repolarization is
more prolonged and o lower amplitude than that o
depolarization.
o the cardiac muscle cell in our example begins to repolarize, its sur ace charge becomes
positive once again. An electrical potential is there ore generated, and current ows rom the
still negatively charged sur ace toward the positively charged region. Since this current is
directed away rom the voltmeter’s (+ ) electrode, a downward de ection is recorded, opposite
to that which was observed during the process o depolarization.
Repolarization is a slower process than depolarization, so the inscribed de ection o repolarization is usually wider and o lower magnitude. Once the cell has returned to the resting
state, the sur ace charges are once again homogeneous and no urther electrical potential is
detected, resulting in a neutral at line on the voltmeter recording (Fig. 4-2C).
The depolarization and repolarization o a single cardiac muscle cell have been considered
here. As a wave o depolarization spreads through the entire heart, each cell generates electrical orces, and it is the sum o these orces, measured at the skin’s sur ace, that is recorded
by the ECG machine.
It is important to note that in the intact heart, the sequence by which regions repolarize
is actually opposite to that o their depolarization. This occurs because myocardial action
potential durations are more prolonged in cells near the inner endocardium (the f rst cells
stimulated by Purkinje f bers) than in myocytes near the outer epicardium (the last cells to
depolarize). Thus, the cells close to the endocardium are the f rst to depolarize but are the
last to repolarize. As a result, the direction o repolarization recorded by the ECG machine
is usually the in verse o what was presented in the single-cell example in Figure 4-2. That
is, unlike the single-cell model, the electrical de ections o depolarization and repolarization in the intact heart are usually oriented in the sa me direction on the ECG tracing (see
Fig. 4-2D).
The direction and magnitude o the de ections on an ECG recording depend on how the
generated electrical orces are aligned to a set o specif c re erence axes, known as ECG leads,
as described in the next section.
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The Electrocardiogram 77
Right a rm
e le ctrode
Le ft a rm
e le ctrode
Che s t
e le ctrode s
V1
V2
FIGURE 4-3. Placement of
electrocardiogram ( ECG) electrodes.
A. Standard positions. B. Close-up view of
chest electrode placement, at the standard
positions listed in Table 4-1.
Right le g
e le ctrode
V3
Le ft le g
e le ctrode
A
V6
V5
V4
B
ELECTROCARDIOGRAPHIC LEAD REFERENCE SYSTEM
When the f rst device to produce an ECG was invented over a century ago, the recording was
made by dunking the patient’s arms and legs into large buckets o electrolyte solution that
were wired to the machine. That process was likely airly messy and ortunately is no longer
necessary. Instead, wire electrodes are placed directly on the skin, held in place by adhesive
tabs, on each o the our limbs and on the chest in the standard arrangement as shown in
Figure 4-3. The right-leg electrode is not used or the measurement but serves as an electrical
ground. Table 4-1 lists the standard locations o the chest electrodes.
A complete ECG (termed a “12-lead ECG”) is produced by recording electrical activity
between the electrodes in specif c patterns. This results in six re erence axes in the body’s
rontal plane (termed limb leads) plus six in the transverse plane (termed chest leads). Figure
4-4 demonstrates the orientation o the six limb leads, which are electronically constructed as
described in the ollowing paragraphs.
The ECG machine records lead aVR by selecting the right-arm electrode as the (+ ) pole with
respect to the other electrodes. This is known as a unipolar lead, because though there is a (+ )
pole, there is no single (− ) pole; rather, the other limb electrodes are averaged to create a composite (− ) re erence. When the instantaneous electrical activity o the heart points in the direction o the right arm, an upward de ection is recorded in lead aVR. Conversely, when electrical
orces are directed away rom the right arm, the ECG inscribes a downward de ection in aVR.
Similarly, lead aVF is recorded by setting the le t leg as the (+ ) pole, such that a positive
de ection is recorded when orces are directed toward the eet. Lead aVL is selected when the
le t-arm electrode is made the (+ ) pole, and it records an upward de ection when electrical
activity is aimed in that direction.
In addition to these three unipolar leads, three bipolar limb leads are part o the standard
ECG recording (Fig. 4-4). Bipolar indicates that one limb electrode is the (+ ) pole and another
single electrode provides the (− ) re erence. In this case, the ECG machine inscribes an upward
TABLE 4-1 Positions of ECG Chest Electrodes
V1
V2
V3
V4
V5
V6
4th ICS, 2 cm to the right of the sternum
4th ICS, 2 cm to the left of the sternum
Midway between V2 and V4
5th ICS, left midclavicular line
Same level as V4, left anterior axillary line
Same level as V4, left midaxillary line
ICS, intercostal space.
78
Chapter 4
Unipo lar Limb Le ads
(+)
(+)
(+)
a VR
a VF
a VL
Bipo lar Limb Le ads
(–)
(+)
(–)
(–)
(+)
I
II
(+)
III
FIGURE 4-4. The six limb leads are derived from the electrodes placed on the arms and left leg. Top,
each unipolar lead has a single (+ ) designated electrode; the (− ) pole is an average o the other electrodes.
Bottom, each bipolar lead has specif c (− ) and (+ ) designated electrodes. Although these illustrations show
outstretched arms to depict the location o the electrodes, such positioning is not necessary when acquiring
a patient’s ECG recording. Even in the natural position o the arms by the patient’s sides, directionality o the
leads is maintained.
def ection i electrical orces are heading toward the (+ ) electrode and records a downward
def ection i the orces are heading toward the (− ) electrode. A simple mnemonic to remember
the orientation o the bipolar leads is that the lead name indicates the number o l’s in the
placement sites. For example, lead I connects the le t arm to the right arm, lead II connects the
right arm to the le t leg, and lead III connects the le t arm to the le t leg. Table 4-2 summarizes
how the six limb leads are derived.
TABLE 4-2 Limb Leads
Lead
Bipolar leads
I
II
III
Unipolar leads
aVR
aVL
aVF
( + ) Electrode
( − ) Electrode
LA
LL
LL
RA
RA
LA
RA
LA
a
LL
a
a
Indicates the (− ) electrode or this lead is constructed by combining the other limb electrodes.
LA, le t arm; LL, le t leg; RA, right arm.
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a
The Electrocardiogram 79
By overlaying these six limb leads, an axial re erence
system is established (Fig. 4-5). In the f gure, each lead
is presented with its (+ ) pole designated by an arrowhead and the (− ) aspect by dashed lines. Note that
each 30-degree sector o the circle alls along the (+ )
or (− ) pole o one o the standard six ECG limb leads.
Also note that the (+ ) pole o lead I points to 0 degrees
and that, by convention, measurement o the angles
proceeds clockwise rom 0 degrees as + 30 degrees, +
60 degrees, and so orth. The complete ECG recording provides a simultaneous “snapshot” o the heart’s
electrical activity, taken rom the perspective o each
o these lead re erence axes.
Figure 4-6 demonstrates how the magnitude and
direction o electrical activity are represented by the
ECG recording in each lead. This f gure should be
studied until the ollowing our points are clear:
–90°
–120°
–60°
–150°
aVR
–30°
aVL
+180°
I 0°
+30°
+150°
III
+120°
aVF
+90°
II
+60°
FIGURE 4-5. The axial reference system is created
by combining the six limb leads shown in Figure 4-4.
Each lead has a (+ ) region indicated by the arrowhead
and a (− ) region indicated by the dashed line.
Le a d I
(–)
Le a d I
(+)
(+)
(–)
ECG
A
B
Le a d I
(–)
C
Le a d I
(+)
(–)
(+)
D
FIGURE 4-6. Relationship of the magnitude and direction of electrical activity to the ECG lead. This
example uses lead I, but the same principles apply to all leads. A. The electrical vector is oriented parallel to
lead I and is directed toward the (+ ) electrode; there ore, a tall upward def ection is recorded by the lead.
B. The vector is still oriented toward the (+ ) electrode o lead I but not parallel to the lead, so that only
a component o the orce is recorded. Thus, the recorded def ection is still upward but o lower amplitude
compared with that shown in ( A) . C. The electrical vector is perpendicular to lead I so that no def ection is
generated. D. The vector is directed toward the (− ) region o lead I, causing the ECG to record a downward
def ection.
80
Chapter 4
V6
V5
LV
RV
A
B
V1
V4
V2
V3
FIGURE 4-7. The chest ( precordial) leads. A. The
cross-sectional plane of the chest. B. Arrangement of
the six chest electrodes shown in the cross-sectional
plane. Note that the right ventricle is anterior to the
left ventricle.
1. An electrical orce directed toward the (+ ) pole o a lead results in an upward de ection on
the ECG recording o that lead.
2. Forces that head away rom the (+ ) electrode result in a downward de ection in that lead.
3. The magnitude o the de ection, either upward or downward, re ects how parallel the
electrical orce is to the axis o the lead being examined. The more parallel the electrical
orce is to the lead, the greater the magnitude o the de ection.
4. An electrical orce directed perpendicular to an electrocardiographic lead does not register
any activity by that lead (a at line on the recording).
The six standard limb leads examine the electrical orces in the rontal plane o the body.
However, because electrical activity travels in three dimensions, recordings rom a perpendicular plane are also essential (Fig. 4-7). This is accomplished by the use o the six electrodes placed on the anterior and le t lateral aspect o the chest (see Fig. 4-3B), creating the
chest (also termed “precordial”) leads. The orientation o these leads around the heart in the
cross-sectional plane is shown in Figure 4-7B. These are unipolar leads and, as with the unipolar limb leads, electrical orces directed toward these individual (+ ) electrodes result in an
upward de ection on the recording o that lead, and orces heading away record a downward
de ection.
A complete ECG records samples rom each o the six limb leads and each o the six chest
leads in a standard order, examples o which are presented later in this chapter (see Figs. 4-28
to 4-36).
SEQUENCE OF NORMAL CARDIAC ACTIVATION
Conduction o electrical impulses through the heart is an orderly process. The normal beat
begins at the sinoatrial node, located at the junction o the right atrium and the superior
vena cava (Fig. 4-8). The wave o depolarization spreads rapidly through the right and le t
atria and then reaches the atrioventricular (AV) node, where it encounters an expected delay.
The impulse then travels rapidly through the bundle o His and into the right and le t bundle
branches. The latter divide into the Purkinje f bers, which radiate toward the myocardial
f bers, stimulating them to depolarize and contract.
Each heartbeat is represented on the ECG by three major de ections that record the
sequence o electrical propagation (see Fig. 4-8B). The P w ave represents depolarization o
the atria. Following the P wave, the tracing returns to its baseline as a result o the conduction delay at the AV node. The second de ection o the ECG, the QRS complex, represents
depolarization o the ventricular muscle cells. A ter the QRS complex, the tracing returns
to baseline once again, and a ter a brie delay, repolarization o the ventricular cells is signaled by the T wave. Occasionally, an additional small de ection ollows the T wave (the U
wave), which is believed to represent late phases o ventricular repolarization.
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The Electrocardiogram 81
AV node
Bundle of His
SA node
1
2
3
FIGURE 4-8. Cardiac conduction pathway.
A. The electrical impulse begins at the sinoatrial
(SA) node (1) then traverses the atria (2). A ter
a delay at the AV node (3), conduction continues
through the bundle o His and into the right
and le t bundle branches (4). The latter divide
into Purkinje f bers, which stimulate contraction
o the myocardial cells. B. Corresponding
wave orms on the ECG recording: (1) the SA node
discharges (too small to generate any de ection
on ECG), (2) P wave inscribed by depolarization
o the atria, (3) delay at the AV node, and
(4) depolarization o the ventricles (QRS
complex). The T wave represents ventricular
repolarization.
Right
bundle
bra nch
4
4
Le ft bundle
bra nch
A
QRS
P
B
T
12 3 4
The QRS complex may take one o several shapes but can always be subdivided into individual components (Fig. 4-9). I the f rst de ection o the QRS complex is downward, it is
known as a Q wave. However, i the initial de ection is upward, then that particular complex
does not have a Q wave. The R wave is def ned as the f rst upward de ection, whether or not
a Q wave is present. Any downward de ection following the R wave is known as an S wave.
Figure 4-9 demonstrates several common variations o the QRS complex. In certain pathologic
states, such as bundle branch blocks, additional de ections may be inscribed, as shown in
the f gure. Please study Figure 4-9 until you can conf dently di erentiate a Q rom an S wave.
Figure 4-10 illustrates the course o normal ventricular depolarization as it is recorded in
the rontal plane by two o the ECG leads: aVF and aVL. The recording in aVF represents
electrical activity rom the perspective o the in erior (i.e., underside) aspect o the heart,
A
B
C
D
E
FIGURE 4-9. Examples of QRS complexes. A. The f rst de ection is downward (Q wave), ollowed by an
upward de ection (R wave), and then another downward wave (S wave). B. Because the f rst de ection is
upward, this complex does not have a Q wave; rather, the downward de ection after the R wave is an S wave.
C. A QRS complex without downward de ections lacks Q and S waves. D. QRS composed o only a downward
de ection; this is simply a Q wave but is o ten re erred to as a QS complex. E. A second upward de ection
(seen in bundle branch blocks) is re erred to as R′.
82
Chapter 4
+
– +
S e ptum
– – +
+
+– – +
+– +
+ – – +
–
+–+
+––
+– – +
+
+
+–
+–
– +
+
+
–
– +
+–
+
–
–
+ + –+
–
+ – + – ++ – – +
–
–+
–
+
Right
– – –
+
+
ve ntricle
+
a VL
(+)
Le ft
ve ntricle
a VF
(+)
A
a VL
a VL
+ –
– ++ –
–+
– + + –– + –
++
+
–
–
+
+
+ –
–
–
+–
+ –
a VF
a VF
B
C
–
+
–+– –+ + –
– +– – + + –
–+ – – +
+
–
+
+
–
–
+
–
+
–
D
a VL
–+
+
–
+ –
– + + –
– +
+–
– +
+–
–
+
–
–– + –
+ + +
–
+
+
–
–
+
–+– –+ + –
– +– – +
+ –
–+ – – +
+
–
+
+
–
–
+
–
+
–
+ –
–
a VL
–+ +
+
–
+ –
– + + –
– +
+–
– +
+–
–
+
–
–– + –
+ + +
–
+
+
–
–
a VF
a VF
E
FIGURE 4-10. Normal ventricular depolarization in the frontal plane as recorded by leads aVL and aVF.
A. In the resting state, the sur ace is homogeneously charged so that the leads do not record any electrical
potential. B. The f rst area to depolarize is the le t side o the ventricular septum. This results in orces
heading away rom aVL (downward de ection on aVL recording) but toward the (+ ) region o aVF, such that
an upward de ection is recorded by that lead. C, D. Depolarization continues; the orces rom the thickerwalled le t ventricle outweigh those o the right, such that the electrical vector swings le tward and posteriorly
toward aVL (upward de ection) and away rom aVF. E. At the completion o depolarization, the sur ace is again
homogeneously charged, and no urther electrical orces are recorded.
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The Electrocardiogram 83
and aVL records rom the perspective o the le t lateral side. Recall that in the resting state,
the sur aces o myocardial cells are homogeneously charged such that no electrical activity is
detected by the external ECG leads and the machine records zero voltage.
The initial portion o ventricular myocardium that is stimulated to depolarize with each
cardiac cycle is the midportion o the interventricular septum, on the le t side. Because depolarization reverses the cellular charge, the sur ace o that region becomes negative with respect
to the inside, and an electrical potential is generated (see Fig. 4-10B, arrow). The initial current is directed toward the right ventricle and in eriorly. Because the orce is directed away
rom the (+ ) pole region o lead aVL, an initial downward de ection is recorded in that lead.
At the same time, the electrical orce is directed toward the (+ ) pole region o lead aVF, causing an initial upward de ection to be recorded there. As the wave o depolarization spreads
through the ventricular myocardium, the progression o net electrical vectors is depicted by
the series o arrows in Figure 4-10.
As the lateral walls o the ventricles are depolarized, the electrical orces o the thicker le t
side outweigh those o the right. There ore, the arrow’s orientation is increasingly directed
toward the le t ventricle (le tward and posteriorly). At the completion o depolarization, the
myocytes are again homogeneously charged, no urther net electrical orce is generated, and
the ECG voltage recording returns to baseline in both leads. Thus, in this example o depolarization in a normal heart, lead aVL inscribes an initial small Q wave ollowed by a tall R
wave. Conversely, in lead aVF, there is an initial upward de ection (R wave) ollowed by a
downward S wave.
The sequence o ventricular depolarization can similarly be examined in the transverse
(horizontal) plane o the body rom the six chest (precordial) leads (Fig. 4-11). Once
again, recall that the f rst region to depolarize is the midportion o the interventricular
septum on the le t side. Depolarization proceeds rom there toward the right ventricle
(which is anterior to the le t ventricle), then toward the cardiac apex, and f nally around
the lateral walls o both ventricles. Because the initial orces are directed anteriorly—that
is, toward the (+ ) pole o V1—the initial de ection recorded by lead V1 is upward. These
same initial orces are directed away rom V6 (which overlies the lateral wall o the le t
ventricle), so an initial downward de ection is recorded there. As the wave o depolarization spreads, the electrical orces o the le t ventricle outweigh those o the right, and
the vector swings posteriorly toward the bulk o the le t ventricular muscle. As the orces
swing away rom lead V1, the de ection there becomes down wa rd, whereas it becomes
more upright in lead V6. Leads V2 through V5 record intermediate steps in this process,
such that the R wave becomes progressively taller rom lead V1 through lead V6 (see Fig.
4-11E), a pattern known as “R-wave progression.” Typically, the height o the R wave
becomes greater than the depth o the S wave in lead V3 or V4; the lead in which this
occurs is termed the “transition” lead.
INTERPRETATION OF THE ELECTROCARDIOGRAM
From a technical standpoint, the ECG is recorded on a special grid divided into lines
spaced 1 mm apart in both the horizontal and the vertical directions. Each f th line is
made heavier to acilitate measurement. On the vertical axis, voltage is measured in millivolts (mV), and in the standard case, each 1-mm line separation represents 0.1 mV. The
horizontal axis represents time. Because the standard recording speed is 25 mm/ sec, each
1 mm division represents 0.04 seconds and each heavy line (5 mm) represents 0.2 seconds
(Fig. 4-12).
Many cardiac disorders alter the ECG recording in a diagnostically use ul way, and
it is important to interpret each tracing in a standard ashion to avoid missing subtle
84
Chapter 4
V6
V6
LV
RV
A
V1
V1
B
V6
V6
V1
V1
C
D
V6
V5
LV
RV
V4
V3
V1
V2
E
FIGURE 4-11. Sequence of
depolarization in the transverse
( horizontal) plane recorded by
the chest ( precordial) leads. A–D.
Depolarization begins at the le t side
o the septum. The electrical vector
then progresses posteriorly toward
the thick-walled le t ventricle. Thus,
V1, which is an anterior lead, records
an initial upward def ection ollowed
by a downward wave, whereas V6, a
posterior lead, inscribes the opposite.
E. In the normal pattern o the QRS
rom V1 to V6, the R wave becomes
progressively taller and the S wave less
deep.
abnormalities. Here is a commonly followed sequence of analysis, followed by a description of each:
1. Check voltage calibration
2. Heart rhythm
3. Heart rate
4. Intervals (PR, QRS, QT)
5. Mean QRS axis
6. Abnormalities of the P wave
7. Abnormalities of the QRS (hypertrophy, bundle branch block, infarction)
8. Abnormalities of the ST segment and T wave
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The Electrocardiogram 85
Pa pe r S pe e d: 25 mm/s e c
PR
QT
5 mm = 0.5 mV
1 mm = 0.1 mV
QRS
5 mm = 0.2 s e c
(1 mm = 1 s ma ll box = 0.04 s e c)
FIGURE 4-12. Enlarged view of an ECG strip. A standard ECG is recorded at 25 mm/ sec, so that each
1 mm on the horizontal axis represents 0.04 seconds. Each 1 mm on the vertical axis represents 0.1 mV.
Measurements in this example are as follows: PR interval (from the beginning of the P wave to the beginning
of the QRS) = 4 small boxes = 0.16 seconds; QRS duration (from the beginning to the end of the QRS
complex) = 1.75 small boxes = 0.07 seconds; and QT interval (from the beginning of the QRS to the end of
QT
the T wave) = 8 small boxes = 0.32 seconds. The corrected QT interval =
. Because the R–R interval = 15
R− R
0.32
= 0.41 seconds .
small boxes (0.6 seconds), the corrected QT interval =
0.6
Calibration
ECG machines routinely inscribe a 1.0-mV vertical signal at the beginning or end o each
12-lead tracing to document the voltage calibration o the machine. In the normal case, each
1-mm vertical box on the ECG paper represents 0.1 mV, so that the calibration signal records
a 10-mm de ection (e.g., as shown later in Fig. 4-28). However, in patients with markedly
increased voltage o the QRS complex (e.g., some patients with le t ventricular hypertrophy or
bundle branch blocks), the very large de ections do not f t on the standard tracing. To acilitate interpretation in such a case, the recording is o ten purposely made at hal the standard
voltage (i.e., each 1-mm box = 0.2 mV), and this is indicated on the ECG tracing by a change
in the height o the 1.0-mV calibration signal (at hal the standard voltage, the signal would be
5 mm tall). It is important to check the height o the calibration signal on each ECG to ensure
that the voltage criteria used to def ne specif c abnormalities are applicable.
Heart Rhythm
The normal cardiac rhythm, initiated by depolarization o the sinus node, is known as sinus
rhythm. An ECG tracing shows sinus rhythm i the ollowing criteria are met: (1) each P wave
is ollowed by a QRS; (2) each QRS is preceded by a P wave; (3) the P wave is upright in leads
I, II, and III; and (4) the PR interval is greater than 0.12 seconds (three small boxes).
I the heart rate in sinus rhythm is between 60 and 100 bpm, then normal sinus rhythm
is present. I less than 60 bpm, the rhythm is sinus bradycardia; i greater than 100 bpm, the
rhythm is sinus tachycardia. Other abnormal rhythms (termed arrhythmias or dysrhythmias)
are described in Chapters 11 and 12.
86
Chapter 4
Heart Rate
The standard ECG recording paper speed is 25 mm/ sec. There ore,
Heart rate ( beats per minute ) =
25 mm/ sec × 60 sec/ min
Number o mm betw e en beats
or more simply, as shown in Figure 4-13:
Heart rate =
1, 500
Number o small boxes between
two consecutive beat s
It is rarely necessary, however, to determine the exact heart rate, and a more rapid determination can be made with just a bit o memorization. Simply “count o ” the number o large
boxes between two consecutive QRS complexes, using the sequence
300 — 150 — 100 — 75 — 60 — 50
which corresponds to the heart rate in beats per minute, as illustrated in Figure 4-13 (method 2).
When the rhythm is irregular, these estimates cannot be easily applied, so the heart rate
in such a case may be better approximated by counting the number o complexes during
6 seconds o the recording and multiplying that number by 10. ECG paper usually has time
markers, spaced 3 seconds apart, printed at the top or bottom o the tracing that acilitates
this measurement (see Fig. 4-13, method 3).
Intervals ( PR, QRS, QT)
The PR interval, QRS interval, and QT interval are measured as demonstrated in Figure 4-12.
For each o these, it is appropriate to take the measurement in the lead in which the interval
is the longest in duration (the intervals can vary a bit in each lead). The PR interval is measured rom the onset o the P wave to the onset o the QRS. The QRS interval is measured
rom the beginning to the end o the QRS complex. The QT interval is measured rom the
beginning o the QRS to the end o the T wave. The normal ranges o the intervals are listed
in Table 4-3, along with conditions associated with abnormal values.
Because the QT interval varies with heart rate (the aster the heart rate, the shorter the
QT), the corrected QT interval is determined by dividing the measured QT by the square root
o the RR interval (see Fig. 4-12). When the heart rate is in the normal range (60 to 100 bpm),
a rapid rule can be applied: i the QT interval is visually less than hal the interval between
two consecutive QRS complexes, then the QT interval is within the normal range.
Mean QRS Axis
The mean QRS axis represents the average o the instantaneous electrical orces generated
during the sequence o ventricular depolarization as measured in the rontal plane. The normal value is between − 30 degrees and + 90 degrees (Fig. 4-14). A mean axis that is more negative than − 30 degrees implies left axis deviation, whereas an axis greater than + 90 degrees
represents right axis deviation. The mean axis can be determined precisely by plotting the
QRS complexes o di erent leads on the axial re erence diagram or the limb leads (see Fig.
4-5), but this is tedious and is rarely necessary. The ollowing rapid approach to axis determination generally provides su f cient accuracy.
First, recall rom Figure 4-5 that each ECG lead has a (+ ) region and a (− ) region.
Electrical activity directed toward the (+ ) hal results in an upward de ection, whereas
activity toward the (− ) hal results in a downward de ection on the ECG recording o that
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The Electrocardiogram 87
Me thod 1
Firs t, count the numbe r of s ma ll boxe s (1 mm e a ch) be twe e n two a dja ce nt
QRS complexe s (i.e ., be twe e n 2 “be a ts ”). The n, s ince the s ta nda rd pa pe r
s pe e d is 25 mm/s e c:
He art Rate
(be a ts /min)
Numbe r of mm be twe e n be a ts
1,500
numbe r of mm be twe e n be a ts
In this exa mple, the re a re 23 mm be twe e n the firs t 2 be a ts.
23 mm be twe e n be a ts
1,500
23
Me thod 2
65 bpm
The “count-off” me thod re quire s me morizing the s e que nce :
300—150—100—75—60—50
The n us e this s e que nce to count the numbe r of la rge boxe s be twe e n two
cons e cutive be a ts :
300
S ta rt
he re
100
150
60
75
50
The s e cond QRS fa lls be twe e n 75 a nd 60 bpm; the re fore , the
he a rt ra te is a pproxima te ly midway be twe e n the m ~67 bpm. Knowing
tha t the he a rt ra te is a pproxima te ly 60–70 bpm is ce rta inly clos e e nough.
Me thod 3
ECG re cording pa pe r ofte n indica te s 3-s e c time ma rke rs a t the top or
bottom of the tra cing:
ma rke r
ma rke r
3 sec
FIGURE 4-13. Methods to calculate heart rate.
88
Chapter 4
TABLE 4-3 Electrocardiographic Intervals
Interval
Normal
Decreased Interval
Increased Interval
PR
0.12–0.20 sec
(3–5 small boxes)
≤ 0.10 sec
(≤ 2.5 small boxes)
• Preexcitation syndrome
• Junctional rhythm
• First-degree AV block
Corrected QTa ≤ 0.44 sec
• Hypercalcemia
• Tachycardia
QRS
QT
a
• Bundle branch blocks
• Ventricular ectopic beat
• Toxic drug e ect (e.g., certain
antiarrhythmic drugs—see
Chapter 17)
• Severe hyperkalemia
• Hypocalcemia
• Hypokalemia (↑ QU interval
owing to ↑ U wave)
• Hypomagnesemia
• Myocardial ischemia
• Congenital prolongation o QT
• Toxic drug e ect
QT
.
R−R
Corrected QT =
lead. To determine whether the axis is normal or abnormal, examine the QRS complexes
in limb leads I and II. As illustrated in Figure 4-15, i the QRS is primarily positive in both
o these leads (i.e., the upward def ection is greater than the downward def ection in each
o them), then the mean vector alls within the normal range and no urther calculation is
necessary. However, i the QRS in either lead I or II is not primarily upward, then the axis is
abn orma l, and the approximate axis should then be determined by the more precise method
Le ft a
xis
de
vi
a
–150°
aVR
–30°
aVL
+180°
Le ft axis de viatio n
• Infe rior wa ll myoca rdia l infa rction
• Le ft a nte rior fa s cicula r block
• Le ft ve ntricula r hype rtrophy
(s ome time s )
I 0°
+30°
+150°
R
n
–60°
–120°
ti
o
–90°
ig
h
III
+120°
ta
xis
de v
aVF
+90°
Rig ht axis de viatio n
• Right ve ntricula r hype rtrophy
• Acute right he a rt s tra in
(e.g., massive pulmonary embolism)
• Le ft pos te rior fa s cicula r block
II
+60°
ia tio n
FIGURE 4-14. A normal mean QRS axis falls within the shaded area ( between − 30 degrees and + 90
degrees) . A mean axis more negative than − 30 degrees is termed left axis deviation, whereas an axis more
positive than + 90 degrees is right axis deviation. The f gure shows common conditions that result in axis
deviation.
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The Electrocardiogram 89
S imila rly, if the QRS is pre domina ntly upwa rd in
limb le a d II, the n the me a n a xis fa lls within the
“+” ha lf of le a d II, s hown a s the re d ha lf he re .
If the QRS complex is ma inly upwa rd (pos itive )
in limb le a d I, the n the me a n a xis fa lls within the
“+” re gion of tha t le a d, s hown a s the blue ha lf of
the circle be low.
–90
–
+
–30
–
+
I 0
+150
II
+60
+90
If the QRS is pre domina ntly upright in bo th
le a ds I a nd II, the n the me a n a xis mus t fa ll
within the ir common “+” re gions : be twe e n –30
a nd +90.
–30
Norma l
Axis
+90
FIGURE 4-15. The mean axis is within the normal range if the QRS complex is predominantly upright in
limb leads I and II.
described in the ollowing paragraphs. Please be aware that some ECG teaching resources
recommend examining leads I and aVF, rather than leads I and II, to determine whether the
mean axis alls in the normal range. However, using leads I and aVF or this purpose would
erroneously classi y a mean axis between 0 degrees and − 30 degrees as being abnormal, as
aVF would record a primarily downward de ection in that case. Examining leads I and II
instead avoids that error.
In order to determine the mean axis with greater precision when necessary, f rst consider
the special example demonstrated in Figure 4-16. The sequence o a ventricular depolarization is represented in this f gure by vectors a through e, along with the corresponding
de ections on the ECG recording o lead I. The initial de ection (representing le t septal
depolarization) points to the patient’s right side. Because it is directed completely away rom
the (+ ) pole o lead I, a strong downward de ection is recorded by the lead. As depolarization
continues, the arrow swings downward and to the le t, resulting in less negative de ections
in lead I. A ter arrow c, the electrical vector swings into the positive region o lead I, so that
upward de ections are recorded.
90
Chapter 4
In this special example, in which electrical orces
begin exactly opposite lead I’s (+ ) electrode and termie
d
nate when pointed directly at that electrode, note that
Le ad I
e
a
(–)
(+)
the mean electrical vector points straight downward
c
b
d
(in the direction o arrow c), perpendicular to the lead
b
c
a
I axis. Also note the conf guration o the inscribed QRS
complex in lead I. There is a downward de ection,
ollowed by an upward de ection o equal magnitude
(when the upward and downward de ections o a
Me an
QRS are o equal magnitude, it is termed an isoelecaxis
tric complex). Thus, when an ECG limb lead inscribes
(+)
an isoelectric QRS complex, it indicates that the mean
Le ad aVF
electrical axis of the ventricles is perpendicular to that
particular lead.
FIGURE 4-16. Sequence of ventricular
There ore, an easy way to determine the mean QRS
depolarization when the mean axis is + 90 degrees.
axis is to glance at the six limb lead recordings and
Because the mean axis is perpendicular to limb lead
observe which one has the most isoelectric-appearing
I, an isoelectric QRS complex (height o upward
complex: the mean axis is simply perpendicular to it.
def ection = height o downward def ection) is
One step remains. When the mean axis is perpendicular
recorded by that lead (see text or details).
to a lead, it could be perpendicular in either a clockwise
or a counterclockwise direction. In the example o Figure 4-16, the isoelectric complex appears
in lead I, such that the mean vector could be at + 90 degrees or it could be at − 90 degrees,
because both are perpendicular. To determine which o these is correct requires inspecting the
recording o the ECG lead that is perpendicular to the one inscribing the isoelectric complex
(and is there ore parallel to the mean axis). I the QRS is predominantly upright in that perpendicular lead, then the mean vector points toward the (+ ) pole o that lead. I it is predominantly
negative, then it points away rom the lead’s (+ ) pole. In the example, the isoelectric complex
appears in lead I; there ore, the next step is to inspect the perpendicular lead, which is aVF (see
Fig. 4-5 i this relationship is not clear). Because the QRS complex in aVF is primarily upward,
the mean axis points toward its (+ ) pole, which is in act located at + 90 degrees.
To summarize, the mean QRS axis is calculated as ollows:
1. Inspect limb leads I and II. I the QRS is primarily upward in both, then the axis is normal
and you are done. I not, then proceed to the next step.
2. Inspect the six limb leads and determine which one contains the QRS that is most isoelectric. The mean axis is perpendicular to that lead.
3. Inspect the lead that is perpendicular to the lead containing the isoelectric complex. I the
QRS in that perpendicular lead is primarily upward, then the mean axis points to the (+ )
pole o that lead. I primarily negative, then the mean QRS points to the (− ) pole o that lead.
Conditions that result in le t or right axis deviation are listed in Figure 4-14. In addition, the
vertical position o the heart in many normal children and adolescents may result in a mean
axis that is slightly rightward (greater than + 90 degrees).
In some patients, isoelectric complexes are inscribed in all the limb leads. That situation
arises when the heart is tilted, so that the mean QRS points straight orward or back rom the
rontal plane, as it may be in patients with chronic obstructive lung disease; in such a case,
the mean axis is said to be indeterminate.
Abnormalities of the P Wave
The P wave represents depolarization o the right atrium ollowed quickly by the depolarization o the le t atrium; the two components are nearly superimposed on one another
(Fig. 4-17). The P wave is usually best visualized in lead II, the lead that is most parallel to
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The Electrocardiogram 91
Le ad II
Le ad V1
RA
No rmal
LA
Combine d
FIGURE 4-17. The P wave represents
superimposition of right atrial ( RA)
and left atrial ( LA) depolarization.
RA depolarization occurs slightly earlier
than LA depolarization, because o the
proximity o the RA to the sinoatrial
node. In RA enlargement, the initial
component o the P wave is prominent
(> 2.5 mm tall) in lead II. In LA
enlargement, there is a large terminal
downward def ection in lead V1 (> 1 mm
wide and > 1 mm deep).
RA e nlarg e me nt
(P he ight > 2.5 mm
in le a d II)
LA e nlarg e me nt
(Ne ga tive P in V1
> 1 mm wide a nd
> 1 mm de e p)
RA
LA
RA
LA
RA
LA
RA
LA
the ow o electrical current through the atria rom the sinoatrial to the AV node. When the
right atrium is enlarged, the initial component o the P wave is larger than normal (the P is
taller than 2.5 mm in lead II).
Left atrial enlargement is best observed in lead V1. Normally, V1 inscribes a P wave with an
initial positive de ection re ecting right atrial depolarization (directed anteriorly), ollowed
by a negative de ection, owing to the le t atrial orces oriented posteriorly (see Fig. 1-2 or
anatomic relationships). Le t atrial enlargement is there ore mani ested by a greater-thannormal negative de ection (at least 1 mm wide and 1 mm deep) in lead V1 (see Fig. 4-17).
Abnormalities of the QRS Complex
Ventricular Hypertrophy
Hypertrophy o the le t or right ventricle causes the a ected chamber to generate greaterthan-normal electrical activity. Ordinarily, the thicker-walled le t ventricle produces orces
that are more prominent than those o the right. However, in right ventricular hypertrophy
(RVH), the augmented right-sided orces may outweigh those o the le t. There ore, chest
leads V1 and V2, which overlie the right ventricle, record greater-than-normal upward de ections: the R wave becomes taller than the S wave in those leads, the opposite o the normal
situation (Fig. 4-18). In addition, the increased right ventricular mass shi ts the mean axis o
the heart, resulting in right axis deviation (mean axis greater than + 90 degrees).
In left ventricular hypertrophy, greater-than-normal orces are generated by that chamber, which simply exaggerates the normal situation. Leads that directly overlie the le t ventricle (chest leads V5 and V6 and limb leads I and aVL) show taller-than-normal R waves. Leads
on the other side o the heart (V1 and V2) demonstrate the opposite: deeper-than-normal S
waves. Many di erent criteria are used or the diagnosis o le t ventricular hypertrophy by
ECG. Three o the most help ul criteria are listed in Figure 4-18.
Bundle Branch Blocks
Interruption o conduction through the right or le t bundle branches may develop rom
ischemic or degenerative damage. As a result, the a ected ventricle does not depolarize
in the normal sequence. Rather than rapid uni orm stimulation by the Purkinje f bers, the
cells o that ventricle must rely on relatively slow myocyte-to-myocyte spread o electrical
92
Chapter 4
V6
RIGHT VENTRICULAR HYP ERTROP HY
LV
RV
• R > S in le a d V1
• Right a xis devia tion
1
4
2
3
V1
A
V6
3
LEFT VENTRICULAR HYP ERTROP HY
• S in V1 p lus
R in V5 or V6 ≥ 35 mm or
• R in a VL > 11 mm or
• R in le a d I > 15 mm
1
2
V1
B
FIGURE 4-18. Ventricular hypertrophy. The arrows indicate the sequence of average electrical forces during
ventricular depolarization. A. Right ventricular (RV) hypertrophy. The RV forces outweigh those of the left,
resulting in tall R waves in leads V1 and V2 and a deep S wave in lead V6 (compare to normal QRS complexes
in Fig. 4-11E). B. Left ventricular (LV) hypertrophy exaggerates the normal pattern of depolarization, with
greater-than-normal forces directed toward the LV, resulting in a tall R wave in V6 and a deep S wave in lead V1.
activity traveling rom the una ected ventricle. This delayed process prolongs depolarization and widens the QRS complex. A normal QRS duration is less than or equal to 0.10
seconds (≤ 2.5 small boxes). When a bundle branch block widens the QRS duration to 0.10
to 0.12 seconds (2.5 to 3.0 small boxes), an in complete bundle branch block is present. I
the QRS duration is greater than 0.12 seconds (3.0 small boxes), complete bundle branch
block is identif ed.
In right bundle branch block (RBBB) (Fig. 4-19; see also Fig. 4-29), normal depolarization o the right ventricle is interrupted. In this case, initial depolarization o the ventricular
septum (which is stimulated by a branch o the le t bundle) is una ected so that the normal
small R wave in lead V1 and small Q wave in lead V6 are recorded. As the wave o depolarization spreads down the septum and into the le t ventricular ree wall, the sequence o depolarization is indistinguishable rom normal, because le t ventricular orces normally outweigh
those o the right. However, by the time the le t ventricle has almost ully depolarized, slow
cell-to-cell spread has f nally reached the “blocked” right ventricle and depolarization o that
chamber begins, unopposed by le t ventricular activity (because that chamber has nearly ully
depolarized). This prolonged depolarization process widens the QRS complex and produces a
late depolarization current in the direction o the anteriorly situated right ventricle. Since the
terminal portion o the QRS complex in RBBB represents these right ventricular orces acting
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The Electrocardiogram 93
Rig ht
Bundle Branc h Blo ck
A
V6
Le ft
Bundle Branc h Blo ck
B
V6
LV
1
RV
V1
V1
V6
V6
2
V1
V1
V6
V6
3
V1
• Wide ne d QRS
• RS R' in V1 (ra bbit e a rs )
• Promine nt S in V6
V1
• Wide ne d QRS
• Broa d, notche d R in V6
• Abs e nt R a nd promine nt S
in V1
FIGURE 4-19. Bundle branch blocks. Schematic view o the ventricles in the horizontal plane showing
that interruption o conduction through the right or le t bundles results in delayed, slowed activation o the
respective ventricle and widening o the QRS complex. The blue color shows progressive depolarization o the
ventricles, and the red arrows show the sequence o electrical vectors that result. A. In right bundle branch
block, normal initial activation o the septum (1) is ollowed by depolarization o the le t ventricle (2). Slow
cell-to-cell spread activates the right ventricle (RV) after the le t ventricle (LV) has nearly ully depolarized (3),
so that the late orces generated by the RV are unopposed. There ore, V1 records an abnormal terminal upward
de ection (R′), and V6 records an abnormal, terminal deep S wave, as shown in panel 3. B. In left bundle
branch block, the initial septal depolarization is blocked, such that the f rst orces are oriented rom right to
le t. Thus, the normal initial R wave in V1 and Q wave in V6 are absent (1). A ter the RV depolarizes (2), late,
slow activation o the LV results in a terminal upward de ection in V6 and downward de ection in V1 (3).
94
Chapter 4
alone, the ECG records an abnormal terminal upward de ection (known as an R′ wave) over
the right ventricle in lead V1 and a downward de ection (S wave) in V6 on the opposite side
o the heart. The appearance o the QRS complex in lead V1 in RBBB (upward R, downward S,
then upward R′) is o ten described as having the appearance o “rabbit ears.”
Left bundle branch block (LBBB) produces even more prominent QRS abnormalities. In
this situation, normal initial depolarization o the le t septum does not occur; rather, the right
side o the ventricular septum is f rst to depolarize, through branches o the right bundle.
Thus, the initial orces o depolarization are directed toward the le t ventricle instead o the
right (see Fig. 4-19B; see also Fig. 4-30). There ore, an initial downward de ection is recorded
in V1, and the normal small Q wave in V6 is absent. Only a ter depolarization o the right
ventricle does slow cell-to-cell spread reach the le t ventricular myocytes. These slowly conducted orces inscribe a widened QRS complex with abnormal terminally upward de ections
in the leads overlying the le t ventricle (e.g., V5 and V6), as shown in Figure 4-19B.
Fascicular Blocks
Recall rom Chapter 1 that the le t bundle branch subdivides into two main divisions, termed
ascicles: the le t anterior ascicle and the le t posterior ascicle. Although LBBB implies that
conduction is blocked in the entire le t bundle branch, impairment can also occur in just one
o the two ascicles, resulting in le t anterior or le t posterior ascicular blocks (also termed
hemiblocks). The main signif cance o ascicular blocks in ECG interpretation is that they can
markedly alter the mean QRS axis.
Anatomically, the anterior ascicle o the le t bundle runs along the ront o the le t ventricle toward the anterior papillary muscle (which is located in the anterior and superior portion o the chamber), whereas the posterior ascicle travels to the posterior papillary muscle
(which is located in the posterior, in erior, and medial aspect o the le t ventricle). Under
normal conditions, conduction via the le t anterior and le t posterior ascicles proceeds simultaneously, such that electrical activation o the le t ventricle is uni orm, spreading outward
rom the bases o the two papillary muscles. However, i conduction is blocked in one o the
two divisions, then initial LV depolarization arises exclusively rom the una ected ascicle
(Fig. 4-20).
In the case o left anterior fascicular block (LAFB), le t ventricular activation begins via
the le t posterior ascicle alone, at the posterior papillary muscle, and then spreads to the rest
o the ventricle. Because the le t posterior ascicle f rst activates the posterior, in erior, medial
region o the le t ventricle, the initial impulses are directed downward (i.e., toward the eet)
and toward the patient’s right side (see Fig. 4-20). This results in a positive de ection (initial
small R wave) in the in erior leads (leads II, III, and aVF) and a negative de ection (small Q
wave) in the le t lateral leads, I and aVL. As depolarization then spreads upward and to the
le t, toward the “blocked” anterior, superior, and lateral regions o the le t ventricle, a positive de ection (R wave) is inscribed in leads I and aVL, while a negative de ection (S wave)
develops in the in erior leads. The predominance o these le tward orces, resulting rom the
abnormal activation o the anterior superior le t ventricular wall, results in left axis deviation
(generally more negative than − 45 degrees). A complete 12-lead ECG demonstrating the pattern o LAFB is shown later (see Fig. 4-34).
Left posterior fascicular block (LPFB) is less common than LAFB. In LPFB, ventricular
activation begins via the le t anterior ascicle alone at the base o the anterior papillary muscle
(see Fig. 4-20). As that anterosuperior le t ventricular region depolarizes, the initial orces are
directed upward and to the patient’s le t (creating a positive R wave in leads I and aVL and a
negative Q wave in the in erior leads). As the impulse then spreads downward and to the right
toward the initially blocked region, an S wave is inscribed in leads I and aVL, while an R wave
is recorded in leads II, III, and aVF. Because the bulk o these delayed orces head toward the
patient’s right side, right axis deviation o the QRS mean axis occurs (see Fig. 4-36).
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MV
A
LV
P
Le ft Ante rio r Fas c ic ular Blo ck
Le ft Po s te rio r Fas c ic ular Blo ck
a VL
a VL
X
1
X
a VF
a VF
a VL
a VL
2
a VF
a VF
a VL
a VL
3
a VF
• Le ft a xis devia tion
• S ma ll Q in le a ds a VL a nd I
• S ma ll R in infe rior le a ds (II, III, a VF)
a VF
• Right a xis devia tion
• S ma ll R in le a ds a VL a nd I
• S ma ll Q in infe rior le a ds (II, III, a VF)
FIGURE 4-20. Le t anterior and le t posterior ascicular blocks and their patterns in the ECG limb leads. The
schematic at the top o the f gure shows the le t ventricle (LV) in the rontal plane. The mitral valve (MV) chordae
tendineae insert into the anterior (A) and posterior (P) papillary muscles, which are important landmarks: the anterior
ascicle o the le t bundle branch courses toward the anterior papillary muscle, whereas the posterior ascicle travels to
the posterior papillary muscle (the ascicles are not shown). Notice that the anterior papillary muscle is superior to the
posterior papillary muscle. Le t side o the f gure: In le t anterior ascicular block, activation begins solely in the region
o the posterior papillary muscle (1) because initial conduction to the anterior papillary muscle is blocked (denoted
by the X). As a result, the initial orces o depolarization are directed downward toward the eet, producing an initial
positive de ection (R wave) in lead aVF and a negative de ection (Q wave) in lead aVL. As the wave o depolarization
spreads toward the le t side and superiorly, aVF begins to register a negative de ection and aVL starts to record a positive
de ection (2). Panel 3 shows the complete QRS complexes at the end o depolarization. Right side o the f gure: In le t
posterior ascicular block (denoted by the X), LV activation begins solely in the region o the anterior papillary muscle (1).
Thus, the initial orces are directed upward and toward the patient’s le t side, producing an initial R wave in aVL and
a Q wave in aVF. Panels 2 and 3 show how the spread o depolarization travels in the direction opposite that o LAFB.
96
Chapter 4
In contrast to RBBBs and LBBBs, LAFB and LPFB do not result in
signif cant widening o the QRS because rapidly conducting Purkinje
f bers bridge the territories served by the anterior and posterior ascicles. There ore, although the sequence o conduction is altered,
the total time required or depolarization is usually only slightly prolonged. Also note that although LBBBs and RBBBs are most easily
recognized by analyzing the patterns o depolarization in the precordial (chest) leads, in the case o LAFB and LPFB, it is the recordings
in the limb leads (as in Fig. 4-20) that are most help ul.
Pathologic Q waves in Myocardial Infarction
A
Norma l Q Wave s
B
Pa thologic Q Wave s
As you will learn in Chapter 7, sudden complete occlusion o a FIGURE 4-21. Normal
coronary artery typically results in a syndrome known as acute versus pathologic Q waves.
ST-segment elevation myocardial infarction (STEMI). When this Compared with the small
occurs, a sequence o abnormalities o the ST segment and T wave Q waves generated during
evolves over a period o hours, as described in the next section. normal depolarization (A,
blue arrow), pathologic Q
Unless reper usion o the occluded artery is quickly achieved, irrewaves are more prominent
versible necrosis o the heart muscle served by that vessel ensues with a width ≥ 1 mm (1 small
and is marked by the ormation o pathologic Q waves as part o
box) or depth greater than
the electrocardiographic QRS complex.
25% o the height o the QRS
Recall that it is normal or small initial Q waves to appear in complex (B, green arrow).
some o the ECG leads. For example, initial septal depolarization
routinely inscribes small Q waves in leads V6 and aVL. Such physiologic Q waves are o
short duration (≤ 0.04 seconds or 1 small box) and o low magnitude (less than 25% o the
QRS total height). In distinction, pathologic Q waves are more prominent (Fig. 4-21; also see
Fig. 4-29), typically having a width greater than or equal to 1 small box in duration or a depth
greater than 25% o the total height o the QRS. The ECG lead groupings in which pathologic
Q waves appear re ect the anatomic site o the in arction (Table 4-4; also see Fig. 4-23).
Pathologic Q waves develop in the leads overlying in arcted tissue because necrotic muscle
does not generate electrical orces (Fig. 4-22). This results in an imbalance whereby electrical
orces generated by other regions o healthy myocardium become abnormally unopposed.
Thus, the ECG electrode over the in arcted region detects electrical currents rom the healthy
tissue on opposite regions o the ventricle, which are directed away rom the in arct and
the recording electrode, thus inscribing the downward de ection. Q waves are permanent
evidence o an ST-elevation type o myocardial in arction; only rarely do they disappear over
time.
Notice in Table 4-4 that in the case o a posterior wall myocardial in arction (see Fig. 4-23A),
it is not pathologic Q waves that are evident on the ECG. Because standard electrodes are
TABLE 4-4 Localization of Myocardial Infarction
Anatomic Site
In erior
Anteroseptal
Anteroapical
Anterolateral
Posterior
Leads with Abnormal ECG Complexes a
Coronary Artery Most Often Responsible
II, III, aVF
V1–V2
V3–V4
V5–V6, I, aVL
V1–V2 (tall R wave, not Q wave)
RCA
LAD
LAD (distal)
CFX
RCA
a
Pathologic Q waves in all o leads V1–V6 implies an “extensive anterior MI” usually associated with a proximal le t
coronary artery occlusion.
CFX, le t circumf ex coronary artery; LAD, le t anterior descending coronary artery; RCA, right coronary artery.
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The Electrocardiogram 97
not typically placed on the patient’s back overlying the posterior wall, other leads must be relied
on to indirectly identify the presence of such
an infarction. Chest leads V1 and V2, which are
directly opposite the posterior wall, record the
inverse of what leads placed on the back would
demonstrate. Therefore, taller-than-normal R
waves in leads V1 and V2 are the equivalent of
pathologic Q waves in the diagnosis of a posterior wall MI. It may be recalled that RVH also
produces tall R waves in leads V1 and V2. These
conditions can be distinguished, however, as
RVH causes right axis deviation, which is not a
feature of posterior wall MI.
It is important to note that if a Q wave appears
in only a single ECG lead, it is not diagnostic of
an infarction. True pathologic Q waves should
appear in the groupings listed in Table 4-4 and
Figure 4-23. For example, if a pathologic Q wave
is present in lead III but not in II or aVF, it likely
does not indicate an infarction. Also, Q waves
are disregarded in lead aVR because electrical
forces are normally directed away from the right
arm. Finally, in the presence of LBBB, Q waves
are usually not helpful in the diagnosis of MI
because of the markedly abnormal pattern of
depolarization in that condition.
a VL
LV
RV
1
a VL
2
a VL
3
ST-Segment and T-Wave Abnormalities
Transient Myocardial Ischemia
Among the most important abnormalities of the
ST segments and T waves are those related to
coronary artery disease. Because ventricular
repolarization is very sensitive to myocardial
perfusion, reversible deviations of the ST segments and T waves (usually depression of the
ST segment and/ or inversion of the T wave) are
common during transient episodes of myocardial ischemia, as will be explained in Chapter 6.
Acute ST-Segment Elevation MI
As described in the previous section, pathologic
Q waves are associated with one major type of
myocardial infarction (STEMI) but do not differentiate between an acute event and an MI that
occurred weeks or years earlier. However, an
acute STEMI results in a temporal sequence of
ST and T-wave abnormalities that permits this
distinction (Fig. 4-24). The initial abnormality is
elevation of the ST segment, often with a peaked
a VL
4
Pa thologic
Q wave
FIGURE 4-22. Sequence of depolarization
recorded by lead aVL, overlying a lateral wall
infarction ( dark shaded region) . A pathologic
Q wave is recorded because the necrotic muscle
does not generate electrical orces; rather, at the
time when the lateral wall should be depolarizing
(panel 3), the activation o the healthy muscle
on the opposite side o the heart is unopposed,
such that net orces are directed away rom
aVL. The terminal R wave recorded by aVL
ref ects depolarization o the remaining viable
myocardium beyond the in arct.
98
Chapter 4
Ante rola te ra l
(V5 –V6 ,I, a VL)
Ante ros e pta l
(V1 –V2 )
Ante ros e pta l
(V1 –V2 )
P os te rior
(Ta ll R in
V1 –V2 )
Infe rior
(II, III, a VF)
Ante roa pica l
(V3 –V4 )
A
Ante ros e pta l
Ante roa pica l
I
aVR
V1
V4
I
aVR
V1
V4
II
aVL
V2
V5
II
aVL
V2
V5
III
aVF
V3
V6
III
aVF
V3
V6
Ante rola te ra l
Infe rior
I
aVR
V1
V4
I
aVR
V1
V4
II
aVL
V2
V5
II
aVL
V2
V5
III
aVF
V3
V6
III
aVF
V3
V6
B
FIGURE 4-23. Relationship between ECG leads and cardiac anatomic regions. A. The lead groupings listed
in parentheses represent each region. B. Miniaturized 12-lead ECG schematic drawings showing the standard
orientation of printed samples from each lead. The major anatomic groupings are colored and labeled in each
drawing. While the presence of pathologic Q waves in leads V1 and V2 are indicative of anteroseptal infarction,
be aware that tall initial R waves in those leads can indicate a posterior wall infarction (not shown in part B),
as described in the text.
appearance o the T wave. At this early stage, myocardial cells are still viable and Q waves
have not yet developed. In patients who achieve success ul acute coronary reper usion (by
f brinolytic therapy or percutaneous coronary intervention, as described in Chapter 7), the
ST segments return to baseline and the sequence o changes described in the next paragraph
do not occur.
In patients who do not achieve success ul acute reper usion, within several hours myocyte death leads to loss o the amplitude o the R wave and pathologic Q waves begin to be
inscribed by the ECG leads positioned over the in arction territory. During the f rst 1 to 2 days
ollowing in arction, the ST segments remain elevated, the T wave inverts, and the Q wave
deepens (see Fig. 4-24). Several days later, the ST-segment elevation returns to baseline, but
the T waves remain inverted. Weeks or months ollowing the in arct, the ST segment and
T waves have usually returned to normal, but the pathologic Q waves persist, a permanent
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The Electrocardiogram 99
Norma l
Acute
• ST e leva tion
Hours
Day 1–2
Days
la te r
We e ks
la te r
• ST e leva tion
• T wave inve rs ion • ST norma lize s • ST & T norma l
• R Wave
• Q wave de e pe r • T wave inve rte d • Q wave pe rs is ts
• Q wave be gins
FIGURE 4-24. ECG evolution during acute ST-elevation myocardial infarction. However, as described
in Chapter 7, if successful early reperfusion of the coronary occlusion is achieved, the initially elevated ST
segment returns to baseline without subsequent T-wave inversion or Q-wave development.
marker o the MI. I the ST segment remains elevated several weeks later, it is likely that a
bulging f brotic scar (ventricular aneurysm) has developed at the site o in arction.
These evolutionary changes o the QRS, ST, and T waves are recorded by the leads overlying the zone o in arction (see Table 4-4 and Fig. 4-23). Typically, reciprocal changes are
observed in leads opposite that site. For example, in acute anteroseptal MI, ST-segment elevation is expected in chest leads V1 and V2; simultaneously, however, reciprocal changes (ST
depression) may be inscribed by the leads overlying the opposite (in erior) region, namely
in leads II, III, and aVF. An example o reciprocal ST changes is shown later in Figure 4-32.
The mechanism by which ST-segment deviations develop during acute MI has not been
established with certainty. It is believed, however, that the abnormality results rom injured
myocardial cells immediately adjacent to the in arct zone producing abnormal diastolic or
systolic currents. One explanation, the diastolic current theory, contends that these damaged cells are capable o depolarization but are abnormally “leaky,” allowing ionic ow that
prevents the cells rom ully repolarizing (Fig. 4-25). Because the sur ace o such partially
depolarized cells in the resting state would be relatively negatively charged compared with
normal ully repolarized zones, an electrical current is generated between the two regions.
This current is directed away rom the more negatively charged ischemic area, causing the
baseline o the ECG leads overlying that region to shift down ward. Because the ECG machine
records only relative position, rather than absolute voltages, the downward deviation o the
baseline is not apparent. Following ventricular depolarization (indicated by the QRS complex), a ter all the myocardial cells have ully depolarized (including those o the injured
zone), the net electrical potential surrounding the heart is true zero. However, compared
with the abnormally displaced downward baseline, the ST segment appears elevated (see
Fig. 4-25). As the myocytes then repolarize, the injured cells return to the abnormal state
o diastolic ion leak, and the ECG again inscribes the abnormally depressed baseline. Thus,
ST elevation in acute STEMI may in part re ect an abnormal shi t o the recording baseline.
The systolic current theory o ST segment shi ts contends that in addition to altering the
resting membrane potential, ischemic injury shortens the action potential duration o a ected
cells. As a result, the ischemic cells repolarize aster than neighboring normal myocytes. Since
the positive sur ace charge o the damaged myocytes is restored earlier than that o the normal cells, a voltage gradient develops between the two zones, creating an electrical current
directed toward the ischemic area. This gradient occurs during the ST interval o the ECG,
resulting in ST elevation in the leads overlying the ischemic region (Fig. 4-26).
Acute Non–ST-Segment Elevation MI
As described in Chapter 7, not all acute myocardial in arctions result in ST-segment elevation
and potential Q-wave development. A more limited type o in arction, known as acute non–
ST-elevation MI, typically results rom an acute partially occlusive coronary thrombus. In such
100
Chapter 4
ST-s e g me nt Elevatio n MI
Norma l ba s e line
Injure d s e gme nt is
pa rtia lly de pola rize d
prio r to s timula tion
Re cording
e le ctrode
He a rt fully de pola rize d
Ba s e line s hifte d downwa rd
No n–ST-s e g me nt Elevatio n MI
Ba s e line
s hifte d
upwa rd
Injure d s e gme nt is
pa rtia lly de pola rize d
prio r to s timula tion
Re cording
e le ctrode
He a rt fully de pola rize d
Norma l ba s e line
FIGURE 4-25. ST deviations in acute MI: diastolic injury current. Top, ionic leak results in partial
depolarization of injured myocardium in diastole, prior to electrical stimulation, which produces forces heading
away from that site and shifts the ECG baseline downward. This is not noticeable on the ECG because only
relative, not absolute, voltages are recorded. Following stimulation, when the entire myocardium has fully
depolarized, the voltage is true zero but gives the appearance of ST elevation compared with the abnormally
depressed baseline. Bottom, in non–ST-segment elevation MI, the process is similar, but the ionic leak
typically arises from the subendocardial tissue. As a result, the partial depolarization before stimulation results
in electrical forces directed toward the recording electrode; hence, the baseline is shifted upward. When
fully depolarized, the voltage is true zero, but the ST segment appears depressed compared with the shifted
baseline.
Is che mic
–90 mV
A
Norma l
Is c he mic c e lls
re p ola rize more
ra p id ly tha n norma l
+
B
+
+
ST e leva tion
Re cording
e le ctrode
FIGURE 4-26. ST deviation in acute ST-segment elevation MI: systolic injury current. A. Compared with
normal myocytes (solid line), ischemic myocytes (dashed line) display a reduced resting membrane potential
and repolarize more rapidly. B. More rapid repolarization causes the surface of the ischemic zone to be
relatively positively charged at the time the ST segment is inscribed. The associated electrical current (arrows)
is directed toward the recording electrode overlying that site, so that the ST segment is abnormally elevated.
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The Electrocardiogram 101
Norma l
Digoxin the ra py
• ST “s coope d” de pre s s ion
• Mild P R prolonga tion
Hype rka le mia
• Ta ll “pe a ke d” T wave
S eve re
hype rka le mia
• Fla tte ne d P
• Wide ne d QRS
Hypoka le mia
FIGURE 4-27. Conditions that alter
repolarization of myocytes and therefore result
in ST-segment and T-wave abnormalities.
T U
• ST de pre s s ion, fla tte ne d T
• Promine nt U wave
Hype rca lce mia
• S horte ne d QT inte rva l
Hypoca lce mia
• Prolonge d QT inte rva l
in arctions, it is ST-segment depression and/ or T-wave inversion, rather than ST elevation,
that appears in the leads overlying the in arcting myocardium.
The extent o myocardial damage with this orm o in arction is less than in STEMI, o ten
involving only the subendocardial layers o the myocardium. As a result, pathologic Q waves
do not develop, because the remaining viable cells are able to generate some electrical activity.
In non–ST-elevation MI, the diastolic current theory maintains that diastolic ionic leak o
injured cells adjacent to the subendocardial in arct zone generates electrical orces directed
rom the inner endocardium to the outer epicardium and there ore toward the overlying ECG
electrode. Thus, the baseline o the ECG is shi ted upward (see Fig. 4-25, bottom). Following
ull cardiac depolarization, the electrical potential o the heart returns to true zero but, relative to the abnormal baseline, gives the appearance o ST-segment depression.
In addition to myocardial ischemia and in arction, there are several other causes o
ST-segment and T-wave abnormalities that result rom alterations in myocyte repolarization.
The most commonly encountered o these are illustrated in Figure 4-27.
SUMMARY
• The electrocardiogram (ECG) depicts the sequence o electrical impulses through the heart.
• A complete ECG (12-lead ECG) is produced by recording electrical activity between the
electrodes in specif c patterns, which results in six re erence axes in the body’s rontal plane
(limb leads) plus six in the transverse plane (chest leads).
• Each heartbeat is represented on the ECG by three major de ections that record the
sequence o electrical propagation: (1) the P wave represents depolarization o the atria,
102
Chapter 4
(2) the QRS complex records depolarization o the ventricular muscle cells, and (3) the
T wave indicates repolarization o the ventricular cells.
• Many cardiac disorders alter the ECG recording in a diagnostically use ul way, and it is
important to interpret each tracing in a consistent ashion to avoid missing subtle abnormalities: (1) check voltage calibration, (2) heart rhythm, (3) heart rate, (4) intervals (PR,
QRS, QT), (5) mean QRS axis, (6) abnormalities o the P wave, (7) abnormalities o the
QRS (hypertrophy, bundle branch block, pathologic Q waves), and (8) abnormalities o
the ST segment and T wave (Table 4-5).
• Examples o normal and abnormal ECGs are presented in Figures 4-28 to 4-36; to practice
interpreting clinical tracings in greater depth, the reader should re er to any o the complete
ECG texts listed under “Additional Reading.”
• Disturbances o the cardiac rhythm are identif ed by electrocardiography and are described
in Chapters 11 and 12.
TABLE 4-5 Summary of Sequence of ECG Interpretation
1. Calibration
• Check 1.0-mV vertical box inscription (normal standard = 10 mm)
2. Rhythm
• Sinus rhythm is present if
• Each P wave is followed by a QRS complex
• Each QRS is preceded by a P wave
• P wave is upright in leads I, II, and III
• PR interval is > 0.12 sec (3 small boxes)
• If these criteria are not met, determine type of arrhythmia (see Chapter 12)
3. Heart rate
• Use one of three methods:
• 1,500/ (number of mm between beats)
• Count-off method: 300—150—100—75—60—50
• Number of beats in 6 sec × 10
• Normal rate = 60–100 bpm (bradycardia < 60, tachycardia > 100)
4. Intervals
• Normal PR = 0.12–0.20 sec (3–5 small boxes)
• Normal QRS ≤ 0.10 sec (≤ 2.5 small boxes)
• Normal QT ≤ half the RR interval, if heart rate is normal
5. Mean QRS axis
• Normal if QRS is primarily upright in leads I and II (+ 90 degrees to − 30 degrees)
• Otherwise, determine axis by isoelectric/ perpendicular method
6. P-wave abnormalities
• Inspect P in leads II and V1 for left and right atrial enlargement
7. QRS wave abnormalities
• Inspect for left and right ventricular hypertrophy
• Inspect for bundle branch blocks
• Inspect for pathologic Q waves: What anatomic distribution?
8. ST-segment or T-wave abnormalities
• Inspect for ST elevations:
• ST-segment elevation MI
• Pericarditis (see Chapter 14)
• Inspect for ST depressions or T-wave inversions:
• Myocardial ischemia or non–ST-elevation MI
• Typically accompany ventricular hypertrophy or bundle branch blocks
• Metabolic or chemical abnormalities (see Fig. 4-27)
9. Compare with patient’s previous ECGs
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The Electrocardiogram 103
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The Electrocardiogram 105
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Chapter 4
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110
Chapter 4
The Electrocardiogram 111
I
a VR
V1
V4
II
a VL
V2
V5
III
a VF
V3
V6
FIGURE 4-36. 12-lead ECG ( abnormal) . Rhythm: normal sinus. Rate: 62 bpm. Intervals: PR, 0.14; QRS, 0.10;
QT, 0.52 (corrected QT, 0.53, which is prolonged). Axis: + 95 degrees (right axis deviation [RAD]). QRS: pattern
of left posterior fascicular block (LPFB), with small R wave in leads I and aVL, small Q wave in leads II, III,
and aVF, and RAD (see Fig. 4-20 for further description of LPFB). The prolonged QT interval in this patient is
the result of antiarrhythmic medication.
Ack n ow le d gm en t s
Contributors to previous editions of this chapter were Stephen R. Pomedli, MD; Lilit Garibyan,
MD; Kyle Low, MD; and Price Kerfoot, MD.
Ad d i t i o n a l Rea d i n g
Goldberger AL, Goldberger ZD, Shvilkin A. Goldberger’s
Clinical Electrocardiography: A Simplif ed Approach. 8th ed.
Philadelphia, PA: Elsevier Saunders; 2013.
O’Keefe JH Jr, Hammill SC, Freed MS, et al. The Complete
Guide to ECGs. 3rd ed. Sudbury, MA: Jones and Bartlett
Publishers; 2008.
Surawicz B, Knilans TK. Chou’s Electrocardiography in
Clin ical Practice. 6th ed. Philadelphia, PA: Saunders
Elsevier; 2008.
Surawicz B, Childers R, Deal BJ, et al. AHA/ ACC/ HRS recommendations for the standardization and interpretation
of the electrocardiogram (Parts I–VI). J Am Coll Cardiol.
2007;49:1109-1135 and 2009;53:976–1011.
Thaler MS. The Only EKG Book You’ll Ever Need. 7th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
Wagner GS, Strauss DG. Marriott’s Practical
Electrocardiography. 12th ed. Baltimore, MD: Lippincott
Williams & Wilkins; 2014.
Atherosclerosis
Sa rra h Sha ha wy
Peter Libby
Ch a p t e r O u t l i n e
Vascular Biology of Atherosclerosis
Normal Arterial Wall
Atherosclerotic Arterial Wall
Complications o Atherosclerosis
Atherosclerosis Risk Factors
Genetics
Traditional Risk Factors
Biomarkers o Cardiovascular
Risk
Outlook
5
A
therosclerosis is the leading cause o mortality and
morbidity in developed nations. Through its major maniestations o myocardial in arction and stroke, it has also become
a major cause o death in the developing world. Commonly
known as “hardening o the arteries,” atherosclerosis derives
its name rom the Greek roots athere-, meaning “gruel,” and
-skleros, meaning “hardness.” Recent evidence has demonstrated that chronic in ammation drives the atherosclerotic
process and transduces traditional risk actors (such as hypercholesterolemia) into altered behavior o vascular wall cells,
contributing to the disease and its thrombotic complications.
The course o atherogenesis can smolder throughout adulthood, punctuated by acute cardiovascular events.
This chapter consists o two sections. The f rst part
describes the normal arterial wall, the pathogenesis o atherosclerotic plaque ormation, and the complications that lead
to clinical mani estations o the disease. The second section
describes f ndings rom population studies that have identif ed specif c risk actors or atherosclerotic events, thereby
o ering opportunities or prevention and treatment.
VASCULAR BIOLOGY OF ATHEROSCLEROSIS
Normal Arterial Wall
The arterial wall consists of three layers (Fig. 5-1): the intima,
closest to the arterial lumen and therefore most “intimate”
with the blood; the middle layer, known as the media; and the
outer layer, the adventitia. A single layer of endothelial cells
covers the intimal surface and provides a metabolically active
barrier between circulating blood and the vessel wall. The
media is the thickest layer of the normal artery. Boundaries of
elastin, known as the internal and external elastic laminae,
112
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Atherosclerosis
Inte rna l e la s tic la mina
FIGURE 5-1. Schematic diagram
of the arterial wall. The intima,
the innermost layer, overlies the
muscular media demarcated by
the internal elastic lamina. The
external elastic lamina separates
the media rom the outer layer,
the adventitia. (Modif ed rom
Lieberman M. Marks’ Basic Medical
Biochemistry: A Clinical Approach.
4th ed. Philadelphia, PA: Wolters
Kluwer Health; 2013:649.)
Adve ntitia
Me dia
(S mooth mus cle ce lls )
113
Exte rna l e la s tic la mina
Endothe lia l ce lls
Lume n
Intima
separate this middle layer rom the intima and adventitia, respectively. The media consists o
smooth muscle cells (SMCs) and extracellular matrix and serves the contractile and elastic
unctions o the vessel. The elastic component, more prominent in large arteries (e.g., the aorta
and its primary branches), stretches during the high pressure o systole and then recoils during
diastole, propelling blood orward. The muscular component, more prominent in smaller arteries such as arterioles, constricts or relaxes to alter vessel resistance and there ore luminal blood
ow ( ow = pressure/ resistance; see Chapter 6). The adventitia contains nerves, lymphatics,
and blood vessels (vasa vasorum) that nourish the cells o the arterial wall.
Far rom an inert conduit, the living arterial wall hosts dynamic interchanges between its
cellular components—most importantly, endothelial cells, vascular SMC, and their surrounding extracellular matrix. An understanding o the dys unction that leads to atherosclerosis
requires knowledge o the normal unction o these components.
Endothelial Cells
In a healthy artery, the endothelium per orms structural, metabolic, and signaling unctions
that maintain homeostasis o the vessel wall. The tightly adjoined endothelial cells orm a
barrier that contains blood within the lumen o the vessel and controls the passage o large
molecules rom the circulation into the subendothelial space. As blood traverses the vascular tree, it encounters antithrombotic molecules produced by the normal endothelium that
prevent it rom clotting or that promote f brinolysis (the breakdown o f brin clots). Some
o these molecules reside on the endothelial sur ace (e.g., heparan sul ate, thrombomodulin, and plasminogen activators; see Chapter 7), while other antithrombotic products o the
endothelium enter the circulation (e.g., prostacyclin and nitric oxide [NO]; see Chapter 6).
Although a net anticoagulant state normally prevails, the endothelium can also produce prothrombotic and antif brinolytic molecules when subjected to various stressors.
Furthermore, endothelial cells secrete substances that modulate contraction o SMC in the
underlying medial layer. These substances include vasodilators (e.g., NO and prostacyclin)
and vasoconstrictors (e.g., endothelin) that alter the arteriolar resistance and there ore luminal blood ow. In a normal artery, the predominance o vasodilator substances results in net
smooth muscle relaxation.
Endothelial cells can also modulate the immune response. In the absence o pathologic stimulation, healthy arterial endothelial cells resist leukocyte adhesion and thereby
oppose local in ammation. However, endothelial cells respond to local injury or in ection
by expressing cell sur ace adhesion molecules, which attach mononuclear cells to the endothelium, and chemokines—substances that acilitate leukocyte recruitment to the site o
114
Chapter 5
NORMAL
ACTIVATED
ENDOTHELIAL
CELLS
•
•
•
•
•
Impe rme a ble to la rge mole cule s
Anti-infla mma tory
Re s is t le ukocyte a dhe s ion
Promote va s odila tion
Re s is t thrombos is
Pe rme a bility
Infla mma tory cytokine s
Le ukocyte a dhe s ion mole cule s
Va s odila tory mole cule s
Antithrombotic mole cule s
ARTERIAL
S MOOTH MUS CLE
CELLS
• Norma l contra ctile function
• Ma inta in extra ce llula r ma trix
• Mos t conta ine d in me dia l laye r
Infla mma tory cytokine s
Extra ce llula r ma trix synthe s is
Migra tion into intima a nd
prolife ra tion
FIGURE 5-2. Endothelial and smooth muscle cell activation by inf ammation. Normal endothelial and
SMC maintain the integrity and elasticity o the normal arterial wall while limiting immune cell inf ltration.
In ammatory activation o these vascular cells corrupts their normal unctions and avors proatherogenic
mechanisms that drive plaque development.
injury. These e ects result in part by activation o the transcription actor nuclear actor
kappa B (NFκB.)
In summary, the normal endothelium provides a protective, nonthrombogenic sur ace with
homeostatic vasodilatory and anti-in ammatory properties (Fig. 5-2).
Vascular Smooth Muscle Cells
SMC within the medial layer o normal muscular arteries have both contractile and synthetic
capabilities. Various vasoactive substances modulate the contractile unction, resulting in
vasoconstriction or vasodilation. Such agonists include circulating molecules (e.g., angiotensin II), those released rom local nerve terminals (e.g., acetylcholine), and others originating
rom the overlying endothelium (e.g., endothelin and NO). SMC also synthesize the collagen,
elastin, and proteoglycans that orm the bulk o the vascular extracellular matrix (see Fig. 5-2).
In addition, SMC produce vasoactive and in ammatory mediators, including interleukin-6 (IL6) and tumor necrosis actor (TNF).
In normal arteries, most SMC reside in the medial layer, although human arteries also
contain some SMC in the intima, particularly in sites predisposed to atherosclerosis. During
atherogenesis, medial SMC can migrate into the intima, proli erate, and augment synthesis o
extracellular matrix macromolecules while they dampen contractile protein content.
Extracellular Matrix
In healthy arteries, f brillar collagen, elastin, and proteoglycans make up most o the extracellular matrix in the medial layer. Interstitial collagen f brils, constructed rom intertwining helical proteins, possess great biomechanical strength, while elastin provides exibility. Together
these components maintain the structural integrity o the vessel, despite the high pressure
within the lumen. The extracellular matrix also regulates the growth o its resident cells.
Native f brillar collagen, in particular, can inhibit SMC proli eration in vitro. Furthermore,
the matrix in uences cellular responses to stimuli—matrix-bound cells respond in a specif c
manner to growth actors and resist apoptosis (programmed cell death).
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Atherosclerosis
115
Atherosclerotic Arterial Wall
The arterial wall is a dynamic and regulated structure, but certain stimuli can disturb normal
homeostasis and pave the way or atherogenesis. For example, as described later, vascular
endothelial cells, as well as SMC, react readily to in ammatory mediators, such as IL-1 and
TNF, and can produce them as well.
With the recognition that vascular wall cells respond to, and produce, proin ammatory
agents, investigations into the role o “activated” endothelial and SMC in atherogenesis burgeoned. As a consequence, vascular endothelium and SMC joined classical in ammatory
cells, such as mononuclear phagocytes and T lymphocytes, as key players in early atheroma
ormation and in advanced plaque progression. This undamental research has identif ed several key components that contribute to the atherosclerotic in ammatory process, including
endothelial dys unction, accumulation o lipids within the intima, recruitment o leukocytes
and SMC to the vessel wall, ormation o oam cells, and deposition o extracellular matrix
(Fig. 5-3), as described in the ollowing sections. Rather than ollow a sequential path, the
cells o atherosclerotic lesions continuously interact and modi y each other’s behavior, shaping the plaque over decades into one o many possible prof les. This section categorizes these
mechanisms into three pathologic stages: the atty streak, plaque progression, and plaque disruption (Fig. 5-4). In the arterial tree, lesions o all three stages can coexist, o ten side by side.
Fatty Streak
Fatty streaks represent the earliest visible lesions o atherosclerosis. On gross inspection, they
appear as areas o yellow discoloration on the artery’s inner sur ace, but they neither protrude substantially into the arterial lumen nor impede blood ow. Surprisingly, atty streaks
exist in the aorta and coronary arteries o most people by age 20. They do not cause symptoms, and in some locations in the vasculature, they may regress over time. Although the
precise initiation o atty streak development is not known, observations in animals suggest
that various stressors cause early endothelial dys unction, as described in the next section.
Foa m ce ll
8
1
LDL
Monocyte s
4
Ce ll
a dhe s ion
mole cule
Va s cula r
e ndothe lium
IL-1 MCP-1
2
Ce ll a poptos is
7
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Inte rna l e la s tic
la mina
Ma cropha ge
5
3
S cave nge r
re ce ptor
6
S mooth mus cle
mitoge ns
S mooth mus cle
prolife ra tion
S mooth mus cle
migra tion
FIGURE 5-3. Schematic diagram of the evolution of atherosclerotic plaque. (1) Accumulation o lipoprotein particles in
the intima. The darker color depicts modif cation o the lipoproteins (e.g., by oxidation or glycation). (2) Oxidative stress,
including constituents o modif ed LDL, induces local cytokine elaboration. (3) These cytokines promote increased expression
o adhesion molecules that bind leukocytes and o chemoattractant molecules (e.g., monocyte chemoattractant protein-1
[MCP-1]) that direct leukocyte migration into the intima. (4) A ter entering the artery wall in response to chemoattractants,
blood monocytes encounter stimuli such as macrophage colony–stimulating actor (M-CSF) that augment their expression
o scavenger receptors. (5) Scavenger receptors mediate the uptake o modif ed lipoprotein particles and promote the
development o oam cells. Macrophage oam cells are a source o additional cytokines and e ector molecules such as
superoxide anion (O2−) and matrix metalloproteinases. (6) SMC migrate into the intima rom the media. Note the increasing
intimal thickness. (7) Intimal SMC divide and elaborate extracellular matrix, promoting matrix accumulation in the growing
atherosclerotic plaque. In this manner, the atty streak evolves into a f bro atty lesion. (8) In later stages, calcif cation can
occur (not depicted) and f brosis continues, sometimes accompanied by smooth muscle cell death (including programmed cell
death or apoptosis), yielding a relatively acellular f brous capsule surrounding a lipid-rich core that may also contain dying
or dead cells. IL-1, interleukin 1; LDL, low-density lipoprotein. (Modif ed rom Mann DL, Zipes D, Libby P, Bonow RO,eds.
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier Saunders; 2015.)
116
Chapter 5
FATTY STREAK
P LAQUE P ROGRES S ION
P LAQUE DIS RUP TION
Endothe lia l dys function
Lipoprote in e ntry a nd
modifica tion
Le ukocyte re cruitme nt
Foa m ce ll forma tion
S mooth mus cle ce ll migra tion
Alte re d ma trix synthe s is a nd
de gra da tion
Lipid core forma tion
Dis rupte d pla que inte grity
Thrombus forma tion
A
B
C
FIGURE 5-4. Stages of plaque development. A. The atty streak develops as a result o endothelial dys unction,
lipoprotein entry and modif cation, leukocyte recruitment, and oam cell ormation. B. Plaque progression involves
migration o SMC into the intima, where they divide and elaborate extracellular matrix. The f brous cap contains
a lipid core. C. Hemodynamic stresses and degradation o extracellular matrix increase the susceptibility o the
f brous cap to rupture, allowing superimposed thrombus ormation. (Modif ed rom Libby P, Ridker PM, Maseri A.
In ammation and atherosclerosis. Circulation. 2002;105:1136.)
Such dys unction allows entry and modif cation o lipids within the subendothelial space,
where they serve as proin ammatory mediators that initiate leukocyte recruitment and oam
cell ormation—the pathologic hallmarks o the atty streak (Fig. 5-3).
Endothelial Dys unction
Injury to the arterial endothelium represents a primary event in atherogenesis. Such injury
can result rom exposure to diverse agents, including physical orces and chemical irritants.
The predisposition o certain regions o arteries (e.g., branch points) to develop atheromata supports the role o hydrodynamic stress. In straight sections o arteries, the normal
laminar (i.e., smooth) shear orces avor the endothelial production o NO, which is an
endogenous vasodilator, an inhibitor o platelet aggregation, and an anti-in ammatory substance (see Chapter 6). Moreover, laminar ow and high shear stress activates transcription
actors such as Krüppel-like actor 2 (KLF2) that evokes an “atheroprotective” panel o
endothelial unctions and accentuates expression o the antioxidant enzyme superoxide dismutase, which protects against reactive oxygen species. Conversely, disturbed ow occurs
near arterial branch points, causing low shear stress, which impairs these locally atheroprotective endothelial unctions. Accordingly, arteries with ew branches (e.g., the internal
mammary artery) show relative resistance to atherosclerosis, whereas bi urcated vessels
(e.g., the common carotid and le t coronary arteries) contain common sites or atheroma
ormation.
Endothelial dys unction may also result rom exposure to a “toxic” chemical environment.
For example, tobacco smoking, abnormal circulating lipid levels, and diabetes—all known
risk actors or atherosclerosis—can promote endothelial dys unction. Each o these stimuli
increases endothelial production o reactive oxygen species—notably, superoxide anion—that
interact with other intracellular molecules to in uence the metabolic and synthetic unctions
o the endothelium. In such an environment, the cells promote local in ammation.
When physical and chemical stressors interrupt normal endothelial homeostasis, an activated state ensues, mani ested by impairment o the endothelium’s role as a permeability
barrier, the release o in ammatory cytokines, increased production o cell sur ace adhesion
molecules that recruit leukocytes, altered release o vasoactive substances (e.g., prostacyclin
and NO), and inter erence with normal antithrombotic properties. These undesired e ects o
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Atherosclerosis
117
dys unctional endothelium lay the groundwork or subsequent events in the development o
atherosclerosis (see Figs. 5-2 and 5-3).
Lipoprotein Entry and Modif cation
The activated endothelium no longer serves as an e ective barrier to the passage o circulating lipoproteins into the arterial wall. Increased endothelial permeability allows the entry o
low-density lipoprotein (LDL) into the intima, a process acilitated by an elevated circulating
LDL concentration in patients with hypercholesterolemia. In addition to high LDL concentrations in part rom diet, several monogenic causes o elevated LDL exist, including mutations
o the LDL receptor, o apolipoprotein B, and o PCSK9, a protease involved in regulation o
the LDL receptor. Once within the intima, LDL accumulates in the subendothelial space by
binding to proteoglycans in the extracellular matrix. This “trapping” increases the residence
time o LDL within the vessel wall, where the lipoprotein may undergo chemical modif cations that can promote the development o atherosclerotic lesions. Hypertension, a major
risk actor or atherosclerosis, may urther promote retention o lipoproteins in the intima by
accentuating the production o LDL-binding proteoglycans by SMC.
Oxidation is one type o modif cation that be alls LDL trapped in the subendothelial space.
It can result rom the local action o reactive oxygen species and prooxidant enzymes derived
rom activated endothelial or SMC, or rom macrophages that penetrate the vessel wall. In
addition, the microenvironment o the subendothelial space sequesters oxidized LDL rom
antioxidants in the plasma. In diabetic patients with sustained hyperglycemia, glycation o
LDL can occur—a modif cation that may ultimately render LDL antigenic and proin ammatory. These biochemical alterations o LDL act early and contribute to the in ammatory mechanisms initiated by endothelial dys unction, and they may continue to promote in ammation
throughout the li e span o the plaque. In the atty streak, and likely throughout plaque development, modif ed LDL (mLDL) promotes leukocyte recruitment and oam cell ormation.
Leukocyte Recruitment
Recruitment o leukocytes (primarily monocytes and T lymphocytes) to the vessel wall is
a key step in atherogenesis. The process depends on the expression o leukocyte adhesion
molecules (LAMs) on the normally nonadherent endothelial luminal sur ace and on chemoattractant signals (e.g., monocyte chemotactic protein-1 [MCP-1]) that direct diapedesis
(passage o cells through the intact endothelial layer) into the subintimal space. Two major
subsets o LAM persist in the in amed atherosclerotic plaque: the immunoglobulin gene
super amily (especially vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecule-1 [ICAM-1]) and the selectins (particularly, E- and P-selectin). These LAMs and
chemoattractant signals direct mainly monocytes to the orming lesion. Hypercholesterolemia
avors accumulation in blood o a subset o monocytes that is characterized by expression
o high levels o proin ammatory cytokines (e.g., IL-1 and TNF), distinguished in mice by
expression o the cell sur ace marker Ly6c. Although outnumbered by monocytes, T lymphocytes also localize within plaques and direct the adaptive immune response.
mLDL and proin ammatory cytokines can induce LAM and chemoattractant cytokine
(chemokine) expression independently, but mLDL may also stimulate endothelial and SMC
to produce proin ammatory cytokines, thereby rein orcing the direct action. This dual ability
o mLDL to promote leukocyte recruitment and in ammation directly and indirectly persists
throughout atherogenesis.
Foam Cell Formation
A ter monocytes adhere to and penetrate the intima, they di erentiate into macrophages
and imbibe lipoproteins to orm oam cells. Foam cells do not arise rom uptake o LDL cholesterol by classic cell sur ace LDL receptor–mediated endocytosis as described in Box 5-1
Chapter 5
BOX 5-1
The Lipoprotein Transport System
Lipoproteins erry water-insoluble ats through the bloodstream. These particles consist o a lipid
core surrounded by more hydrophilic phospholipid, ree cholesterol, and apolipoproteins (also
called apoproteins). The apoproteins present on various classes o lipoprotein molecules serve
as the “conductors” o the system, directing the lipoproteins to specif c tissue receptors and
mediating enzymatic reactions. Five major classes o lipoproteins exist, distinguished by their
densities, lipid constituents, and associated apoproteins. In order o increasing density, they
are chylomicrons, very-low-density lipoproteins ( VLDL) , intermediate-density lipoproteins
( IDL) , low-density lipoproteins ( LDL) , and high-density lipoproteins ( HDL) . The major steps
in the lipoprotein pathways are labeled in the f gure below and described as ollows. The key
apoproteins (apo) at each stage are indicated in the f gure in parentheses.
Exo g e no us Pathway
Die ta ry fa t
Endo g e no us Pathway
5
Nonhe pa tic
ce lls
Bile a cids a nd
chole s te rol
1
10
LDL
(Apo B-100)
Live r
Inte s tine
9
4
8
T
,
P
)
E
VLDL
(Apo B-100, C, E)
IDL
(Apo B-100, E)
Lip op rote in lip a s e
E
7
LP L
HL
A
(
p
C
o
E
,
C
o
p
2
3
Lip op rote in lip a s e
6
C
Chylomicron
re mna nts
(Apo B-48, E)
Chylomicrons
(Apo B-48, A,C, E)
A
118
FFA
FFA
HDL
HDL
Mus cle
Adipos e tis s ue
Mus cle
Adipos e tis s ue
Exogenous ( Intestinal) Pathway
1. Dietary ats are absorbed by the small intestine and repackaged as chylomicrons, accompanied
by apo B-48. Chylomicrons are large particles, particularly rich in triglycerides, that enter the
circulation via the lymphatic system.
2. Apo E and subtypes o apo C are trans erred to chylomicrons rom HDL particles in the bloodstream.
3. Apo C (subtype CII) enhances interactions o chylomicrons with lipoprotein lipase (LPL) on the
endothelial sur ace o adipose and muscle tissue. This reaction hydrolyzes the triglycerides
within chylomicrons into ree atty acids (FFAs), which are stored by adipose tissue or used or
energy in cardiac and skeletal muscle.
4. Chylomicron remnants are removed rom the circulation by the liver, mediated by apo E.
5. One ate o cholesterol in the liver is incorporation into bile acids, which are exported to the
intestine, completing the exogenous pathway cycle.
Endogenous ( Hepatic) Pathway
Because dietary at availability is not constant, the endogenous pathway provides a reliable
supply o triglycerides or tissue energy needs:
6. The liver packages cholesterol and triglycerides into VLDL particles, accompanied by apo B-100
and phospholipid. The triglyceride content o VLDL is much higher than that o cholesterol,
but this is the main means by which the liver releases cholesterol into the circulation.
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Atherosclerosis
BOX 5-1
119
The Lipoprotein Transport System ( continued)
7. VLDL is catabolized by LPL (similar to chylomicrons, as described in step 3), releasing atty
acids to muscle and adipose tissue. During this process, VLDL also interacts with HDL,
exchanging some o its triglyceride or apo C subtypes, apo E, and cholesteryl ester rom
HDL. The latter exchange (important in reverse cholesterol transport, as described in the next
section) is mediated by cholesteryl ester trans er protein (CETP).
8. Approximately 50% o the VLDL remnants (termed intermediate-density lipoproteins [IDL]) are
then cleared in the liver by hepatic receptors that recognize apo E.
9. The remaining IDL is catabolized urther by LPL and hepatic lipase (HL), which remove
additional triglyceride, apo E, and apo C, orming LDL particles.
10. Plasma clearance o LDL occurs primarily via LDL receptor–mediated endocytosis in the liver
and peripheral cells, directed by LDL’s apo B-100 and apo E.
Cholesterol Homeostasis and Reverse Cholesterol Transport
Intracellular cholesterol content is tightly maintained by de novo synthesis, cellular uptake,
storage, and e ux rom the cell. The enzyme HMG-CoA reductase is the rate-limiting element o
cholesterol biosynthesis, and cellular uptake o cholesterol is controlled by receptor-mediated
endocytosis o circulating LDL (see step 10). When intracellular cholesterol levels are low,
the transcription actor sterol regulatory element–binding protein (SREBP) is released rom the
endoplasmic reticulum. The active ragment o SREBP enters the nucleus to increase transcription
o HMG-CoA reductase and the LDL receptor—which, through their subsequent actions, tend to
normalize the intracellular cholesterol content.
a po AI
Fre e
a po AI
Inte rna lize d
chole s te ryl
e s te r
Na s ce nt
HDL
ABCAI
LCAT
ABCGI
Pe riphe ral
c e lls
S R-BI
re c e p tor
Ma ture
HDL
Upta ke by
live r a nd s te roid
hormone producing tis s ue s
CETP
Tra ns fe r of
chole s te rol to
VLDL, IDL, LDL
for tra ns port to live r
Exce s s
chole s te rol
Under conditions o intracellular cholesterol excess (as in the f gure above), peripheral cells
increase the transcription o the ATP-binding cassette A1 and G1 genes (ABCA1 and ABCG1,
respectively). The ABCA1 gene codes or a transmembrane protein transporter that initiates
e ux o cholesterol rom the cell to lipid-poor circulating apo AI (which is synthesized by
the liver and intestine), thus orming nascent (immature) HDL particles. ABCG1 acilitates
urther e ux o cholesterol to orm more mature HDL particles. As ree cholesterol is acquired
by circulating HDL, it is esterif ed by lecithin cholesterol acyltransferase (LCAT), an enzyme
activated by apo AI. The hydrophobic cholesteryl esters move into the particle’s core. Most
cholesteryl esters in HDL can then be exchanged or triglycerides in the circulation (via the
enzyme CETP) with any o the apo B–containing lipoproteins (i.e., VLDL, IDL, LDL), which
deliver the cholesterol back to the liver. HDL can also transport cholesterol to the liver and
steroid hormone–producing tissues via the SR-B1 scavenger receptor.
120
Chapter 5
(e.g., as occurs in normal hepatocytes), because the high cholesterol content in these cells
suppresses expression o that receptor. Furthermore, the classic LDL receptor does not recognize modif ed LDL particles. Rather, macrophages rely on a amily o “scavenger” receptors
that pre erentially bind and internalize mLDL. Unlike uptake via the classic LDL receptor,
mLDL ingestion by scavenger receptors evades negative eedback inhibition and permits
engorgement o the macrophages with cholesterol and cholesteryl ester, resulting in the
typical appearance o oam cells. Although such uptake may initially provide benef t by
sequestering potentially damaging mLDL particles, the impaired e ux o these cells as compared to the rate o in ux, as well as local proli eration, leads to their accumulation in the
plaque. This mitigates their protective role by ueling oam cell apoptosis and the release o
proin ammatory cytokines that promote atherosclerotic plaque progression. During atherogenesis, the clearance o dead oam cells can become ine f cient, thus promoting the accumulation o cellular debris and extracellular lipids, orming the lipid-rich center o a plaque
(o ten termed the n ecrotic core).
Plaque Progression
Whereas endothelial cells play a central role in the ormation o the atty streak, SMC in the
intima promote plaque progression by producing extracellular matrix that traps lipoproteins and
adds to the bulk o the lesion. During decades o development, the typical atherosclerotic plaque
acquires a distinct thrombogenic lipid core that underlies a protective f brous cap. Not all atty
streaks progress into f bro atty lesions, and it is unknown why some evolve and others do not.
Early plaque growth typically involves a compensatory outward remodeling o the arterial
wall that preserves the diameter o the lumen and permits plaque accumulation without limitation o blood ow, hence producing no ischemic symptoms. Lesions at this stage can thus
evade detection by angiography. Later plaque growth, however, can outstrip the compensatory arterial enlargement, restrict the vessel lumen, and impede per usion. Such ow-limiting
plaques can result in tissue ischemia, causing symptoms such as angina pectoris (see Chapter 6)
or intermittent claudication o the extremities (see Chapter 15).
Many acute coronary syndromes (acute myocardial in arction and unstable angina pectoris) result when the f brous cap o an atherosclerotic plaque ruptures, exposing prothrombotic
molecules within the lipid core and precipitating an acute thrombus that suddenly occludes
the arterial lumen. As described in this section, the extracellular matrix plays a pivotal role
in orti ying the f brous cap, isolating the thrombogenic plaque interior rom coagulation
substrates in the circulation.
Smooth Muscle Cell Migration
The transition rom atty streak to f brous atheromatous plaque involves the migration o
SMC rom the arterial media into the intima, proli eration o the SMC within the intima, and
secretion o extracellular matrix macromolecules by the SMC. Foam cells, activated platelets
entering through microf ssures in the plaque sur ace, and endothelial cells can all elaborate
substances that signal SMC migration and proli eration (Fig. 5-5).
Foam cells produce several actors that contribute to SMC recruitment. For example, they
release platelet-derived growth actor (PDGF)—also released by platelets and endothelial
cells—which likely stimulates the migration o SMC across the internal elastic lamina and
into the subintimal space, where they subsequently replicate. PDGF additionally stimulates
the growth o resident SMC in the intima. Foam cells also release cytokines and growth
actors (e.g., TNF, IL-1, f broblast growth actor, and trans orming growth actor-β [TGF-β])
that urther incite SMC proli eration and/ or the synthesis o extracellular matrix proteins.
Furthermore, these stimulatory cytokines induce SMC and leukocyte activation, promoting
urther cytokine release, thus rein orcing and maintaining in ammation in the lesion.
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Atherosclerosis
121
Foa m Ce lls in Fa tty S tre a k
Endothe lia l
Dys function
Cytokine s
• TNF
• IL-1
• TGF-β
P DGF
NO
P GI2
Tis s ue
fa ctor
Thrombos is
a nd pla te le t
a ctiva tion
• Thrombin
• P DGF
• TGF-β
FIGURE 5-5. Progression from the fatty streak
involves the migration and proliferation of SMC.
Substances released from foam cells, dysfunctional
endothelial cells, and platelets contribute to this
process. IL-1, interleukin-1; NO, nitric oxide; PDGF,
platelet-derived growth factor; PGI2, prostacyclin; TGF-β,
transforming growth factor-β; TNF, tumor necrosis factor.
S mooth mus cle ce lls migra te to intima ,
prolife ra te , a nd produce extra ce llula r ma trix
Fibrous P la que
According to the traditional concept, plaques grow gradually and continuously, but current evidence suggests that this progression may be punctuated by subclinical events with
bursts o smooth muscle replication. For example, morphologic evidence o resolved intraplaque hemorrhages indicates that breaches in plaque integrity can occur without clinical
symptoms or signs. Such plaque disruptions expose tissue actor rom oam cells to blood,
which activates coagulation and microthrombus ormation. Activated platelets within such
microthrombi release additional potent actors—including PDGF—that can spur a local wave
o SMC migration and proli eration.
Activated T cells also contribute to plaque evolution. Cells o the T helper 1 subtype (Th1)
produce proin ammatory cytokines that promote plaque progression and instability, while lymphocytes o the T helper 2 subtype (Th2) and regulatory T cells (Treg) produce actors, including
TGF-β and IL-10, which can inhibit SMC proli eration and potentially mitigate plaque growth.
Extracellular Matrix Metabolism
As the predominant collagen-synthesizing cell type, SMC avor ortif cation o the f brous
cap. Net matrix deposition depends on the balance o its synthesis by SMC and its degradation, mediated in part by a class o proteolytic enzymes known as matrix metalloproteinases (MMP). While PDGF and TGF-β stimulate production o interstitial collagens by SMC,
the Th1-derived cytokine inter eron-γ (IFN-γ) inhibits SMC collagen synthesis. Furthermore,
in ammatory cytokines stimulate local oam cells to secrete collagen- and elastin-degrading
MMP, thereby weakening the f brous cap and predisposing it to rupture (Fig. 5-6).
Plaque Disruption
Plaque Integrity
The tug-o -war between matrix synthesis and degradation continues over decades but not
without consequences. Death o smooth muscle and oam cells, either owing to excess in ammatory stimulation or by contact activation o apoptosis pathways, liberates cellular contents,
contributing imbibed lipids and cellular debris to the growing lipid core. The size o the lipid
122
Chapter 5
S
De g
ra d
a
e s is
h
t
yn
ti o
n
Lume n
MMP
Colla g e n a nd
e la s tin
Fibro us Cap
S mooth mus cle
ce ll
+
P DGF
TGF-β
–
IFN-γ
+
CD40L
T lymphocyte
Foa m
ce ll
+
IL-1
TNF
MCP-1
Lipid core
FIGURE 5-6. Matrix metabolism underlies f brous cap integrity. The net deposition o extracellular matrix
is the result o competing synthesis and degradation reactions. Smooth muscle cells synthesize the bulk o the
f brous cap constituents, such as collagen and elastin. Foam cells elaborate destructive proteolytic enzymes,
such as the collagen-degrading matrix metalloproteinases (MMP) and the elastolytic cathepsins. T-lymphocyte–
derived actors avor destruction o the f brous cap. All plaque residents, however, contribute to the cytokine
milieu o the plaque, providing multiple activating and inhibitory stimuli as shown. IFN-γ, inter eron-γ; IL-1,
interleukin-1; MCP-1, monocyte chemoattractant protein-1; PDGF, platelet-derived growth actor; TGF-β,
trans orming growth actor-β; TNF, tumor necrosis actor. (Modif ed rom Libby P. The molecular bases o
acute coronary syndromes. Circulation. 1995;91:2844–2850; Young JL, Libby P, Schönbeck U. Cytokines in the
pathogenesis o atherosclerosis. Thromb Haemost. 2002;88:554–567.)
core has biomechanical implications or the stability o the plaque. With increasing size and
protrusion into the arterial lumen, mechanical stress ocuses on the plaque border abutting
normal tissue, called the shoulder region.
The structure o the f brous cap contributes to plaque integrity. Whereas lesions with thick
f brous caps may cause pronounced arterial narrowing, they have less propensity to rupture.
Conversely, plaques that have thinner caps (and o ten appear less obstructive by angiography) tend to be ragile and more likely to rupture and incite thrombosis. Current clinical
terminology describes the extreme spectrums o integrity as “stable plaques” (marked by a
thick f brous cap and small lipid core) or “vulnerable plaques” (marked by a thin f brous cap,
rich lipid core, extensive macrophage inf ltrate, and a paucity o SMC; Fig. 5-7). Despite the
common use o these terms, this distinction vastly oversimplif es the heterogeneity o plaques
and may overestimate the ability to oresee a plaque’s “clinical uture” based on structural
in ormation. Most plaques with the so-called “vulnerable” morphology do not actually cause
clinical events; hence, attempts to specif cally identi y such plaques may not direct therapy
in an e ective manner. Moreover, a substantial minority o atal thrombi in coronary arteries
arise rom matrix-rich plaques with intact f brous caps, a morphology that may arise rom
superf cial erosion o the lesion by mechanisms that are not well understood.
Thrombogenic Potential
Rupture o atherosclerotic plaque does not inevitably cause major clinical events such
as myocardial in arction or stroke. As described in the previous section, small nonocclusive thrombi may incorporate into the plaque, stimulating urther smooth muscle growth
and extracellular matrix deposition (see Fig. 5-7). The balance between the thrombogenic
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Atherosclerosis
123
Norma l a rte ry
Ea rly a the roma
“Vulne ra ble” pla que
• La rge lipid pool
• Thin fibrous ca p
• Ma ny infla mma tory ce lls
“S ta ble” pla que
• S ma ll lipid pool
• Thick fibrous ca p
• Pre s e rve d lume n
Rupture d pla que
with thrombus forma tion
He a le d rupture
• Na rrowe d lume n
• Fibrous intima
Acute
myoca rdia l
infa rction
FIGURE 5-7. Stable versus vulnerable plaques. Stable plaque is characterized by a small lipid core and a
thick f brous cap, whereas vulnerable plaque tends to have a large lipid core and a relatively thin f brous cap.
The latter is subject to rupture, resulting in thrombosis. A resulting occlusive clot can cause an acute cardiac
event, such as myocardial in arction. A lesser thrombus may resorb, but the wound-healing response stimulates
smooth muscle cell proli eration and collagen production, thereby thickening the f brous cap and narrowing the
vessel lumen urther. (Modif ed rom Libby P. In ammation in atherosclerosis. Nature. 2002;420:868–874.)
and f brinolytic potential o the plaque, and the uid phase o blood, determines whether
disruption o the f brous cap leads to a transient, nonobstructive mural thrombus or to a
completely occlusive clot.
The probability o a major thrombotic event re ects the balance between the competing
processes o clot ormation and dissolution by f brinolysis. In ammatory stimuli ound in
the plaque microenvironment (e.g., CD40L) elicit tissue actor, the initiator o the extrinsic coagulation pathway, rom many plaque components including SMC, endothelial cells,
124
Chapter 5
Favo r Oc c lus ive Thro mbus
Re s is t Thro mbus Ac c umulatio n
P roc oa g ula nt
Tis s ue fa ctor
Antic oa g ula nts
Thrombomodulin
He pa rin-like mole cule s
Antifib rinolytic
PAI-1
P rofib rinolytic
tPA
FIGURE 5-8. Competing factors in thrombosis. The clinical mani estations o plaque disruption rely not
only on the stability o the f brous cap but also on the thrombogenic potential o the plaque core. The balance
o physiologic mediators dictates the prominence o the thrombus, resulting in either luminal occlusion or
resorption into the plaque. PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator.
and macrophage-derived oam cells. Beyond enhancing expression o the potent procoagulant tissue actor, in ammatory stimuli urther support thrombosis by avoring the expression o antif brinolytics (e.g., plasminogen activator inhibitor-1) over the expression o
anticoagulants (e.g., thrombomodulin, heparin-like molecules) and prof brinolytic mediators
(e.g., t issue plasminogen activator; Fig. 5-8). Moreover, as described earlier, the activated
endothelium also promotes thrombin ormation, coagulation, and f brin deposition at the
vascular wall.
A person’s propensity toward coagulation may be enhanced by genetics, comorbid conditions (e.g., diabetes), and/ or li estyle actors (e.g., smoking, visceral obesity). Consequently,
the concept o the “vulnerable plaque” has expanded to that o the “vulnerable patient,” to
acknowledge other contributors to a person’s vascular risk.
Complications of Atherosclerosis
Atherosclerotic plaques do not distribute homogeneously throughout the vasculature. They
usually develop f rst in the dorsal aspect o the abdominal aorta and proximal coronary arteries, ollowed by the popliteal arteries, descending thoracic aorta, internal carotid arteries, and
renal arteries. There ore, the regions per used by these vessels most commonly su er the
consequences o atherosclerosis.
Complications o atherosclerotic plaques—including calcif cation, rupture, hemorrhage,
and embolization—can have dire clinical consequences due to acute restriction o blood ow
or alterations in vessel wall integrity. These complications, which are discussed in greater
detail in later chapters, include the ollowing:
• Calcif cation o atherosclerotic plaque, which may increase its ragility.
• Rupture or ulceration o atherosclerotic plaque, which exposes procoagulants within the
plaque to circulating blood, causing a thrombus to orm at that site. Such thrombosis can
occlude the vessel and result in in arction o the involved organ. Alternatively, the thrombus
can organize, incorporate into the lesion, and add to the bulk o the plaque.
• Hemorrhage into the plaque owing to rupture o the f brous cap or o the microvessels that
orm within the lesion. The resulting intramural hematoma may urther narrow the vessel
lumen.
• Embolization o ragments o disrupted atheroma to distal vascular sites.
• Weakening o the vessel wall: the f brous plaque subjects the neighboring medial layer to
increased pressure, which may provoke atrophy and loss o elastic tissue with subsequent
expansion o the artery, orming an aneurysm.
• Microvessel growth within plaques, providing a source or intraplaque hemorrhage and
urther leukocyte tra f cking.
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Atherosclerosis
125
The complications o atherosclerotic plaque may result in specif c clinical consequences in
di erent organ systems (Fig. 5-9). When lesion growth eventually outstrips the compensatory
outward enlargement o the plaque, the lesion can narrow the vessel lumen and, in the case
o the coronary arteries, cause intermittent chest discom ort on exertion (angina pectoris). In
contrast, plaque that does not compromise the vessel lumen but has characteristics o vulnerability (e.g., a thin f brous cap, a large lipid core, spotty calcif cations) can rupture, leading
to acute thrombosis and myocardial in arction (see Chapter 7). Such nonstenotic plaques are
o ten numerous and dispersed throughout the arterial tree, and because they do not limit
arterial ow, they do not produce symptoms and o ten evade detection by exercise testing or
angiography.
The description presented here o atherogenesis and its complications can explain the limitations o widely employed treatments. For example, percutaneous intervention (angioplasty
and stent placement) o symptomatic coronary stenoses e ectively relieves angina pectoris,
but does not necessarily prevent uture myocardial in arction or prolong li e, with the exception o patients in the early phase o an acute ST-elevation myocardial in arction, as described
in Chapter 7. This disparity likely re ects the multiplicity o nonocclusive plaques at risk o
precipitating thrombotic events. It ollows that li estyle modif cations and drug therapies that
curb the risk actors or plaque ormation, and lessen eatures associated with “vulnerability,”
provide a critical oundation or preventing progression and complications o atherosclerosis.
S tro ke
• Embolic s troke
4
• Thrombotic s troke
2
3
Co ro nary arte ry dis e as e
1
• Myoca rdia l is che mia
• Uns ta ble a ngina
2
3
• Myoca rdia l infa rction 2
Re nal arte ry dis e as e
• Athe roe mbolic re na l dis e a s e
• Re na l a rte ry s te nos is 1
4
Ane urys ms 5
Pe riphe ral arte ry dis e as e
• Limb cla udica tion 1
1
Na rrowing of ve s s e l by fibrous pla que
2
P la que ulce ra tion or rupture
3
Intra pla que he morrha ge
4
Pe riphe ra l e mboli
5
We a ke ning of ve s s e l wa ll
• Limb is che mia 1
FIGURE 5-9. Clinical sequelae of atherosclerosis. Complications o atherosclerosis arise rom the
mechanisms listed in the f gure.
4
3
126
Chapter 5
ATHEROSCLEROSIS RISK FACTORS
In the early 20th century, most viewed atherosclerosis as an inevitable process o aging. But
in 1948, the landmark Framingham Heart Study began to examine the relationship between
specif c attributes and cardiovascular disease, establishing the concept o atherosclerotic risk
actors. Among later studies, the Multiple Risk Factor Intervention Trial (MRFIT) screened
more than 325,000 men, o ering an opportunity to correlate risk actors with subsequent
cardiovascular disease and mortality. O the major risk actors, those that are not correctable
include advanced age, male gender, and heredity—that is, a history o coronary heart disease
among f rst-degree relatives at a young age (be ore age 55 or a male relative or be ore age 65
or a emale relative). Risk actors or atherosclerosis amenable to modif cation include undesirable concentrations and composition o circulating lipids (dyslipidemia), tobacco smoking,
hypertension, diabetes mellitus, and lack o physical activity and obesity (Table 5-1).
In addition to these standard predictors, certain biologic markers associated with the development o cardiovascular events have been undergoing rigorous evaluation as “novel” risk
markers. These include elevated circulating levels o the special lipoprotein particle Lp(a) and
certain markers o in ammation, including the acute-phase reactant C-reactive protein (CRP).
Furthermore, recent genome-wide association studies (GWAS) have sought to identi y variants in genetic loci associated with increased cardiovascular risk.
The ollowing sections address these risk actors and biologic markers.
Genetics
Genetic predisposition, as re ected by amily history, comprises a major risk actor or atherosclerosis. While directly causative genes remain elusive, recent GWAS have identif ed a number o loci associated with atherosclerotic disease. The strongest connection with CAD and
myocardial in arction localizes to chromosome 9p21.3. This region contains genes that code
or two cyclin-dependent kinase inhibitors that can regulate the cell cycle and may participate
in TGF-β inhibitory pathways. Other associations with CAD include SORT-1 that encodes a
molecule implicated in lipoprotein tra f cking. Such f ndings promise eventually to enhance
identif cation, prevention, and treatment o atherosclerotic disease.
Genetic studies have also shown that loss o unction mutations in the gene that encodes
the enzyme PCSK9 (proprotein convertase subtilisin/ kexin type 9) augment LDL receptor levels on cell sur aces, boosting LDL clearance, and yielding lower LDL concentrations in blood.
Individuals with loss o unction variants in PCSK9, thus exposed to lower levels o LDL rom
childhood than those with the typical genotype, appear protected rom atherosclerotic events.
This observation has spurred the ongoing development o biological agents that limit PCSK9
action.
TABLE 5-1 Common Cardiovascular Risk Factors
Modif able risk actors
Dyslipidemia (elevated LDL, decreased HDL)
Tobacco smoking
Hypertension
Diabetes mellitus, metabolic syndrome
Lack of physical activity
Nonmodif able risk actors
Advanced age
Male sex
Heredity
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Atherosclerosis
127
Traditional Risk Factors
Dyslipidemia
A large and consistent body o evidence establishes abnormal circulating lipid levels as a
major risk actor or atherosclerosis. Observational studies have shown that societies with
high consumption o saturated at and prevalent hypercholesterolemia have greater mortality rom coronary disease than countries with traditionally low saturated at intake and low
serum cholesterol levels (e.g., rural Japan and certain Mediterranean nations). Similarly, data
rom the Framingham Heart Study and other cohorts have shown that the risk o ischemic
heart disease increases with higher total serum cholesterol levels. The coronary risk is approximately twice as high or a person with a total cholesterol level o 240 mg/ dL compared with
a person whose cholesterol level is 200 mg/ dL.
In particular, elevated levels o circulating LDL correlate with an increased incidence o
atherosclerosis and coronary artery disease. When present in excess, LDL can accumulate in
the subendothelial space and undergo the chemical modif cations that urther damage the
intima, as described earlier, initiating and perpetuating the development o atherosclerotic
lesions. Thus, LDL is commonly known as “bad cholesterol.” Conversely, elevated HDL particles (o ten called “good cholesterol”) associate with protection against atherosclerosis, o ten
attributed to HDL’s ability to transport cholesterol away rom the peripheral tissues back to
the liver or disposal (termed “reverse cholesterol transport”) and its putative antioxidative
and anti-in ammatory properties. Elevated serum LDL may persist or many reasons, including a high- at diet or abnormalities in the LDL receptor clearance mechanism. Patients with
genetic de ects in the LDL receptor, which leads to a condition known as familial hypercholesterolemia, cannot remove LDL rom the circulation e f ciently. Heterozygotes with this
condition have one normal and one de ective gene coding or the receptor. They display high
plasma LDL levels and develop premature atherosclerosis. Homozygotes who completely lack
unctional LDL receptors may experience vascular events, such as acute myocardial in arction, as early as the f rst decade o li e.
Increasing evidence also implicates triglyceride-rich lipoproteins, such as VLDL and IDL,
in the development o atherosclerosis. However, it remains undetermined whether these particles participate directly in the disease or simply keep company with low levels o HDL
cholesterol. O note, poorly controlled type 2 diabetes mellitus commonly associates with the
combination o hypertriglyceridemia and low HDL levels.
Lipid-Altering Therapy
Strategies that improve abnormal lipid levels can limit the consequences o atherosclerosis.
Many large studies o patients with coronary disease show that dietary or pharmacologic
reduction o serum cholesterol can prevent cardiovascular events.
Li estyle modif cations that may be benef cial include avoidance o tobacco, maintenance
o healthy diet and weight, and augmented physical activity. Yet, even intensive li estyle modif cation may not be su f cient to prevent cardiovascular events in individuals with long established atherosclerotic risk actors. Hence, many individuals require pharmacologic agents to
optimize cardiovascular outcomes. The major groups o lipid-altering agents (see Chapter 17)
include HMG-CoA reductase inhibitors (also known as “statins”), niacin, f bric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid–binding agents. O these, the
statins have emerged as the key LDL-lowering drugs that reduce cardiovascular events in
broad categories o patients. These agents inhibit the rate-limiting enzyme responsible or
cholesterol biosynthesis. The resulting reduction in intracellular cholesterol concentration
promotes increased LDL receptor expression and thus augments clearance o LDL particles
rom the bloodstream. Statins also lower the rate o VLDL synthesis by the liver (thus lowering circulating triglyceride levels) and raise HDL by an unknown mechanism.
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Chapter 5
Major clinical trials evaluating statin therapy have demonstrated reductions in ischemic
cardiac events, the occurrence o ischemic strokes, and mortality rates in individuals both
with and without a history o prior atherosclerotic cardiovascular events. Based on previous
guideline recommendations, many clinicians use specif c serum LDL targets to adjust the
dose o statin therapy. However, in 2013, the American College o Cardiology and American
Heart Association issued updated guidelines that advocate a di erent approach. Based on
evidence rom multiple randomized controlled clinical trials, the new recommendations ocus
therapy on groups o patients most likely to benef t rom lipid-lowering therapy (Table 5-2)
and recommends dosages o statins that were employed in such trials, rather than titrating
dosages based on serum lipoprotein levels. In particular, such studies have a f rmed that more
intense doses o statins improve outcomes in acute and chronic coronary heart disease more
than lower-dose regimens.
The clinical benef ts o statins likely derive rom several mechanisms. Lowering LDL can
limit lipid accumulation in atherosclerotic plaques and orestall the biological consequences
detailed earlier in this chapter. Other potentially benef cial actions (so-called “pleiotropic
e ects”) include reduced in ammation, a driver o atherosclerosis and its complications.
These pleiotropic e ects likely result rom activation o the transcription actor KLF2 and
inter erence with prenylation o small G proteins implicated in the regulation o in ammatory
unctions o vascular cells and leukocytes. Clinical trials have provided data that support an
anti-in ammatory action o statins by showing reductions in plasma levels o CRP, a serum
marker o in ammation described later. Such analyses cannot separate the LDL-lowering
e ect o statins rom their anti-in ammatory mechanisms because o the prominent role o
LDL in initiating in ammatory cascades. Nonetheless, accumulating clinical and experimental data suggest that at least part o the benef t o statins derives rom mechanisms other than
LDL lowering.
Other classes o drugs that lower LDL (e.g., niacin, f brates, inhibitors o bile acid, or
cholesterol absorption rom the gut) do not share the e f cacy o statins in reducing clinical
events. These agents are now primarily prescribed to patients who do not tolerate statins or
when LDL cholesterol reduction is not adequate on statin therapy alone.
TABLE 5-2
American College of Cardiology/ American Heart Association
Recommended Groups for Statin Therapy
Patient Type
Recommendation
Clinical atherosclerotic cardiovascular disease (ASCVD)
already present (i.e., history of CAD, stroke, or peripheral
vascular disease)
LDL cholesterol ≥ 190 mg/ dL
Diabetics (age 40–75 with LDL 70–189 mg/ dL) and
10-year cardiac riskc ≥ 7.5%
10-year cardiac riskc < 7.5% without clinical ASCVD
Nondiabetics (age 40–75 with LDL 70–189 mg/ dL) without
clinical ASCVD but with 10-year cardiac riskc ≥ 7.5%
High-intensity statina
High-intensity statina
High-intensity statina
Moderate-intensity statinb
Moderate-to-high intensity statina,b
High-intensity statin is intended to lower LDL cholesterol ≥ 50% (e.g., atorvastatin 40–80 mg daily or rosuvastatin
20–40 mg daily); for patients aged ≥ 75, or if at risk of statin adverse effect, consider moderate-intensity statin
instead.
b
Moderate-intensity statin is intended to lower LDL cholesterol 30%–50% (e.g., atorvastatin 10–20 mg daily,
rosuvastatin 5–10 mg daily, or simvastatin 20–40 mg daily).
c
The 10-year ASCVD risk for fatal or nonfatal myocardial infarction or stroke can be estimated using the online
calculator at http:/ / my.americanheart.org/ cvriskcalculator
CAD, coronary artery disease.
a
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Atherosclerosis
129
While elevated serum HDL appears to protect against atherosclerosis, recent clinical
trials have ailed to show clinical benef t o pharmacologically raising HDL in contemporary treated patients. For example, the prospective placebo-controlled AIM-HIGH and HPS2THRIVE studies demonstrated that niacin (the most e ective available agent to raise serum
HDL) did not reduce cardiac event rates in patients who had already achieved desirable LDL
levels on statin therapy. In addition, recent clinical studies o two experimental drugs that
greatly raise HDL cholesterol (known as cholesteryl ester trans er protein [CETP] inhibitors)
showed no clinical benef t. Similarly, clinical trials o drug therapies that reduce elevated
triglyceride levels (i.e., using f brates or omega-3 supplements) have not shown signif cant
improvement in cardiovascular event rates. Such drugs are now used primarily to reduce
severely elevated levels o serum triglycerides to prevent the associated complication o
pancreatitis.
Tobacco Smoking
Numerous studies have shown that tobacco smoking predisposes to atherosclerosis and
ischemic heart disease. Even low level smoking leads to adverse outcomes, but the heaviest smokers have the greatest risk o cardiovascular events. Tobacco smoking could promote atherosclerotic disease in several ways, including enhanced oxidative modif cation
o LDL, decreased circulating HDL levels, endothelial dys unction owing to tissue hypoxia
and increased oxidant stress, increased platelet adhesiveness, increased expression o soluble LAMs, inappropriate stimulation o the sympathetic nervous system by nicotine, and
displacement o oxygen by carbon monoxide rom hemoglobin. Extrapolation rom animal
experiments suggests that smoking not only accelerates atherogenesis but also increases the
propensity or thrombosis—both components o the “vulnerable patient.”
Fortunately, smoking cessation can reverse some o the adverse outcomes. People who
stop smoking greatly reduce their likelihood o coronary heart disease, compared with those
who continue to smoke. In one study, a ter 3 years o cessation, the risk o coronary artery
disease or ormer smokers became similar to subjects who never smoked.
Hypertension
Elevated blood pressure (either systolic or diastolic) augments the risk o developing atherosclerosis, coronary heart disease, and stroke (see Chapter 13). The association o elevated blood
pressure with cardiovascular disease does not appear to have a specif c threshold. Rather, risk
increases continuously with progressively higher pressure values. Systolic pressure predicts
adverse outcomes more reliably than does diastolic pressure, particularly in older persons.
Hypertension may accelerate atherosclerosis in several ways. Animal studies have shown
that elevated blood pressure injures vascular endothelium and may increase the permeability
o the vessel wall to lipoproteins. Cyclic circum erential strain, increased in hypertensive arteries, can enhance SMC production o proteoglycans that bind and retain LDL particles, promoting their accumulation in the intima and acilitating their oxidative modif cation. Angiotensin
II, a mediator o hypertension (described in Chapter 13), acts not only as a vasoconstrictor
but also as a stimulator o oxidative stress (through activation o NADPH oxidases, a source
o superoxide anion, O2− ) and as a proin ammatory cytokine. Thus, hypertension may also
promote atherogenesis by contributing to a prooxidant and in ammatory state.
Antihypertensive Therapy
Like dyslipidemias, treatment o hypertension should start with li estyle modif cations but
o ten requires pharmacologic intervention. The Dietary Approaches to Stop Hypertension
(DASH) studies demonstrate that a diet high in ruits and vegetables, with dairy products low
130
Chapter 5
in at and an overall reduced sodium content, signif cantly improves systolic and diastolic
blood pressures. Regular exercise can also reduce resting blood pressure levels. Many medications e ectively lower blood pressure, as described in Chapters 13 and 17.
Diabetes Mellitus and the “Metabolic Syndrome”
Diabetes mellitus a ects an estimated 170 million people worldwide, a prevalence projected
to grow 40% worldwide by 2030. In the United States alone, 18.2 million people have diabetes, and projections suggest that one in every three children born in 2000 will eventually
develop the condition. With a three- to f ve old increased risk o acute coronary events, 80%
o diabetic patients succumb to atherosclerosis-related conditions, including coronary heart
disease, stroke, and peripheral artery disease.
The predisposition o diabetic patients to atherosclerosis may relate in part to accompanying dyslipidemia, to nonenzymatic glycation o lipoproteins (which enhances uptake o cholesterol by scavenger macrophages, as described earlier), or to the associated prothrombotic
tendency and antif brinolytic state. Diabetics requently have impaired endothelial unction,
gauged by the reduced bioavailability o NO, and increased leukocyte adhesion. Tight control
o serum glucose levels in diabetic patients reduces the risk o microvascular complications,
such as retinopathy and nephropathy. Yet demonstration o a reduction o macrovascular
outcomes, such as myocardial in arction and stroke, by glycemic control remains much more
elusive. Indeed, studies have suggested that intense glucose lowering may even augment the
incidence o adverse cardiovascular events. In contrast to the uncertain benef ts o intense
glycemic control or macrovascular events, treatment o hypertension and dyslipidemia in
diabetic patients convincingly reduces the risk o cardiac and cerebrovascular complications.
The metabolic syndrome (also known as the “insulin resistance syndrome”) re ers to a
cluster o risk actors, including hypertension, hypertriglyceridemia, reduced HDL, hyperglycemia, and visceral obesity (excessive adipose tissue in the abdomen). This constellation
associates with a high risk or atherosclerosis in both diabetic and nondiabetic patients, and
using currently accepted criteria, 25% o Americans have this condition. The presence o
insulin resistance in this syndrome appears to promote atherogenesis long be ore a ected
persons develop overt diabetes.
Lack of Physical Activity
Exercise may mitigate atherogenesis in several ways. In addition to its benef cial e ects on
the lipid prof le and blood pressure, exercise enhances insulin sensitivity and endothelial
production o NO. Observational studies o both men and women indicate that even modest
activities, such as brisk walking, or as little as 30 minutes per day can protect against cardiovascular mortality.
Estrogen Status
Cardiovascular disease dominates other causes o mortality in women, including breast and
other cancers. Be ore menopause, women have a lower incidence o coronary events than
men. A ter menopause, however, men and women have similar rates. This observation suggests that estrogen (the levels o which decline a ter menopause) may have atheroprotective properties. Physiologic estrogen levels in premenopausal women raise HDL and lower
LDL. Experimentally, estrogen also exhibits potentially benef cial antioxidant and antiplatelet
actions and improves endothelium-dependent vasodilation.
Early observational studies suggested that hormone therapy reduced the risk o coronary
artery disease in postmenopausal women, prompting many physicians to prescribe such medications or cardiovascular prevention purposes. However, the Heart and Estrogen/ Progestin
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Atherosclerosis
131
Replacement Study demonstrated an association between such hormone use and an early
increased risk o vascular events in women with preexisting coronary disease. Subsequent
randomized primary prevention studies rom the Women’s Health Initiative were terminated
prematurely because estrogen-plus-progestin treatment increased cardiovascular risk by 24%
overall, with a striking 81% higher risk during the f rst year o therapy. Because currently
available clinical trial data do not show that gonadal hormone therapy lowers cardiovascular
events and that it may actually be harm ul, such therapy should not be commenced or the
sole goal o reducing cardiovascular risk.
Biomarkers o Cardiovascular Risk
Despite identif cation o the well-established risk actors just described, one out o f ve cardiovascular events occurs in patients lacking these attributes. In conjunction with growing
knowledge about the pathogenesis o atherosclerosis, several novel markers o risk have
emerged. These biomarkers serve three primary roles: (1) as a means to help strati y the risk
o atherosclerotic disease and thus guide the choice o therapies, (2) as clinical measures to
assess treatment e ects, and (3) as potential targets o new therapeutic regimens.
Lipoprotein ( a)
Lipoprotein (a), re erred to as Lp(a) and pronounced “L-P-little-a,” independently predicts
cardiovascular events in some studies. Lp(a) is a variant o LDL whose major apolipoprotein (apo B-100) links by a disulf de bridge to another protein, apo(a). Apo(a) structurally
resembles plasminogen, a plasma protein important in the endogenous lysis o f brin clots
(see Chapter 7). Thus, the detrimental e ect attributed to Lp(a) may relate to competition
with normal plasminogen activity. Lp(a) is able to enter the arterial intima, and in vitro studies have shown that it encourages in ammation and thrombosis.
Lp(a) levels in the population are skewed and not normally distributed, showing a trailing prevalence o the higher levels. Not all population studies support a link between Lp(a)
and cardiovascular events, though people with the highest Lp(a) levels do appear to have
increased risk. Recent GWAS and Mendelian randomization analyses also support a causal
link between Lp(a) and cardiovascular events.
Diet and exercise have little impact on Lp(a) levels. O current lipid-lowering agents, niacin
has the greatest e ect on Lp(a), lowering its concentration by as much as 20% . However, thus ar,
there is no evidence that reduction o Lp(a) by drug therapy improves cardiovascular outcomes.
C-Reactive Protein ( CRP) and Other Markers o Inf ammation
Because the pathogenesis o atherosclerosis involves in ammation at every stage, markers o
in ammation have undergone evaluation as predictors o cardiac risk. Recall that the process
o lipoprotein entry and modif cation in the vessel wall triggers the release o cytokines, ollowed by leukocyte inf ltration, more cytokine release, and smooth muscle migration into—
and proli eration within—the intima. Involved cytokines (e.g., IL-6) incite increased hepatic
production o acute-phase reactants, including CRP, f brinogen, and serum amyloid A.
O these molecules, CRP has shown the greatest promise as a marker o low-grade systemic
in ammation associated with atherosclerotic disease. Large studies o apparently healthy
men and women indicate that those with higher basal CRP levels have increased risk o
adverse cardiovascular outcomes, independent o serum cholesterol concentrations and other
traditional risk markers. Multiple prospective studies a f rm that CRP measured by a highly
sensitive assay (hsCRP) independently predicts myocardial in arction, stroke, peripheral
artery disease, and sudden cardiac death. Although it serves as a marker o risk not captured
by traditional algorithms, CRP itsel does not mediate atherogenesis.
132
Chapter 5
Recent data support the use o CRP levels to potentially guide therapy. For example, the
prospective JUPITER trial studied 17,800 healthy individuals with above-median levels o
CRP who did not have elevated LDL and demonstrated a reduced incidence o major cardiovascular events in patients who were treated with statin therapy, compared to those who
received a placebo.
Given the critical role o in ammation in atherogenesis, ongoing clinical trials are testing
available and novel anti-in ammatory medications or the prevention o recurrent cardiovascular events among patients with coronary disease.
Outlook
Despite accumulating knowledge o the pathogenesis o atherosclerosis and its clinical sequelae,
this disease remains a major cause o death throughout the world. Although improvements in
cardiovascular care have reduced age-adjusted mortality rom this condition, it will continue
to grow as a menace as the population ages and as developing countries embrace the adverse
dietary and activity habits o a Western li estyle. Ongoing research o the biology o atherosclerosis, as well as advances in therapeutic procedures and medications, will undoubtedly
continue to urther our abilities to combat this condition. Yet we have not ully capitalized on
what we already know—that much cardiovascular risk is modif able. E ective control o the
risk actors described earlier remains a critical component to tame this global scourge. It is here
that the relationship between the patient and health care provider, and the role o medical proessionals as community leaders advocating healthy li estyles, remain o cardinal importance.
SUMMARY
• Atherosclerosis is the leading cause o mortality and morbidity in developed nations and
has become a major cause o death in the developing world.
• The arterial wall consists o the intima (closest to the arterial lumen), the media (the middle
layer), and the adventitia (the outer layer).
• The normal endothelium provides a protective, nonthrombogenic sur ace with homeostatic
vasodilatory and anti-in ammatory properties.
• Early in atherogenesis, injurious stimuli activate endothelial and smooth muscle cells, which
recruit in ammatory cells to the vessel wall.
• Atherosclerotic plaques orm over decades and can display eatures associated with clinical
stability, or a propensity to provoke thrombotic events (“vulnerable” plaques).
• Clinical atherosclerotic events result rom narrowing o the vessel lumen, aneurysm ormation, or plaque disruption with superimposed thrombus ormation.
• Common mani estations o atherosclerosis include angina pectoris, myocardial in arction,
stroke, and peripheral artery disease.
• Modif able risk actors or atherosclerosis include dyslipidemia, smoking, hypertension, and
diabetes.
• Nonmodif able risk actors include advanced age, male sex, and a amily history o premature coronary disease.
• Novel biomarkers, such as high-sensitivity C-reactive protein (hsCRP), may prove use ul in
def ning risk.
Ack n ow le d gm en t s
Contributors to the previous editions o this chapter were Jordan B. Strom, MD; James L.
Young, MD; Mary Beth Gordon, MD; Rushika Fernandopulle, MD; Gopa Bhattacharyya, MD;
and Joseph Loscalzo, MD, PhD.
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Atherosclerosis
133
Ad d i t i o n a l Rea d i n g
Cholesterol Treatment Trialists’ (CTT) Collaborators.
E f cacy and sa ety o LDL-lowering therapy among
men and women: meta-analysis o individual data rom
174 000 participants in 27 randomised trials. Lancet.
2015;385:1397–1405.
Cook NR, Paynter NP, Eaton CB, et al. Comparison o the
Framingham and Reynolds risk scores or global cardiovascular risk prediction in the multiethnic women’s health
initiative. Circulation. 2012;125:1748–1756.
Gimbrone MA, Jr., Garcia-Cardena G. Vascular endothelium,
hemodynamics, and the pathobiology o atherosclerosis.
Cardiovasc Pathol. 2013;22:9–15.
Born eldt KE, Tabas I. Insulin resistance, hyperglycemia, and
atherosclerosis. Cell Metab. 2011;14:575–585.
Libby P. In ammation in atherosclerosis. Arterioscler Thromb
Vasc Biol. 2012;32:2045–2051.
Libby P. Mechanisms o acute coronary syndromes. N Engl J
Med. 2013;369:883–884.
Libby P, Ridker PM, Hansson GK. Progress and challenges
in translating the biology o atherosclerosis. Nature.
2011;473:317–325.
Moore KJ, Tabas I. Macrophages in the pathogenesis o
atherosclerosis. Cell. 2011;145:341–355.
Schunkert H, et al. Large-scale association analysis identif es
13 new susceptibility loci or coronary artery disease.
Nat Genet. 2011;43:333–338.
Stein EA, Mellis S, Yancopoulos GD, et al. E ect o a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med.
2012;366:1108–1118.
Steinberg D. In celebration o the 100th anniversary o
the lipid hypothesis o atherosclerosis. J Lipid Res.
2013;54:2946–2949.
Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA
guideline on the treatment o blood cholesterol to reduce
atherosclerotic cardiovascular risk in adults. Circulation.
2013;129:S1–S45. DOI: 10.1161/ 01.cir.0000437738.
63853.7a.
Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal
genetic risk actor o cardiovascular disease: A rationale
or increased e orts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol.
2012;60:716–721.
Ischemic Heart Disease
Ja yme Wilder
Ma rc S. Sa ba tine
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Determinants of Myocardial
Oxygen Supply and Demand
Myocardial Oxygen Supply
Myocardial Oxygen Demand
Pathophysiology of Ischemia
Fixed Vessel Narrowing
Endothelial Cell Dys unction
Other Causes o Myocardial
Ischemia
Consequences of Ischemia
Ischemic Syndromes
Clinical Features of Chronic
Stable Angina
History
Physical Examination
Diagnostic Studies
Natural History
Treatment
Medical Treatment o an Acute
Episode o Angina
Medical Treatment to Prevent
Recurrent Ischemic Episodes
Medical Treatment to Prevent
Acute Cardiac Events
Revascularization
Medical versus Revascularization
Therapy
I
6
n 1772, the British physician William Heberden reported a
disorder in which patients developed an uncom ortable sensation in the chest when walking. Labeling it angina pectoris,
Heberden noted that this discom ort would disappear soon a ter
the patient stood still but would recur with similar activities.
Although he did not know the cause, it is likely that he was
the rst to describe the symptoms o ischemic heart disease,
a condition o imbalance between myocardial oxygen supply
and demand most o ten caused by atherosclerosis o the coronary arteries. Ischemic heart disease now a f icts millions o
Americans and is the leading cause o death in industrialized
nations.
The clinical presentation o ischemic heart disease
can be highly variable and orms a spectrum o syndromes
(Table 6-1). For example, ischemia may be accompanied by
the same exertional symptoms described by Heberden. In
other cases, it may occur without any clinical mani estations at all, a condition termed silent ischemia. This chapter
describes the causes and consequences o chronic ischemic
heart disease syndromes and provides a ramework or the
diagnosis and treatment o a ected patients.
Angina pectoris remains the most common mani estation
o ischemic heart disease and literally means “strangling in
the chest.” Although other conditions may lead to similar
discom ort, angina re ers speci cally to the uncom ortable
sensation in the chest and neighboring structures that arises
rom an imbalance between myocardial oxygen supply and
demand.
134
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Ischemic Heart Disease
135
TABLE 6-1 Clinical Def nitions
Syndrome
Description
Ischemic heart disease
Condition in which imbalance between myocardial oxygen supply and
demand results in myocardial hypoxia and accumulation o waste
metabolites, most o ten caused by atherosclerotic disease o the coronary arteries (o ten termed coronary artery disease)
Uncom ortable sensation in the chest and neighboring anatomic structures produced by myocardial ischemia
Chronic pattern o transient angina pectoris, precipitated by physical
activity or emotional upset, relieved by rest within a ew minutes; episodes o ten associated with temporary depression o the ST segment,
but permanent myocardial damage does not result
Typical anginal discom ort, usually at rest, which develops because o
coronary artery spasm rather than an increase o myocardial oxygen
demand; episodes o ten associated with transient shi ts o the ST segment, usually ST elevation (also termed Prinzmetal angina)
Asymptomatic episodes o myocardial ischemia; can be detected by electrocardiogram and other laboratory techniques
Pattern o increased requency and duration o angina episodes produced
by less exertion or at rest; high requency o progression to myocardial
in arction i untreated
Region o myocardial necrosis usually caused by prolonged cessation o
blood supply; most o ten results rom acute thrombus at site o coronary atherosclerotic stenosis; may be a f rst clinical mani estation o
ischemic heart disease, or there may be a history o angina pectoris
Angina pectoris
Stable angina
Variant angina
Silent ischemia
Unstable angina
Myocardial in arction
DETERMINANTS OF MYOCARDIAL OXYGEN SUPPLY AND DEMAND
In the normal heart, the oxygen requirements of the myocardium are continuously matched
by the coronary arterial supply. Even during vigorous exercise, when the metabolic needs of
the heart increase, so does the delivery of oxygen to the myocardial cells so that the balance
is maintained. The following sections describe the key determinants of myocardial oxygen
supply and demand in a normal person (Fig. 6-1) and how they are altered by the presence of
atherosclerotic coronary artery disease (CAD).
Myo c ardial oxyg e n s upply
Myo c ardial oxyg e n de mand
O2 c o nte nt
Wall s tre s s
(P × r / 2h)
Co ro nary blo o d flow
1) corona ry pe rfus ion pre s s ure
He art rate
2) corona ry va s cula r re s is ta nce
FIGURE 6-1. Major determinants
o myocardial oxygen supply and
demand. P, ventricular pressure;
r, ventricular radius; h, ventricular
wall thickness.
a ) exte rna l compre s s ion
b) intrins ic re gula tion
Co ntrac tility
136
Chapter 6
Myocardial Oxygen Supply
The supply o oxygen to the myocardium depends on the oxygen content o the blood and
the rate o coronary blood f ow . The oxygen content is determined by the hemoglobin concentration and the degree o systemic oxygenation. In the absence o anemia or lung disease, oxygen content remains airly constant. In contrast, coronary blood ow is much more
dynamic, and regulation o that ow is responsible or matching the oxygen supply with
metabolic requirements.
As in all blood vessels, coronary artery ow (Q) is directly proportional to the vessel’s perusion pressure (P) and is inversely proportional to coronary vascular resistance (R). That is,
P
Q α
R
However, unlike other arterial systems in which the greatest blood ow occurs during
systole, the predominance o coronary per usion takes place during diastole. The reason or
this is that systolic ow is impaired by the compression o the small coronary branches as
they course through the contracting myocardium. Coronary ow is unimpaired in diastole
because the relaxed myocardium does not compress the coronary vasculature. Thus, in the
case o the coronaries, per usion pressure can be approximated by the aortic diastolic pressure. Conditions that decrease aortic diastolic pressure (such as hypotension or aortic valve
regurgitation) decrease coronary artery per usion pressure and may lessen myocardial oxygen
supply.
Coronary vascular resistance is the other major determinant o coronary blood ow. In
the normal artery, this resistance is dynamically modulated by (1) orces that externally compress the coronary arteries and (2) actors that alter intrinsic coronary tone.
External Compression
External compression is exerted on the coronary vessels during the cardiac cycle by contraction o the surrounding myocardium. The degree o compression is directly related to
intramyocardial pressure and is there ore greatest during systole, as described in the previous
section. Moreover, when the myocardium contracts, the subendocardium, adjacent to the high
intraventricular pressure, is subjected to greater orce than are the outer muscle layers. This
is one reason that the subendocardium is the region most vulnerable to ischemic damage.
Intrinsic Control of Coronary Arterial Tone
Unlike most tissues, the heart cannot increase oxygen extraction on demand because in its
basal state, it removes nearly as much oxygen as possible rom its blood supply. Thus, any
additional oxygen requirement must be met by an increase in blood f ow, and autoregulation
o coronary vascular resistance is the most important mediator o this process. Factors that
participate in the regulation o coronary vascular resistance include the accumulation o local
metabolites, endothelium-derived substances, and neural innervation.
Metabolic Factors
The accumulation o local metabolites signif cantly a ects coronary vascular tone and acts
to modulate myocardial oxygen supply to meet changing metabolic demands. During states
o hypoxemia, aerobic metabolism and oxidative phosphorylation in the mitochondria are
inhibited and generation o high-energy phosphates, including adenosine triphosphate (ATP),
is impaired. Consequently, adenosine diphosphate (ADP) and adenosine monophosphate
(AMP) accumulate and are subsequently degraded to adenosine. Adenosine is a potent
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Ischemic Heart Disease
137
vasodilator and is thought to be the prime metabolic mediator o vascular tone. By binding
to receptors on vascular smooth muscle, adenosine decreases calcium entry into cells, which
leads to relaxation, vasodilatation, and increased coronary blood ow. Other metabolites that
act locally as vasodilators include lactate, acetate, hydrogen ions, and carbon dioxide.
Endothelial Factors
Endothelial cells o the arterial wall produce numerous vasoactive substances that contribute to the regulation o vascular tone. Vasodilators produced by the endothelium include
nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing actor (EDHF).
Endothelin 1 is an example o an endothelium-derived vasoconstrictor.
The discovery and signif cance o endothelium-derived NO are highlighted in Box 6-1.
In brie , NO regulates vascular tone by di using into and then relaxing neighboring arterial
BOX 6-1
Endothelium-Derived Relaxing Factor, Nitric Oxide, and
the Nobel Prize
Normal arterial endothelial cells synthesize potent vasodilator substances that contribute to
the modulation o vascular tone. Among the f rst o these to be identif ed were prostacyclin (an
arachidonic acid metabolite) and a substance termed endothelium-derived relaxing actor (EDRF).
EDRF was f rst studied in the 1970s. In experimental preparations, it was shown that
acetylcholine (ACh) has two opposite actions on blood vessels. Its direct e ect on vascular
smooth muscle cells is to cause vasoconstriction, but when an intact endothelial lining overlies
the smooth muscle cells, vasodilatation occurs instead. Subsequent experiments showed that ACh
causes the endothelial cells to release a chemical mediator (that was termed EDRF), which quickly
di uses to the adjacent smooth muscle cells and results in their relaxation with subsequent
vasodilatation o the vessel.
Further research demonstrated that the mysterious EDRF is actually the nitric oxide (NO) radical.
Binding o ACh (or another endothelial-dependent vasodilator such as serotonin or histamine) to
endothelial cells catalyzes the ormation o NO rom the amino acid l -arginine (see f gure). NO then
di uses to the adjacent vascular smooth muscle, where it activates guanylyl cyclase (G-cyclase).
G-cyclase in turn orms cyclic guanosine monophosphate (cGMP), which results in smooth muscle
cell relaxation through mechanisms that involve a reduction in cytosolic Ca+ + .
AGONIST
(e .g., ACh, his ta mine, s e rotonin)
Endo the lial
c e ll
Nitric oxide
syntha s e
L-Arginine
O2
Nitroprus s ide
or nitroglyce rin
S mo o th
mus cle c e ll
L-Citruline
Nitric oxide
Nitric oxide
GTP
G-cycla s e
cGMP
RELAXATION
(continues on page 138)
138
Chapter 6
BOX 6-1
Endothelium-Derived Relaxing Factor, Nitric Oxide, and
the Nobel Prize ( continued)
In contrast to the endothelial-dependent vasodilators, some agents cause smooth muscle
relaxation independent o the presence o endothelial cells. For example, the drugs sodium
nitroprusside and nitroglycerin result in vasodilatation by providing an exogenous source o NO to
vascular smooth muscle cells, thereby activating G-cyclase and orming cGMP without endothelial
cell participation.
In the cardiac catheterization laboratory, the intracoronary administration o ACh in a normal
person causes vasodilatation o the vessel, presumably through the release o NO. However, in
conditions o endothelial dys unction, such as atherosclerosis, intracoronary ACh administration
results in paradoxical vasoconstriction instead. This likely ref ects reduced production o NO by the
dys unctional endothelial cells, resulting in unopposed direct vasoconstriction o the smooth muscle
by ACh. O particular interest is that the loss o vasodilatory response to in used ACh is evident in
persons with certain cardiac risk actors (e.g., elevated LDL cholesterol, hypertension, cigarette
smoking) even be ore the physical appearance o atheromatous plaque. Thus, the impaired release o
NO may be an early and sensitive predictor or the later development o atherosclerotic lesions.
The signi cance o these discoveries was highlighted in 1998, when the Nobel Prize in
medicine was awarded to the scientists who discovered the critical role o NO as a cardiovascular
signaling molecule.
smooth muscle by a cyclic guanosine monophosphate (cGMP)–dependent mechanism. The
production o NO by normal endothelium occurs in the basal state and is additionally stimulated by many substances and conditions. For example, its release is augmented when the
endothelium is exposed to acetylcholine (ACh), thrombin, products o aggregating platelets
(e.g., serotonin and ADP), or even the shear stress o blood f ow. Although the direct e ect o
many o these substances on vascular smooth muscle is to cause vasoconstriction, the induced
release o NO rom the normal endothelium results in vasodilatation instead (Fig. 6-2).
Prostacyclin, an arachidonic acid metabolite, has vasodilator properties similar to those
o NO (see Fig. 6-2). It is released rom endothelial cells in response to many stimuli, including hypoxia, shear stress, ACh, and platelet products (e.g., serotonin). It causes relaxation o
vascular smooth muscle by a cyclic AMP–dependent mechanism.
EDHF also appears to have important vasodilatory properties. Like endothelial-derived
NO, it is a di usible substance released by the endothelium that hyperpolarizes (and thereore relaxes) neighboring vascular smooth muscle cells. EDHF is released by some o the
Endo the lial-de pe nde nt
vas o dilato rs
(ACh, s e rotonin,
thrombin, s he a r s tre s s )
Endo the lial
c e ll
Prosta cyclin NO
EDHF
Thrombin
Angiote ns in II
Epine phrine
Endothe lin 1
EDHF
S mo o th
mus cle
c e ll
cAMP
cGMP
Re laxatio n
Co ntrac tio n
FIGURE 6-2. Endothelium-derived vasoactive
substances and their regulators. Endotheliumderived vasodilators are shown on the le t and
include nitric oxide (NO), prostacyclin, and
endothelium-derived hyperpolarizing actor
(EDHF). Endothelin 1 is an endothelium-derived
vasoconstrictor. In the normal state, the
vasodilator inf uence predominates over that o
vasoconstriction. ACh, acetylcholine; cGMP, cyclic
guanosine monophosphate; cAMP, cyclic adenosine
monophosphate.
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Ischemic Heart Disease
139
same actors that stimulate NO, including ACh and normal pulsatile blood ow. In the coronary circulation, EDHF appears to be more important in modulating relaxation in small
arterioles than in the large conduit arteries.
Endothelin 1 is a potent vasoconstrictor produced by endothelial cells that partially counteracts the actions o the endothelial vasodilators. Its expression is stimulated by several
actors, including thrombin, angiotensin II, epinephrine, and the shear stress o blood ow.
Under normal circumstances, the healthy endothelium promotes vascular smooth muscle
relaxation (vasodilatation) through elaboration o substances such as NO and prostacyclin,
the in uences o which predominate over the endothelial vasoconstrictors (see Fig. 6-2).
However, as described later in the chapter, dys unctional endothelium (e.g., in atherosclerotic
vessels) secretes reduced amounts o vasodilators, causing the balance to shi t toward vasoconstriction instead.
Neural Factors
The neural control o vascular resistance has both sympathetic and parasympathetic components. Under normal circumstances, the contribution o the parasympathetic nervous system
appears minor, but sympathetic receptors play an important role. Coronary vessels contain
both α-adrenergic and β2-adrenergic receptors. Stimulation o α-adrenergic receptors results in
vasoconstriction, whereas β2-receptors promote vasodilatation.
It is the interplay among the metabolic, endothelial, and neural regulating actors that
determines the net impact on coronary vascular tone. For example, catecholamine stimulation
o the heart may initially cause coronary vasoconstriction via the α-adrenergic receptor neural e ect. However, catecholamine stimulation also increases myocardial oxygen consumption through increased heart rate and contractility (β1-adrenergic e ect), and the resulting
increased production o local metabolites induces net coronary dilatation instead.
Myocardial Oxygen Demand
The three major determinants o myocardial oxygen demand are (1) ventricular wall stress,
(2) heart rate, and (3) contractility (which is also termed the inotropic state). Additionally,
very small amounts o oxygen are consumed in providing energy or basal cardiac metabolism
and electrical depolarization.
Ventricular wall stress (σ) is the tangential orce acting on the myocardial f bers, tending
to pull them apart, and energy is expended in opposing that orce. Wall stress is related to
intraventricular pressure (P), the radius o the ventricle (r), and ventricular wall thickness (h)
and is approximated by Laplace’s relationship:
P ×r
σ=
2h
Thus, wall stress is directly proportional to systolic ventricular pressure. Circumstances
that increase pressure in the le t ventricle, such as aortic stenosis or hypertension, augment
wall stress and myocardial oxygen consumption. Conditions that decrease ventricular pressure, such as antihypertensive therapy, reduce myocardial oxygen consumption.
Because wall stress is also directly proportional to the radius o the le t ventricle, conditions that augment le t ventricular (LV) f lling (e.g., mitral or aortic regurgitation) raise wall
stress and oxygen consumption. Conversely, any physiologic or pharmacologic maneuver that
decreases LV f lling and size (e.g., nitrate therapy) reduces wall stress and myocardial oxygen
consumption.
Finally, wall stress is inversely proportional to ventricular wall thickness because the orce
is spread over a greater muscle mass. A hypertrophied heart has lower wall stress and oxygen
140
Chapter 6
consumption per gram o tissue than a thinned-wall heart. Thus, when hypertrophy develops
in conditions o chronic pressure overload, such as aortic stenosis, it serves a compensatory
role in reducing oxygen consumption.
The second major determinant o myocardial oxygen demand is heart rate. I the heart rate
accelerates—during physical exertion, or example—the number o contractions and the amount
o ATP consumed per minute increases and oxygen requirements rise. Conversely, slowing the
heart rate (e.g., with a β-blocker drug) decreases ATP utilization and oxygen consumption.
The third major determinant o oxygen demand is myocardial contractility, a measure o
the orce o contraction (see Chapter 9). Circulating catecholamines, or the administration
o positive inotropic drugs, directly increase the orce o contraction, which augments oxygen utilization. Conversely, negative inotropic e ectors, such as β-adrenergic–blocking drugs,
decrease myocardial oxygen consumption.
In the normal state, autoregulatory mechanisms adjust coronary tone to match myocardial
oxygen supply with oxygen requirements. In the absence o obstructive coronary disease,
these mechanisms maintain a airly constant rate o coronary ow, as long as the aortic perusion pressure is approximately 60 mm Hg or greater. In the setting o advanced coronary
atherosclerosis, however, the all in per usion pressure distal to the arterial stenosis, along
with dys unction o the endothelium o the involved segment, sets the stage or a mismatch
between the available blood supply and myocardial metabolic demands.
PATHOPHYSIOLOGY OF ISCHEMIA
The traditional view has been that myocardial ischemia in CAD results rom f xed atherosclerotic plaques that narrow the vessel’s lumen and limit myocardial blood supply. However,
research has demonstrated that the reduction o blood ow in this condition results rom
the combination o f xed vessel narrowing and abnormal vascular tone, contributed to by
atherosclerosis-induced endothelial cell dys unction.
Fixed Vessel Narrowing
The hemodynamic signif cance o f xed atherosclerotic coronary artery stenoses relates to
both the uid mechanics and the anatomy o the vascular supply.
Fluid Mechanics
Poiseuille’s law states that or ow through a vessel,
∆P π r 4
Q=
8η L
in which Q is ow, ΔP is the pressure di erence between the points being measured, r is the
vessel radius, η is the uid viscosity, and L is the vessel length. By analogy to Ohm’s law, ow
is also equal to the pressure di erence divided by the resistance (R) to ow:
Q=
∆P
R
By combining these two ormulas and rearranging, resistance to blood ow in a vessel can
be expressed as
R=
8η L
πr 4
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Ischemic Heart Disease
4x
Ma xima l corona ry flow
3x
z
e
d
m
e
a
n
f
l
o
w
5x
2x
o
r
m
a
l
i
Thus, vascular resistance is governed,
in part, by the geometric component L/ r 4.
That is, the hemodynamic signif cance o a
stenotic lesion depends on its length and,
ar more importantly, on the degree o vessel narrowing (i.e., the reduction o r) that
it causes.
141
N
Anatomy
Re s ting corona ry flow
1x
The coronary arteries consist o large,
proximal epicardial segments and smaller,
0
20
40
60
80
100
distal resistance vessels (arterioles). The
Le s ion dia me te r (%)
proximal vessels are subject to overt atherosclerosis that results in stenotic plaques. FIGURE 6-3. Resting and maximal coronary blood
The distal vessels are usually ree o ow- f ows are a ected by the magnitude o proximal
limiting plaques and can adjust their vaso- arterial stenosis ( percent lesion diameter) . The
dotted line indicates resting blood f ow, and the solid
motor tone in response to metabolic needs.
line represents maximal blood f ow (i.e., when there
These resistance vessels serve as a reserve, is ull dilatation o the distal resistance vessels).
increasing their diameter with exertion to Compromise o maximal blood f ow is evident when the
meet increasing oxygen demand and dilat- proximal stenosis reduces the coronary lumen diameter
ing, even at rest, i a proximal stenosis is by more than approximately 70%. Resting f ow may
be compromised i the stenosis exceeds approximately
su f ciently severe.
The hemodynamic signif cance o a coro- 90%. (Modi ed rom Gould KL, Lipscomb K. E ects
o coronary stenoses on coronary f ow reserve and
nary artery narrowing depends on both the
resistance. Am J Cardiol. 1974;34:50.)
degree o stenosis o the epicardial portion o
the vessel and the amount o compensatory
vasodilatation the distal resistance vessels are able to achieve (Fig. 6-3). I a stenosis narrows
the lumen diameter by less than 60% , the maximal potential blood ow through the artery is
not signif cantly altered and, in response to exertion, the resistance vessels can dilate to provide adequate blood ow. When a stenosis narrows the diameter by more than approximately
70% , resting blood ow is normal, but maximal blood ow is reduced even with ull dilatation o the resistance vessels. In this situation, when oxygen demand increases (e.g., rom the
elevated heart rate and orce o contraction during physical exertion), coronary ow reserve is
inadequate, oxygen demand exceeds supply, and myocardial ischemia results. I the stenosis
compromises the vessel lumen by more than approximately 90% , then even with maximal dilatation o the resistance vessels, blood ow may be inadequate to meet basal requirements and
ischemia can develop at rest.
Although collateral connections (see Chapter 1) may become apparent between unobstructed coronaries and sites distal to atherosclerotic stenoses, and such ow can bu er the
all in myocardial oxygen supply, it is o ten not su f cient to prevent ischemia during exertion
in critically narrowed vessels.
Endothelial Cell Dys unction
In addition to f xed vessel narrowing, the other major contributor to reduced myocardial
oxygen supply in chronic CAD is endothelial dys unction. Abnormal endothelial cell unction can contribute to the pathophysiology o ischemia in two ways: (1) by inappropriate vasoconstriction o coronary arteries and (2) through loss o normal antithrombotic
properties.
142
Chapter 6
Inappropriate Vasoconstriction
In normal persons, physical activity or mental stress results in measurable coronary
artery va sodila ta tion . This e ect is thought to be regulated by activation o the sympathetic nervous system, with increased blood f ow and shear stress stimulating the release
o endothelial-derived vasodilators, such as NO. It is postulated that in typical people, the
relaxation e ect o NO outweighs the direct α-adrenergic constrictor e ect o catecholamines on arterial smooth muscle, such that vasodilatation results. However, in patients
with dys unctional endothelium (e.g., atherosclerosis), an impa ired relea se of en dothelia l
va sodila tors leaves the direct catecholamine e ect unopposed, such that relative vasoconstriction occurs instead. The resultant decrease in coronary blood f ow contributes to ischemia. Even the vasodilatory e ect o local metabolites (such as adenosine) is attenuated in
patients with dys unctional endothelium, urther uncoupling the regulation o vascular tone
rom metabolic demands.
In patients with risk actors or CAD, such as hypercholesterolemia, diabetes mellitus,
hypertension, and cigarette smoking, impaired endothelial-dependent vasodilatation is noted
even before visible atherosclerotic lesions have developed. This suggests that endothelial dysunction occurs very early in the atherosclerotic process.
Inappropriate vasoconstriction also appears to be important in acute coronary syndromes,
such as unstable angina and myocardial in arction (MI). As described in Chapter 7, the usual
cause o acute coronary syndromes is disruption o atherosclerotic plaque, with superimposed
platelet aggregation and thrombus ormation. Normally, the products o platelet aggregation
in a developing clot (e.g., serotonin and ADP) result in vasodilatation because they stimulate
the endothelial release o NO. However, with dys unctional endothelium, the direct vasoconstricting actions o platelet products predominate (Fig. 6-4), urther compromising f ow
through the arterial lumen.
Loss of Normal Antithrombotic Properties
In addition to their vasodilatory actions, actors released rom endothelial cells (including NO
and prostacyclin) also exert antithrombotic properties by inter ering with platelet aggregation
(see Fig. 6-4). However, in states o endothelial cell dys unction, release o these substances
is reduced; there ore, the antithrombotic e ect is attenuated. Thus, in syndromes characterized by thrombosis (i.e., the acute coronary syndromes described in Chapter 7), the impaired
release o NO and prostacyclin allows platelets to aggregate and to secrete their potentially
harm ul procoagulants and vasoconstrictors.
Other Causes of Myocardial Ischemia
In addition to atherosclerotic CAD, other conditions may result in an imbalance between
myocardial oxygen supply and demand and result in ischemia. Other common causes
o decreased myocardial oxygen supply include (1) decreased per usion pressure due
to hypotension (e.g., in a patient with hypovolemia or septic shock) and (2) a severely
decreased blood oxygen content (e.g., marked anemia, or impaired oxygenation o blood
by the lungs). For example, a patient with massive bleeding rom the gastrointestinal tract
may develop myocardial ischemia and angina pectoris, even in the absence o atherosclerotic coronary disease, because o reduced oxygen supply (i.e., the loss o hemoglobin
and hypotension).
On the other side o the balance, a pro ound increase in myocardial oxygen demand can
cause ischemia even in the absence o coronary atherosclerosis. This can occur, or example,
with rapid tachycardias, acute hypertension, or severe aortic stenosis.
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Ischemic Heart Disease
143
Aggre ga ting
pla te le ts :
–
ADP 5-HT TXA2
+
Endothe lia l
ce ll
S mooth
mus cle
ce ll
Pros ta cyclin NO
Co ntrac tio n
Re laxatio n
A
FIGURE 6-4. The interaction between platelets
and endothelial cells. A. Normal endothelium.
Aggregating platelets release thromboxane (TXA2)
and serotonin (5-HT), the direct vascular effects
of which cause contraction of vascular smooth
muscle and vasoconstriction. However, platelet
products (e.g., ADP and 5-HT) also stimulate the
endothelial release of the potent vasodilators
nitric oxide (NO) and prostacyclin, such that the
net effect is smooth muscle relaxation instead.
Endothelial production of NO and prostacyclin
also serves antithrombotic roles, which limit
further platelet aggregation. ADP, adenosine
diphosphate. B. Dysfunctional endothelium
demonstrates impaired release of the vasodilator
substances, such that net smooth muscle
contraction and vasoconstriction supervene.
The reduced endothelial release of NO and
prostacyclin diminishes their antiplatelet effect,
such that thrombosis proceeds unchecked.
Aggre ga ting
pla te le ts :
–
ADP 5-HT TXA2
+
Dys functiona l
e ndothe lium
S mooth
mus cle
ce ll
Pros ta cyclin
NO
Re laxatio n
Co ntrac tio n
B
CONSEQUENCES OF ISCHEMIA
The consequences o ischemia ref ect the inadequate myocardial oxygenation and local
accumulation o metabolic waste products. For example, during ischemia, myocytes convert
rom aerobic to anaerobic metabolic pathways. The reduced generation o ATP impairs the
interaction o the contractile proteins and results in a transient reduction o both ventricular systolic contraction and diastolic relaxation, as each are energy-dependent processes.
The consequent elevation o LV diastolic pressure is transmitted (via the le t atrium and
pulmonary veins) to the pulmonary capillaries and can precipitate pulmonary congestion
and the symptom o dyspnea (shortness o breath). In addition, metabolic products such
as lactate, serotonin, and adenosine accumulate locally. It is suspected that one or more o
these compounds activate peripheral pain receptors in the C7 through T4 distribution and
may be the mechanism by which the discom ort o angina is produced. The accumulation o
local metabolites and transient abnormalities o myocyte ion transport may also precipitate
arrhythmias (see Chapter 11).
The ultimate ate o myocardium subjected to ischemia depends on the severity and duration
o the imbalance between oxygen supply and demand. It was previously thought that ischemic
cardiac injury results in either irreversible myocardial necrosis (i.e., MI) or rapid and ull recovery
o myocyte unction (e.g., a ter a brie episode o typical angina). It is now known that in addition
144
Chapter 6
to those outcomes, ischemic insults can sometimes result in a period o prolonged contractile
dys unction without myocyte necrosis, and recovery o normal unction may ultimately ollow.
For example, stunned myocardium re ers to tissue that, a ter su ering an episode o
severe acute, transient ischemia (but not necrosis), demonstrates prolonged systolic dys unction even a ter the return o normal myocardial blood f ow. In this setting, the unctional,
biochemical, and structural abnormalities ollowing ischemia are reversible and contractile
unction gradually recovers. The mechanism responsible or this delayed recovery o unction
involves myocyte calcium overload and the accumulation o oxygen-derived ree radicals during ischemia. In general, the magnitude o stunning is proportional to the degree o the preceding ischemia, and this state is likely the pathophysiologic response to an ischemic insult
that just alls short o causing irreversible necrosis.
In contrast, hibernating myocardium re ers to tissue that mani ests chronic ventricular
contractile dys unction due to a persistently reduced blood supply, usually because o multivessel CAD. In this situation, irreversible damage has not occurred and ventricular unction can promptly improve i appropriate blood f ow is restored by percutaneous or surgical
revascularization. Special “viability” imaging studies (e.g., positron emission tomography or
dobutamine echocardiography, as described in Chapter 3) o patients with CAD and contractile dys unction can di erentiate hibernating rom in arcted myocardium. That distinction
can help guide the decision o whether to undertake coronary revascularization, because
hibernating myocardium would be expected to regain contractile unction with restoration o
blood f ow, whereas in arcted myocardium would not.
Ischemic Syndromes
Depending on the underlying pathophysiologic process and the timing and severity o a myocardial
ischemic insult, a spectrum o distinct clinical syndromes may result, as illustrated in Figure 6-5.
e nd othe lia l
c e ll
A. No rmal
Iume n
• Pa te nt Iume n
• Norma l e ndothe lia l function
• P la te le t a ggre ga tion inhibite d
p la q ue
B. S table
• Lume n na rrowe d by pla que
• Ina ppropria te va s ocons triction
ang ina
C. Uns table
ang ina
p la te le ts
thromb us
• P la que rupture
• P la te le t a ggre ga tion
• Thrombus forma tion
• Unoppos e d va s ocons triction
D. Variant
ang ina
• No ove rt pla que s
• Inte ns e va s os pa s m
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FIGURE 6-5. Pathophysiologic
f ndings in anginal syndromes.
A. Normal coronary arteries are
widely patent, and the endothelium
unctions normally. B. In stable
angina, atherosclerotic plaque and
inappropriate vasoconstriction
(caused by dys unctional
endothelium) reduce the vessel
lumen’s size and coronary blood
f ow. C. In unstable angina,
disruption o the plaque triggers
platelet aggregation, thrombus
ormation, and vasoconstriction,
all o which contribute to reduced
coronary blood supply. D. In variant
angina, atherosclerotic plaques are
absent; rather, ischemia is due to
intense vasospasm that reduces
myocardial oxygen supply.
Ischemic Heart Disease
145
Stable Angina
Chronic stable angina mani ests as a pattern o predictable, transient chest discom ort during
exertion or emotional stress. It is generally caused by f xed, obstructive atheromatous plaque
in one or more coronary arteries (see Fig. 6-5B). The pattern o symptoms is usually related
to the degree o stenosis. As described in the earlier section on pathophysiology, when atherosclerotic stenoses narrow a coronary artery lumen diameter by more than approximately 70% ,
the reduced ow capacity may be su f cient to serve the low cardiac oxygen needs at rest but
is insu f cient to compensate or any signif cant increase in oxygen demand (see Fig. 6-3).
During physical exertion, or example, activation o the sympathetic nervous system results
in increased heart rate, blood pressure, and contractility, all o which augment myocardial
oxygen consumption. During the period that oxygen demand exceeds available supply, myocardial ischemia results, o ten accompanied by the chest discom ort o angina pectoris. The
ischemia and symptoms persist until the increased demand is alleviated and oxygen balance
is restored.
Potentially contributing to the inadequate oxygen supply in stable angina is inappropriate
coronary vasoconstriction caused, at least in part, by atherosclerosis-associated endothelial
dys unction. Recall that normally, the high myocardial oxygen demand during exertion is
balanced by an increased supply o blood as the accumulation o local metabolites induces
vasodilatation. With endothelial cell dys unction, however, vasodilatation is impaired and the
vessels may paradoxically vasoconstrict instead, in response to exercise-induced catecholamine stimulation o α-adrenergic receptors on the coronary artery smooth muscle cells.
As a result, the extent o coronary artery narrowing in patients with atherosclerosis is not
necessarily constant. Rather, it can vary rom moment to moment because o changes in the
superimposed coronary vascular tone. For some patients with stable angina, alterations in
tone play a minimal role in the decreased myocardial oxygen supply, and the level o physical
activity required to precipitate angina is airly constant. These patients have f xed-threshold
angina. In other cases, the degree o dynamic obstruction caused by vasoconstriction or vasospasm plays a more prominent role, and such patients may have variable-threshold angina.
For example, on a given day, a patient with variable-threshold angina can exert hersel or
himsel without chest discom ort, but on another day, the same degree o myocardial oxygen
demand does produce symptoms. The di erence re ects alterations in vascular tone over the
sites o f xed stenosis. Other clinical eatures o chronic stable angina are described in greater
detail later in the chapter.
Unstable Angina
A patient with chronic stable angina may experience a sudden increase in the tempo and
duration o ischemic episodes, occurring with lesser degrees o exertion and even at rest. This
acceleration o symptoms is known as unstable angina, which can be a precursor to an acute
MI. Unstable angina and acute MI are also known as acute coronary syndromes and result
rom specif c pathophysiologic mechanisms, most commonly rupture o an unstable atherosclerotic plaque with subsequent platelet aggregation and thrombosis (see Fig. 6-5C). These
syndromes are described in detail in Chapter 7.
Variant Angina
A small minority o patients mani est episodes o ocal coronary artery spasm in the absence
o overt atherosclerotic lesions, and this syndrome is known as variant angina or Prinzmetal
angina. In this case, intense vasospasm alone reduces coronary oxygen supply and results
in angina (see Fig. 6-5D). The mechanism by which such pro ound spasm develops is not
completely understood but may involve increased sympathetic activity in combination with
146
Chapter 6
endothelial dys unction. It is thought that many patients with variant angina may actually
have early atherosclerosis mani ested only by a dys unctional endothelium, because the
response to endothelium-dependent vasodilators (e.g., ACh and serotonin) is o ten abnormal.
Variant angina o ten occurs at rest because ischemia in this case results rom transient reduction o the coronary oxygen supply rather than an increase in myocardial oxygen demand.
Silent Ischemia
Episodes o cardiac ischemia sometimes occur in the absence o perceptible discom ort or pain,
and such instances are re erred to as silent ischemia. These asymptomatic episodes can occur
in patients who on other occasions experience typical symptomatic angina. Conversely, in some
patients, silent ischemia may be the only mani estation o CAD. It may be di f cult to diagnose
silent ischemia on clinical grounds, but its presence can be detected by laboratory techniques
such as continuous ambulatory electrocardiography or it can be elicited by exercise stress testing, as described later in the chapter. One study estimated that silent ischemic episodes occur in
40% o patients with stable symptomatic angina and in 2.5% to 10% o asymptomatic middleaged men. When considering the importance o anginal discom ort as a physiologic warning
signal, the asymptomatic nature o silent ischemia becomes all the more concerning.
The reason why some episodes o ischemia are silent whereas others are symptomatic has
not been elucidated. The degree o ischemia cannot ully explain the disparity, because even
MI may present without symptoms in some patients. Silent ischemia has been reported to be
more common among diabetic patients (possibly due to impaired pain sensation rom peripheral neuropathy), the elderly, and in women.
Syndrome X
The term syndrome X re ers to patients with typical symptoms o angina pectoris who have
no evidence o signif cant atherosclerotic coronary stenoses on coronary angiograms. Some
o these patients may show def nite laboratory signs o ischemia during exercise testing. The
pathogenesis o ischemia in this situation may be related to inadequate vasodilator reserve o
the coronary resistance vessels. It is thought that the resistance vessels (which are too small
to be visualized by coronary angiography) may not dilate appropriately during periods o
increased myocardial oxygen demand. Microvascular dys unction, vasospasm, and hypersensitive pain perception may each contribute to this syndrome. Patients with syndrome X have
a better prognosis than those with overt atherosclerotic disease.
CLINICAL FEATURES OF CHRONIC STABLE ANGINA
History
The most important part o the clinical evaluation o ischemic heart disease is the history
described by the patient. Because chest pain is such a common complaint, it is important
to ocus on the characteristics that help distinguish myocardial ischemia rom other causes
o discom ort. From a diagnostic standpoint, it would be ideal to interview and examine a
patient during an actual episode o angina, but most people are asymptomatic during routine
clinic examinations. There ore, a care ul history probing several eatures o the discom ort
should be elicited.
Quality
Angina is most o ten described as a “pressure,” “discom ort,” “tightness,” “burning,” or
“heaviness” in the chest. It is rare that the sensation is actually described as a “pain,”
and o ten a patient will correct the physician who re ers to the anginal symptom as such.
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Ischemic Heart Disease
147
Sometimes, a patient likens the sensation to “an elephant sitting on my chest.” Anginal discom ort is neither sharp nor stabbing, and it does not vary signif cantly with inspiration or
movement o the chest wall. It is a steady discom ort that lasts a ew minutes, yet rarely more
than 5 to 10 minutes. It always lasts more than a ew seconds, and this helps to di erentiate
it rom sharper and brie er musculoskeletal pains.
While describing angina, the patient may place a clenched f st over his or her sternum,
re erred to as the Levine sign, as i def ning the constricting discom ort by that tight grip.
Location
Anginal discom ort is usually diffuse rather than localized to a single point. It is most o ten
located in the retrosternal area or in the le t precordium but may occur anywhere in the chest,
back, arms, neck, lower ace, or upper abdomen. It o ten radiates to the shoulders and inner
aspect o the arms, especially on the le t side.
Accompanying Symptoms
During the discom ort o an acute anginal attack, generalized sympathetic and parasympathetic stimulation may result in tachycardia, diaphoresis, and nausea. Ischemia also results in
transient dys unction o LV systolic contraction and diastolic relaxation. The resultant elevation o LV diastolic pressure is transmitted to the pulmonary vasculature and o ten causes
dyspnea during the episode. Transient fatigue and weakness are also common, particularly in
elderly patients. When such symptoms occur as a consequence o myocardial ischemia but
are unaccompanied by typical chest discom ort, they are re erred to as “anginal equivalents.”
Precipitants
Angina, when not caused by pure vasospasm, is precipitated by conditions that increase myocardial oxygen demand (e.g., increased heart rate, contractility, or wall stress). These include
physical exertion, anger, and other emotional excitement. Additional actors that increase myocardial oxygen demand and can precipitate anginal discom ort in patients with CAD include
a large meal or cold weather. The latter induces peripheral vasoconstriction, which in turn
augments myocardial wall stress as the le t ventricle contracts against the increased resistance.
Angina is generally relieved within minutes a ter the cessation o the activity that precipitated it and even more quickly (within 3 to 5 minutes) by sublingual nitroglycerin. This
response can help di erentiate myocardial ischemia rom many o the other conditions that
produce chest discom ort.
Patients who experience angina primarily due to increased coronary artery tone or vasospasm o ten develop symptoms at rest, independent o activities that increase myocardial
oxygen demand.
Frequency
Although the level o exertion necessary to precipitate angina may remain airly constant,
the requency o episodes varies considerably because patients quickly learn which activities
cause their discom ort and avoid them. It is thus important to inquire about reductions in
activities o daily living when taking the history.
Risk Factors
In addition to the description o chest discom ort, a care ul history should uncover risk actors that predispose to atherosclerosis and CAD, including cigarette smoking, dyslipidemia,
hypertension, diabetes, and a amily history o premature coronary disease (see Chapter 5).
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Chapter 6
Differential Diagnosis
Several conditions can give rise to symptoms that mimic the transient chest discom ort o
angina pectoris, including other cardiac causes (e.g., pericarditis), gastrointestinal disorders (e.g., gastroesophageal re ux, peptic ulcer disease, esophageal spasm, or biliary pain),
and musculoskeletal conditions (including chest wall pain, spinal osteoarthritis, and cervical radiculitis). The history remains o paramount importance in distinguishing myocardial ischemia rom these disorders. In contrast to angina pectoris, gastrointestinal causes o
recurrent chest pain are o ten precipitated by certain oods and are unrelated to exertion.
Musculoskeletal causes o chest discom ort tend to be more superf cial or can be localized
to a discrete spot (i.e., the patient can point to the pain with one f nger) and o ten vary
with changes in position. Similarly, the presence o pleuritic pain (sharp pain aggravated by
respiratory movements) argues against angina as the cause; this symptom is more likely a
result o pericarditis, or an acute pulmonary condition such as pulmonary embolism or acute
pneumothorax. Use ul di erentiating eatures o recurrent chest pain are listed in Table 6-2.
TABLE 6-2 Causes of Recurrent Chest Pain
Condition
Cardiac
Myocardial ischemia
Pericarditis
Gastrointestinal
Gastroesophageal ref ux
Peptic ulcer disease
Esophageal spasm
Biliary colic
Musculoskeletal
Costochondral syndrome
Cervical radiculitis
Differentiating Features
• Retrosternal tightness or pressure; typically radiates to the neck, jaw,
or le t shoulder and arm
• Lasts a ew minutes (usually < 10)
• Brought on by exertion, relieved by rest or nitroglycerin
• ECG: transient ST depressions or elevations, or f attened or inverted
T waves
• Sharp, pleuritic pain that varies with position; riction rub may be
present on auscultation
• Can last or hours to days
• ECG: di use ST elevations and PR deviation (see Chapter 14)
• Retrosternal burning
• Precipitated by certain oods, worsened by supine position, una ected by exertion
• Relieved by antacids
• Epigastric ache or burning
• Occurs a ter meals, una ected by exertion
• Relieved by antacids, not by nitroglycerin
• Retrosternal pain accompanied by dysphagia
• Precipitated by meals, una ected by exertion
• May be relieved by nitroglycerin
• Constant, deep pain in right upper quadrant; can last or hours
• Brought on by atty oods, una ected by exertion
• Not relieved by antacids or nitroglycerin
•
•
•
•
•
Sternal pain worsened by chest movement
Costochondral junctions tender to palpation
Relieved by anti-inf ammatory drugs, not by nitroglycerin
Constant ache or shooting pains, may be in a dermatomal distribution
Worsened by neck motion
ECG, electrocardiogram.
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Ischemic Heart Disease
149
Physical Examination
I it is possible to examine a patient during an anginal attack, several transient physical signs
may be detected (Fig. 6-6). An increased heart rate and blood pressure are common because
o the augmented sympathetic response. Myocardial ischemia may lead to papillary muscle
dys unction and there ore mitral regurgitation. Ischemia-induced regional ventricular contractile abnormalities can sometimes be detected as an abnormal bulging impulse on palpation
o the le t chest. Ischemia decreases ventricular compliance, producing a sti ened ventricle
and there ore an S4 gallop on physical examination during atrial contraction (see Chapter 2).
However, i the patient is ree o chest discom ort during the examination, there may be no
abnormal cardiac physical f ndings.
Physical examination should also assess or signs o atherosclerotic disease in more accessible vascular beds. For example, carotid bruits may indicate the presence o cerebrovascular
disease, whereas emoral artery bruits or diminished pulses in the lower extremities can be a
clue to peripheral arterial disease (see Chapter 15).
Diagnostic Studies
Once angina is suspected, several diagnostic procedures may be help ul in conf rming myocardial ischemia as the cause. Because many o these tests are costly, it is important to choose
the appropriate studies or each patient.
Electrocardiogram
One o the most use ul tools is an electrocardiogram (ECG) obtained during an anginal episode. Although this is easy to arrange when symptoms occur in hospitalized patients, it may
not be possible to “catch” episodes in people seen on an outpatient basis. During myocardial
ischemia, ST-segment and T-wave changes can appear (Fig. 6-7). Acute ischemia usually
results in transient horizontal or downsloping ST-segment depressions and T-wave attening
or inversions. Occasionally, ST-segment elevations are seen, suggesting more severe transmural myocardial ischemia, and can also be observed during the intense vasospasm o variant
angina. In contrast to the ECG o a patient with an acute MI, the ST deviations seen in patients
with stable angina quickly normalize with resolution o the patient’s symptoms. In act,
Myoca rdia l Is che mia
S ys tolic
function
Dia s tolic
complia nce
P a pilla ry mus cle
dys function
S4
Mitra l
re gurgita tion
S ympa the tic
tone
P ulmona ry
conge s tion
Dys kine tic
a pica l
impuls e
Ra le s
Dia phore s is
He a rt ra te
Blood pre s s ure
FIGURE 6-6. Pathophysiology of physical signs during acute myocardial ischemia.
150
Chapter 6
Norma l
S ube ndoca rdia l is che mia
ST de pre s s ion
(horizonta l)
ST de pre s s ion
(downs loping)
Tra ns mura l
is che mia
T wave
inve rs ion
ST e leva tion
FIGURE 6-7. Common transient ECG abnormalities during ischemia. Subendocardial ischemia causes
ST-segment depressions and/ or T-wave f attening or inversions. Severe transient transmural ischemia can result
in ST-segment elevations, similar to the early changes in acute myocardial in arction. When transient ischemia
resolves, so do the electrocardiographic changes.
ECGs obtained during periods ree o ischemia are completely normal in approximately hal
o patients with stable angina. In others, chronic “nondiagnostic” ST and T-wave deviations
may be present. Evidence o a previous MI (e.g., pathologic Q waves) on the ECG also points
to the presence o underlying coronary disease.
Stress Testing
Because ECGs obtained during or between episodes o chest discom ort may be normal, such
tracings do not rule out underlying ischemic heart disease. For this reason, provocative exercise or pharmacologic stress tests are valuable diagnostic and prognostic aids.
Standard Exercise Testing
For many patients suspected o having CAD, a standard exercise test is per ormed. During
this test, the patient exercises on a treadmill or a stationary bicycle to progressively higher
workloads and is observed or the development o chest discom ort or excessive dyspnea.
The heart rate and ECG are continuously monitored, and blood pressure is checked at regular
intervals. The test is continued until angina develops, signs o myocardial ischemia appear
on the ECG, a target heart rate is achieved (85% o the maximal predicted heart rate [MHR];
the MHR is calculated as 220 beats/ min minus the patient’s age), or the patient becomes too
atigued to continue.
The test is considered abnormal i the patient’s typical chest discom ort is reproduced or
i ECG abnormalities consistent with ischemia develop (i.e., greater than 1 mm horizontal or
downsloping ST-segment depressions). Among patients who later undergo diagnostic coronary angiography, the ECG changes noted above have a sensitivity o approximately 65% to
70% and specif city o 75% to 80% or the detection o anatomically signif cant CAD.
The stress test is considered markedly positive i one or more o the ollowing signs o
severe ischemic heart disease occur: (1) ischemic ECG changes develop in the f rst 3 minutes o exercise or persist 5 minutes a ter exercise has stopped; (2) the magnitude o the
ST-segment depressions is greater than 2 mm; (3) the systolic blood pressure abnormally alls
during exercise (i.e., resulting rom ischemia-induced impairment o contractile unction);
(4) high-grade ventricular arrhythmias develop; or (5) the patient cannot exercise or at least
2 minutes because o cardiopulmonary limitations. Patients with markedly positive tests are
more likely to have severe multivessel coronary disease.
The utility o a stress test may be a ected by the patient’s medications. For example,
β-blockers or certain calcium channel blockers (verapamil, diltiazem) may blunt the ability to
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Ischemic Heart Disease
151
achieve the target heart rate. In these situations, one must consider the purpose o the stress
test. I it is to determine whether ischemic heart disease is present, then those medications
are typically withheld or 24 to 48 hours be ore the test. On the other hand, i the patient has
known ischemic heart disease and the purpose o the test is to assess the e f cacy o the current medical regimen, testing should be per ormed while the patient takes his or her usual
antianginal medications.
Nuclear Imaging Studies
Since a standard exercise test relies on ischemia-related changes on the ECG, the test is
less use ul in patients with baseline abnormalities o the ST segments (e.g., as seen in le t
bundle branch block or LV hypertrophy). In addition, the standard exercise stress test sometimes yields equivocal results in patients or whom the clinical suspicion o ischemic heart
disease is high. In these situations, radionuclide imaging can be combined with exercise
testing to overcome these limitations and to increase the sensitivity and specif city o the
study.
As described in Chapter 3, during such myocardial per usion imaging, a radionuclide
(commonly either a technetium-99m–labeled compound or thallium-201) is injected intravenously at peak exercise, a ter which imaging is per ormed. The radionuclide accumulates in
proportion to the degree o per usion o viable myocardial cells. There ore, areas o poor perusion (i.e., regions o ischemia) during exercise do not accumulate radionuclide and appear
as “cold spots” on the image. However, irreversibly in arcted areas also do not take up the
radionuclide, and they too will appear as cold spots. To di erentiate between transient ischemia and in arcted tissue, imaging is also per ormed at rest (either be ore or several hours
a ter the exercise portion o the test). I the cold spot f lls in, a region o transient ischemia
has been identif ed (Fig. 3-18). I the cold spot remains unchanged, a region o irreversible
infarction is likely.
Standard radionuclide exercise tests are 80% to 90% sensitive and approximately 80%
specif c or the detection o clinically signif cant CAD. Positron emission tomography (PET;
see Chapter 3), another orm o nuclear stress imaging that is not as widely available, o ers
superior spatial and temporal resolution, with sensitivity and specif city o 90% or greater.
Because these nuclear imaging techniques are expensive, their use in screening or CAD
should be reserved or (1) patients in whom baseline ECG abnormalities preclude interpretation o a standard exercise test or or (2) improvement in test sensitivity when standard stress
test results are discordant with the clinical suspicion o coronary disease.
Exercise Echocardiography
Exercise testing with echocardiographic imaging is another technique to diagnose myocardial
ischemia in patients with baseline ST or T-wave abnormalities or in those with equivocal standard stress tests. In this procedure, LV contractile unction is assessed by echocardiography
at baseline and immediately a ter treadmill or bicycle exercise. The test indicates inducible
myocardial ischemia i regions o ventricular contractile dys unction develop with exertion
and has a sensitivity o approximately 80% and a specif city o about 90% or the detection
o clinically signif cant CAD.
Pharmacologic Stress Tests
For patients unable to exercise (e.g., those with hip or knee arthritis), pharmacologic stress
testing can be per ormed instead using various agents, including vasodilators or inotropes.
The most common approach is to use a coronary vasodilator such as adenosine, regadenoson,
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Chapter 6
or dipyridamole. Adenosine and regadenoson bind to adenosine A2a receptors on vascular
smooth muscle cells, resulting in coronary vasodilatation. As ischemic regions are already
maximally dilated (in compensation or the epicardial coronary stenoses), the vasodilatation
induced by these agents increases ow to the myocardium per used by healthy coronary
arteries and thus “steals” blood away rom the diseased segments. Dipyridamole causes a
similar e ect indirectly, as it blocks normal cellular uptake and destruction o adenosine,
thereby increasing adenosine’s circulating concentration and subsequent stimulation o the
A2a receptor. Administration o these pharmacologic agents is typically coupled with nuclear
imaging, to reveal regions o impaired myocardial per usion.
An alternative to vasodilating agents, pharmacologic stress testing can also be per ormed
using the inotrope dobutamine, which increases myocardial oxygen demand by augmenting heart rate and the orce o contraction, thus simulating some o the e ects o exercise.
Accompanying imaging (typically nuclear imaging or echocardiography) reveals regions o
drug-induced ischemia. Vasodilator pharmacologic stress testing is generally pre erred over
dobutamine testing or the assessment o ischemia, as the ormer produces greater incremental myocardial blood ow, and is technically easier and aster to per orm. However, the
vasodilator agents can cause bronchospasm in patients with reactive airways disease (by
stimulating bronchiolar adenosine A2b receptors) and should be avoided in that population,
in whom dobutamine pharmacologic testing is there ore pre erred. In addition, a vasodilator
study cannot be per ormed success ully in a patient who has been exposed to methylxanthines (e.g., ca eine consumption or use o the bronchodilator theophylline) on the day o
the study, as such agents competitively antagonize adenosine’s interaction with its receptor
and blunt its e ect.
Coronary Angiography
The most direct m eans o identi ying coronary artery stenoses is by coronary angiography, in which atherosclerotic lesions are visualized radiographically ollowing the
injection o radiopaque contrast material into the artery (Fig. 6-8; also see Chapter 3).
Although gen erally sa e, th e procedu re is associated with a small risk o complications directly related to its invasive nature. There ore, coronary angiography is typically
reserved or patients whose anginal symptoms do
not respond adequately to pharm acologic th erapy,
or those with an u nstable presentation , or when
the resu lts o non in vasive testin g are so abn ormal
that severe CAD warran ting revascu larization is
likely.
When the degree o stenosis o a region o intracoronary plaque, or its hemodynamic signif cance,
is not clear, additional techniques can be applied in
the cardiac catheterization laboratory. For example,
ractional f ow reserve (FFR) measurement is a
technique that can assess the unctional severity o a
stenosis identif ed at angiography. A special manometer-tipped guidewire inserted through the catheter
measures the pressure in the coronary artery distal to
the stenosis during induced vasodilatation. The FFR
FIGURE 6-8. Example of coronary angiography.
value is equal to the pressure distal to the stenosis
Injection of the right coronary artery demonstrates a
(P d ) relative to the pressure proximal to the stenosis
stenosis in the midportion of the vessel, indicated by
in the aorta (Pao ).
the arrow. (Courtesy of Pinak B. Shah, MD, Brigham
and Women’s Hospital, Boston, MA.)
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FFR = Pd / Pao
Ischemic Heart Disease
153
A higher FFR value indicates a less severe stenosis. FFR values less than 0.75 to 0.80 identi y severe stenoses that typically warrant mechanical intervention.
Although coronary angiography is considered the “gold standard” or the diagnosis o
CAD, it should be noted that it provides only anatomic in ormation. The clinical signif cance o lesions detected by angiography depends on both the degree o narrowing and
also on the pathophysiologic consequences. There ore, treatment decisions are made not
only on the f nding o such stenoses but also by their unctional e ects, mani ested by the
patient’s symptoms, the viability o the myocardial segments served by stenotic vessels, and
the degree o ventricular contractile dys unction. Furthermore, standard arteriography does
not reveal the composition o coronary atherosclerotic plaque or its vulnerability to rupture
(see Chapter 5).
Noninvasive Imaging of Coronary Arteries
Diagnostic alternatives to coronary angiography have been developed to noninvasively visualize the coronary arteries. Coronary CT angiography (CCTA) per ormed with administration o
intravenous contrast (see Fig. 3.21) can visualize stenoses o greater than 50% o the coronary
lumen with an approximate sensitivity o 90% and specif city o 65% to 90% . CCTA is considered an alternative to stress testing to help exclude signif cant CAD in low- to intermediaterisk patients who present with undef ned chest pain. The quality o images in CCTA is limited
by cardiac motion, which can be reduced by slowing the heart rate with administration o a
beta-blocker.
Cardiac CT without contrast administration can be used as a screening test to detect coronary artery calcif cation (CAC) as described in Chapter 3. CAC correlates with the extent o
atherosclerosis and thus estimates plaque burden, but does not quanti y individual coronary
stenoses. The absence o CAC is a clinically use ul f nding as it strongly predicts the absence
o CAD.
Natural History
The patient with chronic angina may show no change in a stable pattern o ischemia or many
years. In some patients, however, the course may be punctuated by the occurrence o unstable
angina, MI, or sudden cardiac death. These complications are o ten related to acute thrombosis at the site o disrupted atherosclerotic plaque (see Chapter 7). Why some patients, but
not others, sustain these complications remains a subject o intense clinical and basic science
investigation and may relate to the vulnerability o plaque to rupture.
The mortality associated with CAD has declined signif cantly in recent decades: the ageadjusted death rate has allen by more than 50% . This is likely related to (1) atherosclerotic
risk reduction through improved li estyle changes (e.g., less tobacco use, less dietary at
consumption, and more exercise); (2) improved therapeutic strategies and longevity ollowing acute coronary syndromes (see Chapter 7); and (3) advances in the pharmacologic and
mechanical therapies or chronic CAD.
TREATMENT
The goals o therapy in chronic ischemic heart disease are to decrease the requency o anginal attacks, to prevent acute coronary syndromes such as MI, and to prolong survival. A longterm crucial step is to address the risk actors that led to the development o atherosclerotic
coronary disease. Data convincingly demonstrate the benef t o smoking cessation, cholesterol
improvement, and blood pressure control in lowering the risk o coronary disease events (see
Chapter 5). Improvements in other risk actors or CAD, including serum glucose in diabetics,
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Chapter 6
obesity and physical inactivity, may also reduce the risk o adverse outcomes although the
benef ts o these interventions are less well documented.
The ollowing sections describe medical and surgical strategies to (1) reduce ischemia and
its symptoms by restoring the balance between myocardial oxygen supply and demand and
(2) prevent acute coronary syndromes and death in patients with chronic CAD.
Medical Treatment of an Acute Episode of Angina
When experiencing acute angina, the patient should cease physical activity. Sublingual nitroglycerin, an organic nitrate, is the drug o choice in this situation. Placed under the tongue,
this medication produces a slight burning sensation as it is absorbed through the mucosa, and
it begins to take e ect in 1 to 2 minutes. Nitrates relieve ischemia primarily through vascular
smooth muscle relaxation, particularly venodilatation. Venodilatation reduces venous return
to the heart, with a subsequent decline in LV volume (a determinant o wall stress). The latter decreases myocardial oxygen consumption, thus helping to restore oxygen balance in the
ischemic heart.
A second action o nitrates is to dilate the coronary vasculature, with subsequent augmentation o coronary blood ow. This e ect may be o little value in patients with angina
in whom maximal coronary dilatation has already resulted rom the accumulation o local
metabolites. However, when coronary vasospasm plays a role in the development o ischemia,
nitrate-induced coronary vasodilatation may be particularly benef cial.
Medical Treatment to Prevent Recurrent Ischemic Episodes
Pharmacologic agents are also the f rst line o de ense in the preven tion o anginal attacks.
The goal o these agents is to decrease the cardiac workload (i.e., reduce myocardial oxygen demand) and to increase myocardial per usion. The three classes o medications most
commonly used are β-adrenergic blockers, organic nitrates, and calcium channel blockers
(Table 6-3).
β-Blockers (see Chapter 17) exert their antianginal e ect primarily by reducing myocardial oxygen demand. They are directed against β-receptors, o which there are two classes:
β1-adrenergic receptors are restricted to the myocardium, whereas β2-adrenergic receptors are located throughout the blood vessels and the bronchial tree. The stimulation o
β1-receptors by endogenous catecholamines and exogenous sympathomimetic drugs
increases heart rate and contractility. Consequently, β-adrenergic a n ta gon ists decrease the
orce o ventricular contraction and heart rate, thereby relieving ischemia by reducing myocardial oxygen demand. In addition, slowing the heart rate may benef t myocardial oxygen
supply by augmenting the time spent in diastole, the phase when coronary per usion primarily occurs.
In addition to suppressing angina, several studies have shown that β-blockers decrease the
rates o recurrent in arction and mortality ollowing an acute MI (see Chapter 7). Moreover,
they have been shown to reduce the likelihood o an initial MI in patients with hypertension.
Thus, β-blockers are f rst-line chronic therapy in the treatment o CAD.
β-Blockers are generally well tolerated but have several potential side e ects. For example, they may precipitate bronchospasm in patients with underlying asthma by antagonizing
β2-receptors in the bronchial tree. Although β1-selective blockers are theoretically less likely to
exacerbate bronchospasm in such patients, drug selectivity or the β1-receptor is not complete,
and in general, all β-blockers should be used cautiously, or avoided, in patients with signif cant obstructive airway disease.
β-Blockers are also generally not used in patients with acutely decompensated LV dysunction because they could intensi y heart ailure symptoms by urther reducing inotropy.
(However, as described in Chapter 9, β-blockers actually improve outcomes in patients with
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Ischemic Heart Disease
TABLE 6-3
Pharmacologic Agents Used in the Prevention and Treatment
of Angina
Drug Class
Mechanism of Action
Adverse Effects
Organic nitrates
↓ Myocardial O2 demand
↓ Preload (venodilatation)
↑ O2 supply
↑ Coronary per usion
↓ Coronary vasospasm
↓ Myocardial O2 demand
↓ Contractility
↓ Heart rate
• Headache
• Hypotension
• Ref ex tachycardia
β-Blockers
Calcium channel blockers (agent
speci c; see ootnote)
Ranolazine
155
↓ Myocardial O2 demand
↓ Preload (venodilatation)
↓ Wall stress (↓BP)
↓ Contractility (V, D)
↓ Heart rate (V, D)
↑ O2 supply
↑ Coronary per usion
↓ Coronary vasospasm
↓ Late phase inward
sodium current
•
•
•
•
•
•
•
•
•
•
Excessive bradycardia
↓ LV contractile unction
Bronchoconstriction
May mask hypoglycemic
symptoms
Fatigue
Headache, f ushing
↓ LV contractility (V, D)
Marked bradycardia (V, D)
Edema (especially N, D)
Constipation (especially V)
• Dizziness, headache
• Constipation, nausea
BP, blood pressure; D, diltiazem; LV, le t ventricular; N, ni edipine and other dihydropyridine calcium channel
antagonists; V, verapamil.
stable chronic heart failure conditions.) β-Blockers are also relatively contraindicated in
patients with marked bradycardia or certain types of heart block to avoid additional impairment of electrical conduction.
β-Blockers sometimes cause fatigue and sexual dysfunction. They should be used with
caution in insulin-treated diabetic patients because they can mask tachycardia and other
catecholamine-mediated responses that can warn of hypoglycemia. One might also expect
that β-blockers would decrease myocardial blood perfusion by blocking the vasodilating β2adrenergic receptors of the coronary arteries. However, this effect is usually attenuated by
autoregulation and vasodilatation of the coronary vessels owing to the accumulation of local
metabolites.
Organic nitrates (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate), as previously mentioned, relieve ischemia primarily through venodilatation (i.e., lower wall stress
results from a smaller ventricular radius) and possibly through coronary vasodilatation. The
organic nitrates are the oldest of the antianginal drugs and come in several preparations (also
described in Chapter 17). Sublingual nitroglycerin tablets or sprays are used in the treatment
of acute attacks because of their rapid onset of action. In addition, when taken immediately
before a person engages in activities known to provoke angina, these rapidly acting nitrates
are useful as prophylaxis against anginal attacks.
Longer-acting anginal prevention can be achieved through a variety of nitrate preparations, including oral tablets of isosorbide dinitrate (or mononitrate) or a transdermal nitroglycerin patch, which is applied once a day. A limitation to chronic nitrate therapy is the
development of drug tolerance (i.e., decreased effectiveness of the drug during continued
156
Chapter 6
administration), which occurs to some degree in most patients. This undesired e ect can be
overcome by providing a nitrate- ree interval or several hours each day, usually while the
patient sleeps.
There is no evidence that nitrates improve survival or prevent in arctions in patients
with chronic CAD, and they are used purely or symptomatic relie . Common side e ects
include headache, light-headedness, and palpitations induced by vasodilatation and re ex
sinus tachycardia. The latter can be prevented by combining a β-blocker with the nitrate
regimen.
Calcium channel blockers (see Chapter 17) antagonize voltage-gated L-type calcium
channels, but the actions o the individual drugs o this group vary. The dihydropyridines
(e.g., ni edipine and amlodipine) are potent vasodilators. They relieve myocardial ischemia
by (1) decreasing oxygen demand (venodila ta tion reduces ventricular f lling and size, a rteria l dila tion reduces the resistance against which the le t ventricle contracts, and both
actions reduce wall stress) and (2) increasing myocardial oxygen supply via coronary dilatation. By the latter mechanism, they are also potent agents or the relie o coronary artery
vasospasm.
Nondihydropyridine calcium channel blockers (verapamil and diltiazem) also act as vasodilators but are not as potent in this regard as the dihydropyridines. However, these agents
have additional benef cial antianginal e ects stemming rom their more potent cardiac depressant actions: they reduce the orce o ventricular contraction (contractility) and slow the heart
rate. Accordingly, verapamil and diltiazem also decrease myocardial oxygen demand by these
mechanisms.
Questions have been raised about the sa ety o short-acting calcium channel–blocking
drugs in the treatment o ischemic heart disease. In meta-analyses o randomized trials, these
drugs have been associated with an increased incidence o MI and mortality. The adverse
e ect may relate to the rapid hemodynamic e ects and blood pressure swings induced by the
short-acting agents. There ore, only long-acting calcium channel blockers (i.e., preparations
taken once a day) are recommended in the treatment o chronic angina, generally as secondline drugs i symptoms are not controlled by β-blockers and nitrates.
The three standard groups o antianginal drugs described in this section can be used
alone or in combination. However, care should be taken in combining a β-blocker with a
nondihydropyridine calcium channel blocker (verapamil or diltiazem) because the additive
negative chronotropic e ect can cause excessive bradycardia and the combined negative
inotropic e ect could precipitate heart ailure in patients with LV contractile dys unction.
Ranolazine, a ourth type o anti-ischemic therapy, has been shown to decrease the requency o anginal episodes and improve exercise capacity in patients with chronic CAD but
di ers rom other anti-ischemic drugs in that it does not a ect the heart rate or blood pressure. Although its mechanism o action has not been ully elucidated, it is believed to inhibit
the late phase o the action potential’s inward sodium current (INa + ) in ventricular myocytes.
That late phase tends to be abnormally enhanced in ischemic myocardium, and the associated increased sodium in ux results in higher-than-normal intracellular Ca + + (mediated by
the trans-sarcolemmal Na + –Ca + + exchanger; see Fig. 1.10). Such calcium overload is thought
to result in impaired diastolic relaxation and contractile ine f ciency. Inhibition o the late INa +
by ranolazine counters these pathologic e ects. Clinical studies have supported ranolazine’s
e ectiveness in reducing angina, and its long-term sa ety, when used alone or in combination
with other antianginal agents.
Although use ul in controlling symptoms o angina, none o the antianginal drug groups
has been shown to slow or reverse the atherosclerotic process responsible or the arterial
lesions o chronic CAD. Moreover, although β-blockers have demonstrated mortality benef ts
in patients a ter MI, none o these agents has been shown to improve longevity in patients
with chronic stable angina and preserved LV unction.
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Ischemic Heart Disease
157
Medical Treatment to Prevent Acute Cardiac Events
Platelet aggregation and thrombosis are key elements in the pathophysiology o acute MI and
unstable angina (see Chapter 7). Antiplatelet therapy reduces the risk o these acute coronary syndromes in patients with chronic angina and should be a standard part o the regimen
used to treat CAD. For example, aspirin has antithrombotic actions through the inhibition
o synthesis o thromboxane A2, a mediator o platelet activation and aggregation, as well
as anti-in ammatory properties that may be important in stabilizing atheromatous plaque.
Unless contraindications are present (e.g., allergy or gastric bleeding), aspirin should be continued indef nitely in all patients with CAD.
Platelet P2Y12 ADP receptor antagonists, such as clopidogrel, also prevent platelet activation and aggregation (see Chapter 17). They can be used as an antiplatelet substitute in
patients who are allergic to aspirin. In addition, the combination o aspirin and a P2Y12 inhibitor is superior to aspirin alone in reducing death and ischemic complications in patients
with acute coronary syndromes, in those undergoing elective percutaneous coronary stenting, and in patients with a history o MI.
Lipid-regulating therapy is an additional approach to reduce cardiovascular clinical
events in patients with CAD. In particular, HMG-CoA reductase inhibitors (“statins”) lower
MI and death rates in patients with established coronary disease and in those at high risk
o developing CAD. The benef ts o statin therapy are believed to extend beyond their lipidaltering e ects, because there is evidence that they decrease vascular in ammation and
improve endothelial cell dys unction and thus may help stabilize atherosclerotic plaques.
Moreover, trials o patients with established atherosclerotic disease have demonstrated a
linear relationship between the magnitude o LDL lowering and the reduction in cardiovascular risk. Thus, high-in ten sity lipid lowering (resulting in reduction o LDL by more than
50% ) is superior to less intense lipid-lowering therapy in preventing uture ischemic events
and cardiovascular death. An LDL less than 70 mg/ dL is a common goal or patients with
CAD, and recent evidence suggests that even patients with a baseline LDL o 70 mg/ dL
benef t rom high-intensity lipid lowering. As a result, current national guidelines no longer recommend treating to a specif c target LDL level. Rather, it is recommended that all
patients with CAD receive a high-intensity statin regimen, with the goal o at least 50%
reduction in LDL.
Angiotensin-converting enzyme (ACE) inhibitors, benef cial in the treatment o hypertension (see Chapter 13), heart ailure (see Chapter 9), and ollowing MI (see Chapter 7), have
also been studied as chronic therapy or patients with stable CAD not complicated by heart
ailure. Some (but not all) o these trials have shown reduced rates o death, MI, and stroke.
Thus, many cardiologists recommend that an ACE inhibitor be included in the medical regimen o patients with chronic CAD.
Revascularization
Patients with angina that becomes asymptomatic during pharmacologic therapy are usually
monitored by their physicians with continued emphasis on cardiac risk actor reduction.
However, coronary revascularization is pursued i (1) the patient’s symptoms o angina do not
respond adequately to antianginal drug therapy, (2) unacceptable side e ects o medications
occur, or (3) the patient is ound to have high-risk coronary disease or which revascularization is known to improve survival (as described in the next section). The two techniques used
to accomplish mechanical revascularization are percutaneous coronary intervention (PCI)
and coronary artery bypass gra t (CABG) surgery.
PCI includes percutaneous transluminal coronary angioplasty (PTCA), a procedure perormed under uoroscopy in which a balloon-tipped catheter is inserted through a peripheral
artery (usually emoral, radial, or brachial) and maneuvered into the stenotic segment o a
158
Chapter 6
coronary vessel. The balloon at the end o the catheter is then in ated under high pressure
to dilate the stenosis, a ter which the balloon is de ated and the catheter is removed rom
the body. The improvement in the size o the coronary lumen increases coronary per usion
and myocardial oxygen supply. E ective dilatation o the stenosis results rom compression
o the atherosclerotic plaque and o ten by creating a racture within the lesion and stretching
the underlying media. The risk o MI during the procedure is less than 1.5% , and mortality is
less than 1% . Un ortunately, approximately one third o patients who undergo balloon angioplasty develop recurrent symptoms within 6 months owing to restenosis o the dilated artery
and require additional coronary interventions.
For this reason, coronary stents were developed or implantation at the time o PCI, and
have been shown to signif cantly reduce the rate o restenosis. Such stents are slender, cagelike metal support devices that in their collapsed conf guration can be threaded into the
region o stenosis by a catheter. Once in position, the stent is expanded into its open position by in ating a high-pressure balloon in its interior (Fig. 6-9). The balloon and attached
catheter are then removed, but the stent is le t permanently in place to serve as a sca old to
maintain arterial patency. Because stents are thrombogenic, a combination o oral antiplatelet
agents (commonly, aspirin plus a platelet P2Y12 receptor antagonist, such as clopidogrel) is
crucial a ter stent implantation.
Compared with conventional balloon angioplasty, stent implantation decreases restenosis
rates and reduces the need or repeat PCIs. Although restenosis resulting rom vessel elastic
recoil is greatly diminished by standard metal stent placement, neointimal proli eration (i.e.,
migration o smooth muscle cells and production o extracellular matrix) remains an important cause o in-stent restenosis and recurrent anginal symptoms.
To address the problem o in-stent restenosis a ter PCI, drug-eluting stents were devised.
These special stents are abricated with a polymer coat that incorporates an antiproli erative
medication such as sirolimus (an immunosuppressive agent that inhibits T-cell activation),
everolimus (an immunosuppressive similar to sirolimus), or paclitaxel (which inter eres with
cellular microtubule unction). The medication is released rom the stent over a period o
2 to 4 weeks, and this approach has shown great e ect at preventing neointimal proli eration
Arte ry wa ll
Ba lloon
ca the te r
A
B
C
S te nos is
S te nt in
colla ps e d
configura tion
Ba lloon infla tion to expa nd s te nt
FIGURE 6-9. Placement of a coronary artery stent.
A. A stent, in its original collapsed state, is advanced into
the coronary stenosis on a balloon catheter. B. The balloon
is inf ated to expand the stent. C. The balloon is def ated,
and the catheter is removed rom the body, leaving the
stent permanently in place.
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Ischemic Heart Disease
159
and reducing the need or repeat revascularization by
more than hal . However, just as neointimal proli eraInte rna l
tion is slowed, so too is protective endothelialization
ma
mma
ry
Aorta
o the stent. The delay in endothelial cell coverage o
a rte ry gra ft
the metal struts leaves patients at risk or thrombus
SVC
Pulmona ry
ormation within the stent should antiplatelet agents
a
rte
ry
S a phe nous
be discontinued prematurely. There ore, prolonged
ve in gra ft
courses o combination antiplatelet therapy (e.g., aspiLCx
rin plus a platelet P2Y12 receptor antagonist or at least
RCA
12 months) ollowed by aspirin indef nitely are necesLAD
sary or patients who receive drug-eluting stents.
Although percutaneous revascularization techniques are generally superior to standard medical
therapy or relie o angina, it is important to note that
in the setting o stable coronary disease (i.e., not an
Obs tructing
acute coronary syndrome), they have not been shown
pla que
to reduce the risk o MI or death.
FIGURE 6-10. Coronary artery bypass surgery. Two
CABG surgery entails gra ting portions o a
types of bypasses are illustrated: (1) the left internal
patient’s native blood vessels to bypass obstructed
mammary artery originates from the left subclavian
coronary arteries. Two types o surgical gra ts are used
artery, and in this schematic, it is anastomosed to the
(Fig. 6-10). The f rst employs native veins—typically, a
left anterior descending (LAD) coronary artery distal
section o the saphenous vein (a “super uous” vessel
to obstructing plaque; (2) one end of a saphenous
vein graft is sutured to the proximal aorta and the
removed rom the leg) that is sutured rom the base
other end to the right coronary artery (RCA) distal to
o the aorta to a coronary segment downstream rom
a stenotic segment.
the region o stenosis. The second method uses arterial
gra ts—most commonly, an internal mammary artery
(IMA, a “super uous” branch o each subclavian artery)—that can be directly anastomosed
distal to a stenotic coronary site. Vein gra ts have a patency rate o up to 80% at 12 months
but are vulnerable to accelerated atherosclerosis; 10 years a ter surgery, more than 50% have
occluded. In contrast, IMA gra ts are more resistant to atherosclerosis with a patency rate o
90% at 10 years. There ore, IMA gra ts are o ten used to per use sites o critical ow such as
the le t anterior descending artery. Clinical trial evidence supports the use o aggressive lipidlowering drug therapy a ter CABG to improve the long-term patency rates o bypass gra ts.
In recent years, less invasive surgical alternatives to conventional CABG have been
explored. These include “minimally invasive” operations with smaller incisions, the use o
transcutaneous ports with videoscopic robotic assistance, and “o -pump” procedures, which
avoid the use o cardiopulmonary bypass (heart–lung) machines. While there are theoretical
advantages o avoiding the latter, studies examining o -pump procedures in comparison with
standard CABG have shown comparable mortality benef t, but poorer gra t patency over time
and an increased need or uture revascularization. Additionally, there have been no major
high-quality studies comparing benef ts o minimally invasive operations to conventional
CABG. In general, patient-specif c risks and characteristics are considered by the surgeon
when selecting which type o bypass procedure to undertake.
Medical versus Revascularization Therapy
Many patients with chronic, stable angina can be success ully managed with pharmacologic
therapy alone. However, i anginal symptoms prove re ractory despite maximal pharmacologic
therapy, or i intolerable drug side e ects develop, coronary angiography is recommended or
urther therapeutic planning. Moreover, or patients whose angina is controlled by medications, it is standard to per orm noninvasive testing (e.g., exercise testing, echocardiography)
to identi y those with high-risk disease, because the long-term prognosis or such patients can
160
Chapter 6
TABLE 6-4 Coronary Revascularization Procedures
Percutaneous Coronary Interventions ( PCI)
Coronary Artery Bypass Graft Surgery ( CABG)
Less invasive than CABG
More effective for long-term relief of angina than
PCI or pharmacologic therapy
Most complete revascularization
Shorter hospital stay and
easier recuperation than CABG
Superior to pharmacologic therapy for
relief of angina
Survival advantage in patients with
• > 50% left main coronary artery stenosis
• Multivessel coronary disease, especially if LV contractile function is impaired
LV, left ventricle.
be improved by coronary revascularization. Those with high-risk noninvasive test f ndings
then typically proceed to coronary angiography.
In general, patients with stable angina ound to have a large amount o myocardium at
ischemic risk, such as those with severe (≥ 70% ) stenoses in all three major coronary arteries (especially when LV contractile unction is reduced), those with multivessel disease
that includes a critical narrowing o the proximal le t anterior descending artery (which
thereby threatens a large portion o the le t ventricle), or those with a high-grade (≥ 50% )
stenosis o the le t main coronary artery, achieve a survival benef t rom CABG compared
with medical therapy. More recent studies that have compared percutaneous coronary
revascularization with CABG have demonstrated that CABG leads to a survival benef t in
patients with stable angina who have severe stenoses in all three coronary arteries, a highgrade stenosis in the le t main coronary artery, or diabetes (especially with multivessel
disease). In contrast, PCI is a reasonable approach in patients with less extensive disease
(in whom survival benef t o CABG over PCI has not been shown) and in those at high risk
o undergoing surgery (Table 6-4).
Each o the described approaches or the treatment o coronary disease is benef ting
rom rapidly developing research advancements. New surgical techniques (increased use
o various arterial gra ts, less invasive operations), new drug-eluting stents (e.g., incorporation o bioabsorbable/ biodegradable polymers to decrease late stent thrombosis),
novel adjuncts to stenting (potent antithrombotic drugs), and progress in pharmacologic
management (e.g., aggressive use o statins and antithrombotic drugs) will likely urther
improve outcomes and better def ne the best therapeutic approaches or specif c subsets
o patients with chronic CAD.
SUMMARY
• Cardiac ischemia results rom an imbalance between myocardial oxygen supply and
demand.
• Determinants o myocardial oxygen supply are (1) the oxygen content o the blood and
(2) coronary blood ow (which is dependent on the coronary per usion pressure and coronary vascular resistance).
• Key regulators o myocardial oxygen demand include (1) the heart rate, (2) contractility, and
(3) myocardial wall stress.
• In the presence o coronary artery disease, myocardial oxygen supply is compromised by
atherosclerotic plaques that narrow the vascular lumen (reducing coronary blood ow) and
by endothelial cell dys unction that causes inappropriate vasoconstriction o coronary resistance vessels.
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Ischemic Heart Disease
161
• Angina pectoris is the most requent symptom o intermittent myocardial ischemia.
• The diagnosis o angina relies heavily on the patient’s description o the discom ort and can
be aided by laboratory studies (e.g., exercise or pharmacologic stress testing).
• Angina may be accompanied by signs and symptoms o adrenergic stimulation, pulmonary
congestion, and transient le t ventricular systolic and diastolic dys unction.
• Standard pharmacologic therapy or chronic angina includes agents to prevent ischemia and
relieve symptoms (β-blockers, nitrates, calcium channel antagonists, alone or in combination) as well as agents that reduce the risk o acute coronary syndromes and death (aspirin,
statins, angiotensin-converting enzyme inhibitors).
• Modif able risk actors or atherosclerosis (i.e., dyslipidemia, smoking, hypertension, and
diabetes) should be addressed.
• Revascularization with PCI or CABG surgery provides relie rom ischemia in patients with
chronic angina who are re ractory to, or unable to tolerate, medical therapy. CABG con ers
improved survival rates to certain high-risk groups.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were June-Wha Rhee, MD; Haley Naik, MD;
Christopher P. Chiodo, MD; Carey Farquhar, MD; Anurag Gupta, MD; Rainu Kaushal, MD;
William Carlson, MD; Michael E. Mendelsohn MD; and Patrick T. O’Gara, MD.
Ad d i t i o n a l Rea d i n g
Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use o
ticagrelor in patients with prior myocardial in arction.
N Engl J Med. 2015;372:1791–1800.
Douglas PS, Ho man U, Patel MR, et al. Outcomes o
Anatomical versus Functional Testing or Coronary Artery
Disease. N Engl J Med. 2015;372:1291–1300.
Farkouh ME, Domanski M, Sleeper LA, et al. FREEDOM Trial
Investigators. Strategies or multivessel revascularization in
patients with diabetes. N Engl J Med. 2012;367:2375–2384.
Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ AHA/ ACP/
AATS/ PCNA/ SCAI/ STS Guideline or the diagnosis and
management o patients with stable ischemic heart disease:
executive Summary. Circulation. 2012;126:3097–3137.
Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/ AHA/
SCAI guideline or percutaneous coronary intervention:
executive summary. Circulation. 2011;124:2574–2609.
Mohr FW, Morice MC, Kappetein AP, et al. Coronary
artery bypass gra t surgery versus percutaneous
coronary intervention in patients with three-vessel
disease and le t main coronary disease: 5-year ollowup o the randomized, clinical SYNTAX trial. La n cet.
2013;381(9867):629–638.
Park S-J, Ahn J-M, Kim Y-H, et al. Trial o everolimus-eluting
stents or bypass surgery or coronary disease. N Engl J Med.
2015;372:1204-1212.
Tonino PA, De Bruyne B, Pijls NH, et al. FAME Study
Investigators. Fractional ow reserve versus angiography or
guiding percutaneous coronary intervention. N Engl J Med.
2009;360:213–224.
Velazquez EJ, Lee KL, Deja MA, et al. STITCH Investigators.
Coronary-artery bypass surgery in patients with le t ventricular dys unction. N Engl J Med. 2011;364:1607–1616.
Acute Coronary
Syndromes
7
Ja yme Wilder
Ma rc S. Sa ba tine
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Pathogenesis o Acute Coronary
Syndromes
Normal Hemostasis
Endogenous Antithrombotic
Mechanisms
Pathogenesis o Coronary Thrombosis
Nonatherosclerotic Causes o
Acute Myocardial In arction
Pathology and Pathophysiology
Pathologic Evolution o In arction
Functional Alterations
Clinical Features o Acute Coronary
Syndromes
Clinical Presentation
Diagnosis o Acute Coronary
Syndromes
Treatment o Acute Coronary
Syndromes
Acute Treatment o Unstable
Angina and Non–ST-Elevation
Myocardial In arction
Acute Treatment o ST-Elevation
Myocardial In arction
Adjunctive Therapies
Complications
Recurrent Ischemia
Arrhythmias
Myocardial Dys unction
Right Ventricular In arction
Mechanical Complications
Pericarditis
Thromboembolism
Risk Stratif cation and Management
Following Myocardial In arction
A
cute coronary syndromes (ACSs) are li e-threatening conditions that can punctuate the course o patients with
coronary artery disease at any time. These syndromes orm a
continuum that ranges rom an unstable pattern o angina pectoris to the development o a large acute myocardial in arction (MI), a condition o irreversible necrosis o heart muscle
(Table 7-1). All orms o ACS share a common initiating pathophysiologic mechanism, as this chapter examines.
The requency o ACS is staggering: more than 1.4 million people are admitted to hospitals in the United States
each year with these conditions. Within the year a ter a f rst
MI, 19% o men and 26% o women will die. Despite these
daunting statistics, mortality associated with ACS has actually substantially and continuously declined in recent decades
as a result o major therapeutic and preventive advances. This
chapter considers the events that lead to an ACS, the pathologic and unctional changes that ollow, and therapeutic
approaches that ameliorate the aberrant pathophysiology.
PATHOGENESIS OF ACUTE CORONARY
SYNDROMES
More than 90% o ACSs result rom disruption o an atherosclerotic plaque with subsequent platelet aggregation
and ormation o an intracoronary thrombus. The thrombus trans orms a region o plaque narrowing to one o
severe or complete occlusion, and the impaired blood f ow
causes a marked imbalance between myocardial oxygen
supply and demand. The orm o ACS that results depends
on the degree o coronary obstruction and associated ischemia (see Table 7-1). A partially occlusive thrombus is the
typical cause o the closely related syndromes unstable
angina (UA) and non–ST-elevation myocardial infarction
162
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Acute Coronary Syndromes
163
TABLE 7-1 Spectrum of Acute Coronary Syndromes
Usual coronary
pathology
Myocyte necrosis
Unstable Angina
Non–ST-Elevation MI
ST-Elevation MI
Partially occlusive
thrombus
No
Partially occlusive
thrombus
Yes
Completely occlusive
thrombus
Yes
MI, myocardial infarction.
(NSTEMI), with the latter being distinguished rom the ormer by the presence o myocardial
necrosis. At the other end o the spectrum, i the thrombus completely obstructs the coronary
artery, the results are more severe ischemia and a larger amount o necrosis, mani esting as
an ST-elevation myocardial infarction (STEMI).
The responsible thrombus in ACS is generated by interactions among the atherosclerotic plaque,
the coronary endothelium, circulating platelets, and the dynamic vasomotor tone o the vessel
wall, which overwhelm the natural antithrombotic mechanisms described in the next section.
Normal Hemostasis
When a normal blood vessel is injured, the endothelial sur ace becomes disrupted and thrombogenic connective tissue is exposed. Primary hemostasis is the f rst line o de ense against
bleeding. This process begins within seconds o vessel injury and is mediated by circulating
platelets, which adhere to collagen in the vascular subendothelium and aggregate to orm a
“platelet plug.” While the primary hemostatic plug orms, the exposure o subendothelial tissue actor triggers the plasma coagulation cascade, initiating the process o secondary hemostasis. The plasma coagulation proteins involved in secondary hemostasis are sequentially
activated at the site o injury and ultimately orm a f brin clot by the action o thrombin. The
resulting clot stabilizes and strengthens the platelet plug.
The normal hemostatic system minimizes blood loss rom injured vessels, but there is little
di erence between this physiologic response and the pathologic process o coronary thrombosis triggered by disruption o atherosclerotic plaques.
Endogenous Antithrombotic Mechanisms
Normal blood vessels, including the coronary arteries, are replete with sa eguards that prevent
spontaneous thrombosis and occlusion, some examples o which are shown in Figure 7-1.
Inactivation of Clotting Factors
Several natural inhibitors tightly regulate the coagulation process to oppose clot ormation
and maintain blood uidity. The most important o these are antithrombin, proteins C and S,
and tissue actor pathway inhibitor (TFPI).
Antithrombin is a plasma protein that irreversibly binds to thrombin and other clotting actors, inactivating them and acilitating their clearance rom the circulation (see mechanism 1
in Fig. 7-1). The e ectiveness o antithrombin is increased 1,000- old by binding to heparan
sul ate, a heparin-like molecule normally present on the luminal sur ace o endothelial cells.
Protein C, protein S, and thrombomodulin orm a natural anticoagulant system that
inactivates the “acceleration” actors o the coagulation pathway (i.e., actors Va and VIIIa).
Protein C is synthesized in the liver and circulates in an inactive orm. Thrombomodulin is a
thrombin-binding receptor normally present on endothelial cells. Thrombin bound to thrombomodulin cannot convert f brinogen to f brin (the f nal reaction in clot ormation). Instead,
164
Chapter 7
4
Tis s ue
fa c tor
tPA
P la s minoge n
VII
–
Fib rin
c lot
3
Xa
P la s min
TFP I
Prote in S
Prote in C*
TM
Fibrin
s plit
products
Ina ctiva te d
Va ,VIIIa
fa ctors
5
2
Thrombin
Prote in C
Inhibits
pla te le t
a ctiva tion
Irreve rs ible
thrombin
inhibition
Thrombin
1
Pros ta cyclin
a nd
NO
Antithrombin
He p a ra n
s ulfa te
FIGURE 7-1. Endogenous protective
mechanisms against thrombosis and
vessel occlusion. (1) Inactivation o
thrombin by antithrombin (AT), the
e ectiveness o which is enhanced by
binding o AT to heparan sul ate. (2)
Inactivation o clotting actors Va and
VIIIa by activated protein C (protein
C*), an action that is enhanced by
protein S. Protein C is activated by
the thrombomodulin (TM)–thrombin
complex. (3) Inactivation o actor VII/
tissue actor complex by tissue actor
pathway inhibitor (TFPI). (4) Lysis
o f brin clots by tissue plasminogen
activator (tPA). (5) Inhibition o
platelet activation by prostacyclin and
nitric oxide (NO).
the thrombin–thrombomodulin complex activates protein C. Activated protein C degrades actors Va and VIIIa (see mechanism 2 in Fig. 7-1), thereby inhibiting coagulation. The presence
o protein S in the circulation enhances the inhibitory unction o protein C.
TFPI is a plasma serine protease inhibitor that is activated by coagulation actor Xa. The
combined actor Xa–TFPI binds to and inactivates the complex o tissue actor with actor VIIa
that normally triggers the extrinsic coagulation pathway (see mechanism 3 in Fig. 7-1). Thus,
TFPI serves as a negative eedback inhibitor that inter eres with coagulation.
Lysis of Fibrin Clots
Tissue plasminogen activator (tPA) is a protein secreted by endothelial cells in response to
many triggers o clot ormation. It cleaves the protein plasminogen to orm active plasmin,
which in turn enzymatically degrades f brin clots (see mechanism 4 in Fig. 7-1). When tPA binds
to f brin in a orming clot, its ability to convert plasminogen to plasmin is greatly enhanced.
Endogenous Platelet Inhibition and Vasodilatation
Prostacyclin is synthesized and secreted by endothelial cells (see mechanism 5 in Fig. 7-1),
as described in Chapter 6. Prostacyclin increases platelet levels o cyclic AMP and thereby
strongly inhibits platelet activation and aggregation. It also indirectly inhibits coagulation via
its potent vasodilating properties. Vasodilatation helps guard against thrombosis by augmenting blood ow (which minimizes contact between procoagulant actors) and by reducing
shear stress (an inducer o platelet activation).
Nitric oxide (NO) is similarly secreted by endothelial cells, as described in Chapter 6. It
acts locally to inhibit platelet activation, and it too serves as a potent vasodilator.
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Acute Coronary Syndromes
165
Athe ro s c le ro s is
Dys functiona l
e ndothe lium
P la que rupture
Intra pla que
he morrha ge
Re le a s e of
tis s ue fa ctor
Ve s s e l
lume n
dia me te r
Activa tion of
coa gula tion
ca s ca de
Expos ure of
s ube ndothe lia l
colla ge n
Turbule nt
blood flow
P la te le t
a ctiva tion a nd
a ggre ga tion
Va s odila tor
e ffe ct
Antithrombotic
e ffe ct
Va s ocons triction
Co ro nary thro mbo s is
FIGURE 7-2. Mechanisms of coronary thrombus formation. Factors that contribute to this process include
plaque disruption (e.g., rupture) and inappropriate vasoconstriction and loss of normal antithrombotic
defenses because of dysfunctional endothelium.
Pathogenesis of Coronary Thrombosis
Normally, the mechanisms shown in Figure 7-1 serve to prevent spontaneous intravascular thrombus ormation. However, abnormalities associated with atherosclerotic lesions may
overwhelm these de enses and result in coronary thrombosis and vessel occlusion (Fig. 7-2).
Atherosclerosis contributes to thrombus ormation by (1) plaque rupture, which exposes the
circulating blood elements to thrombogenic substances, and (2) endothelial dys unction with
the loss o normal protective antithrombotic and vasodilatory properties.
Atherosclerotic plaque rupture is considered the major trigger o coronary thrombosis.
The underlying causes o plaque disruption are (1) chemical actors that destabilize atherosclerotic lesions and (2) physical stresses to which the lesions are subjected. As described
in Chapter 5, atherosclerotic plaques consist o a lipid-laden core surrounded by a f brous
external cap. Substances released rom in ammatory cells within the plaque can compromise
the integrity o the f brous cap. For example, T lymphocytes release inter eron-γ (IFN-γ),
which inhibits collagen synthesis by smooth muscle cells and thereby inter eres with the
usual strength o the cap. Additionally, cells within atherosclerotic lesions produce enzymes
(e.g., metalloproteinases) that degrade the interstitial matrix, urther compromising plaque
stability. A weakened or thin-capped plaque is subject to rupture, particularly in its “shoulder” region (the border with the normal arterial wall that is subjected to high circum erential
stress) either spontaneously or by physical orces, such as intraluminal blood pressure and
torsion rom the beating myocardium.
ACSs sometimes occur in the setting o certain triggers, such as strenuous physical activity or emotional upset. The activation o the sympathetic nervous system in these situations
increases the blood pressure, heart rate, and orce o ventricular contraction—actions that
may stress the atherosclerotic lesion, thereby causing the plaque to f ssure or rupture. In addition, MI is most likely to occur in the early morning hours. This observation may relate to the
tendency o key physiologic stressors (such as systolic blood pressure, blood viscosity, and
166
Chapter 7
plasma epinephrine levels) to be most elevated at that time o day, and these actors subject
vulnerable plaques to rupture.
While rupture o the f brous cap is responsible or the majority o ACSs, superf cial erosion
without rupture is a less common, important mechanism o plaque disruption and thrombus
ormation. Eroded plaques o ten do not have a substantial lipid burden but have been associated with smoking and are also requently ound to be the cause o ACS in premenopausal
women.
Following plaque disruption, thrombus ormation is provoked via mechanisms shown in
Figure 7-2. For example, during plaque rupture, the exposure o tissue actor rom the atheromatous core triggers the coagulation pathway, while subendothelial collagen activates
platelets. Activated platelets release the contents o their granules, which include acilitators
o platelet aggregation (e.g., adenosine diphosphate [ADP] and f brinogen), activators o the
coagulation cascade (e.g., actor Va), and vasoconstrictors (e.g., thromboxane and serotonin).
The developing intracoronary thrombus, intraplaque hemorrhage, and vasoconstriction all
contribute to narrowing the vessel lumen, creating turbulent blood ow that contributes to
shear stress and urther platelet activation.
Dysfunctional endothelium, which is apparent even in mild atherosclerotic coronary
disease, also increases the likelihood o thrombus ormation. In the setting o endothelial
dys unction, reduced amounts o vasodilators (e.g., NO and prostacyclin) are released and
inhibition o platelet aggregation by these actors is impaired, resulting in the loss o a key
de ense against thrombosis.
Not only is dys unctional endothelium less equipped to prevent platelet aggregation but
also is less able to counteract the vasoconstricting products o platelets. During thrombus
ormation, vasoconstriction is promoted both by platelet products (thromboxane and serotonin) and by thrombin within the developing clot. The normal platelet-associated vascular
response is vasodilatation, because platelet products stimulate endothelial NO and prostacyclin release, the in uences o which predominate over direct platelet-derived vasoconstrictors
(see Fig. 6-4). However, reduced secretion o endothelial vasodilators in atherosclerosis allows
vasoconstriction to proceed unchecked. Similarly, thrombin in a orming clot is a potent vascular smooth muscle constrictor in the setting o dys unctional endothelium. Vasoconstriction
causes torsional stresses that can contribute to plaque rupture or can transiently occlude the
stenotic vessel through heightened arterial tone. The reduction in coronary blood ow caused
by vasoconstriction also reduces the washout o coagulation proteins, thereby enhancing
thrombogenicity.
Signif cance o Coronary Thrombosis
The ormation o an intracoronary thrombus results in one o the several potential outcomes
(Fig. 7-3). For example, plaque rupture is sometimes superf cial, minor, and sel -limited,
such that only a small, nonocclusive thrombus orms. In this case, the thrombus may simply
become incorporated into the growing atheromatous lesion through f brotic organization, or
it may be lysed by natural f brinolytic mechanisms. Recurrent asymptomatic plaque ruptures
o this type may cause gradual progressive enlargement o the coronary stenosis.
However, deeper plaque rupture may result in greater exposure o subendothelial collagen
and tissue actor, with ormation o a larger thrombus that more substantially occludes the
vessel’s lumen. Such obstruction may cause prolonged severe ischemia and the development o an ACS. I the intraluminal thrombus at the site o plaque disruption totally occludes
the vessel, blood ow beyond the obstruction will cease, prolonged ischemia will occur,
and an MI (usually an ST-elevation MI) will result. Conversely, i the thrombus partially
occludes the vessel (or i it totally occludes the vessel but only transiently because o spontaneous recanalization or by relie o superimposed vasospasm), the severity and duration o
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Acute Coronary Syndromes
167
Co ro nary thro mbus
S ma ll thrombus
(nonflow limiting)
Pa rtia lly occlus ive
thrombus
Occlus ive
thrombus
(With prolonge d
is che mia )
No ECG
cha nge s
ST-s e gme nt
de pre s s ion a nd/or
T-wave inve rs ion
He a ling a nd
pla que e nla rge me nt
– S e rum
bioma rke rs
Uns ta ble a ngina
(With tra ns ie nt
is che mia )
+ S e rum
bioma rke rs
Non–ST-s e gme nt
e leva tion MI
ST e leva tion
(Q wave s la te r)
+ S e rum
bioma rke rs
ST-s e gme nt
e leva tion MI
FIGURE 7-3. Consequences of coronary thrombosis. A small thrombus ormed on super cial plaque rupture
may not result in symptoms or electrocardiogram (ECG) abnormalities, but healing and brous organization
may incorporate the thrombus into the plaque, causing the atherosclerotic lesion to enlarge. A partially
occlusive thrombus narrows the arterial lumen, restricts blood f ow, and can cause unstable angina or a
non–ST-elevation MI, either o which may result in ST-segment depression and/ or T-wave inversion on the
ECG. A totally occlusive thrombus with prolonged ischemia is the most common cause o ST-elevation MI, in
which the ECG initially shows ST-segment elevation, ollowed by Q-wave development i early reper usion is
not achieved. An occlusive thrombus that recanalizes, or one that develops in a region served by adequate
collateral blood f ow, may result in less prolonged ischemia and a non–ST-elevation MI instead. Serum
biomarkers o myocardial necrosis include cardiac-speci c troponins and creatine kinase MB isoenzyme.
ischemia will be less, and a smaller NSTEMI or UA is the more likely outcome. The distinction between NSTEMI and UA is based on the degree o the ischemia and whether the event
is severe enough to cause necrosis, indicated by the presence o certain serum biomarkers
(see Fig. 7-3). Nonetheless, NSTEMI and UA act quite alike, and the management o these
entities is similar.
Occasionally, a non–ST-elevation in arct may result rom total coronary occlusion. In this
case, it is likely that a substantial collateral blood supply (see Chapter 1) limits the extent o
necrosis, such that a larger ST-elevation MI is prevented.
Nonatherosclerotic Causes of Acute Myocardial Infarction
In requently, mechanisms other than acute thrombus ormation can precipitate an acute MI
(Table 7-2). These should be suspected when an ACS occurs in a young patient or a person without atherosclerotic risk actors. For example, coronary emboli rom mechanical or
in ected cardiac valves may lodge in the coronary circulation, inf ammation rom acute vasculitis can initiate coronary occlusion, or patients with connective tissue disorders, or peripartum women, can rarely experience a spontaneous coronary artery dissection (a tear in
168
Chapter 7
TABLE 7-2 Causes of Myocardial Infarction
•
•
•
•
•
•
•
•
•
Atherosclerotic plaque rupture with superimposed thrombus
Vasculitic syndromes (see Chapter 15)
Coronary embolism (e.g., rom endocarditis, artif cial heart valves)
Congenital anomalies o the coronary arteries
Coronary trauma or aneurysm
Spontaneous coronary artery dissection
Severe coronary artery spasm (primary or cocaine-induced)
Increased blood viscosity (e.g., polycythemia vera, thrombocytosis)
Markedly increased myocardial oxygen demand (e.g., severe aortic stenosis)
the vessel wall that may lead to occlusion, described in Chapter 15). Occasionally, intense
transient coronary spasm can su f ciently reduce myocardial blood supply to result in UA
or in arction.
Cocaine abuse can also lead to an ACS. Cocaine increases sympathetic tone by blocking the presynaptic reuptake o norepinephrine and by enhancing the release o adrenal
catecholamines, which can lead to vasospasm and there ore decreased myocardial oxygen
supply. An ACS may ensue because o increased myocardial oxygen demand resulting rom
cocaine-induced sympathetic myocardial stimulation (increased heart rate and blood pressure) in the ace o the decreased oxygen supply.
These nonatherosclerotic causes are relatively rare causes o acute MI. However, they are
important to recognize as their treatments di er rom those o typical ACSs due to plaque
rupture and superimposed thrombus ormation, as discussed in this chapter.
PATHOLOGY AND PATHOPHYSIOLOGY
MI (either STEMI or NSTEMI) results when myocardial ischemia is su f ciently severe to cause
myocyte necrosis. Although by def nition UA does not result in necrosis, it may subsequently
progress to MI i the underlying pathophysiology is not promptly corrected.
In addition to their clinical classif cations, in arctions can be described pathologically by
the extent o necrosis they produce within the myocardial wall. Transmural infarcts span
the entire thickness o the myocardial wall and result rom total, prolonged occlusion o an
epicardial coronary artery. Conversely, subendocardial infarcts exclusively involve the innermost layers o the myocardium. The subendocardium is particularly susceptible to ischemia
because it is the zone subjected to the highest pressure rom the ventricular chamber, has ew
collateral connections that supply it, and is per used by vessels that must pass through layers
o contracting myocardium.
In arction represents the culmination o a disastrous cascade o events, initiated by
ischemia, that progresses rom a potentially reversible phase to irreversible cell death.
Myocardium that is supplied directly by an occluded vessel may die quickly. The adjacent
tissue may not necrose immediately because it may be su f ciently per used by nearby patent vessels. However, the neighboring cells may become increasingly ischemic over time,
as demand or oxygen continues in the ace o reduced oxygen supply. Thus, the region o
in arction may subsequently extend outward. The amount o tissue that ultimately succumbs
to in arction there ore relates to (1) the mass o myocardium per used by the occluded vessel,
(2) the magnitude and duration o impaired coronary blood ow, (3) the oxygen demand o
the a ected region, (4) the adequacy o collateral vessels that provide blood ow rom neighboring nonoccluded coronary arteries, and (5) the degree o tissue response that modif es the
ischemic process.
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Acute Coronary Syndromes
169
Pathologic Evolution of Infarction
The pathophysiologic alterations that transpire during MI occur in two stages: early
changes at the time o acute in arction and late changes during myocardial healing and
remodeling (Table 7-3).
Early Changes in Infarction
Early changes include the histologic evolution o the in arct and the unctional impact o
oxygen deprivation on myocardial contractility. These changes culminate in coagulative
necrosis o the myocardium in 2 to 4 days.
As oxygen levels all in the myocardium supplied by an abruptly occluded coronary vessel,
there is a rapid shi t rom aerobic to anaerobic metabolism (Fig. 7-4). Because mitochondria can
no longer oxidize ats or products o glycolysis, high-energy phosphate production drops dramatically and anaerobic glycolysis leads to the accumulation o lactic acid, resulting in a lowered pH.
Furthermore, the paucity o high-energy phosphates such as adenosine triphosphate (ATP)
inter eres with transmembrane Na + –K+ -ATPase, with resultant elevation in the concentrations
o intracellular Na + and extracellular K+ . Rising intracellular Na + contributes to cellular edema.
Membrane leak and rising extracellular K+ concentration contributes to alterations in the transmembrane electrical potential, predisposing the myocardium to lethal arrhythmias. Intracellular
calcium accumulates in the damaged myocytes and is thought to contribute to the f nal common pathway o cell destruction through the activation o degradative lipases and proteases.
Collectively, these metabolic changes decrease myocardial unction as early as 2 minutes
ollowing occlusive thrombosis. Without intervention, irreversible cell injury ensues in
20 minutes and is marked by the development o membrane de ects. Proteolytic enzymes
leak across the myocyte’s altered membrane, damaging adjacent myocardium, and the release
o certain macromolecules into the circulation serves as a clinical marker o acute in arction.
Early histological changes include myocardial edema, wavy myof bers, and the presence o
contraction bands (see Table 7-3). Edema o the myocardium develops within 4 to 12 hours, as
vascular permeability increases and interstitial oncotic pressure rises (because o the leak o
intracellular proteins). Wavy myof bers appear as intercellular edema separates the myocardial
TABLE 7-3 Pathologic Time Line in Transmural Infarction
Time
Early changes
1–2 min
10 min
20–24 min
1–3 h
4–12 h
18–24 h
2–4 d
Late changes
5–7 d
7+ d
7 wk
Event
ATP levels all; cessation o contractility
50% depletion o ATP; cellular edema, decreased membrane potential, and
susceptibility to arrhythmias
Irreversible cell injury
Wavy myof bers
Hemorrhage, edema, PMN inf ltration begins
Coagulation necrosis (pyknotic nuclei with eosinophilic cytoplasm), edema
Total coagulation necrosis (no nuclei or striations, rimmed by hyperemic tissue);
monocytes appear; PMN inf ltration peaks
Yellow so tening rom resorption o dead tissue by macrophages
Granulation tissue orms, ventricular remodeling
Fibrosis and scarring complete
ATP, adenosine triphosphate; PMN, polymorphonuclear leukocyte.
170
Chapter 7
Myo c ardial hypoxia
ATP
Impa ire d
Na , K+-ATPa s e
Ana e robic
me ta bolis m
+
Extra ce llula r
K+
Intra ce llula r
Na +
Alte re d
me mbra ne
pote ntia l
Intra ce llula r
Ca ++
Chroma tin clumping
Prote in de na tura tion
Intra ce llula r
e de ma
Arrhythm ia s
Intra ce llula r
H+
ATP
Prote a s e s
Lip a s e s
Ce ll de a th
FIGURE 7-4. Mechanisms of cell death in myocardial infarction. Acute ischemia rapidly depletes the
intracellular supply of adenosine triphosphate (ATP) as aerobic metabolism fails. Subsequent intracellular
acidosis and impairment of ATP-dependent processes culminate in intracellular calcium accumulation, edema,
and cell death.
cells that are tugged about by the surrounding, unctional myocardium. Contraction bands
can o ten be seen near the borders o the in arct: sarcomeres are contracted and consolidated
and appear as bright eosinophilic belts (Fig. 7-5A).
An acute in ammatory response, with inf ltration o neutrophils, begins a ter approximately
4 hours and incites urther tissue damage. Within 18 to 24 hours, coagulation necrosis is evident on light microscopy (Fig. 7-5B) with pyknotic nuclei and bland eosinophilic cytoplasm.
Gross morphologic changes (dark, mottled discoloration o in arcted tissue) do not appear
until 18 to 24 hours a ter coronary occlusion, although certain staining techniques (e.g., tetrazolium) permit the pathologist to identi y regions o in arction earlier.
Late Changes in Infarction
Late pathologic change in the course o an MI includes (1) the clearing o necrotic myocardium and (2) the deposition o collagen to orm scar tissue.
Five to seven days a ter in arction, the process o wound healing progresses. Irreversibly
injured myocytes do not regenerate; rather, the cells are removed and replaced by f brous tissue. Macrophages invade the in amed myocardium shortly a ter neutrophil inf ltration and
remove necrotic tissue (Fig. 7-5C). This period o tissue resorption is termed yellow softening
because connective tissue elements are destroyed and removed along with dead myocardial
cells. The phagocytic clearing, combined with thinning and dilatation o the in arcted zone,
results in structural weakness o the ventricular wall and the possibility o myocardial wall
rupture at this stage.
Approximately 1 week a ter in arction, granulation tissue appears, representing the beginning o the scarring process (Fig. 7-5D). This is observed grossly as a red border at the edge o
the in arct. Fibrosis subsequently ensues, and scarring is complete by 7 weeks a ter in arction
(Fig. 7-5E).
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Acute Coronary Syndromes
A
B
C
D
E
FIGURE 7-5. Pathologic evolution in myocardial infarction. A. Acute in arct approximately 12 hours old
showing contraction band necrosis, nuclear karyolysis, ocal hemorrhage, and an absence o inf ammation.
B. Acute in arct approximately 24 to 48 hours old showing coagulation necrosis and dense in ltration o
neutrophils. C. Healing in arct approximately 5 days old showing necrotic myocytes undergoing removal by
macrophages, with the neutrophilic response having largely dissipated. D. Healing in arct approximately
10 days old showing granulation tissue with new blood vessels (neovascularization), mild chronic inf ammation
(macrophages and lymphocytes), broblasts, and early collagen deposition; viable myocardium is present at
the upper le t. E. Healed in arct approximately 1 to 2 months old showing dense brosis; the inf ammation and
new vessels have largely regressed; viable myocardium is present at the upper le t. All images are hematoxylin
and eosin–stained sections.(Courtesy o Robert Padera, MD, PhD, Brigham and Women’s Hospital, Boston, MA).
171
172
Chapter 7
Functional Alterations
Impaired Contractility and Compliance
The destruction o unctional myocardial cells in in arction quickly leads to impaired ventricular contraction (systolic dysfunction). Cardiac output is urther compromised because
syn chronous contraction o myocytes is lost. Specif c terms are used to describe the types
o wall motion abnormalities that can result. A localized region o reduced contraction is
termed hypokin etic, a segment that does not contract at all is called akinetic, and a dyskin etic
region is one that bulges outward during contraction o the remaining unctional portions o
the ventricle.
During an ACS, the le t ventricle is also adversely compromised by diastolic dysfunction. Ischemia and/ or in arction impair diastolic relaxation (an energy-dependent process;
see Chapter 1), which reduces ventricular compliance and contributes to elevated ventricular
f lling pressures.
Stunned Myocardium
Sometimes transient myocardial ischemia can result in a very prolonged, but gradually reversible, period o contractile dys unction. For example, as described in Chapter 6, stunned myocardium is tissue that demonstrates prolonged systolic dys unction a ter a discrete episode o
severe ischemia, despite restoration o adequate blood ow, and gradually regains contractile
orce days to weeks later. For example, stunning may occur ollowing reper usion therapy
or acute STEMI, in which case prolonged contractile dys unction o a ected ventricular segments may simulate in arcted tissue. However, i the tissue is simply stunned rather than
necrotic, its unction will recover over time.
Ischemic Preconditioning
Brie ischemic insults to a region o myocardium may render that tissue more resistant to subsequent episodes, a phenomenon termed ischemic preconditioning. The clinical relevance is
that patients who sustain an MI in the context o recent angina experience less morbidity and
mortality than those without preceding ischemic episodes. The mechanism o this phenomenon is not ully understood but appears to involve multiple signaling pathways that involve
both local and systemic mediators. Substances released during ischemia, including adenosine
and bradykinin, are believed to be key triggers o these pathways.
Ventricular Remodeling
Following an MI, changes occur in the geometry o both in arcted and nonin arcted ventricular muscle. Such alterations in chamber size and wall thickness a ect long-term cardiac
unction and prognosis.
In the early post-MI period, in arct expansion may occur, in which the a ected ventricular
segment enlarges without additional myocyte necrosis. In arct expansion represents thinning
and dilatation o the necrotic zone o tissue, likely because o “slippage” between the muscle
f bers, resulting in a decreased volume o myocytes in the region. In arct expansion can be
detrimental because it increases ventricular size, which (1) augments wall stress, (2) impairs
systolic contractile unction, and (3) increases the likelihood o aneurysm ormation.
In addition to early expansion o the in arcted territory, remodeling o the ventricle may also
involve dilatation o the overworked noninfarcted segments, which are subjected to increased
wall stress. This dilatation begins in the early postin arct period and continues over the ensuing
weeks and months. Initially, chamber dilatation serves a compensatory role because it increases
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Acute Coronary Syndromes
173
cardiac output via the Frank–Starling mechanism (see Chapter 9), but progressive enlargement
may ultimately lead to heart ailure and predisposes to ventricular arrhythmias.
Adverse ventricular remodeling can be benef cially modif ed by certain interventions.
At the time o in arction, or example, reper usion therapies limit in arct size and there ore
decrease the likelihood o in arct expansion. In addition, drugs that inter ere with the renin–
angiotensin system have been shown to attenuate progressive remodeling and to reduce
short- and long-term mortality a ter in arction (as discussed later in the chapter).
CLINICAL FEATURES OF ACUTE CORONARY SYNDROMES
Because ACSs represent disorders along a continuum, their clinical eatures overlap. In
general, the severity o symptoms and associated laboratory f ndings progress rom UA on
one side o the continuum, through NSTEMI, to STEMI on the other end o the continuum.
Distinguishing among these syndromes is based on the clinical presentation, electrocardiographic f ndings, and serum biomarkers o myocardial damage. To institute appropriate
immediate therapy, the most important distinction to make is between an ACS that causes
ST-segment elevation on the electrocardiogram (STEMI) and those acute syndromes that do
not (UA and NSTEMI).
Clinical Presentation
Unstable Angina
UA presents as an acceleration o ischemic symptoms in one o the ollowing three ways:
(1) a crescendo pattern in which a patient with chronic stable angina experiences a sudden
increase in the requency, duration, and/ or intensity o ischemic episodes; (2) episodes o
angina that unexpectedly occur at rest, without provocation; or (3) the new onset o anginal
episodes, described as severe, in a patient without previous symptoms o coronary artery
disease. These presentations are di erent rom the pattern o chronic stable angina, in which
instances o chest discom ort are predictable, brie , and nonprogressive, occurring only during physical exertion or emotional stress. Patients with UA may progress urther along the
continuum o ACS and develop evidence o necrosis (i.e., acute NSTEMI or STEMI) unless the
condition is recognized and promptly treated.
Acute Myocardial Infarction
The symptoms and physical f ndings o acute MI (both STEMI and NSTEMI) can be predicted
rom the pathophysiology described earlier in this chapter and are summarized in Table 7-4.
The discom ort experienced during an MI resembles angina pectoris qualitatively but is usually more severe, lasts longer, and may radiate more widely. Like angina, the sensation may
result rom the release o mediators such as adenosine and lactate rom ischemic myocardial cells onto local nerve endings. Because ischemia in acute MI persists and proceeds to
necrosis, these provocative substances continue to accumulate and activate a erent nerves
or longer periods. The discom ort is o ten re erred to other regions o the C7 through T4
dermatomes, including the neck, shoulders, and arms. Initial symptoms are usually rapid in
onset and briskly crescendo to leave the patient with a pro ound “ eeling o doom.” Unlike a
transient attack o angina, the pain does not wane with rest, and there may be little response
to the administration o sublingual nitroglycerin.
The chest discom ort associated with an acute MI is o ten severe but not always. In act,
up to 25% o patients who sustain an MI are asymptomatic during the acute event, and the
diagnosis is made only in retrospect. This is particularly common among diabetic patients
who may not adequately sense pain because o associated neuropathy.
174
Chapter 7
TABLE 7-4 Signs and Symptoms o Myocardial In arction
1. Characteristic pain
2. Sympathetic e ect
3. Parasympathetic ( vagal
e ect)
4. Inf ammatory response
5. Cardiac ndings
6. Other
•
•
•
•
•
•
•
•
•
•
•
Severe, persistent, typically substernal
Diaphoresis
Cool and clammy skin
Nausea, vomiting
Weakness
Mild fever
S4 (and S3 if systolic dysfunction present) gallop
Dyskinetic bulge (in anterior wall MI)
Systolic murmur (if mitral regurgitation or VSD)
Pulmonary rales (if heart failure present)
Jugular venous distention (if heart failure or right ventricular MI)
MI, myocardial infarction; S3, third heart sound; S4, fourth heart sound; VSD, ventricular septal defect.
The combination o intense discom ort and baroreceptor unloading (i hypotension is
present) may trigger a dramatic sympathetic nervous system response. Systemic signs o
subsequent catecholamine release include diaphoresis (sweating), tachycardia, and cool and
clammy skin caused by vasoconstriction.
I the ischemia a ects a su f ciently large amount o myocardium, le t ventricular (LV)
contractility can be reduced (systolic dys unction), thereby decreasing the stroke volume and
causing the diastolic volume and pressure within the LV to rise. The increase in LV pressure,
compounded by the ischemia-induced sti ness o the chamber (diastolic dys unction), is conveyed to the le t atrium and pulmonary veins. The resultant pulmonary congestion decreases
lung compliance and stimulates juxtacapillary receptors. These J receptors e ect a re ex that
results in rapid, shallow breathing and evokes the subjective eeling o dyspnea. Transudation
o uid into the alveoli exacerbates this symptom.
Physical f ndings during an acute MI depend on the location and extent o the in arct. The
S4 sound, indicative o atrial contraction into a noncompliant le t ventricle, is requently present
(see Chapter 2). An S3 sound, indicative o volume overload in the presence o ailing LV systolic unction, may also be heard. A systolic murmur may appear i ischemia-induced papillary
muscle dys unction causes mitral valvular insu f ciency or i the in arct ruptures through the
interventricular septum to create a ventricular septal de ect (as discussed later in the chapter).
Myocardial necrosis also activates systemic responses to in ammation. Cytokines such
as interleukin-1 (IL-1) and tumor necrosis actor (TNF) are released rom macrophages and
vascular endothelium in response to tissue injury. These mediators evoke an array o clinical
responses, including low-grade ever.
Not all patients with severe chest pain are in the midst o MI or UA. Table 7-5 lists other
common causes o acute chest discom ort and clinical, laboratory, and radiographic eatures
to di erentiate them rom an ACS.
Diagnosis o Acute Coronary Syndromes
The diagnosis o , and distinctions among, the ACSs is made on the basis o (1) the patient’s
presenting symptoms, (2) acute ECG abnormalities, and (3) detection o specif c serum markers o myocardial necrosis (see Table 7-6 and Fig. 7-3). Specif cally, UA is a clinical diagnosis
supported by the patient’s symptoms, transient ST abnormalities on the ECG (usually ST
depression and/ or T-wave inversion), and the absence o serum biomarkers o myocardial
necrosis. Non–ST-segment elevation MI is distinguished rom UA by the detection o serum
markers o necrosis and o ten more persistent ST or T-wave abnormalities. The hallmark o
ST-elevation MI is an appropriate clinical history coupled with ST elevations on the ECG plus
detection o serum markers o myocardial necrosis.
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Acute Coronary Syndromes
TABLE 7-5
175
Conditions That May Be Confused with Acute Coronary Syndromes
Condition
Differentiating Features
Cardiac
Acute coronary syndrome
Pericarditis
Aortic dissection
Pulmonary
Pulmonary embolism
Pneumonia
Pneumothorax
Gastrointestinal
Esophageal spasm
Acute cholecystitis
• Retrosternal pressure, radiating to the neck, jaw, or le t shoulder and arm; more
severe and lasts longer than previous anginal attacks
• ECG: localized ST elevations or depressions
• Sharp pleuritic pain (worsens with inspiration)
• Pain varies with position (relieved by sitting orward)
• Friction rub auscultated over precordium
• ECG: di use ST elevations (see Chapter 14)
• Tearing, ripping pain that migrates over time (chest and back; see Chapter 15)
• Asymmetry o arm blood pressures
• Widened mediastinum on chest radiograph
•
•
•
•
•
•
•
•
•
•
Localized pleuritic pain, accompanied by dyspnea
Pleural riction rub may be present
Predisposing conditions or venous thrombosis
Pleuritic chest pain
Cough and sputum production
Abnormal lung auscultation and percussion (i.e., consolidation)
Inf ltrate on chest radiograph
Sudden sharp, pleuritic unilateral chest pain
Decreased breath sounds and hyperresonance o a ected side
Chest radiograph: increased lucency and absence o pulmonary markings
•
•
•
•
•
Retrosternal pain, worsened by swallowing
History o dysphagia
Right upper quadrant abdominal tenderness
O ten accompanied by nausea
History o atty ood intolerance
ECG Abnormalities
ECG abnormalities, which ref ect abnormal electrical currents during an ACS, are usually maniest in characteristic ways. In UA or NSTEMI, ST-segment depression and/ or T-wave inversions may occur (Fig. 7-6). These abnormalities may be transient, occurring just during chest
pain episodes in UA, or they may persist in patients with NSTEMI. In contrast, as described
in Chapter 4, STEMI presents with a temporal sequence o abnormalities: initial ST-segment
TABLE 7-6
Distinguishing Features of Acute Coronary Syndromes
Myocardial Infarction
Feature
Typical symptoms
Serum biomarkers
Electrocardiogram initial
f ndings
Unstable Angina
Crescendo, rest, or newonset severe angina
No
ST depression and/ or
T-wave inversion
NSTEMI
STEMI
Prolonged “crushing” chest pain, more severe
and wider radiation than usual angina
Yes
Yes
ST depression and/ or
ST elevation (and
T-wave inversion
Q waves later)
NSTEMI, non–ST-elevation myocardial in arction; STEMI, ST-elevation myocardial in arction.
176
Chapter 7
elevation, ollowed over the course o several hours
by inversion o the T wave and the appearance o
pathologic Q waves (Fig. 7-7). Importantly, these
Acute
characteristic patterns o ECG abnormalities in ACS
can be minimized or prevented by early therapeutic
interventions.
We e ks
Norma l
Historically, MIs had been classif ed as “Q-wave”
la te r
• T-wave inve rs ion
or “non–Q-wave” in arctions be ore the advent o
the terms “STEMI” and “NSTEMI,” respectively. The
or
older terminology, which is still occasionally encountered, re ected the act that pathologically transmu• ST & T norma l
ral in arctions typically produce pathologic Q waves
• no Q wave s
(a ter an initial period o ST elevation), whereas subendocardial in arctions do not. However, it is now
• ST de pre s s ion
known that the development o Q waves does not
FIGURE 7-6. ECG abnormalities in unstable angina
reliably correlate with pathologic f ndings and that
and non–ST-elevation myocardial infarction.
much overlap exists among the types o in arction.
Moreover, the f nding o new pathologic Q waves to classi y ACSs now has little therapeutic
relevance because Q waves, when they occur, take hours to develop and there ore are not
help ul in making acute treatment decisions.
Uns table Ang ina/No n–ST-Elevatio n
Myo c ardial Infarc tio n
Serum Markers of Infarction
Necrosis o myocardial tissue causes disruption o the sarcolemma, so that intracellular macromolecules leak into the cardiac interstitium and ultimately into the bloodstream (Fig. 7-8).
Detection o such molecules in the serum, particularly cardiac-specif c troponins, serves
important diagnostic and prognostic roles. In patients with STEMI or NSTEMI, these markers
rise above a threshold level in a def ned temporal sequence.
Cardiac-specif c Troponins
Troponin is a regulatory protein in muscle cells that controls interactions between myosin
and actin (see Chapter 1). It consists o three subunits: TnC, TnI, and TnT. Although these
subunits are ound in both skeletal and cardiac muscles, the cardiac orms o troponin I
(cTnI) and troponin T (cTnT) are structurally unique, and highly specif c and sensitive assays
or their detection in the serum are in wide clinical use. The presence o even minor serum
elevations o these biomarkers serves as evidence o cardiomyocyte injury, is diagnostic o
in arction in the appropriate clinical setting, and conveys power ul prognostic in ormation.
However, as new generations o these assays have become ever more sensitive, small serum
ST-Elevatio n Myo c ardial Infarc tio n
Norma l
Acute
Hours
• ST e leva tion
• ST e leva tion
• R Wave
• Q wave be gins
Days 1–2
• T-wave inve rs ion
• Q wave de e pe r
FIGURE 7-7. ECG evolution during ST-elevation myocardial infarction.
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Days
la te r
• ST norma lize s
• T wave inve rte d
We e ks
la te r
• ST & T norma l
• Q wave pe rs is ts
Acute Coronary Syndromes
177
20
Troponins
10
5
e
s
o
f
M
I
t
h
r
e
s
h
o
l
d
50
M
u
l
t
i
p
l
CK-MB
2
1
FIGURE 7-8. Evolution of serum
biomarkers in acute myocardial
infarction ( MI) .
MI Thre s hold
1
2
3
4
5
6
7
8
9
10
Days a fte r ons e t of infa rction
elevations can also be detected in conditions other than MI, related to acute cardiac strain or
in ammation (e.g., in heart ailure, myocarditis, hypertensive crises, or pulmonary embolism
[due to right ventricular strain]).
In the case o MI, cardiac troponin serum levels begin to rise 3 to 4 hours a ter the onset o
chest discom ort, achieve a peak level between 18 and 36 hours, and then decline slowly, allowing or detection or 10 days or more a ter a large MI. Thus, their measurement may be help ul
or detection o MI or nearly 2 weeks a ter the event occurs. Given their high sensitivity and
specif city, cardiac troponins are the pre erred serum biomarkers to detect myocardial necrosis.
Creatine Kinase
The enzyme creatine kinase (CK) is ound in the heart, skeletal muscle, brain, and other
organs. Injury to any o these tissues may lead to elevation in serum concentrations o the
enzyme. There are, however, three isoenzymes o CK that improve diagnostic specif city o
its origin: CK-MM ( ound mainly in skeletal muscle), CK-BB (located predominantly in the
brain), and CK-MB (localized mainly in the heart). Elevation o CK-MB is highly suggestive
o myocardial injury. To acilitate the diagnosis o MI using this marker, it is common to
calculate the ratio o CK-MB to total CK. The ratio is usually greater than 2.5% in the setting
o myocardial injury and less than that when CK-MB elevation is rom another source. The
serum level o CK-MB starts to rise 3 to 8 hours ollowing in arction, peaks at 24 hours, and
returns to normal within 48 to 72 hours (see Fig. 7-8). As CK-MB is not as sensitive or specif c
or detection o myocardial injury as is cardiac troponin, the latter is the pre erred diagnostic
biomarker in clinical use. Because troponin and CK-MB levels do not become elevated in the
serum until at least a ew hours a ter the onset o MI symptoms, a single normal value drawn
early in the course o evaluation (e.g., in the hospital emergency department) does not rule
out an acute MI; thus, the diagnostic utility o these biomarkers is limited in that critical
period. As a result, early decision making in patients with ACS o ten relies most heavily on
the patient’s history and ECG f ndings.
Imaging
Sometimes, the early diagnosis o MI can remain uncertain even a ter care ul evaluation o the
patient’s history, ECG, and serum biomarkers. In such a situation, an additional diagnostic
study that may be use ul in the acute setting is echocardiography, which o ten reveals new
abnormalities o ventricular contraction in the region o ischemia or in arction.
178
Chapter 7
TREATMENT OF ACUTE CORONARY SYNDROMES
Success ul management o ACS requires rapid initiation o therapy to limit myocardial damage
and minimize complications. Therapy must address the intracoronary thrombus that incited
the syndrome and provide anti-ischemic measures to restore the balance between myocardial
oxygen supply and demand. Although certain therapeutic aspects are common to all ACS,
there is a critical di erence in the approach to patients who present with ST-segment elevation (STEMI) compared with those without ST-segment elevation (UA and NSTEMI). Patients
with STEMI typically have total occlusion o a coronary artery and or optimal therapy require
very rapid reper usion therapy (mechanical or pharmacologic), whereas patients without ST
elevation generally do not (see Fig. 7-9 and as discussed later in the chapter).
General in-hospital measures or any patient with ACS include admitting the patient to
an intensive care setting where continuous ECG monitoring or arrhythmias is undertaken.
The patient is initially maintained at bed rest to minimize myocardial oxygen demand, while
supplemental oxygen is provided (by ace mask or nasal cannula), i there is any degree o
hypoxemia, to improve oxygen supply. Analgesics, such as morphine, may be administered
to reduce chest pain and associated anxiety.
Acute Treatment of Unstable Angina and Non–ST-Elevation Myocardial
Infarction
The management o UA and NSTEMI is essentially the same and is there ore discussed as one
entity, whereas the approach to STEMI is described later. The primary ocus o treatment or
UA and NSTEMI consists o anti-ischemic medications to restore the balance between myocardial oxygen supply and demand, and antithrombotic therapy to prevent urther growth, and to
acilitate resolution o , the underlying partially occlusive coronary thrombus.
Anti-ischemic Therapy
The same pharmacologic agents used to decrease myocardial oxygen demand in chronic stable angina are appropriate in UA and NSTEMI but are o ten administered more aggressively.
β-Blockers decrease sympathetic drive to the myocardium, thus reducing oxygen demand,
and contribute to electrical stability. This group o drugs reduces the likelihood o progression rom UA to MI and lowers mortality rates in patients who present with in arction. In the
absence o contraindications (e.g., marked bradycardia, bronchospasm, decompensated heart
ailure, or hypotension), a β-blocker is usually initiated in the f rst 24 hours to achieve a target
heart rate o approximately 60 beats/ min. Such therapy is usually continued indef nitely a ter
hospitalization because o proven long-term mortality benef ts ollowing an MI.
Nitrates help bring about anginal relie through venodilation, which lowers myocardial
oxygen demand by diminishing venous return to the heart (reduced preload and there ore
less ventricular wall stress). Nitrates may also improve coronary ow and prevent vasospasm
through coronary vasodilation. In UA or NSTEMI, nitroglycerin is o ten initially administered
by the sublingual route, ollowed by a continuous intravenous in usion. In addition to providing symptomatic relie o angina, intravenous nitroglycerin is use ul as a vasodilator in
patients with ACS accompanied by heart ailure or severe hypertension.
Nondihydropyridine calcium channel antagonists (i.e., verapamil and diltiazem) exert antiischemic e ects by decreasing heart rate and contractility and through their vasodilatory properties (see Chapter 6). These agents do not con er mortality benef t to patients with ACS and
are reserved or those in whom ischemia persists despite β-blocker and nitrate therapies or or
those with contraindications to β-blocker use. They should not be prescribed to patients with LV
systolic dys unction, because clinical trials have shown adverse outcomes in that case.
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Acute Coronary Syndromes
179
Ac ute Co ro nary S yndro me
Revas c ularizatio n Pathways
ST Ele vatio n
(STEMI)
No n-ST Ele vatio n
(UA and NSTEMI)
Eme rge nt P CI ava ila ble within 90 min?
(120 min if tra ns fe rring to a P CI-ca pa ble hos pita l)
Ris k As s e s s me nt
(e.g., Troponin, ECG, TIMI S core )
Ye s
Primary PCI
No
Low
Fibrino lytic
The rapy
(if no contra indica tion)
Co ns e rvative s trate gy
(Proce e d to ca rdia c
ca th if a ngina re curs
or s ubs e que nt s tre s s
te s t s hows s ubs ta ntia l
is che mia )
High
Invas ive s trate gy
(Ea rly ca rdia c ca th
with P CI or CABG
a s dicta te d by
corona ry a na tomy)
A
Ac ute Co ro nary Syndro me
Co nc urre nt Tre atme nts
Anti-is c he mic
the rapie s
• -blocke r
• Nitra te s
• +/– CCB
Antithro mbo tic
the rapie s
Adjunc tive
the rapie s
Antiplate le t
ag e nts
Antic o ag ulants
(us e one )
• As pirin
• P 2Y12 inhibitor
• +/– GP IIb/IIIa
inhibitor
• UFH
• LMWH
• Biva lirudin
• S ta tin
• ACE inhibitor
B
FIGURE 7-9. Initial management strategies in acute coronary syndromes ( ACS) . A. Revascularization
options. Primary percutaneous coronary intervention (PCI) is the preferred approach for STEMI patients if it
is available rapidly. In UA/ NSTEMI, early invasive assessment is advised in patients with high-risk features.
B. Pharmacologic agents that are typically indicated in ACS. Platelet P2Y12 inhibitors include clopidogrel,
ticagrelor, and prasugrel. Note that when a glycoprotein (GP) IIb/ IIIa receptor antagonist is used as an
additional antiplatelet agent, it is typically initiated at the time of PCI. Bivalirudin is an anticoagulant
option for patients with ACS undergoing PCI. ECG, electrocardiogram; CCB, calcium channel blocker; LMWH,
low molecular weight heparin; UFH, unfractionated intravenous heparin; ACE, angiotensin-converting enzyme.
Antithrombotic Therapy
The purpose of antithrombotic therapy, including antiplatelet and anticoagulant medications,
is to prevent further propagation of the partially occlusive intracoronary thrombus while
facilitating its dissolution by endogenous mechanisms.
180
Chapter 7
Antiplatelet Drugs
The majority o patients with UA or NSTEMI should receive at least two orms o antiplatelet
therapy, typically aspirin and an inhibitor o the platelet P2Y12 ADP receptor.
Aspirin inhibits platelet synthesis o thromboxane A2, a potent mediator o platelet activation (see Chapter 17), and is one o the most important interventions to reduce mortality in
patients with all orms o ACS. It should be administered immediately on presentation and
continued indef nitely in patients without contraindications to its use (e.g., allergy or underlying bleeding disorder).
Aspirin inhibits only a single pathway o platelet activation. Another important agonist is
ADP, which activates platelets in part by binding to the platelet P2Y12 receptor (see Chapter 17).
Antagonists o this receptor inhibit platelet activation and include clopidogrel, prasugrel, and
ticagrelor. Clopidogrel is an oral thienopyridine derivative (described in Chapter 17) that
urther reduces cardiovascular death, recurrent MI, and stroke rates in patients with UA or
NSTEMI who are treated with aspirin.
However, not all patients respond to clopidogrel with similar benef t as it is a prodrug that
requires cytochrome P-450–mediated biotrans ormation to its active metabolite. Patients with
reduced unction polymorphisms o the CYP2C19 gene produce lower concentrations o clopidogrel’s activate metabolite, less platelet inhibition, and attenuated clinical benef ts. Thus,
newer P2Y12 ADP receptor blockers have been developed that do not have this metabolic
shortcoming, have more rapid onsets o action, and achieve greater degrees o platelet inhibition than clopidogrel. For example, prasugrel is also a thienopyridine derivative. Compared to
clopidogrel, it reduces coronary event rates in patients with ACS who undergo percutaneous
coronary intervention (PCI), but because it is more potent, it also increases the risk o bleeding complications.
Both clopidogrel and prasugrel are irreversible platelet inhibitors. Ticagrelor is a nonthienopyridine drug that is a reversible P2Y12 ADP receptor blocker. Compared to clopidogrel, it
has been shown to urther decrease major cardiovascular events and mortality, without an
increased risk o li e-threatening bleeding episodes; minor bleeding is, however, more common than with clopidogrel.
In some circumstances, even more power ul antiplatelet agents are utilized in ACSs. The
glycoprotein (GP) IIb/ IIIa receptor antagonists (which include the monoclonal antibody
abciximab and the small molecules eptif batide and tirof ban) are potent antiplatelet agents
that block the f nal common pathway o platelet aggregation (see Chapter 17). These agents
are e ective in reducing adverse coronary events in patients undergoing PCI. In patients presenting with UA or NSTEMI, their benef t is mani est primarily in those at the highest risk o
complications (e.g., the presence o elevated serum troponin levels or recurrent episodes o
chest pain). When used, GP IIb/ IIIa receptor antagonists are most commonly initiated in the
cardiac catheterization laboratory at the time o PCI.
Anticoagulant Drugs
Intravenous unfractionated heparin (UFH) has long been standard anticoagulant therapy or
UA and NSTEMI. It binds to antithrombin, which greatly increases the potency o that plasma
protein in the inactivation o clot- orming thrombin. UFH additionally inhibits coagulation
actor Xa, slowing thrombin ormation and thereby urther impeding clot development. In
patients with UA or NSTEMI, UFH improves cardiovascular outcomes and reduces the likelihood o progression rom UA to MI. It is administered as a weight-based bolus, ollowed by
continuous intravenous in usion. Because o a high degree o pharmacodynamic variability,
its anticoagulant e ect must be monitored and its dose adjusted, through serial measurements o the serum activated partial thromboplastin time (aPTT). It is the least expensive o
the anticoagulant drugs described in this section.
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Acute Coronary Syndromes
181
To overcome the pharmacologic shortcomings o UFH, low molecular weight heparins
(LMWHs) were developed. Like UFH, LMWHs interact with antithrombin but pre erentially
inhibit coagulation actor Xa. They provide a more predictable pharmacologic response than
UFH. As a result, LMWHs are easier to use, prescribed as one or two daily subcutaneous
injections based on the patient’s weight. Unlike UFH, repeated monitoring o blood tests
and dosage adjustments are not generally necessary. In clinical trials in patients with UA or
NSTEMI, the LMWH enoxaparin (see Chapter 17) has demonstrated reduced death and ischemic event rates compared with UFH.
Two other types o anticoagulants have also been shown to be benef cial in UA and
NSTEMI and are sometimes used in place o UFH or LMWH. Bivalirudin is an intravenous
direct thrombin inhibitor (see Chapter 17), which is equivalent to UFH plus a GP IIb/ IIIa
inhibitor in preventing adverse ischemic outcomes, with less associated bleeding, in patients
with UA or NSTEMI treated with an early invasive strategy. Fondaparinux is a subcutaneously administered agent that is a very specif c actor Xa inhibitor (see Chapter 17). Its e ect
is similar to the LMWH enoxaparin at reducing cardiac adverse events but with ewer bleeding complications.
With all o these choices, the decision o which anticoagulant to prescribe to an individual
patient o ten depends on whether an initial conservative versus invasive approach is ollowed.
Conservative versus Early Invasive Management of UA and NSTEMI
Many patients with UA or NSTEMI stabilize ollowing institution o the therapies described
in the previous section, while others have recurrent ischemic events. There is currently no
def nitive way to predict which direction a patient will take or to quickly determine which
individuals have such severe underlying CAD that coronary revascularization is warranted.
These uncertainties have led to two therapeutic strategies in UA/ NSTEMI: (1) an early invasive approach, in which urgent cardiac catheterization is per ormed and coronary revascularization undertaken as indicated, and (2) a conservative approach, in which the patient is
managed with medications (as detailed in the previous section) and undergoes angiography
only i ischemic episodes spontaneously recur or i the results o a subsequent stress test indicate substantial residual inducible ischemia. The conservative approach o ers the advantage
o avoiding costly and potentially risky invasive procedures. Conversely, an early invasive
strategy allows rapid identif cation and def nitive treatment (i.e., revascularization) or those
with critical coronary disease.
In general, an early invasive approach is recommended to patients with re ractory angina,
with complications such as shock or ventricular arrhythmias, or those with the most concerning clinical eatures. Risk assessment algorithms consider such eatures and help identi y
patients at high likelihood o a poor outcome. One commonly used tool is the Thrombolysis
in Myocardial Infarction (TIMI) risk score that employs seven variables to predict a patient’s
risk level:
1. Age greater than 65 years old
2. ≥ 3 risk actors or coronary artery disease (as described in Chapter 5)
3. Known coronary stenosis o ≥ 50% by prior angiography
4. ST-segment deviations on the ECG at presentation
5. At least two anginal episodes in prior 24 hours
6. Use o aspirin in prior 7 days (i.e., implying resistance to aspirin’s e ect)
7. Elevated serum troponin or CK-MB
Clinical studies have conf rmed that a patient’s TIMI risk score predicts the likelihood o
death or subsequent ischemic events, such that an early invasive strategy is recommended in
patients with higher scores (≥ 3). I an early invasive approach is adopted, the patient should
undergo angiography within 72 hours, or within 24 hours or patients at especially high risk.
182
Chapter 7
Acute Treatment of ST-Elevation Myocardial Infarction
In contrast to UA and NSTEMI, the culprit artery in STEMI is typically completely occluded.
Thus, to limit myocardial damage, the major ocus o acute treatment is to achieve very rapid
reper usion o the jeopardized myocardium using either percutaneous coronary mechanical
revascularization or f brinolytic drugs. These approaches reduce the extent o myocardial
necrosis and greatly improve survival. To be e ective, they must be undertaken as soon as
possible; the earlier the intervention occurs, the greater the amount o myocardium that can
be salvaged. Decisions about therapy must be made within minutes o a patient’s assessment,
based on the history and electrocardiographic f ndings, o ten be ore serum markers o necrosis would be expected to rise.
In addition, as is the case in UA and NSTEMI, specif c medications should be initiated
promptly to prevent urther thrombosis and to restore the balance between myocardial oxygen
supply and demand. For example, antiplatelet therapy with aspirin decreases mortality rates
and rates o rein arction a ter STEMI. It should be administered immediately on presentation (by
chewing a tablet to acilitate absorption) and continued orally daily therea ter. An anticoagulant
(e.g., intravenous UFH) is typically initiated to help maintain patency o the coronary vessel and
is an important adjunct to PCI and f brinolytic regimens. β-Blockers reduce myocardial oxygen
demand and lower the risk o recurrent ischemia, arrhythmias, and rein arction. In the absence
o contraindications (e.g., asthma, hypotension, or signif cant bradycardia), an oral β-blocker
should be administered to achieve a heart rate o 50 to 60 beats/ min. Intravenous β-blocker
therapy should be reserved or patients who are hypertensive at presentation, as that route o
administration has otherwise been associated with an increased risk o cardiogenic shock in
STEMI. Nitrate therapy, usually intravenous nitroglycerin, is used to help control ischemic pain
and also serves as a benef cial vasodilator in patients with heart ailure or severe hypertension.
Primary Percutaneous Coronary Intervention
The pre erred method o reper usion therapy in patients with acute STEMI is immediate cardiac catheterization and percutaneous coronary intervention o the lesion responsible or the
in arction. This approach, termed primary PCI, is a very e ective method or reestablishing
coronary per usion and, in clinical trials per ormed at highly experienced medical centers,
has achieved optimal ow in the in arct-related artery in more than 95% o patients. During
the procedure, per ormed under uoroscopy, a catheter is inserted into a peripheral artery
and directed to the site o coronary occlusion. A balloon at the end o the catheter is then
in ated, compressing the thrombus and atherosclerotic plaque, and a stent is usually inserted
(see Chapter 6), thereby restoring and maintaining coronary blood ow. In order to salvage
as much myocardium as possible, the goal is that the time rom f rst medical contact to PCI
be less than 90 minutes. At medical centers without PCI availability, the decision to trans er
a patient to a PCI-capable hospital or to treat with f brinolytic therapy (discussed in next
section) must be made rapidly. A delay in reper usion leads to worse outcomes or patients
regardless o the mechanism chosen, and the longer the delay, the less benef t primary PCI
has over f brinolytic therapy. Generally, trans er to a PCI-capable hospital is recommended i
the procedure can be per ormed within 120 minutes o f rst medical contact.
To reduce thrombotic complications, patients undergoing primary PCI receive a combination o medications. Aspirin and a P2Y12 receptor inhibitor (e.g., ticagrelor, prasugrel,
or clopidogrel) are the antiplatelet agents typically administered prior to the procedure. A
more potent GP IIb/ IIIa platelet inhibitor is also sometimes used with PCI. Anticoagulation
therapy consists o either UFH or bivalirudin as the primary choices. Recent evidence shows
that bivalirudin results in lower rates o bleeding in STEMI when compared to UFH plus a GP
IIb/ IIIa inhibitor. However, it is also associated with a higher rate o acute stent thrombosis
in this setting.
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Acute Coronary Syndromes
183
A ter primary PCI, aspirin is continued indef nitely. For patients who receive coronary
stents during PCI, a prolonged course o a P2Y12 receptor inhibitor reduces the risk o ischemic
complications and stent thrombosis.
Fibrinolytic Therapy
Primary PCI is the pre erred reper usion approach in acute STEMI, as it leads to greater survival
with lower rates o rein arction and bleeding when compared to f brinolytic therapy. However,
i PCI is not available or is likely to be delayed, f brinolytic therapy is the reper usion alternative. Fibrinolytic drugs accelerate lysis o the occlusive intracoronary thrombus in STEMI,
thereby restoring blood ow and limiting myocardial damage. This section does not pertain
to patients with UA or NSTEMI, as such individuals do not benef t rom f brinolytic therapy.
Currently used f brinolytic agents include recombinant tissue–type plasminogen activator
(alteplase, tPA), reteplase (rPA), and tenecteplase (TNK-tPA). Each drug unctions by stimulating the natural f brinolytic system, trans orming the inactive precursor plasminogen into the active
protease plasmin, which lyses f brin clots. Although the intracoronary thrombus is the target,
plasmin has poor substrate specif city and can degrade other proteins, including f brin’s precursor
f brinogen. As a result, bleeding is the most common complication o these drugs. Administration
o f brinolytic agents in the early hours o an acute STEMI restores blood ow in most (70% to
80% ) coronary occlusions and signif cantly reduces the extent o tissue damage. Improved artery
patency translates into substantially increased survival rates and ewer postin arction complications. The rapid initiation o f brinolysis is crucial: patients who receive therapy within 2 hours o
the onset o symptoms o STEMI have half the mortality rate o those who receive it a ter 6 hours.
To prevent immediate vessel reocclusion a ter success ul thrombolysis, anticoagulants
(UFH or LMWHs) and antiplatelet therapy, including aspirin and a platelet P2Y12 inhibitor,
are administered. For those initially treated with f brinolytic therapy who do not demonstrate
an adequate acute response, including expeditious resolution o symptoms and ST-segment
elevations, trans er o the patient to a hospital capable o per orming “rescue” PCI is recommended as soon as possible.
Because the major risk o thrombolysis is bleeding, contraindications to such therapy
include situations in which necessary f brin clots within the circulation would be jeopardized
(e.g., patients with active peptic ulcer disease or an underlying bleeding disorder, patients who
have had a recent stroke, or patients who are recovering rom recent surgery). Consequently,
approximately 30% o patients may not be suitable candidates or thrombolysis.
Adjunctive Therapies
Angiotensin-converting enzyme (ACE) inhibitors limit adverse ventricular remodeling and
reduce the incidence o heart ailure, recurrent ischemic events, and mortality ollowing an
MI. Their benef t is additive to that o aspirin and β-blocker therapies, and they have shown
avorable improvements especially in higher-risk patients—those with anterior wall in arctions or LV systolic dys unction.
Cholesterol-lowering statins (HMG-CoA reductase inhibitors) reduce mortality rates o
patients with coronary artery disease (see Chapter 5). Clinical trials o patients with ACS
have demonstrated that it is sa e to begin statin therapy early during hospitalization and that
a high-intensity lipid-lowering regimen, designed to reduce low-density lipoprotein (LDL)
levels by greater than 50% (ideally to < 70 mg/ dL), provides greater protection against subsequent cardiovascular events and death than less intense regimens. The benef ts o statin
therapy may extend beyond lipid lowering, because this group o drugs has attributes that can
improve endothelial dys unction, inhibit platelet aggregation, and impair thrombus ormation.
Additional LDL lowering with the cholesterol absorption inhibitor ezetimibe (see Chapter 17)
a ter an ACS was recently shown to urther reduce subsequent cardiovascular event rates.
184
Chapter 7
In addition to the short-term use o heparin anticoagulation described earlier, a more prolonged course, ollowed by oral anticoagulation (i.e., war arin), is appropriate or patients
at high risk o thromboembolism. This includes patients with documented intraventricular
thrombus (typically identif ed by echocardiography), those with atrial f brillation, and persons who have su ered a large acute anterior MI with akinesis o that territory (which is
susceptible to thrombus ormation because o the stagnant blood ow).
As discussed later in the chapter, impaired ventricular contractility a ter MI can lead to
heart ailure. Patients with a le t ventricular ejection raction o less than 40% and symptoms
o heart ailure a ter STEMI should be considered or therapy with an aldosterone antagonist
(spironolactone or eplerenone) in addition to an ACE inhibitor and beta-blocker. Aldosterone
augments sodium reabsorption rom the distal nephron (contributing to uid retention, an
undesired e ect in heart ailure) and also promotes in ammation and myocardial f brosis.
Chronic administration o an aldosterone antagonist mitigates these e ects and has been
shown to decrease mortality ollowing MI in patients with le t ventricular dys unction.
COMPLICATIONS
In UA, potential complications include death (5% to 10% o patients) or progression to in arction (10% to 20% o patients) over the ensuing days and weeks. Once in arction has transpired, especially STEMI, complications can result rom the in ammatory, mechanical, and
electrical abnormalities induced by regions o necrosing myocardium (Fig. 7-10). Early complications result rom myocardial necrosis itsel . Those that develop several days to weeks
later re ect the in ammation and healing o necrotic tissue.
Recurrent Ischemia
Postin arction angina has been reported in 20% to 30% o patients ollowing an MI. This rate
has not been reduced by the use o thrombolytic therapy, but it is lower in those who have
undergone acute percutaneous coronary revascularization. Indicative o inadequate residual
Myo c ardial Infarc tio n
Ve ntricula r
thrombus
Contra ctility
Ele ctrica l
ins ta bility
Embo lis m
Cardio g e nic
s ho ck
Arrhythmias
Is che mia
Tis s ue
ne cros is
Pe rica rdia l
infla mma tion
Pe ric arditis
Hypote ns ion
Corona ry
pe rfus ion
pre s s ure
Pa pilla ry
mus cle
infa rction/
is che mia
Ve ntricula r
s e pta l
de fe ct
Mitra l
re gurgita tion
Ve ntricula r
rupture
Cardiac
tampo nade
Co ng e s tive he art failure
FIGURE 7-10. Complications of MI. Infarction may result in decreased contractility, electrical instability, and
tissue necrosis, which can lead to the indicated sequelae.
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Acute Coronary Syndromes
185
TABLE 7-7 Arrhythmias in Acute Myocardial Infarction
Rhythm
Cause
Sinus bradycardia
•
•
•
•
•
•
•
•
•
•
•
•
Sinus tachycardia
APBs, atrial brillation
VPBs, VT, VF
AV block (1° , 2° , 3° )
↑Vagal tone
↓SA nodal artery per usion
Pain and anxiety
Heart ailure
Volume depletion
Chronotropic drugs (e.g., dopamine)
Heart ailure
Atrial ischemia
Ventricular ischemia
Heart ailure
IMI: ↑vagal tone and ↓AV nodal artery f ow
AMI: extensive destruction o conduction tissue
AMI, anterior myocardial in arction; APBs, atrial premature beats; AV, atrioventricular; IMI, in erior myocardial in arction; SA, sinoatrial; VPBs, ventricular premature beats; VF, ventricular brillation; VT, ventricular tachycardia.
coronary blood f ow, it is a poor omen and correlates with an increased risk or rein arction.
Such patients usually require urgent cardiac catheterization, o ten ollowed by revascularization by percutaneous techniques or coronary artery bypass surgery.
Arrhythmias
Arrhythmias occur requently during acute MI and are a major source o mortality prior to
hospital arrival. Fortunately, modern coronary care units are highly attuned to the detection and treatment o rhythm disturbances; thus, once a patient is hospitalized, arrhythmiaassociated deaths are uncommon. Mechanisms that contribute to arrhythmogenesis a ter MI
include the ollowing (Table 7-7):
1. Anatomic interruption o blood f ow to structures o the conduction pathway (e.g., sinoatrial node, atrioventricular node, and bundle branches); the normal per usion o pertinent
components o the conduction system is summarized in Table 7-8.
2. Accumulation o toxic metabolic products (e.g., cellular acidosis) and abnormal transcellular ion concentrations owing to membrane leaks.
3. Autonomic stimulation (sympathetic and parasympathetic).
4. Administration o potentially arrhythmogenic drugs (e.g., dopamine).
TABLE 7-8 Blood Supply of the Conduction System
Conduction Pathway
Primary Arterial Supply
SA node
AV node
Bundle o His
Right bundle branch
•
•
•
•
•
Le t bundle branch
Le t anterior ascicle
Le t posterior ascicle
RCA (70% o patients)
RCA (85% o patients)
LAD (septal branches)
Proximal portion by LAD
Distal portion by RCA
• LAD
• LAD and PDA
AV, atrioventricular; LAD, le t anterior descending coronary artery; PDA, posterior descending artery; RCA, right
coronary artery; SA, sinoatrial.
186
Chapter 7
Ventricular Fibrillation
Ventricular f brillation (rapid, disorganized electrical activity o the ventricles) is largely
responsible or sudden cardiac death during the course o acute MI. Most atal episodes occur
be ore hospital arrival, a trend that can be impacted by increasing availability o automatic
external def brillators in public places. Episodes o ventricular f brillation that occur during
the f rst 48 hours o MI are o ten related to transient electrical instability, and the long-term
prognosis o survivors o such events is not adversely a ected. However, ventricular f brillation occurring later than 48 hours a ter the acute MI usually re ects severe LV dys unction
and is associated with high subsequent mortality rates.
Ventricular ectopic beats, ventricular tachycardia, and ventricular f brillation during an
acute MI arise rom either reentrant circuits or enhanced automaticity o ventricular cells (see
Chapter 11). Ventricular ectopic beats are common and usually not treated unless the beats
become consecutive, multi ocal, or requent. Cardiac care unit personnel are prof cient at
arrhythmia detection and institution o treatment should more malignant ventricular arrhythmias develop. Therapy or ventricular arrhythmias is described in Chapter 12.
Supraventricular Arrhythmias
Supraventricular arrhythmias are also common in acute MI. Sinus bradycardia results rom
either excessive vagal stimulation or sinoatrial nodal ischemia, usually in the setting o an in erior wall MI. Sinus tachycardia occurs requently and may result rom pain and anxiety, heart
ailure, drug administration (e.g., dopamine), or intravascular volume depletion. Because sinus
tachycardia increases myocardial oxygen demand and could exacerbate ischemia, identi ying
and treating its cause are important. Atrial premature beats and atrial f brillation (see Chapter
12) may result rom atrial ischemia or atrial distention secondary to LV ailure.
Conduction Blocks
Conduction blocks (atrioventricular nodal block and bundle branch blocks) develop commonly in acute MI. They may result rom ischemia or necrosis o conduction tracts, or in the
case o atrioventricular blocks, they may develop transiently because o increased vagal tone.
Vagal activity may be increased because o stimulation o a erent f bers by the in amed myocardium or as a result o generalized autonomic activation in association with the discom ort
o an acute MI.
Myocardial Dysfunction
Heart Failure
Acute cardiac ischemia results in impaired ventricular contractility (systolic dys unction)
and increased myocardial sti ness (diastolic dys unction), both o which may lead to symptoms o heart ailure. In addition, ventricular remodeling, arrhythmias, and acute mechanical
complications o MI (described later in the chapter) may culminate in heart ailure. Signs
and symptoms o such decompensation include dyspnea, pulmonary rales, and a third heart
sound (S3). Treatment consists o standard heart ailure therapy, which typically includes
diuretics or relie o volume overload, and ACE inhibitor and β-blocker therapies or longterm mortality benef t (see Chapter 9). As noted earlier, or patients with post-MI heart ailure and an LV ejection raction less than 40% , an aldosterone antagonist (spironolactone or
eplerenone—described in Chapter 17) should be considered. However, when an aldosterone
antagonist is prescribed concurrently with an ACE inhibitor, the serum potassium level should
be care ully monitored to prevent hyperkalemia.
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Cardiogenic Shock
Cardiogenic shock is a condition o severely decreased cardiac output and hypotension
(systolic blood pressure < 90 mm Hg) with inadequate per usion o peripheral tissues that
develops when more than 40% o the LV mass has in arcted. It may also ollow certain
severe mechanical complications o MI described later. Cardiogenic shock is sel -perpetuating
because (1) hypotension leads to decreased coronary per usion, which exacerbates ischemic
damage, and (2) decreased stroke volume increases LV size and there ore augments myocardial oxygen demand (see Fig. 7-10). Cardiogenic shock occurs in up to 10% o patients a ter
MI, and the mortality rate is greater than 70% . Early cardiac catheterization and revascularization can improve the prognosis.
Patients in cardiogenic shock require intravenous inotropic agents (e.g., dobutamine) to
increase cardiac output and, once the blood pressure has improved, arterial vasodilators to
reduce the resistance to LV contraction. Patients may be stabilized by the placement o an
intra-aortic balloon pump. Inserted into the aorta through a emoral artery, the pump consists o an in atable, exible chamber that expands during diastole to increase intra-aortic
pressure, thus augmenting per usion o the coronary arteries. During systole, it de ates to
create a “vacuum” that serves to reduce the a terload o the le t ventricle, thus aiding the
ejection o blood into the aorta and improving cardiac output and peripheral tissue per usion.
I more extensive and prolonged hemodynamic support is required, a percutaneous left
ventricular assist device (LVAD) can be placed. Using cannulae inserted via the emoral vessels, a motor pumps oxygenated blood rom the LA or the LV (depending on the model) to the
aorta and its branches, bypassing or “assisting” the LV.
Right Ventricular Infarction
Approximately one third o patients with in arction o the LV in erior wall also develop necrosis o portions o the right ventricle, because the same coronary artery (usually the right
coronary) per uses both regions in most individuals. The resulting abnormal contraction and
decreased compliance o the right ventricle lead to signs o right-sided heart ailure (e.g.,
jugular venous distention) out o proportion to signs o le t-sided ailure. In addition, proound hypotension may result when the right ventricular dys unction impairs blood ow
through the lungs, leading to the le t ventricle becoming underf lled. In this setting, intravenous volume in usion serves to correct hypotension, o ten guided by hemodynamic measurements via a transvenous pulmonary artery catheter (see Chapter 3).
Mechanical Complications
Mechanical complications ollowing MI result rom cardiac tissue ischemia and necrosis.
Papillary Muscle Rupture
Ischemic necrosis and rupture o an LV papillary muscle may be rapidly atal because o acute
severe mitral regurgitation, as the valve lea ets lose their anchoring attachments. Partial rupture, with more moderate regurgitation, is not immediately lethal but may result in symptoms
o heart ailure or pulmonary edema. Because it has a more precarious blood supply, the
posteromedial LV papillary muscle is more susceptible to in arction than the anterolateral one.
Ventricular Free Wall Rupture
An in requent but deadly complication, rupture o the LV ree wall through a tear in the
necrotic myocardium may occur within the f rst 2 weeks ollowing MI. It is more common
188
Chapter 7
among women and patients with a history o hypertension. Hemorrhage into the pericardial space owing to LV ree wall rupture results in rapid cardiac tamponade, in which blood
f lls the pericardial space and severely restricts ventricular f lling (see Chapter 14). Survival
is rare.
On occasion, a pseudoaneurysm results i rupture o the ree wall is incomplete and held
in check by thrombus ormation that “plugs” the hole in the myocardium. This situation is
the cardiac equivalent o a time bomb, because subsequent complete rupture into the pericardium and tamponade could ollow. I detected (usually by imaging studies), surgical repair
may prevent an otherwise disastrous outcome.
Ventricular Septal Rupture
This complication is analogous to LV ree wall rupture, but the abnormal ow o blood is not
directed across the LV wall into the pericardium. Rather, blood is shunted across the ventricular septum rom the le t ventricle to the right ventricle, usually precipitating congestive heart
ailure because o subsequent volume overload o the pulmonary capillaries. A loud systolic
murmur at the le t sternal border, representing transseptal ow, is common in this situation.
Although each results in a systolic murmur, ventricular septal rupture can be di erentiated
rom acute mitral regurgitation by the location o the murmur (see Fig. 2-11), by Doppler
echocardiography, or by measuring the O2 saturation o blood in the right-sided heart chambers through a transvenous catheter. The O2 content in the right ventricle is abnormally higher
than that in the right atrium i there is shunting o oxygenated blood rom the le t ventricle
across the septal de ect.
True Ventricular Aneurysm
A late complication o MI, a true ventricular aneurysm, may come to attention weeks to
months a ter the acute in arction. It develops as the ventricular wall is weakened, but not
per orated, by the phagocytic clearance o necrotic tissue, and it results in a localized outward bulge (dyskinesis) when the residual viable heart muscle contracts. Unlike the pseudoaneurysm described earlier, a true aneurysm does not involve communication between
the LV cavity and the pericardium, so that rupture and tamponade do not develop. Potential
complications o LV aneurysm include (1) thrombus ormation within this region o stagnant
blood ow, serving as a source o emboli to peripheral organs; (2) ventricular arrhythmias
associated with the stretched myof bers; and (3) heart ailure resulting rom reduced orward
cardiac output, because some o the LV stroke volume is “wasted” by f lling the aneurysm
cavity during systole.
Clues to the presence o an LV aneurysm include persistent ST-segment elevations on the
ECG weeks a ter an acute ST-elevation MI and a bulge at the LV border on chest radiography.
The abnormality can be conf rmed by echocardiography or other imaging modalities.
Pericarditis
Acute pericarditis may occur in the early (in-hospital) post-MI period as in ammation
extends rom the myocardium to the adjacent pericardium. Sharp pain, ever, and a pericardial riction rub are typically present in this situation and help distinguish pericarditis
rom the discom ort o recurrent myocardial ischemia (see Chapter 14). The symptoms usually promptly respond to aspirin therapy. Anticoagulants are relatively contraindicated in
MI complicated by pericarditis to avoid hemorrhage rom the in amed pericardial lining.
The requency o MI-associated pericarditis has declined since the introduction o acute
reper usion strategies, because those approaches limit the extent o myocardial damage and
in ammation.
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Acute Coronary Syndromes
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Dressler Syndrome
Dressler syndrome is now a rare orm o pericarditis that can occur weeks ollowing an
MI. The cause is unclear, but an immune process directed against damaged myocardial
tissue is suspected to play a role. The syndrome is heralded by ever, malaise, and sharp;
pleuritic chest pain typically accompanied by leukocytosis; an elevated erythrocyte sedimentation rate; and a pericardial e usion. Similar to other orms o acute pericarditis,
Dressler syndrome generally responds to aspirin or other nonsteroidal anti-in ammatory
therapies.
Thromboembolism
Stasis o blood ow in regions o impaired LV contraction a ter an MI may result in intracavity thrombus ormation, especially when the in arction involves the LV apex or when a
true aneurysm has ormed. Subsequent thromboemboli can result in in arction o peripheral
organs (e.g., a cerebrovascular event [stroke] caused by embolism to the brain).
RISK STRATIFICATION AND MANAGEMENT FOLLOWING MYOCARDIAL
INFARCTION
The most important predictor o post-MI outcome is the extent o LV dys unction. Other eatures that portend adverse outcomes include early recurrence o ischemic symptoms, a large
volume o residual myocardium still at risk because o severe underlying coronary disease,
and high-grade ventricular arrhythmias.
To identi y patients at high risk or complications who may benef t rom cardiac catheterization and revascularization, exercise treadmill testing is o ten per ormed (unless the patient
has already undergone catheterization and corrective percutaneous revascularization or the
presenting coronary syndrome). Patients with signif cantly abnormal results, or those who
demonstrate an early spontaneous recurrence o angina, are customarily re erred or cardiac
catheterization to def ne their coronary anatomy.
Standard postdischarge therapy or the long-term includes aspirin, a β-blocker, and a
high-intensity HMG-CoA reductase inhibitor (statin). A P2Y12 platelet inhibitor is continued
or 12 months or longer. ACE inhibitors are prescribed to patients who have LV contractile dys unction; an aldosterone antagonist should be considered in those with heart ailure
symptoms. Rigorous attention to underlying cardiac risk actors, such as smoking, hypertension, and diabetes, is mandatory, and a ormal exercise rehabilitation program o ten speeds
convalescence.
Patients who have an LV ejection raction o ≤ 30% a ter MI are at high risk o sudden cardiac death and are candidates or prophylactic placement o an implantable
cardioverter–def brillator. Current guidelines recommend postponing such implantation
or at least 40 days post-MI because clinical trials have not shown a survival benef t at
earlier stages.
SUMMARY
• Acute coronary syndromes (ACSs) include unstable angina (UA), non–ST-segment elevation myocardial in arction (NSTEMI), and ST-segment elevation myocardial in arction
(STEMI).
• Most ACS episodes are precipitated by intracoronary thrombus ormation at the site o atherosclerotic plaque disruption.
• Distinctions among types o ACS are based on the severity o ischemia and whether myocardial necrosis results: STEMI is associated with an occlusive thrombus and severe ischemia
190
Chapter 7
•
•
•
•
•
•
•
•
•
•
•
•
with necrosis, whereas ACSs without ST elevation (NSTEMI and UA) usually result rom partially occlusive thrombi with less intense ischemia; however, compared with UA, the insult
in NSTEMI is o su f cient magnitude to cause some myocardial necrosis.
ACSs result in biochemical and mechanical changes that impair systolic contraction, decrease
myocardial compliance, and predispose to arrhythmias; in arction initiates an in ammatory
response that clears necrotic tissue and leads to scar ormation.
The diagnosis o specif c ACS relies on the patient’s history, ECG abnormalities, and the presence o specif c biomarkers in the serum (e.g., cardiac troponin T or troponin I).
Acute treatment o UA and NSTEMI includes anti-ischemic therapy to restore the balance
between myocardial oxygen supply and demand (e.g., β-blockers, nitrates), antithrombotic
therapy to acilitate resolution o the intracoronary thrombus (e.g., aspirin, a P2Y12 ADP
receptor antagonist, an anticoagulant [e.g., intravenous or low molecular weight heparin],
and sometimes a glycoprotein IIb/ IIIa receptor antagonist), and high-intensity statin therapy.
Early coronary angiography, with subsequent coronary revascularization, is benef cial or UA
or NSTEMI patients with high-risk eatures.
Acute treatment o STEMI includes rapid coronary reper usion, ideally with percutaneous
catheter-based intervention i available or else f brinolytic therapy.
Other important therapies or STEMI include antiplatelet therapy (aspirin, P2Y12 receptor
antagonist), an anticoagulant, a β-blocker, sometimes nitrate therapy, and a statin; an ACE
inhibitor is requently appropriate.
Potential complications o in arction include arrhythmias (e.g., ventricular tachycardia and
f brillation, and supraventricular tachycardias) and conduction blocks (atrioventricular
blocks and bundle branch blocks).
Heart ailure or cardiogenic shock may develop because o ventricular dys unction or
mechanical complications (e.g., acute mitral regurgitation or ventricular septal de ect); wall
motion abnormalities o the in arcted segment may predispose to thrombus ormation.
Right ventricular in arction results in signs o right heart ailure out o proportion to le t heart
ailure, o ten with intravascular volume sensitivity and hypotension.
Standard pharmacologic therapy ollowing discharge rom the hospital a ter an ACS includes
measures to reduce the risks o thrombosis (aspirin and a P2Y12 receptor antagonist), recurrent ischemia (a β-blocker), progressive atherosclerosis (high-intensity statin), and adverse
ventricular remodeling (an ACE inhibitor, especially i le t ventricular [LV] dys unction is
present).
Adding an aldosterone antagonist should be considered or patients with heart ailure.
Systemic anticoagulation with war arin is indicated i an intraventricular thrombus, a large
akinetic segment, or atrial f brillation is present.
Ack n ow le d gm en t s
The authors thank Frederick Schoen, MD, or his help ul suggestions. Contributors to previous editions o this chapter were June-Wha Rhee, MD; Haley Naik, MD; Anurag Gupta, MD;
J. G. Fletcher, MD; William Carlson, MD; and Patrick T. O’Gara, MD.
Ad d i t i o n a l Rea d i n g
Giugliano RP, Braunwald E. The year in non-ST-segment
elevation acute coronary syndrome. J Am Coll Cardiol.
2014;63:201–214.
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/
ACC Guideline or the Management o Patients With
Non–ST-Elevation Acute Coronary Syndromes: A report
o the American College o Cardiology/ American Heart
Association Task Force on Practice Guidelines. Circulation.
2014;130:e344-e426.
Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/ AHA
Focused update o the guideline or the management o
patients with unstable angina/ non-ST-elevation myocardial in arction: A report o the American College o
Cardiology Foundation/ American Heart Association
Task Force on Practice Guidelines. Circula tion .
2012;126:875–910.
Mega JL, Simon T, Collet JP, et al. Reduced unction CYP2C19
genotype and risk o adverse clinical outcomes among
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Acute Coronary Syndromes
patients treated with clopidogrel predominately for PCI: a
meta-analysis. JAMA. 2010;304:1821–1830.
O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/ AHA
Guideline for the management of ST-elevation myocardial
infarction: Executive summary: a report of the American
College of Cardiology Foundation/ American Heart
Association Task Force on Practice Guidelines. Circulation.
2013;127:529–555.
Stone GW, Clayton T, Deliargyris EN, et al. Reduction
in cardiac mortality with bivalirudin in patients with
and without major bleeding: The HORIZONS-AMI trial
(harmonizing outcomes with revascularization and
191
stents in acute myocardial infarction). J Am Coll Ca rdiol.
2014;63:15–20.
Cavender MA and Sabatine MS. Bivalirudin versus heparin in
patients planned for percutaneous coronary intervention:
a meta-analysis of randomised controlled trials. Lancet.
2014;384:599-606.
Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA
guideline on the treatment of blood cholesterol to reduce
atherosclerotic cardiovascular risk in adults: A report
on the American College of Cardiology/ American Heart
Association task force on practice guidelines. J Am Coll
Cardiol. 2014;63:2889–934.
Valvular Heart Disease
Eliza beth Ryzna r
Pa trick T. O’Ga ra
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Mitral Valve Disease
Mitral Stenosis
Mitral Regurgitation
Mitral Valve Prolapse
Aortic Valve Disease
Aortic Stenosis
Aortic Regurgitation
Tricuspid Valve Disease
Tricuspid Stenosis
Tricuspid Regurgitation
Pulmonic Valve Disease
Pulmonic Stenosis
Pulmonic Regurgitation
Prosthetic Valves
Infective Endocarditis
Pathogenesis
Clinical Mani estations
Treatment
Prevention
T
8
his chapter describes the pathophysiologic abnormalities in patients with common valvular heart diseases. Each condition is discussed separately because
uni ying principles do not govern the behavior o all stenotic or regurgitant valves. E ective patient management
requires accurate identif cation o the valve lesion, a determination o its severity, and a clear understanding o the
pathophysiologic consequences and natural history o t he
condition.
The evaluation o a patient with suspected valvular
disease begins at the bedside with a care ul history and
physical examination rom which the trained clinician can
usually identi y the type o abnormality present. Def nitive diagnosis is most o ten achieved with transthoracic
echocardiography (TTE), which allows or staging o disease
severity. In selected patients, additional investigation with
exercise testing or cardiac catheterization may be necessary to ully def ne the signif cance o the condition and
guide therapy.
Management o patients with heart valve disease o ten
involves serial clinical and echocardiographic assessments.
Pharmacologic therapy is sometimes prescribed or symptomatic improvement, but recognition o timely indications or
valve repair or replacement is essential, as will be described
or each valve lesion.
192
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Valvular Heart Disease
193
MITRAL VALVE DISEASE
Mitral Stenosis
Etiology
By ar, the most common underlying cause o mitral stenosis (MS) is prior rheumatic ever
(see Box 8-1). Approximately 50% to 70% o patients with symptomatic MS provide a history
o acute rheumatic ever occurring, on average, 20 years be ore presentation. Other rare etiologies o MS include calci cation o the mitral annulus that extends onto the leaf ets, in ective
BOX 8-1
Rheumatic Fever
Acute rheumatic ever (ARF) is an inf ammatory condition that primarily a ects the heart, skin,
and connective tissues. Its incidence has waned greatly in the past century in industrialized
societies, where it is now rare, but it remains a major burden in developing countries. ARF arises
as a complication o pharyngitis caused by group A beta-hemolytic streptococci and mainly a f icts
children and young adults. During prior epidemics, approximately 3% o patients with acute
streptococcal pharyngitis developed ARF 2 to 3 weeks a ter the initial throat in ection. Common
presenting symptoms are chills, ever, atigue, and migratory arthritis. The cardinal clinical
mani estations that establish the diagnosis are known as Jones criteria (see Table below).
Involvement o the heart is thought to result rom autoimmune cross-reactivity between bacterial
and cardiac antigens. Pathologically, carditis (cardiac inf ammation) a f icts all layers o the heart
(pericardium, myocardium, and endocardium). Histopathologic examination may demonstrate
Aschoff bodies, areas o ocal brinoid necrosis surrounded by inf ammatory cells (see Figure) that
later resolve to orm brous scar tissue. During the acute episode, carditis may cause tachycardia,
impaired ventricular contractility, a pericardial riction rub, and transient heart murmurs that ref ect
turbulent f ow across inf amed valve leaf ets. Treatment o the acute episode includes high-dose
aspirin to reduce inf ammation and penicillin to eliminate residual streptococcal in ection.
The most important sequela o ARF is chronic rheumatic heart disease (RHD) characterized
by permanent de ormity and impairment o one or more cardiac valves. Symptoms o valvular
dys unction, however, do not mani est until 10 to 30 years a ter ARF has subsided. This latency
period may be shorter with more aggressive disease sometimes observed in developing countries.
RHD a ects the mitral valve in almost all cases, the aortic valve in 20% to 30%, and rarely the
tricuspid valve as well. Stenosis and/ or regurgitation o each valve can result.
Management o RHD includes prophylaxis against recurrent streptococcal in ection and
treatment o the chronic valve lesions. Recurrences o ARF can incite urther cardiac damage, so
individuals with ARF should receive preventive low-dose penicillin prophylaxis at least until early
adulthood, by which time exposure and susceptibility to streptococcal in ections have diminished.
Figure. Histopathology of an Aschoff body in acute rheumatic carditis. Mononuclear
inf ammatory cells surround a center o ocal necrosis. (Courtesy o Dr. Frederick J. Schoen,
Brigham and Women’s Hospital, Boston.)
(continues on page 194)
194
Chapter 8
BOX 8-1
Rheumatic Fever ( continued )
Criteria for Diagnosis of Rheumatic Fevera
Major criteria
Carditis (inf ammation o all three heart layers)
Migratory arthritis (mainly large joints)
Sydenham chorea (involuntary movements)
Erythema marginatum (skin rash with advancing edge and clearing center)
Subcutaneous nodules
Minor criteria
Arthralgias
Fever
Elevated acute-phase reactants (ESR, CRP)
Prolonged PR interval on electrocardiogram
Evidence of group A streptococcal infection
Antistreptolysin O antibodies
Positive throat culture or rapid antigen test
a
Diagnosis requires evidence o streptococcal in ection and either: two major criteria or one major plus two
minor criteria.
ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
endocarditis with large vegetations that obstruct the valve ori ce, and rare congenital stenosis
o the valve.
Pathology
Acute and recurrent inf ammation produces the typical pathologic eatures o MS due to rheumatic heart disease. These include brous thickening and calci cation o the valve leaf ets,
usion o the commissures (the borders where the leaf ets meet), and thickening and shortening o the chordae tendineae.
Pathophysiology
In early diastole in the normal heart, the mitral valve opens and blood f ows reely rom the
le t atrium (LA) into the le t ventricle (LV), such that there is a negligible pressure di erence
between the two chambers. In MS, however, there is obstruction to blood f ow across the
valve such that emptying o the LA is impeded and there is an abnormal pressure gradient
between the LA and LV (Figs. 8-1 and 8-2). As a result, the le t atrial pressure increases.
Hemodynamic changes become apparent when the cross-sectional area o the valve, normally
4 to 6 cm 2, is reduced to less than 2 cm 2.
The high le t atrial pressure in MS is transmitted retrograde to the pulmonary circulation,
resulting in increased pulmonary venous and capillary pressures (see Fig. 8-1). This elevation
o hydrostatic pressure in the pulmonary vasculature may cause transudation o plasma into
the lung interstitium and alveoli. The patient may there ore experience dyspnea and other
symptoms o heart ailure (as described in Chapter 9). In severe cases, signi cant elevation
o pulmonary venous pressure leads to the opening o collateral channels between the pulmonary and bronchial veins. Subsequently, an engorged bronchial vein may rupture into a
bronchus, resulting in hemoptysis (coughing up blood).
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Valvular Heart Disease
195
Eleva te d pulmona ry
a nd right he a rt pre s s ure s
Pre s s ure
Volume
Aorta
LA
FIGURE 8-1. Pathophysiology o
mitral stenosis. In the normal heart,
blood f ows reely rom the le t atrium
(LA) into the le t ventricle (LV) during
diastole (blue arrow). In mitral stenosis,
there is obstruction to LA emptying
(red arrow). Thus, the LA pressure
increases, which in turn elevates
pulmonary and right heart pressures.
LV
No rmal (dias to le )
Mitral s te no s is
The elevation o le t atrial pressure in MS can result in two distinct orms o pulmonary
hypertension: passive and reactive. Most patients with MS exhibit passive pulmonary hypertension, related to the backward transmission o the elevated LA pressure into the pulmonary
vasculature as described in the previous paragraph. This actually represents an “obligatory”
increase in pulmonary artery pressure that preserves orward f ow in the setting o increased
le t atrial and pulmonary venous pressures. Additionally, approximately 40% o patients with
MS demonstrate reactive pulmonary hypertension with medial hypertrophy and intimal brosis o the pulmonary arterioles. Reactive pulmonary hypertension initially serves a “bene cial” role because the increased arteriolar resistance impedes blood f ow into the engorged
pulmonary capillary bed and thus reduces capillary hydrostatic pressure (thereby “protecting” the pulmonary capillaries rom even higher pressures). However, this bene t is at the
cost o decreased blood f ow through the pulmonary vasculature and elevation o the rightsided heart pressures, as the right ventricle pumps against the increased resistance. Chronic
ECG
FIGURE 8-2. Hemodynamic prof le
o mitral stenosis. The le t atrial (LA)
pressure is elevated, and there is a
pressure gradient (shaded area) between
the LA and le t ventricle (LV) during
diastole. Compare with schematic o
normal tracing (see Fig. 2-1). Abnormal
heart sounds are present: there is
a diastolic opening snap (OS) that
corresponds to the opening o the mitral
valve, ollowed by a decrescendo murmur.
There is an accentuation o the murmur
just be ore S1 owing to the increased
pressure gradient when the LA contracts
in patients in sinus rhythm (presystolic
accentuation).
LA
OS
196
Chapter 8
elevation o right ventricular pressure leads to hypertrophy and dilatation o that chamber and
ultimately to right-sided heart ailure.
Chronic pressure overload o the LA in MS leads to le t atrial enlargement. Le t atrial
dilatation stretches the atrial conduction bers and may disrupt the integrity o the cardiac conduction system, resulting in atrial f brillation (a rapid irregular heart rhythm; see Chapter 12).
Atrial brillation contributes to a decline in cardiac output in MS because the increased heart
rate shortens diastole. This reduces the time available or blood to f ow across the obstructed
mitral valve to ll the LV, and, at the same time, urther augments the elevated le t atrial pressure. In addition, with atrial brillation, there is a loss o the late diastolic atrial contraction
that normally contributes to LV lling.
The relative stagnation o blood f ow in the dilated LA in MS, especially when combined
with the development o atrial brillation, predisposes to intra-atrial thrombus ormation.
Thromboemboli to the brain and other organs may ollow, leading to devastating complications such as cerebrovascular occlusion (stroke). Thus, MS patients who develop atrial brillation require chronic anticoagulation therapy.
The consequences o MS primarily a ect the le t atrium and the pulmonary vasculature,
as described above. Le t ventricular pressures are usually normal, but impaired lling o the
chamber through the stenotic valve may reduce LV stroke volume and cardiac output.
Clinical Manifestations and Evaluation
Presentation
The natural history o MS is variable. Survival exceeds 80% in asymptomatic or minimally symptomatic patients at 10 years. However, the 10-year survival o untreated patients a ter onset o
symptoms is only 50-60% . Longevity is much more limited or patients with advanced symptoms
and is dismal or those who develop signi cant pulmonary hypertension, with a mean survival o
less than 3 years.
The clinical presentation o MS depends largely on the degree o reduction o the valve
area. The more severe the stenosis, the greater the symptoms related to elevation o le t
atrial and pulmonary venous pressures. The earliest mani estations are those o dyspnea and
reduced exercise capacity. In mild MS, dyspnea may be absent at rest; however, it develops
on exertion as LA pressure rises with the exercise-induced increase in blood f ow through the
heart and aster heart rate (i.e., decreased diastolic lling time). Other conditions and activities that augment heart rate and cardiac blood f ow and precipitate or exacerbate symptoms
o MS include ever, anemia, hyperthyroidism, pregnancy, rapid arrhythmias such as atrial
brillation, emotional stress, and sexual intercourse.
With more severe MS (i.e., a smaller valve area), dyspnea occurs even at rest. Increasing
atigue and more severe signs o pulmonary congestion, such as orthopnea and paroxysmal nocturnal dyspnea (described in Chapter 9), occur. With advanced MS and pulmonary
hypertension, signs o right-sided heart ailure ensue, including jugular venous distention,
hepatomegaly, ascites, and peripheral edema. Compression o the recurrent laryngeal nerve
by an enlarged pulmonary artery or LA may cause hoarseness (known as Ortner syndrome).
Less o ten, the diagnosis o MS is heralded by one o its complications: atrial brillation,
thromboembolism, in ective endocarditis, or hemoptysis, as described in the earlier section
on Pathophysiology.
Examination
On examination, there are several typical ndings o MS. Palpation o the chest may reveal
a right ventricular “tap” in patients with increased right ventricular pressure. Auscultation
discloses a loud S1 (the rst heart sound, which is associated with mitral valve closure) in the
early stages o the disease. The increased S1 results rom the high pressure gradient between
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Valvular Heart Disease
197
the atrium and ventricle, which keeps the mobile portions o the mitral valve leaf ets widely
separated throughout diastole; at the onset o systole, ventricular contraction abruptly slams
the leaf ets together rom a relatively wide position, causing the closure sound to be more
prominent (see Chapter 2). In late stages o the disease, the intensity o S1 may normalize or
become reduced as the valve leaf ets thicken, calci y, and become less mobile.
A main eature o auscultation in MS is a high-pitched “opening snap” (OS) that ollows
S2. The OS is thought to result rom the sudden tensing o the chordae tendineae and stenotic leaf ets on opening o the abnormal valve. The interval between S2 and the OS relates
inversely to the severity o MS. That is, the more severe the MS, the higher the LA pressure
and the earlier the valve is orced open in diastole. The OS is ollowed by a low- requency
decrescendo murmur (termed diastolic rumble) caused by turbulent f ow across the stenotic
valve during diastole (see Fig. 8-2). The duration, but not the intensity, o the diastolic murmur relates to the severity o MS. The more severe the stenosis, the longer it takes or the
LA to empty and or the gradient between the LA and LV to dissipate. Near the end o diastole, contraction o the LA in patients in sinus rhythm causes the pressure gradient between
the LA and LV to rise again (see Fig. 8-2); there ore, the murmur brief y becomes louder at
that time (termed presystolic accentuation). This nal accentuation o the murmur does not
occur i atrial brillation has developed because there is no e ective atrial contraction in that
situation.
Murmurs caused by other valve lesions are o ten ound concurrently in patients with MS.
For example, mitral regurgitation (discussed later in this chapter) requently coexists with MS.
Additionally, right-sided heart ailure caused by severe MS may induce tricuspid regurgitation
as a result o right ventricular enlargement. A diastolic decrescendo murmur along the le t
sternal border may be present owing to coexistent aortic regurgitation (because o rheumatic
involvement o the aortic leaf ets) or pulmonic regurgitation (because o MS-induced pulmonary hypertension).
The electrocardiogram in MS routinely shows le t atrial enlargement and, i pulmonary
hypertension has developed, right ventricular hypertrophy. Atrial brillation may be present. The chest radiograph reveals le t atrial enlargement, pulmonary vascular redistribution,
interstitial edema, and Kerley B lines resulting rom edema within the pulmonary septae (see
Chapter 3). With the development o pulmonary hypertension, right ventricular enlargement
and prominence o the pulmonary arteries appear.
Echocardiography is o major diagnostic value in MS. Structural ndings include thickened mitral leaf ets with abnormal usion o their commissures and restricted separation
during diastole. The degree o le t atrial enlargement can be quanti ed, and i present, intraatrial thrombus may be visualized. The mitral valve area can be measured directly on crosssectional views or calculated rom Doppler velocity measurements (a technique known as
the “diastolic pressure hal -time”). Patients can be strati ed into stages o disease severity
based partly on the mitral valve area. A normal mitral valve ori ce measures between 4 and
6 cm 2. Current guidelines de ne clinically important “severe” MS as a valve area ≤ 1.5 cm 2, a
state that is typically accompanied by LA enlargement and elevated pulmonary artery systolic
pressure. A valve area ≤ 1.0 cm 2 is termed “very severe” MS. I the ndings determined by
echocardiography seem milder than the patient’s history and examination suggest, an exercise
test with accompanying Doppler assessment, or cardiac catheterization may be warranted to
urther de ne hemodynamic measurements.
Treatment
Salt intake restriction and diuretic therapy may improve symptoms due to vascular congestion. Heart rate slowing agents, such as β-blockers or nondihydropyridine calcium channel
blockers (e.g., diltiazem or verapamil, see Chapter 17), increase diastolic LV lling time and
there ore ease symptoms that occur during exercise. These drugs, or digoxin, are similarly
use ul to slow the ventricular rate in patients with accompanying rapid atrial brillation.
198
Chapter 8
Anticoagulant therapy to prevent thromboembolism is recommended or MS patients with
atrial brillation, or an identi ed atrial thrombus, or prior embolic events.
Percutaneous or surgical valve interventions are the only treatments that alter the natural
history o MS and are indicated in patients with severe, symptomatic MS. Percutaneous balloon
mitral valvuloplasty is the treatment o choice in appropriately selected patients (those without
advanced anatomic de ormity o the valve, mitral regurgitation, or le t atrial thrombus). During
this procedure, a balloon catheter is advanced rom the emoral vein into the right atrium,
across the atrial septum (by intentionally puncturing the interatrial septum), and through the
narrowed mitral valve ori ce. The balloon is then rapidly inf ated, thereby “cracking” open the
used commissures. The short- and long-term results o this procedure are typically excellent
and compare avorably with those o surgical treatment in anatomically appropriate patients.
In young adults with the most suitable anatomy or the procedure, the event- ree survival rate
approaches 80% to 90% over 3 to 7 years o ollow-up. Approximately 5% o patients undergoing balloon mitral valvuloplasty are le t with a residual atrial septal de ect due to the transseptal
puncture. Less requent complications include cerebral emboli at the time o valvuloplasty, cardiac per oration by the catheter, or the unintentional creation o substantial mitral regurgitation.
Open mitral valve commissurotomy (an operation in which the stenotic commissures are
separated under direct visualization) may be undertaken in patients or whom percutaneous
balloon valvuloplasty is not easible or success ul. It is e ective in relieving obstruction, and
restenosis occurs in ewer than 20% o patients over 10 to 20 years o ollow-up. Perioperative
mortality rates are low (2% ). Mitral valve replacement is considered in patients who are not
appropriate candidates or balloon valvuloplasty or open commissurotomy.
Mitral Regurgitation
Etiology
The mitral valve apparatus is a complex structure composed o an annulus, two leaf ets,
chordae tendineae, and papillary muscles, supported by the adjacent myocardium to which
the annulus and papillary muscles are attached (Fig. 8-3). Disruption to the structural integrity o any o these components or their coordinated action can result in abnormal closure
o the valve during systole, with ensuing mitral regurgitation (MR). MR is categorized as
Mitra l a nnulus
Le ft a trium
• Annula r ca lcifica tion
Le a fle ts
• Myxoma tous de ge ne ra tion (“MVP ”)
• Rhe uma tic dis e a s e
• Endoca rditis
• SAM (hype rtrophic ca rdiomyopa thy)
Chorda e te ndine a e
• Rupture (idiopa thic)
• Endoca rditis
Pa pilla ry mus cle s
• Dys function or rupture
Le ft ve ntricle
• Cavity dila ta tion
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FIGURE 8-3. The mitral valve
apparatus and associated common
etiologies of mitral regurgitation.
MVP, mitral valve prolapse; SAM,
systolic anterior motion.
Valvular Heart Disease
199
primary i it is due to a structural de ect o one or more o the valve components, or secondary i the valve is structurally normal, but regurgitation instead results rom le t ventricular
enlargement. In the latter case, MR arises rom abnormal coaptation and closure o the mitral
leaf ets owing to dilatation o the mitral annulus by the enlarged LV, and/ or spatial separation o the papillary muscles, which places traction o the chordae and attached leaf ets.
Furthermore, depending on the nature o the valvular insult, MR can present as an “acute” or
“chronic” condition, with di erent pathophysiologic consequences.
Most cases o acute MR are primary in nature and result rom sudden damage to components o the valve apparatus. For example, rupture o an in arcted papillary muscle can occur
within days o an acute ST-segment elevation MI, o ten resulting in severe MR (see Chapter 7).
Acute MR due to sudden rupture o chordae tendineae can result rom in ective endocarditis,
blunt trauma to the chest, or rom degeneration o the chordae owing to connective tissue
disorders such as Mar an syndrome.
Chronic MR has multiple primary causes, including myxomatous degeneration o the valve,
in which “f oppy” leaf ets allow regurgitation to occur by bowing excessively into the LA
during systole (termed “mitral valve prolapse” and described in the next section). Other
causes o chronic primary MR include rheumatic de ormity o the valve, congenital valve
de ects, and extensive calci cation o the mitral annulus, which prevents normal movement
o the valve leaf ets, thus inter ering with valve closure.
Secondary (also termed “ unctional”) chronic MR results rom LV enlargement and/ or
dys unction as described above, as may occur with prior myocardial in arction, chronic
ischemic heart disease, or dilated cardiomyopathy (see Chapter 10).
Pathophysiology
In MR, a portion o the le t ventricular stroke volume is ejected backward into the lowpressure LA during systole (Fig. 8-4). As a result, the orward cardiac output (into the
aorta) is less than the LV’s total output ( orward f ow plus backward leak). There ore, the
Pulmona ry
e de ma
Aorta
LA
High LA
pre s s ure
Dila te d LA
with le s s
e leva te d
pre s s ure
LV
No rmal
(s ys to le )
Ac ute mitral
re g urg itatio n
Chro nic mitral
re g urg itatio n
FIGURE 8-4. Pathophysiology of mitral regurgitation. In the normal heart, le t ventricular (LV) contraction during
systole orces blood exclusively through the aortic valve into the aorta (green arrow); the closed mitral valve prevents
regurgitation into the le t atrium (LA). In mitral regurgitation (MR), a portion o LV output is orced backward into the
LA (red arrows), so that orward cardiac output into the aorta is reduced. In acute MR, the LA is o normal size and is
relatively noncompliant, such that the LA pressure rises signif cantly and pulmonary edema may result. In chronic MR, the
LA has enlarged and is more compliant, so that the LA pressure is less elevated and pulmonary congestive symptoms are
less common. The LV enlargement and the eccentric hypertrophy result rom the chronically elevated volume load.
200
Chapter 8
direct consequences o MR include (1) an elevation o le t atrial volume and pressure, (2) a
reduction o orward cardiac output, and (3) a volume-related stress on the LV because the
regurgitant volume returns to the LV in diastole along with the normal pulmonary venous
return. To meet normal circulatory needs and to eject the additional volume, LV stroke volume
must rise. This increase is accomplished by the Frank–Starling mechanism (see Chapter 9),
whereby the elevated LV diastolic volume augments myo ber stretch and stroke volume. The
hemodynamic consequences o MR vary depending on the degree o regurgitation and how
long it has been present.
The severity o MR and the ratio o orward cardiac output to backward f ow are dictated
by ve actors: (1) the size o the mitral ori ce during regurgitation, (2) the systolic pressure
gradient between the LV and LA, (3) the systemic vascular resistance opposing orward LV
blood f ow, (4) le t atrial compliance, and (5) the duration o regurgitation with each systolic
contraction.
The regurgitant fraction in MR is de ned as ollows:
Volume o MR
Total LV stroke volume
P
r
e
s
s
u
r
e
(
m
m
H
g
)
This ratio rises whenever the resistance to aortic outf ow is increased (i.e., blood ollows the path o least resistance). For example, high systemic blood pressure or the presence o aortic stenosis will increase the regurgitant raction. The extent to which le t
atrial pressure rises in response to the regurgitant volume
is determined by the le t atrial compliance. Compliance is
a measure o the chamber’s pressure–volume relationship,
ECG
ref ecting the ease or di culty with which the chamber can
be lled (see Table 9.1).
In acute MR, le t atrial compliance undergoes little imme110
diate change. Because the LA is a relatively sti chamber, its
pressure increases substantially when it is suddenly exposed
90
Ta ll v
LV
to a regurgitant volume load (see Fig. 8-4). This elevated preswa ve
sure is transmitted backward to the pulmonary circulation and
70
can result in rapid pulmonary congestion and edema, a medical emergency.
50
In acute MR, the LA pressure, or the pulmonary capillary
30
wedge pressure (an indirect measurement o LA pressure; see
Chapter 3), demonstrates a prominent v wave (o ten re erred
LA
10
to as a “cv” wave when it merges with the preceding c wave),
ref ecting the increased LA lling during systole (Fig. 8-5).
Time
Additionally, as in MS, pulmonary artery and right-heart pressures passively rise.
He a rt
s ounds :
In acute MR, th e LV accommodates the in creased volum e
load returning rom the LA according to the Frank–Starling
S1
S2
relationship. The result is a compensatory increase in the
FIGURE 8-5. Hemodynamic prof le o
LV stroke volume and ejection raction, such that at the
mitral regurgitation ( MR) . A large systolic v
en d o each systolic contraction , LV volu me rem ain s normal
wave is noted in the le t atrial (LA) pressure
tracing. A holosystolic murmur is present in
in th e n on ailin g h eart. Systolic emptying o the ven tricle
chronic MR (as shown here), beginning at the is acilitated in MR by th e redu ced total impedance to LV
rst heart sound (S1) and continuing through
con traction (i.e., th e a terload is lower than normal), since
the second heart sound (S2). In acute severe
a portion o th e LV outpu t is directed in to th e relatively
MR, the systolic murmur may actually have
low-im pedan ce LA, rath er th an in to th e h igh er-pressu re
a decrescendo quality, ref ecting rapid
aorta.
equilibration o LV and LA pressures owing
In contrast to the acute situation, the more gradual developto the relatively low LA compliance. ECG,
electrocardiogram; LV, le t ventricle.
ment o chronic MR permits the LA to undergo compensatory
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Valvular Heart Disease
201
changes that lessen the e ects o regurgitation on the pulmonary circulation (see Fig. 8-4).
In particular, the LA dilates and its compliance increases such that the chamber is able to
accommodate a larger volume without a substantial increase in pressure. Le t atrial dilatation
is there ore adaptive in that it prevents signi cant increases in pulmonary vascular pressures.
However, this adaptation occurs at the cost o reduced orward cardiac output, because the
compliant LA becomes a pre erred low-pressure “sink” or le t ventricular ejection, compared
with the aorta. Consequently, as progressively larger ractions o blood regurgitate into the
LA, symptoms o chronic MR include those o low orward cardiac output (e.g., weakness
and atigue). In addition, chronic le t atrial dilatation predisposes to the development o atrial
brillation.
Thus, major pathophysiologic di erences between acute and chronic MR relate to a great
extent to le t atrial size and compliance (see Fig. 8-4):
Acute MR: Normal LA size and compliance → High LA pressure → High pulmonary
venous pressure → Pulmonary congestion and edema
Chronic MR: Increased LA size and compliance → Relatively normal LA and pulmonary
venous pressures, but decreased orward cardiac output
In chronic MR, the LV also undergoes gradual compensatory dilatation in response to
the volume load through eccentric hypertrophy (see Chapter 9). Compared with acute MR,
the resulting increased ventricular compliance accommodates the augmented lling volume with relatively normal diastolic pressures. Forward output in chronic MR is preserved
to near-normal levels or an extended period by maintaining a higher stroke volume via
the Frank–Starling mechanism. Over years, however, chronic volume overload results in
deterioration o systolic ventricular unction, a decline in orward output, and symptoms
o heart ailure.
Clinical Manifestations and Evaluation
Presentation
As should be clear rom the pathophysiology discussion, patients with acute MR usually
present with symptoms o pulmonary edema (see Chapter 9). The symptoms o chronic MR
are predominantly due to low cardiac output, especially during exertion, and include atigue
and weakness. Patients with severe MR or those who develop LV contractile dys unction o ten
complain o dyspnea, orthopnea, and/ or paroxysmal nocturnal dyspnea. In chronic severe
MR, symptoms o right heart ailure (e.g., increased abdominal girth, peripheral edema) may
develop as well.
Examination
The physical examination o a patient with chronic MR typically reveals an apical holosystolic (also termed pansystolic) murmur that o ten radiates to the axilla. The holosystolic
nature o the murmur ref ects the continued pressure gradient between LV and LA throughout
systole (see Fig. 8-5). This description, accurate or rheumatic MR, has several exceptions.
For example, in patients with isolated posterior mitral leaf et prolapse, the regurgitant jet is
directed anteriorly. In this setting, the murmur may instead radiate to the base o the heart
and could be con used with the murmur o aortic stenosis (AS) in that location. Fortunately,
the distinction between the systolic murmur o MR and that o AS can be made by simple
bedside maneuvers. I the patient is instructed to clench his/ her sts and orearms, systemic
vascular resistance will increase and the murmur o MR will intensi y, whereas the murmur
o AS will not. Even more help ul in this distinction is the e ect o varying cardiac cycle
length (the time between consecutive heart beats) on the intensity o the systolic murmur. In
a patient with atrial brillation or with requent premature beats, the LV lls to a degree that
202
Chapter 8
directly depends on the preceding cycle length (i.e., a longer cycle length permits greater le t
ventricular lling). The systolic murmur o AS becomes louder in the beat a ter a long cycle
length because even small pressure gradients are ampli ed as more blood is ejected across
the reduced aortic ori ce. In MR, however, the intensity o the murmur does not vary signi cantly because the change in the LV-LA pressure gradient is minimally a ected by alterations
in the cycle length. In addition to the systolic murmur, a common nding in chronic MR is the
presence o an S3, which ref ects increased volume returning to the LV in early diastole (see
Chapter 2). Additionally, in chronic MR, the cardiac apical impulse is o ten laterally displaced
toward the axilla because o LV enlargement.
In patients with severe acute MR, the character o the systolic murmur is o ten di erent,
occurring in early to mid systole with a decrescendo quality. The length and quality o the
murmur are dictated by the systolic pressure gradient between the le t ventricle and the relatively noncompliant le t atrium. That is, as the LA pressure rises in systole in acute MR, the
LV and LA pressures quickly equalize, thus truncating the murmur. Patients with acute MR
o ten display signs o pulmonary congestion.
The chest ra diogra ph may display pulmonary edema in acute MR bu t in chronic
asymptomatic MR more likely demonstrates le t ventricu lar and atrial en largement, without pulmonary con gestion. Calci cation o the mitral annu lu s may be seen i that is the
cau se o the MR. In chron ic MR, the electroca rdiogra m typically demonstrates le t atrial
enlargement an d signs o le t ventricu lar hypertrophy. Echoca rdiogra phy can o ten identi y the structural cause o MR and assess its severity. Ca rdia c ca theteriza tion is used to
identi y accompanying coronary artery disease and le t ventriculography can con rm
MR severity. The characteristic hemodynamic nding is a large v wave in the pu lmon ary
capillary wedge pressure tracing (ref ective o LA pressure—see Chapter 3). The v wave
becomes less conspicuous, however, with progressive LA dilatation and greater complian ce over time.
Natural History and Treatment
Acute severe MR is a surgical emergency with a poor prognosis, even with appropriate
treatment, with a 30-day mortality rate o 20% to 25% . The natural history o chronic
MR is related to its underlying cause. For example, in RHD, the course is one o very slow
progression with a 15-year survival rate o 70% . On the other hand, abrupt worsening
o chronic MR o any cause can occur with superimposed complications, such as rupture o chordae tendineae or endocarditis, and can result in an immediate li e-threatening
situation.
The treatment o acute MR almost always requires surgical intervention. Pharmacologic
therapy is use ul only to stabilize patients until surgery. For example, intravenous nitroprusside is a potent vasodilator that decreases arterial resistance, thereby augmenting orward
f ow and diminishing the regurgitant volume. In this way, cardiac output and pulmonary congestion may improve at least transiently. Surgical intervention consists o either mitral valve
repair (reconstruction o the native valve as described below) or replacement, depending on
the underlying cause and valve anatomy.
Management o chronic MR depends on the etiology. In chronic primary MR, the continuous le t ventricular volume overload can slowly impair le t ventricular contractile unction,
ultimately, resulting in heart ailure. Medical treatment with vasodilators is less use ul than in
acute MR and has not been shown to delay the need or valve surgery in chronic MR. Surgical
intervention should be undertaken in symptomatic patients, or at the earliest sign o LV contractile dys unction on imaging studies (e.g., a all in EF to < 60% by echocardiography) even
be ore symptoms develop. Surgical intervention is also sometimes recommended or patients
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Valvular Heart Disease
203
with chronic asymptomatic severe primary MR with recent onset atrial brillation or ndings
o pulmonary hypertension.
Surgical options or chronic MR include mitral valve repair or replacement. Mitral valve
repair is the pre erred operative technique when easible, and involves the reconstruction o
parts o the valve responsible or the regurgitation. For example, a per orated leaf et may be
patched with transplanted autologous pericardium, or ruptured chordae may be reattached
to a papillary muscle. Mitral repair preserves native valve tissue, and eliminates many o
the problems associated with arti cial valves described later in the chapter. In patients who
undergo repair, the postoperative survival rate appears to be better than the natural history o
MR and has provided impetus toward earlier surgical intervention. Operative mortality rates
or unselected patients with MR in the Society or Thoracic Surgeons database are less than
2% or mitral valve repair and 5% to 7% or mitral valve replacement. These rates are higher
i concurrent coronary artery bypass gra ting is per ormed. In general, mitral valve repair
is more o ten appropriate or younger patients with myxomatous involvement o the mitral
valve, and mitral replacement is more o ten undertaken in older patients with more extensive
valve pathology.
In patients with chronic, severe, symptomatic prima ry MR who are at prohibitive operative risk, a recently developed technique o transcatheter mitral valve repair can be
considered. In this procedure, a catheter is advanced percutaneously rom the emoral
vein into the right side o the heart, then into the le t atrium via a puncture through the
interatrial septum (similar to mitral balloon valvuloplasty), and advanced into the le t
ventricle. A mechanical clip is then deployed, which grasps and tethers the anterior and
posterior mitral leaf ets together at one location and is le t in place, reducing the size o
the regurgitant ori ce. The procedure has been shown to be sa e and e ective in prospective observational studies o high surgical risk patients, with improvement in the severity o MR and unctional status. However, in a randomized trial o percutaneous repair
versus valve surgery or patients with severe primary MR, surgery proved more e ective
and remains the intervention o choice is patients who are acceptable candidates or an
operation.
Because chronic, secondary MR is o ten a result o le t ventricular dys unction, pharmacologic rather than mechanical intervention is the mainstay o treatment, using a standard
combination o heart ailure medications, including diuretics, ACE inhibitors or angiotensin
receptor blockers, beta-blockers, and aldosterone antagonists (see Chapter 9). Surgical intervention is considered only when a patient with chronic, severe secondary MR has persistent
symptoms despite optimal medical therapy.
Mitral Valve Prolapse
Mitral valve prolapse (MVP) is characterized by abnormal billowing o a portion o one or
both mitral leaf ets into the LA during ventricular systole, and is requently accompanied
by MR (Fig. 8-6). Other names or this condition include f oppy mitral valve, myxomatous
mitral valve, and Barlow syndrome. MVP may be inherited as a primary autosomal dominant
disorder with variable penetrance, or it may accompany certain connective tissue diseases,
such as Mar an syndrome or Ehlers–Danlos syndrome. Pathologically, the valve leaf ets, particularly the posterior leaf et, are enlarged, and the normal dense collagen and elastin matrix
o the valvular brosa is ragmented and replaced with loose myxomatous connective tissue.
Additionally, in more severe lesions, elongated or ruptured chordae, annular enlargement, or
thickened leaf ets may be present. A recent rigorous echocardiographic study indicated that
MVP occurs in about 2% o the population and is more common among women, especially
those who are thin and lean.
204
Chapter 8
MVP is o ten asymptomatic but a ected individuals may describe chest pain or palpitations because
Aorta
o associated arrhythmias. Most o ten it is identi ed
on routine physical examination by the presence o a
LA
midsystolic click and late systolic murmur heard best
at the cardiac apex. The midsystolic click is thought
to correspond to the sudden tensing o the involved
mitral leaf et or chordae tendineae as the leaf et is
orced back toward the LA; the murmur corresponds
to regurgitant f ow through the incompetent valve.
RV
The click and murmur are characteristically altered
LV
during dynamic auscultation at the bedside: maneuvers that increase the volume o the LV (e.g., sudden
squatting, which increases venous return) place traction o the chordae tendineae, limiting and delaying
FIGURE 8-6. Mitral valve prolapse. Long-axis view
the occurrence o prolapse in systole and cause the
o the le t ventricle (LV) demonstrates a myxomatous,
click and murmur to occur later (i.e., urther rom
elongated appearance o the mitral valve with prolapse
S1). Conversely, i the volume o blood in the LV is
o the posterior leaf et (arrow) into the le t atrium
decreased (e.g., on sudden standing), prolapse occurs
(LA). RV, right ventricle. (From Schoen FJ, Mitchell
earlier and the click and murmur move closer to S1.
RN. The heart. In: Kumar V, Abbas A, Aster JC, eds.
Robbins and Cotran Pathologic Basis of Disease. 9th ed.
Con rmation o the diagnosis is obtained by echoPhiladelphia, PA: Elsevier Saunders; 2015.)
cardiography, which demonstrates posterior displacement o a portion o one or both mitral leaf ets into
the LA during systole. The electrocardiogram and chest radiograph are usually normal unless
chronic MR has resulted in le t atrial and le t ventricular enlargement.
The clinical course o MVP is most o ten benign. Treatment consists o reassurance
about the usually good prognosis and monitoring or the development o progressive MR.
Occasionally, rupture o myxomatous chordae in this condition can cause sudden, severe
regurgitation and pulmonary edema. Other potential complications include in ective endocarditis, peripheral emboli owing to microthrombus ormation on the redundant valve tissue,
and atrial or ventricular arrhythmias.
AORTIC VALVE DISEASE
Aortic Stenosis
Etiology
Among adult patients, there are three major causes o aortic stenosis (AS): (1) degenerative calci cation o a previously normal trileaf et aortic valve, (2) calci cation o a congenitally bicuspid aortic valve, and (3) rheumatic aortic valve disease. Degenerative disease o a
trileaf et valve shares many pathologic eatures in common with atherosclerosis, as described
below. Bicuspid aortic valves are present in 1% to 2% o the population (with men a ected
more commonly than women) and such patients typically develop signs o severe valve
disease about a decade earlier than patients with the trileaf et, degenerative type o AS.
Rheumatic aortic valve disease is now uncommon in developed countries. It is nearly always
accompanied by rheumatic involvement o the mitral valve.
Pathology
The pathologic appearance in AS is dependent on its etiology. Degenerative, calci c AS
results rom a dynamic process o endothelial dys unction, lipid accumulation, inf ammation,
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Valvular Heart Disease
and alteration o signaling pathways that appears similar to
atherogenesis. Over time, valvular myo broblasts di erentiate into osteoblasts and deposit calcium hydroxyapatite
crystals, resulting in leaf et thickening and sti ening. This
process is likely exacerbated by abnormal shear orces, as
occur with congenitally de ormed (bicuspid) valves, and
could explain the earlier presentation o such patients. As
with atherosclerosis, risk actors or calci c, degenerative
AS include dyslipidemia, smoking, and hypertension (see
Chapter 5).
In rheumatic AS, endocardial inf ammation leads to organization and brosis o the valve and ultimately to usion o
the commissures and ormation o calci ed masses within the
aortic cusps.
Pathophysiology
205
Aorta
LA
Pre s s ure
FIGURE 8-7. Pathophysiology
o aortic stenosis ( AS) . The
impediment to le t ventricular
(LV) outf ow in AS results in
elevated LV pressures and
secondary concentric ventricular
hypertrophy.
P
r
e
s
s
u
r
e
(
m
m
H
g
)
In AS, blood f ow across the aortic valve is impeded during
systole (Fig. 8-7). Progressive reduction o the aortic valve
area requires elevation o le t ventricular systolic pressure to overcome the impedance to f ow
to drive blood into the aorta (Fig. 8-8).
Since the obstruction in AS develops gradually, the LV is able to compensate by undergoing concentric hypertrophy in response to the increased pressure load. Initially, such hypertrophy serves an important role in reducing LV wall stress
(remember rom Chapter 6 that wall stress = (P × r) ÷ 2 h,
ECG
in which h represents wall thickness). Over time, however,
it also reduces the compliance o the ventricle. The resulting
150
elevation o diastolic LV pressure causes the LA to hypertro130
phy, which acilitates lling o the “sti ened” LV. Whereas
le t atrial contraction contributes only a small portion o
110
LV
the le t ventricular stroke volume in normal individuals,
it may provide more than 25% o the stroke volume to the
90
sti ened LV in AS patients. Thus, le t atrial hypertrophy is
Aorta
70
bene cial, and the loss o e ective atrial contraction (e.g.,
development o atrial brillation) can cause marked clinical
50
deterioration.
Three major mani estations occur in patients with
30
advanced AS: (1) angina, (2) exertional syncope, and (3)
heart ailure, all o which can be explained on the basis
10
o the underlying pathophysiology. Each mani estation, in
order, heralds an increasingly ominous prognosis (Table 8-1).
AS may result in an gin a because it creates a substantial imbalance between myocardial oxygen supply and
demand. Myocardial oxygen dema n d is increased in two
ways. First, the muscle mass o the hypertrophied LV
FIGURE 8-8. Hemodynamic prof le o aortic
is increased, requiring greater-than-normal per usion.
stenosis. A systolic pressure gradient (shaded
Second, wall stress is increased because o the elevated
area) is present between the le t ventricle
systolic ventricular pressure. In addition, AS reduces myo(LV) and aorta. The second heart sound (S2) is
diminished in intensity, and there is a crescendo– cardial oxygen supply because the elevated le t ventricular
diastolic pressure reduces the coronary per usion pressure
decrescendo systolic murmur that does not extend
gradient between the aorta and the myocardium.
beyond S2. ECG, electrocardiogram.
206
Chapter 8
TABLE 8-1
Median Survival Time in Symptomatic
Severe Aortic Stenosis
Clinical Symptoms
Angina
Syncope
Heart failure
Median Survival
5 years
3 years
2 years
Derived from Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968;38(suppl.v):61.
AS may cause syncope during exertion. Although le t ventricular hypertrophy allows the
chamber to generate a high pressure and maintain a normal cardiac output at rest, the ventricle cannot signi cantly increase its cardiac output during exercise because o the xed
stenotic aortic ori ce. In addition, exercise leads to vasodilatation o the peripheral muscle
beds. Thus, the combination o peripheral vasodilatation and the inability to augment cardiac
output contributes to decreased cerebral per usion pressure and, potentially, loss o consciousness on exertion.
Finally, AS can result in symptoms o heart failure. Early in the course o AS, an abnormally increased le t atrial pressure occurs primarily at the end o diastole, when the LA
contracts into the thickened noncompliant LV. As a result, the mean le t atrial pressure and
the pulmonary venous pressure are not greatly a ected early in the disease. However, with
progression o the stenosis, the LV may develop contractile dys unction because o the insurmountably high a terload, leading to increased le t ventricular diastolic volume and pressure.
The accompanying marked elevation o LA and pulmonary venous pressures incites pulmonary alveolar congestion and symptoms o heart ailure.
A normal aortic valve has a cross-sectional area o 3 to 4 cm 2 and a mean systolic pressure
gradient between the LV and aorta o less than 5 mm Hg. As the valve area decreases in AS,
the pressure gradient rises. When the valve area declines to less than 1.0 cm 2, or the mean
pressure gradient increases to greater than 40 mm Hg, a patient is considered to have severe
aortic stenosis and symptoms typically appear.
Clinical Manifestations and Evaluation
Presentation
Angina, syncope, and heart ailure may appear a ter many asymptomatic years o slowly progressive valve stenosis. Once these symptoms develop, they con er a signi cantly decreased
survival i invasive correction o AS is not undertaken (see Table 8-1).
Examination
Physical examination o ten permits accurate detection and estimation o the severity o
AS. The key eatures o advanced AS include (1) a coarse late-peaking systolic ejection
murmur and (2) a weakened (pa rvus) and delayed (ta rdus) upstroke o the carotid
artery owing to the obstructed LV outf ow. Other common ndings on cardiac examination include the presence o an S4 (because o atrial contraction into the “sti ” LV—see
Chapter 2) and reduced intensity, or complete absence, o the aortic component o the
second heart sound (see Fig. 8-8).
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Valvular Heart Disease
207
On the electroca rdiogra m, le t ventricular hypertrophy is common in advanced AS.
Echoca rdiogra phy is a more sensitive technique to assess LV wall thickness and displays the
abnormal anatomy and reduced excursion o the stenotic valve. The transvalvular pressure
gradient and aortic valve area can be readily calculated by Doppler echocardiography (see
Chapter 3). Ca rdia c ca theteriza tion is sometimes used to con rm the severity o AS and to
de ne the coronary anatomy, because concurrent coronary artery bypass surgery is o ten
appropriate at the time o aortic valve replacement in patients with coexisting coronary
disease.
Natural History and Treatment
Mild, asymptomatic AS has a slow rate o progression such that over a 20-year period, only
20% o patients will progress to severe or symptomatic disease. There is no current e ective
medical therapy or slowing the rate o progression o aortic stenosis. Since the natural history o severe, symptomatic, uncorrected AS is very poor (see Table 8-1), e ective treatment
requires replacement o the valve.
Aortic va lve repla cemen t (AVR) is indicated when a patient with severe AS develops symptoms, or when there is evidence o progressive LV dys unction in the absence
o symptoms. The le t ventricular ejection raction almost always increases a ter valve
replacement, even in patients with impaired preoperative le t ventricular unction. The
e ect o AVR on the natural history o AS is dramatic, as the 10-year survival rate rises to
approximately 60% .
Unlike its success ul role in mitral stenosis, percutaneous balloon valvuloplasty has been
disappointing as a sole treatment o adults with calci c AS. Although balloon dilatation o the
aortic valve ori ce can racture calci ed masses leading to a slight reduction in valve obstruction, up to 50% o patients develop restenosis within 6 months. Valvuloplasty is occasionally
used as a temporizing measure in patients too ill to proceed directly to valve replacement, and
can also be an e ective treatment in young patients with noncalci ed bicuspid AS.
In distinction, or patients with severe AS who are at prohibitive or high risk or cardiac
surgery, transcatheter aortic valve replacement (TAVR) has emerged as a success ul treatment
option. This technique involves percutaneous insertion o a specially designed bioprosthetic
valve into the narrowed ori ce o the stenotic native valve that is rst prepared with balloon
valvuloplasty. TAVR has been validated in randomized prospective trials, and or inoperable patients, TAVR outcomes are superior to standard medical therapy. In high surgical risk
patients, TAVR is nonin erior to surgical AVR, with similar 1- and 2-year survival rates, though
its use is associated with higher risks o periprocedural stroke and paravalvular regurgitation. Longer-term data indicate that the di erence in stroke rates equalizes over time, and
it is likely that the use o TAVR will gradually be extended to greater numbers o high and
intermediate surgical risk patients.
Aortic Regurgitation
Etiology
Aortic regurgitation (AR), also termed aortic insu f ciency, may result either rom abnormalities o the aortic valve leaf ets or rom dilatation o the aortic root. Primary valvular causes
include: (1) bicuspid aortic valve (in some patients AR predominates over aortic stenosis), (2)
in ective endocarditis (due to per oration or erosion o a leaf et), and (3) rheumatic heart disease (due to thickening and shortening o the aortic valve cusps). Primary aortic root disease
results in AR when the aortic annulus dilates su ciently to cause separation o the leaf ets,
preventing normal coaptation in diastole. Examples include age-related degenerative dilation
o the aortic root, aortic aneurysms, and aortic dissection, which are described in Chapter 15.
208
Chapter 8
Pathophysiology
In AR, abnormal regurgitation o blood occurs rom the aorta into the LV during diastole.
There ore, with each contraction, the LV must pump that regurgitant volume plus the normal
quantity o blood entering rom the LA. Hemodynamic compensation relies on the Frank–
Starling mechanism to augment stroke volume. Factors inf uencing the severity o AR are
analogous to those o MR: (1) the size o the regurgitant aortic ori ce, (2) the pressure gradient across the aortic valve during diastole, and (3) the duration o diastole.
As in MR, the hemodynamic abnormalities and symptoms di er in acute and chronic AR
(Fig. 8-9). In acute AR, the LV is o normal size and relatively noncompliant. Thus, the volume load o regurgitation causes the LV diastolic pressure to rise substantially. The sudden
high diastolic LV pressure is transmitted to the LA and pulmonary circulation, o ten producing dyspnea and pulmonary edema. Thus, acute severe AR is usually a surgical emergency,
requiring immediate valve replacement.
In chron ic AR, the LV undergoes compensatory adaptation in response to the longstanding regurgitation. AR subjects the LV primarily to volume overload but also to an
excessive pressure load; there ore, the ventricle compensates through chronic dilatation
(eccentric hypertrophy, with replication o sarcomeres in series—see Chapter 9) and, to a
lesser degree, increased thickness. Over time, the dilatation increases the compliance o
the LV and allows it to accommodate a larger regurgitant volume with less o an increase
in diastolic pressure, reducing the pressure transmitted into the LA and pulmonary circulation. However, by accommodating the large regurgitant volume, the aortic (and there ore
systemic arterial) diastolic pressure drops substantially. The combination o a high LV
stroke volume (and high systolic arterial pressure) with a reduced aortic diastolic pressure
produces a widened pulse pressure (the di erence between arterial systolic and diastolic pressures), a hallmark o chronic AR (Fig. 8-10). As a result o the decreased aortic
diastolic pressure, the coronary artery per usion pressure alls, potentially reducing myocardial oxygen supply. This, coupled with the increase in LV size (which causes increased
wall stress and myocardial oxygen demand), can produce angina, even in the absence o
atherosclerotic coronary disease.
Compensatory le t ventricular dilatation and hypertrophy are generally adequate to meet
the demands o chronic AR or many years, during which a ected patients are asymptomatic. Gradually, however, progressive remodeling o the LV occurs, resulting in systolic
Pulmona ry
conge s tion
Aorta
Pre s s ure
Pre s s ure
Ac ute ao rtic
re g urg itatio n
Pre s s ure
N-
Pre s s ure
N-
Chro nic ao rtic
re g urg itatio n
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FIGURE 8-9. Pathophysiology of acute
and chronic aortic regurgitation ( AR) .
Abnormal regurgitation o blood rom the
aorta into the le t ventricle (LV) is shown
in each schematic drawing (red arrows).
In acute AR, the LV is o normal size
and relatively low compliance, such that
its diastolic pressure rises signi cantly;
this pressure increase is ref ected back
to the le t atrium (LA) and pulmonary
vasculature, resulting in pulmonary
congestion or edema. In chronic AR,
adaptive LV and LA enlargement have
occurred, such that a greater volume
o regurgitation can be accommodated
with less o an increase in diastolic LV
pressure, so that pulmonary congestion is
less likely. N, normal.
Valvular Heart Disease
dys unction. This causes decreased orward cardiac
output as well as an increase in le t atrial and pulmonary vascular pressures. At that point, the patient
develops symptoms o heart ailure.
Clinical Mani estations and Assessment
209
ECG
Aorta
Presentation
Common symptoms o chronic AR include dyspnea
on exertion, atigue, decreased exercise tolerance, and
the uncom ortable sensation o a orce ul heartbeat
associated with the high pulse pressure.
LV
Examination
FIGURE 8-10. Hemodynamic prof le o
Physical examination may show bounding pulses aortic regurgitation. During diastole, the
and other stigmata o the widened pulse pressure aortic pressure alls rapidly (arrow), and
(Table 8-2), in addition to a hyperdynamic LV impulse le t ventricular (LV) pressure rises as blood
and a blowing murmur o AR in early diastole along regurgitates rom the aorta into the LV. A
the le t sternal border (see Fig. 8-10). It is best heard diastolic decrescendo murmur, beginning at
with the patient leaning orward, a ter exhaling. In the second heart sound (S2), corresponds
with the abnormal regurgitant f ow. ECG,
addition, a low- requency mid-diastolic rumbling
electrocardiogram.
sound may be auscultated at the cardiac apex in some
patients with severe AR. Known as the Austin Flint murmur, it is thought to ref ect turbulence
o blood f ow through the mitral valve during diastole owing to downward displacement o
the mitral anterior leaf et by the regurgitant stream o AR. It can be distinguished rom the
murmur o mitral stenosis by the absence o an OS or presystolic accentuation.
In chronic AR, the chest radiograph shows an enlarged le t ventricular silhouette. This
is usually absent in acute AR, in which pulmonary vascular congestion is the more likely
nding. Doppler echocardiography can identi y and quanti y the degree o AR and o ten can
identi y its cause. Cardiac catheterization with contrast angiography can be obtained or urther quanti cation o the degree o AR, and assessment o coexisting coronary artery disease.
Treatment
Data rom natural history studies indicate that clinical progression o patients with asymptomatic chronic AR and normal LV contractile unction is very slow. There ore, asymptomatic
patients are monitored with periodic examinations and assessment o LV unction, usually by
TABLE 8-2
Examples o Physical Findings Associated with Widened
Pulse Pressure in Chronic Aortic Regurgitation
Name
Description
Bis eriens pulse
Corrigan pulse
Hill sign
Double systolic impulse in carotid or brachial artery
“Water-hammer” pulses with marked distention and collapse
Popliteal systolic pressure more than 60 mm Hg greater than brachial
systolic pressure
Capillary pulsations visible at the lip or proximal nail beds
Quincke sign
210
Chapter 8
serial echocardiography. Patients with asymptomatic severe AR may bene t rom a terload
reducing vasodilators (e.g., a calcium channel blocker or an angiotensin-converting enzyme
inhibitor) or treatment o accompanying hypertension. However, such agents do not prolong
the compensated stage o chronic AR.
Symptomatic patients, or asymptomatic patients with severe AR and impaired LV contractile unction (i.e., an ejection raction less than 0.50), should be o ered surgical correction to
prevent progressive deterioration. Studies o such patients show that without surgery, death
usually occurs within 4 years a ter the development o angina or 2 years a ter the onset o
heart ailure symptoms.
TRICUSPID VALVE DISEASE
Tricuspid Stenosis
Tricuspid stenosis (TS) is rare and is usually a long-term consequence o rheumatic ever. The
OS and diastolic murmur o TS are similar to those o MS, but the murmur is heard closer
to the sternum and it intensi es on inspiration because o increased right heart blood f ow.
In TS, the neck veins are distended and may show a large a wave as a result o right atrial
contraction against the stenotic tricuspid valve ori ce when sinus rhythm is present (see
Chapter 2). Patients may develop abdominal distention and hepatomegaly owing to passive
venous congestion. Percutaneous balloon dilatation or surgical correction (valvuloplasty or
valve replacement) is usually required.
Tricuspid Regurgitation
Tricuspid regurgitation (TR) is usually functional rather than structural in nature; that is, it
most commonly results rom right ventricular enlargement (e.g., owing to pressure or volume
overload) rather than rom primary valve disease. Among patients with rheumatic mitral stenosis, 20% also have signi cant TR (o whom 80% have unctional TR because o pulmonary
hypertension with right ventricular enlargement, and 20% have structural TR resulting rom
rheumatic involvement o the tricuspid valve). A rare cause o TR is carcinoid syndrome,
in which a type o neuroendocrine tumor (usually in the small bowel or appendix, with
metastases to the liver) releases serotonin metabolites into the bloodstream. These metabolites are thought to be responsible or the ormation o endocardial plaques in the right side
o the heart. Involvement o the tricuspid valve immobilizes the leaf ets, o ten resulting in
substantial TR and, less o ten, TS.
The most common physical signs o TR are prominent v waves in the jugular veins
(see Chapter 2) and a pulsatile liver because o regurgitation o right ventricular blood into
the systemic veins. The systolic murmur o TR is heard at the lower le t sternal border. It is
o ten so t but becomes louder on inspiration. Doppler echocardiography readily detects TR
and can quanti y it. The treatment o unctional TR is directed at the conditions responsible
or the elevated right ventricular size or pressure, and diuretic therapy; surgical repair o the
valve is indicated in severe cases.
PULMONIC VALVE DISEASE
Pulmonic Stenosis
Pulmonic stenosis (PS) is rare, and its cause is almost always congenital de ormity o
the valve. Carcinoid syndrome, described in the previous section, is another rare etiology, in which encasement and immobilization o the valve leaf ets can occur. The systolic
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Valvular Heart Disease
211
crescendo–decrescendo murmur o PS is usually loudest at the second or third le t intercostal
space close to the sternum. It may radiate to the neck or le t shoulder and is o ten preceded
by an ejection click (see Chapter 2).
PS is considered to be severe i the peak systolic pressure gradient across the valve is
greater than 80 mm Hg, moderate i the gradient is 40 to 80 mm Hg, and mild i the gradient
is less than 40 mm Hg. Only patients with moderate-to-severe gradients are symptomatic. In
such cases, transcatheter balloon valvuloplasty is usually e ective therapy.
Pulmonic Regurgitation
Pulmonic regurgitation (PR) most commonly develops in the setting o severe pulmonary
hypertension and results rom dilatation o the valve ring by the enlarged pulmonary artery.
Auscultation reveals a high-pitched decrescendo murmur along the le t sternal border that
is o ten indistinguishable rom AR (the two conditions are easily di erentiated by Doppler
echocardiography).
PROSTHETIC VALVES
The patient who undergoes valve replacement surgery o ten bene ts dramatically rom hemodynamic and symptomatic improvement, but also acquires a new set o potential complications related to the valve prosthesis itsel . Because all available valve substitutes have certain
limitations, valve replacement surgery is not a true “cure.”
Currently available valve substitutes include mechanical and bioprosthetic (derived
rom animal or human tissue) devices (Fig. 8-11). One example o a mechanical valve is
the St. Jude prosthesis, a hinged bileaf et valve consisting o two pyrolytic carbon discs
that open opposite one another. Mechanical valves, while durable, present oreign thrombogenic sur aces to the circulating blood and require li elong anticoagulation to prevent
thromboembolism.
In contrast, bioprosthetic valves display a very low rate o thromboembolism and do not
require long-term anticoagulation therapy. The most commonly used bioprostheses are made rom
glutaraldehyde- xed porcine (pig) valves secured in a support rame. In addition, bovine (cow)
pericardium and human homogra t (aortic valves harvested and cryopreserved rom cadavers)
A
B
FIGURE 8-11. Examples of prosthetic heart valves. A. St. Jude mechanical bileaf et valve in the open
position. (Courtesy o St. Jude Medical, Inc., St. Paul, MN.) B. A bioprosthetic aortic valve with leaf ets in the
closed position. (Courtesy o Medtronic, Inc., Minneapolis, MN.)
212
Chapter 8
prostheses are used. For patients who undergo AVR because o endocarditis, human homogra t
replacements are especially use ul because they have low rates o subsequent rein ection.
Bioprosthetic valves have limited durability compared with mechanical valves, and structural ailure occurs in up to 50% by 15 years a ter implantation. The principal causes o ailure
are leaf et tears and calci cation. Failure rates vary greatly depending on the position o the
valve. For example, bioprosthetic valves in the mitral position deteriorate more rapidly than
those in the aortic position. This is likely because the mitral valve is exposed to higher closing
orces, resulting in greater leaf et stress than that experienced by aortic prostheses.
Common to all types o valve replacement is the risk o in ective endocarditis (discussed
in the next section), which occurs with an incidence o 1% to 2% per patient per year. I
endocarditis occurs in the rst 60 days a ter valve surgery, the mortality rate is exceedingly
high (50% to 80% ). I endocarditis occurs later, mortality rates range rom 20% to 50% .
Reoperation is usually required when endocarditis involves a mechanical prosthesis because
an adjacent abscess is requently present. Some cases o bioprosthetic valve endocarditis may
respond to antibiotic therapy alone.
Given their respective advantages and disadvantages, the mortality and complication
rates o mechanical and bioprosthetic valves are similar or the rst 10 years a ter replacement. In 20-year ollow-up studies o randomized, controlled trials, mechanical valves have
been shown to be superior to bioprosthetic valves or event- ree survival, except or bleeding complications related to anticoagulation therapy. There ore, the decision about which
type o prosthesis to use in a patient o ten centers on (1) the patient’s expected li espan in
comparison to the unctional longevity o the valve, (2) risk-versus-bene t considerations
o chronic anticoagulation therapy, and (3) patient and surgeon pre erences. Mechanical
valves are o ten recommended or younger patients and or those who will be tolerant
o , and compliant with, anticoagulant therapy. Bioprosthetic valves are generally suitable
choices or patients 65 years o age or older and or patients with contraindications to
chronic anticoagulation.
INFECTIVE ENDOCARDITIS
In ection o the endocardial sur ace o the heart, including the cardiac valves, can lead to
extensive tissue damage and is o ten atal. In ective endocarditis (IE) carries an overall
6-month mortality rate o 20% to 25% , even with appropriate therapy, and a 100% mortality
rate i it is not recognized and treated correctly.
There are three clinically use ul ways to classi y IE: (1) by clinical course, (2) by host
substrate, or (3) by the speci c in ecting microorganism. In the rst classi cation scheme,
IE is termed acute bacterial endocarditis (ABE) when the syndrome presents as an acute,
ulminant in ection, and a highly virulent and invasive organism such as Staphylococcus
aureus is causal. Because o the aggressiveness o the responsible microorganism, ABE may
occur on previously healthy heart valves. When IE presents with a more insidious clinical
course, it is termed subacute bacterial endocarditis (SBE) and less virulent organisms such
as viridans streptococci are typically involved. SBE most requently occurs in individuals with
prior underlying valvular damage.
The second means o classi cation o IE is according to the host substrate: (1) native
valve endocarditis, (2) prosthetic valve endocarditis, or (3) endocarditis in the setting o
intravenous drug abuse. O these, native valve endocarditis accounts or 60% to 80% o
patients. Di erent microorganisms and clinical courses are associated with each o these categories. For example, the skin contaminant Staphylococcus epidermidis is a common cause o
prosthetic valve endocarditis, but that is rarely the case when endocarditis occurs on a native
heart valve. Intravenous drug users have a propensity or S. aureus endocarditis o the rightsided heart valves.
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Valvular Heart Disease
213
The third classi cation o IE is according to the speci c in ecting microorganism
(e.g. S. aureus endocarditis). As described below, the most common responsible organisms
are gram-positive cocci. Certain bacterial strains that cause endocarditis are associated with
particular anatomic sources. For example, viridans group streptococci usually originate rom
oropharyngeal tissue. Endocarditis due to Streptococcus bovis (more recently termed S. gallolyticus) commonly arises rom the gastrointestinal tract and should prompt investigation or
colonic polyps or adenocarcinoma.
Although the remainder o this discussion ocuses on the endocarditis syndromes based on
clinical course, it is important to recognize that all three classi cations o IE are used.
Pathogenesis
The pathogenesis o endocarditis requires several conditions: (1) endocardial sur ace
injury, (2) platelet– brin–thrombus ormation at the site o injury, (3) bacterial entry
into the circulation, and (4) bacterial adherence to the injured endocardial sur ace. The
rst two conditions provide an environment avorable to in ection, whereas the latter two
permit implantation o the organism on the endocardial sur ace. The most common cause
o endothelial injury is turbulent blood f ow resulting rom preexisting cardiac or intravascular abnormalities, including acquired valvular heart lesions (e.g., mitral regurgitation or aortic stenosis), congenital heart diseases, and hypertrophic cardiomyopathy (see
Chapter 10). Endothelial injury may also be incited by oreign material within the circulation, such as indwelling venous catheters, prosthetic heart valves, and other implanted
cardiac devices.
Once an endocardial sur ace is injured, platelets adhere to the exposed subendocardial connective tissue and initiate the ormation o a sterile thrombus (termed a vegetation) through
brin deposition. This process is re erred to as nonbacterial thrombotic endocarditis (NBTE).
NBTE makes the endocardium more hospitable to microbes in two ways. First, the brin–
platelet deposits provide a sur ace or adherence by bacteria. Second, the brin covers adherent organisms and protects them rom host de enses by inhibiting chemotaxis and migration
o phagocytes.
When NBTE is present, the delivery o microorganisms in the bloodstream to the injured
sur ace can lead to IE. Three actors determine the ability o an organism to induce IE: (1)
access to the bloodstream, (2) survival o the organism in the circulation, and (3) adherence
o the bacteria to the endocardium. Bacteria can be introduced into the bloodstream whenever a mucosal or skin sur ace harboring an organism is traumatized, such as rom the mouth
during dental procedures, or rom the skin during illicit intravenous drug use. However, while
transient bacteremia is a relatively common event, only microorganisms suited or survival
in the circulation and able to adhere to the platelet– brin mesh overlying the endocardial
de ect will cause IE. For example, gram-positive organisms account or the majority o cases
o endocarditis largely because o their resistance to destruction in the circulation by complement and their particular tendency to adhere to endothelial and platelet sur ace proteins.
The ability o certain streptococcal species to produce dextran, a bacterial cell wall component that adheres to thrombus, correlates with their inciting endocarditis. Table 8-3 lists the
in ectious agents reported to be the most common causes o endocarditis in modern tertiary
centers; staphylococci (especially S. aureus) and streptococci are the most requent. O note,
the proportion o patients with viridans group streptococci is higher in series o patients with
community-acquired endocarditis.
Once organisms adhere to the injured sur ace, they may be protected rom phagocytic
activity by the overlying brin. The organisms are then ree to multiply, which enlarges the
in ected vegetation. The latter provides a source or continuous bacteremia and can lead
to several complications, including (1) mechanical cardiac injury, (2) thrombotic or septic
214
Chapter 8
TABLE 8-3
Microbiology of Infective Endocarditis
in Tertiary Centers
Organism
Incidence ( %)
Staphylococci
S. aureus
Coagulase negative
Streptococci
Viridans
Enterococci
S. bovis
Other streptococci
Other organisms ( e.g., gram-negative
bacteria, fungi)
Culture negative or polymicrobial
31.6
10.5
18.0
10.6
6.5
5.1
8.7
~9.4
Derived from Fowler VG Jr, Miro JM, Hoen B, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293:3012–3021.
emboli, and (3) immune injury mediated by antigen–antibody deposition. For example,
local extension o the in ection within the heart can result in progressive valvular damage,
abscess ormation, or erosion into the cardiac conduction system. Portions o a vegetation
may embolize, o ten to the central nervous system, kidneys, or spleen, and incite in ection or in arction o the target organs. Each o these is a potentially atal complication.
Additionally, immune complex deposition can result in glomerulonephritis, arthritis, or
vasculitis.
The epidemiology o IE has evolved in recent decades as bacteria resistant to antibiotics have become ubiquitous in the hospital setting and have spread into the community.
Antibiotic resistant strains such as methicillin-resistant S. aureus and vancomycin-resistant
enterococci have become more common and are associated with increased mortality rates
rom IE.
Clinical Manifestations
A patient with a cute IE is likely to report an explosive and rapidly progressive illness with
high ever and shaking chills. In contrast, suba cute IE presents less dramatically with lowgrade ever o ten accompanied by nonspeci c constitutional symptoms such as atigue,
anorexia, weakness, myalgia, and night sweats. These symptoms are not speci c or IE and
could easily be mistaken or inf uenza or an upper respiratory tract in ection. Thus, the
diagnosis o subacute IE requires a high index o suspicion. A history o a valve lesion or
other condition known to predispose to endocarditis is help ul. A thorough history should
also inquire about injection drug use, recent dental procedures, or other potential sources
o bacteremia.
Cardiac examination may reveal a murmur representing underlying valvular pathology that
predisposed the patient to IE, or a new murmur o valvular insu ciency owing to IE-induced
damage. The development o right-sided valve lesions (e.g., tricuspid regurgitation), although
rare in normal hosts, is particularly common in endocarditis associated with intravenous drug
abuse. Serial examination in ABE may be especially use ul because changes in a murmur
(i.e., worsening regurgitation) over time may correspond with rapidly progressive valvular
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Valvular Heart Disease
215
destruction. During the course o endocarditis, severe valvular destruction may result in signs
o heart ailure, which is the leading cause o death in patients with IE.
Other physical ndings that may appear in IE are those associated with septic embolism or
immune complex deposition. Central nervous system emboli occur in up to 40% o patients,
o ten resulting in new neurologic ndings on physical examination. Injury to the kidneys, o
embolic or immunologic origin, may mani est as f ank pain, hematuria, or renal ailure. Lung
in arction (septic pulmonary embolism) or in ection (pneumonia) is particularly common in
endocarditis that involves right-sided valves.
Embolic in arction and seeding o the vasa vasorum o arteries can cause localized aneurysm ormation (termed a mycotic aneurysm) that weakens the vessel wall and may rupture.
Mycotic aneurysms may be ound in the aorta, viscera, or peripheral organs, and are particularly dangerous in cerebral vessels, because rupture there can result in atal intracranial
hemorrhage.
Skin ndings resulting rom septic embolism or immune complex vasculitis are o ten collectively re erred to as peripheral stigmata o endocarditis. For example, petechiae may appear
as tiny, circular, red-brown discolorations on mucosal sur aces or skin. Splinter hemorrhages,
the result o subungual microemboli, are small, longitudinal hemorrhages ound beneath
nails. Other peripheral stigmata o IE, which are now rarely encountered, include painless,
f at, irregular discolorations ound on the palms and soles called Janeway lesions; tender, peasized, erythematous nodules ound primarily in the pulp space o the ngers and toes termed
Osler nodes; and emboli to the retina that produce Roth spots, microin arctions that appear as
white dots surrounded by hemorrhage.
The systemic inf ammatory response produced by the in ection is responsible or ever and
splenomegaly, as well as or a number o laboratory ndings, including an elevated white
blood cell count with a le tward shi t (increase in proportion o neutrophils and immature
granulocytes), an elevated erythrocyte sedimentation rate and C-reactive protein level, and in
approximately 50% o cases, an elevated serum rheumatoid actor.
The electrocardiogram may help identi y extension o the in ection into the cardiac conduction system, mani est by various degrees o heart block or new arrhythmias. Echocardiography
is used to visualize vegetations, valvular dys unction, and associated abscess ormation.
Echocardiographic assessment can consist o transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE), as described in Chapter 3. TTE is use ul in detecting
large vegetations and has the advantage o being noninvasive and easy to obtain. However,
while the specif city o TTE or vegetations is high, the sensitivity or nding vegetations is
less than 60% . TEE, on the other hand, is much more sensitive (> 90% ) or the detection o
vegetations and myocardial abscess ormation and can be particularly use ul or the evaluation o in ection involving prosthetic valves.
Central to the diagnosis and appropriate treatment o endocarditis is the identi cation o
the responsible microorganism by blood culture. Once positive culture results are obtained,
treatment can be tailored to the causative organism according to its antibiotic sensitivities. A
speci c etiologic agent is identi ed approximately 90% o the time. However, blood cultures
may return negative i antibiotics have already been administered or i the organism has
unusual growth requirements.
Even a ter a care ul history, examination, and evaluation o laboratory data, the diagnosis o IE can be elusive. There ore, attempts have been made to standardize the diagnosis, resulting in the now widely used Duke criteria (Table 8-4). By this standard, the
diagnosis o endocarditis rests on the presence o either two major criteria, one major
and three minor criteria, or ve minor criteria. Positive blood cultures and endocardial
involvement detected by echocardiography provide the strongest evidence or IE and are
considered major criteria. Minor criteria relate to clinical risk actors and ndings on
physical examination.
216
Chapter 8
TABLE 8-4
Modif ed Duke Criteria or Diagnosis o In ective
Endocarditis ( IE) a
Major Criteria
Minor Criteria
I. Positive blood culture, def ned as either A or B
A. Typical microorganism or IE rom two
separate blood cultures
1. Streptococci viridans, S. bovis, HACEK
group; or
2. Staphylococcus aureus or enterococci, in
the absence o a primary ocus
B. Microorganisms consistent with IE rom
persistently positive blood cultures
1. Blood cultures drawn > 12 hr apart, or
2. All o three, or most o our separate cultures drawn at least 1 hr apart
3. Single positive blood culture or Coxiella
burnetii or antiphase I IgG antibody titer
> 1:800
Predisposing cardiac condition or intravenous
drug use
Fever (≥ 38.0°C)
Vascular phenomena (septic arterial or pulmonary
emboli, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway
lesions)
Immunologic phenomena (glomerulonephritis,
Osler nodes, Roth spots, rheumatoid actor)
Positive blood cultures not meeting major
criteria or serologic evidence o in ection with
organism consistent with IE
II. Evidence o endocardial involvement, def ned
as A or B
A. Echocardiogram positive or endocarditis:
1. Oscillating intracardiac mass, or
2. Myocardial abscess, or
3. New partial detachment o prosthetic
valve
B. New valvular regurgitation
a
Clinical diagnosis o def nite endocarditis requires two major criteria, one major plus three minor criteria, or f ve
minor criteria. Possible endocarditis requires one major plus one minor criteria or three minor criteria.
HACEK, Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and
Kingella kingae.
Derived rom Li JS, Sexton DJ, Mick N, et al. Proposed modif cations to the Duke criteria or the diagnosis o
in ective endocarditis. Clin Infect Dis. 2000;30:633–638.
Treatment
Treatment o endocarditis entails 4 to 6 weeks o high-dose intravenous antibiotic therapy.
Although empiric broad-spectrum antibiotics may be used initially (a ter blood cultures are
obtained) or patients who are severely ill or hemodynamically unstable, specif c, directed
therapy is appropriate once the causative microorganism has been identif ed. Surgical intervention, usually with valve replacement, is indicated or patients with persistent bacteremia
or ever despite appropriate antibiotic therapy, or those with severe valvular dys unction
leading to heart ailure, and or individuals who develop myocardial abscesses or recurrent
endocarditis-related thromboemboli.
Prevention
An additional essential concept is prevention o endocarditis by administering antibiotics to
certain susceptible individuals be ore invasive procedures that are likely to result in bacteremia. The American Heart Association recommends such antibiotic prophylaxis or the cardiac
conditions that place them at the highest risk or developing an adverse outcome rom IE, as
delineated in Table 8-5, when such individuals are subjected to procedures listed in the table.
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Valvular Heart Disease
TABLE 8-5
217
Antibiotic Prophylaxis for Infective Endocarditis
Cardiac conditions for which antibiotic prophylaxis is reasonable a
1. Presence o a prosthetic heart valve or prior valve repair with prosthetic material
2. Prior history o endocarditis
3. Certain congenital heart diseases (CHD):
• Unrepaired cyanotic CHD (described in Chapter 16)
• Completely repaired congenital heart de ects with prosthetic material, during the f rst 6 months
a ter the procedure (i.e., prior to protective endothelialization)
• Repaired CHD with residual de ects adjacent to the site o prosthetic material (which inhibits
endothelialization)
4. Cardiac transplant recipients who develop cardiac valve abnormalities
Procedures that warrant antibiotic therapy for conditions listed above
1. Dental procedures that involve manipulation o gingival tissue, manipulation o periapical region
o the teeth, or per oration o the oral mucosa
2. Upper respiratory tract procedures, only if involves incision or biopsy o mucosa
(e.g., tonsillectomy, bronchoscopy with biopsy)
3. Genitourinary or gastrointestinal procedures, only if in ections o those systems are present
4. Procedures on infected skin or musculoskeletal tissue
a
The conditions on this list have the highest risk o adverse outcomes rom endocarditis.
Derived rom Wilson W, Taubert KA, Gewitz M, et al. Prevention o in ective endocarditis: guidelines rom the
American Heart Association: a guideline rom the American Heart Association Rheumatic Fever, Endocarditis, and
Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology,
Council on Cardiovascular Surgery and Anesthesia, and the Quality o Care and Outcomes Research Interdisciplinary
Working Group. Circulation. 2007;116:1736–1754.
SUMMARY
• Uni ying principles do not govern the behavior o all valvular heart diseases—e ective
management requires identi cation o the valve abnormality, a determination o its severity, and an understanding o the pathophysiologic consequences and natural history o
the condition (Table 8-6).
• Diagnosis o valvular disease is assisted by transthoracic echocardiography (TTE), which
allows or staging o disease severity; in selected patients, additional investigation with
exercise testing or cardiac catheterization may be necessary to de ne the signi cance o
the condition.
• Management o patients with stenotic or regurgitant valves involves serial clinical and
echocardiographic assessments; pharmacologic therapy is sometimes prescribed or
symptomatic improvement, but recognition o timely indications or valve repair or
replacement is essential.
• Mitral stenosis usually results rom prior rheumatic ever; le t atrial (LA) enlargement and
atrial brillation are common.
• Mitral regurgitation (MR) results rom disruption o the structural integrity o any o the
components o the mitral valve apparatus or their coordinated action; with chronic MR,
LA enlargement, and le t ventricular (LV) volume overload are typical.
• In mitral valve prolapse, the valve leaf ets are elongated, and the normal dense collagen and
elastin matrix o the valvular brosa is ragmented and replaced with loose myxomatous
connective tissue; one or both leaf ets bow into the LA during systole resulting in lack o
coaptation and mitral regurgitation.
• Aortic stenosis has three primary causes: (1) degenerative calci cation o a previously
normal trileaf et aortic valve, (2) calci cation o a congenitally bicuspid aortic valve, and
(3) rheumatic valve disease; the primary hemodynamic consequence is LV pressure overload
with compensatory LV hypertrophy; cardinal symptoms are chest discom ort, exertional
dyspnea, and exertional light-headedness.
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218
Chapter 8
Valvular Heart Disease
219
• Aortic regurgitation may result either rom abnormalities o the aortic valve leaf ets or rom
dilatation o the aortic root; the primary hemodynamic perturbation is LV volume overload.
• Tricuspid stenosis is rare and is usually a long-term consequence o rheumatic ever.
• Tricuspid regurgitation is usually unctional (due to RV enlargement) rather than structural
in nature.
• Pulmonic stenosis is rare, and its cause is almost always congenital de ormity o the valve.
• Pulmonic regurgitation most commonly develops in the setting o severe pulmonary hypertension and results rom dilatation o the valve ring by an enlarged pulmonary artery.
• The pathogenesis o endocarditis requires endocardial sur ace injury, platelet– brin–
thrombus ormation at the site o injury, bacterial entry into the circulation, and bacterial
adherence to the injured endocardial sur ace.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Christopher A. Miller, MD; Mia M.
Edwards, MD; Patrick Yachimski, MD; Stephen K. Frankel, MD; Edward Chan, MD; Elia Duh, MD;
Brian Stidham, MD; and John A. Bittl, MD.
Ad d i t i o n a l Rea d i n g
Gerber MA, Baltimore RS, Eaton CB, et al. Prevention
o rheumatic ever and diagnosis and treatment
o acute streptococcal pharyngitis. Circula tion .
2009;119:1541–1551.
Habib G, Hoen B, Tomos P, et al. Guidelines on the prevention, diagnosis, and treatment o in ective endocarditis
(new version 2009); The Task Force on the Prevention,
Diagnosis, and Treatment o In ective Endocarditis o the
European Society o Cardiology. Eur Heart J. 2009;30:
2369–2413.
Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ ACC
guideline or the management o patients with valvular heart disease: a report o the American College o
Cardiology/ American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol. 2014;63:e57-e185.
O’Gara P, Loscalzo J. Valvular heart disease. In: Longo DL,
Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of
Internal Medicine. 18th ed. New York, NY: McGraw-Hill;
2012:1929–1950.
Vahanian A, Al eri O, Andreotti F, et al. Guidelines on the
management o valvular heart disease (version 2012); The
Joint Task Force on the Management o Valvular Heart
Disease o the European Society o Cardiology and the
European Association or Cardio-Thoracic Surgery. Eur
Heart J. 2012;33:2451–2496.
Wilson W, Taubert KA, Gewitz M, et al. Prevention o
in ective endocarditis: guidelines rom the American
Heart Association: a guideline rom the American Heart
Association Rheumatic Fever, Endocarditis, and Kawasaki
Disease Committee, Council on Cardiovascular Disease in
the Young, and the Council on Clinical Cardiology, Council
on Cardiovascular Surgery and Anesthesia, and the Quality
o Care and Outcomes Research Interdisciplinary Working
Group. Circulation. 2007;116:1736–1754.
Heart Failure
Da vid Mira nda
Gregory D. Lewis
Micha el A. Fifer
Ch a p t e r O u t l i n e
Physiology
Determinants o Contractile
Function in the Intact Heart
Pressure–Volume Loops
Pathophysiology
Heart Failure with Reduced EF
Heart Failure with Preserved EF
Right-Sided Heart Failure
Compensatory Mechanisms
Frank–Starling Mechanism
Neurohormonal Alterations
Ventricular Hypertrophy and
Remodeling
Myocyte Loss And Cellular
Dysfunction
Precipitating Factors
Clinical Manifestations
Symptoms
Physical Signs
Diagnostic Studies
Prognosis
Treatment Of Heart Failure With
Reduced Ejection Fraction
Diuretics
Vasodilators
Positive Inotropic Drugs
β-Blockers
Aldosterone Antagonist Therapy
Additional Therapies
Treatment Of Heart Failure With
Preserved Ejection Fraction
Acute Heart Failure
Acute Pulmonary Edema
T
9
he heart normally accepts blood at low f lling pressures
during diastole and then propels it orward at higher
pressures in systole. Heart ailure is present when the heart
is unable to pump blood orward at a su f cient rate to meet
the metabolic demands o the body or is able to do so only
i cardiac f lling pressures are abnormally high. Although
conditions outside the heart may cause this def nition to be
met through inadequate tissue per usion (e.g., severe hemorrhage) or increased metabolic demands (e.g., hyperthyroidism), in this chapter, only cardiac causes o heart ailure are
considered.
Heart ailure results in a clinical syndrome o atigue, shortness o breath, and o ten volume overload. It may be the f nal
and most severe mani estation o nearly every orm o cardiac disease, including coronary atherosclerosis, myocardial
in arction, valvular diseases, hypertension, congenital heart
disease, and the cardiomyopathies. More than 550,000 new
cases are diagnosed each year in the United States, where the
current prevalence is approximately 5.8 million. The number
o patients with heart ailure is increasing, not only because
the population is aging but also because o interventions
that prolong survival a ter damaging cardiac insults such as
myocardial in arction. As a result, heart ailure now accounts
or more than 12 million medical o f ce visits annually and
is the most common diagnosis o hospitalized patients aged
65 years and older.
Heart ailure most commonly results rom conditions o
impaired le t ventricular unction. Thus, this chapter begins
by reviewing the physiology o normal myocardial contraction
and relaxation.
220
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Heart Failure
221
PHYSIOLOGY
Experimental studies o isolated cardiac muscle segments have revealed several important principles that can be applied to the intact heart. As a muscle segment is stretched
apart, the relation between its length and the tension it passively develops is curvilinear, re ecting its intrinsic elastic properties (Fig. 9-1A, lower curve). I the muscle is
f rst passively stretched and then stimulated to contract while its ends are held at f xed
d
b
e
a
c
a
c
B
A
f
b
g
e
a
C
FIGURE 9-1. Physiology of normal cardiac muscle segments. A. Passive (lower curve) and total (upper
curve) length–tension relations or isolated cat papillary muscle. Lines ab and cd represent the orce developed
during isometric contractions. Initial passive muscle length c is longer (i.e., has been stretched more) than
length a and there ore has a greater passive tension. When the muscle segments are stimulated to contract,
the muscle with the longer initial length generates greater total tension (point d vs. point b). B. I the
muscle f ber preparation is allowed to shorten against a f xed load, the length at the end o the contraction
is dependent on the load but not the initial f ber length; stimulation at point a or c results in the same f nal
f ber length (e). Thus, the muscle that starts at length c shortens a greater distance (∆ Lc) than the muscle at
length a (∆ La). C. The uppermost curve is the length–tension relation in the presence o the positive inotropic
agent norepinephrine. For any given initial length, an isometric contraction in the presence o norepinephrine
generates greater orce (point f) than one in the absence o norepinephrine (point b). When contracting
against a f xed load, the presence o norepinephrine causes greater muscle f ber shortening and a smaller f nal
muscle length (point g) compared with contraction in the absence o the inotropic agent (point e). (Adapted
rom Downing SE, Sonnenblick EH. Cardiac muscle mechanics and ventricular per ormance: orce and time
parameters. Am J Physiol. 1964;207:705–715.)
222
Chapter 9
positions (termed an isometric contraction), the total tension (the sum o active plu s
passive tension) generated by the f bers is proportional to the length o the muscle at the
time o stimulation (see Fig. 9-1A, upper curve). That is, stretching the muscle be ore
stimu lation optimizes the overlap and in teraction o myosin and actin f lamen ts, increasing the number o cross bridges and the orce o contraction. Stretching cardiac muscle
f bers also increases the sensitivity o the myof laments to calcium, which urther augments orce development.
This relationship between the initial f ber length and orce development is o great importance in the intact heart: within a physiologic range, the larger the ventricular volume during
diastole, the more the f bers are stretched be ore stimulation and the greater the orce o the
next contraction. This is the basis o the Frank–Starling relationship, the observation that
ventricular output increases in relation to the preload (the stretch on the myocardial f bers
be ore contraction).
A second observation rom isolated muscle experiments arises when the f bers are not
tethered at a f xed length but are allowed to shorten during stimulation against a f xed load
(termed the afterload). In this situation (termed an isotonic contraction), the f nal length o
the muscle at the end o contraction is determined by the magnitude o the load but is independent o the length o the muscle be ore stimulation (see Fig. 9-1B). That is, (1) the tension
generated by the f ber is equal to the f xed load; (2) the greater the load opposing contraction,
the less the muscle f ber can shorten; (3) i the f ber is stretched to a longer length be ore
stimulation but the a terload is kept constant, the muscle will shorten a greater distance to
attain the same f nal length at the end o contraction; and (4) the maximum tension that can
be produced during isotonic contraction (i.e., using a load su f ciently great such that the
muscle is just unable to shorten) is the same as the orce produced by an isometric contraction at that initial f ber length.
This concept o a terload is also relevant to the intact heart: the pressure generated by
the ventricle and the size o the chamber at the end o each contraction depend on the load
against which the ventricle contracts but are independent o the stretch on the myocardial
f bers be ore contraction.
A third key experimental observation relates to myocardial contractility, which accounts
or changes in the orce o contraction independent o the initial f ber length and a terload.
Contractility re ects chemical and hormonal in uences on cardiac contraction, such as exposure to catecholamines. When contractility is enhanced pharmacologically (e.g., by a norepinephrine in usion), the relation between initial f ber length and orce developed during
contraction is shi ted upward (see Fig. 9-1C) such that a greater total tension develops with
isometric contraction at any given preload. Similarly, when contractility is augmented and
the cardiac muscle is allowed to shorten against a f xed a terload, the f ber contracts to a
greater extent and achieves a shorter f nal f ber length compared with the baseline state. At
the molecular level, enhanced contractility is likely related to an increased cycling rate o
actin–myosin cross-bridge ormation.
Determinants of Contractile Function in the Intact Heart
In a healthy person, cardiac output is matched to the body’s total metabolic need. Cardiac
output (CO) is equal to the product o stroke volume (SV, the volume o blood ejected with
each contraction) and the heart rate (HR):
CO = SV × HR
The three major determinants o stroke volume are preload, a terload, and myocardial
contractility, as shown in Figure 9-2.
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Heart Failure
Preload
Contra ctility
Pre loa d
223
Afte rloa d
The concept o preload (Table 9-1) in the
+
intact heart was described by physiologists
Frank and Starling a century ago. In experS troke
+
–
imental preparations, they showed that
volume
within physiologic limits, the more a nor+
mal ventricle is distended (i.e., f lled with
blood) during diastole, the greater the volHe a rt
Ca rdia c
+
rate
output
ume that is ejected during the next systolic
contraction. This relationship is illustrated
graphically by the Frank–Starling curve, FIGURE 9-2. Key mediators o cardiac output.
also known as the ventricular unction Determinants o the stroke volume include contractility,
curve (Fig. 9-3). The graph relates a mea- preload, and a terload. Cardiac output = heart rate ×
surement o cardiac per ormance (such as stroke volume.
cardiac output or stroke volume) on the
vertical axis as a unction o preload on the horizontal axis. As described earlier, the preload can be thought o as the amount o myocardial stretch at the end o diastole, just
be ore contraction. Measurements that correlate with myocardial stretch, and that are o ten
used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV) or end-diastolic pressure (EDP). Conditions that decrease intravascular volume,
and thereby reduce ventricular preload (e.g., dehydration or severe hemorrhage), result
in a smaller EDV and hence a reduced stroke volume during contraction. Conversely, an
increased volume within the le t ventricle during diastole (e.g., a large intravenous uid
in usion) results in a greater-than-normal stroke volume.
TABLE 9-1 Terms Related to Cardiac Per ormance
Term
Def nition
Preload
The ventricular wall tension at the end o diastole. In clinical terms, it
is the stretch on the ventricular bers just be ore contraction, o ten
approximated by the end-diastolic volume or end-diastolic pressure.
The ventricular wall tension during contraction; the orce that must be
overcome or the ventricle to eject its contents. O ten approximated by
the systolic ventricular (or arterial) pressure
Property o heart muscle that accounts or changes in the strength
o contraction, independent o the preload and a terload. Ref ects
chemical or hormonal inf uences (e.g., catecholamines) on the orce o
contraction
Volume o blood ejected rom the ventricle during systole
SV = End-diastolic volume – end-systolic volume
The raction o end-diastolic volume ejected rom the ventricle during
each systolic contraction (normal range = 55%–75%)
EF = Stroke volume ÷ end-diastolic volume
Volume o blood ejected rom the ventricle per minute
CO = SV × Heart rate
Intrinsic property o a chamber that describes its pressure–volume
relationship during illing. Re lects the ease or di iculty wit h
which t he chamber can be illed. Compliance = ∆ volume ÷
∆ pressure
A terload
Contractility (inotropic state)
Stroke volume (SV)
Ejection raction (EF)
Cardiac output (CO)
Compliance
224
Chapter 9
c
o
l
o
u
u
t
m
p
e
u
t
)
Incre a s e d
contra ctility
(
o
r
S
t
c
r
a
o
r
k
d
e
i
a
v
Norma l
a
c
He a rt fa ilure
H
yp
o
t
e
n
s
i
o
n
b
Pulmona ry conge s tion
Le ft ve ntricula r e nd-dia s tolic pre s s ure
(or e nd-dia s tolic volume )
FIGURE 9-3. Left ventricular ( LV) performance (Frank–Starling) curves relate preload, measured as LV enddiastolic volume ( EDV) or pressure (EDP), to cardiac performance, measured as ventricular stroke volume
or cardiac output. On the curve o a normal heart (middle line), cardiac per ormance continuously increases as
a unction o preload. States o increased contractility (e.g., norepinephrine in usion) are characterized by an
augmented stroke volume at any level o preload (upper line). Conversely, decreased LV contractility (commonly
associated with heart ailure) is characterized by a curve that is shi ted downward (lower line). Point a is an
example o a normal person at rest. Point b represents the same person a ter developing systolic dys unction and
heart ailure (e.g., a ter a large myocardial in arction): stroke volume has allen, and the decreased LV emptying
results in elevation o the EDV. Because point b is on the ascending portion o the curve, the elevated EDV serves
a compensatory role because it results in an increase in subsequent stroke volume, albeit much less than i
operating on the normal curve. Further augmentation o LV lling (e.g., increased circulating volume) in the heart
ailure patient is represented by point c, which resides on the relatively f at part o the curve: stroke volume is
only slightly augmented, but the signi cantly increased EDP results in pulmonary congestion.
Afterload
A terload (see Table 9-1) in the intact heart re ects the resistance that the ventricle must
overcome to empty its contents. It is more ormally def ned as the ventricular wall stress that
develops during systolic ejection. Wall stress (σ), like pressure, is expressed as orce per unit
area and, or the le t ventricle, may be estimated rom Laplace relationship:
s =
P ×r
2h
where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall
thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g.,
hypertension) or an increased chamber size (e.g., a dilated le t ventricle). Conversely, as
would be expected rom Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the orce is distributed over a greater mass per
unit sur ace area o ventricular muscle.
Contractility ( Also Termed “Inotropic State”)
In the intact heart, as in the isolated muscle preparation, contractility accounts or changes in
myocardial orce or a given set o preload and a terload conditions, resulting rom chemical
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Heart Failure
225
and hormonal in uences. By relating a measure o ventricular per ormance (stroke volume
or cardiac output) to preload (le t ventricular EDP or EDV), each Frank–Starling curve is a
re ection o the heart’s current inotropic state (see Fig. 9-3). The e ect on stroke volume by
an alteration in preload is re ected by a change in position along a particular Frank–Starling
curve. Conversely, a change in contractility shi ts the entire curve in an upward or downward
direction. Thus, when contractility is enhanced pharmacologically (e.g., by an in usion o
norepinephrine), the ventricular per ormance curve is displaced upward such that at any
given preload, the stroke volume is increased. Conversely, when a drug that reduces contractility is administered, or the ventricle’s contractile unction is impaired (as in certain types
o heart ailure), the curve shi ts in a downward direction, leading to reductions in stroke
volume and cardiac output at any given preload.
Pressure–Volume Loops
Another use ul graphic display to illustrate the determinants o cardiac unction is the ventricular pressure–volume loop, which relates changes in ventricular volume to corresponding changes in pressure throughout the cardiac cycle (Fig. 9-4). In the le t ventricle, f lling
o the chamber begins a ter the mitral valve opens in early diastole (point a). The curve
between points a and b represents diastolic f lling. As the volume increases during diastole,
d
c
AV ope ns ;
Eje ction be gins
m
H
g
)
AV clos e s ;
Eje ction e nds
Is ovolume tric
re la xa tion
Is ovolume tric
contra ction
P
r
e
s
s
u
r
e
(
m
S troke
volume
( = EDV – ESV)
MV ope ns ;
LV Filling be gins
b
a
ESV
LV contra ction;
MV clos e s
EDV
Volume (mL)
FIGURE 9-4. Example of a normal left ventricular ( LV) pressure–volume loop. At point a, the mitral valve
(MV) opens and f lling o the LV commences. During passive diastolic f lling o the LV (line ab), its volume
increases with a gradual rise in pressure. When ventricular contraction commences and its pressure exceeds
that o the le t atrium, the MV closes (point b) and isovolumetric contraction o the LV ensues (the aortic valve
is not yet open, and no blood leaves the chamber), as shown by line bc. When LV pressure rises to that in the
aorta, the aortic valve (AV) opens (point c) and ejection begins. The volume within the LV declines during
ejection (line cd), but LV pressure continues to rise until ventricular relaxation commences, then it begins to
lessen. At point d, the LV pressure during relaxation alls below that in the aorta, and the AV closes, leading
to isovolumetric relaxation (line da). As LV pressure declines urther to below that in the le t atrium, the MV
reopens (point a). Point b represents the end-diastolic volume (EDV) and pressure, and point d is the endsystolic volume (ESV) and pressure. Stroke volume is calculated as the di erence between the EDV and ESV.
226
Chapter 9
it is associated with a small rise in pressure, in accordance with the passive length–tension
properties or compliance (see Table 9-1) o the myocardium, analogous to the lower curve in
Figure 9-1A or an isolated muscle preparation.
Next, the onset o le t ventricular systolic contraction causes the ventricular pressure to
rise. When the pressure in the le t ventricle (LV) exceeds that o the le t atrium (point b), the
mitral valve is orced to close. As the pressure continues to increase, the ventricular volume
does not immediately change, because the aortic valve has not yet opened; there ore, this
phase is called isovolumetric contraction. When the rise in ventricular pressure reaches
the aortic diastolic pressure, the aortic valve is orced to open (point c) and ejection o blood
into the aorta commences. During ejection, the volume within the ventricle decreases, but
its pressure continues to rise until ventricular relaxation begins. The pressure against which
the ventricle ejects (a component o a terload) is represented by the curve cd. Ejection ends
during the relaxation phase, when the ventricular pressure alls below that o the aorta and
the aortic valve closes (point d).
As the ventricle continues to relax, its pressure declines while its volume remains constant
because the mitral valve has not yet opened (this phase is known as isovolumetric relaxation). When the ventricular pressure alls below that o the le t atrium, the mitral valve
opens again (point a) and the cycle repeats.
Note that point b represents the pressure and volume at the end o diastole, whereas point
d represents the pressure and volume at the end o systole. The di erence between the EDV
and end-systolic volume (ESV) represents the quantity o blood ejected during contraction
(i.e., the stroke volume).
Changes in any o the determinants o cardiac unction are re ected by alterations in the
pressure–volume loop. By analyzing the e ects o a change in an individual parameter (preload, a terload, or contractility) on the pressure–volume relationship, the resulting modif cations in ventricular pressure and stroke volume can be predicted (Fig. 9-5).
Alterations in Preload
I a terload and contractility are held constant but preload is caused to increase (e.g., by
administration o intravenous uid), le t ventricular EDV rises. This increase in preload augments the stroke volume via the Frank–Starling mechanism such that the ESV achieved is the
same as it was be ore increasing the preload (see Fig. 9-5A). This means that the normal le t
ventricle is able to adjust its stroke volume and e ectively empty its contents to match its
diastolic f lling volume, as long as contractility and a terload are kept constant.
Although EDV and EDP are o ten used interchangeably as markers o preload, the relationship between f lling volume and pressure (i.e., ventricular compliance; see Table 9-1) largely
governs the extent o ventricular f lling. I ventricular compliance is reduced (e.g., in severe
LV hypertrophy), the slope o the diastolic f lling curve (segment ab in Fig. 9-4) becomes
steeper. A “sti ” or poorly compliant ventricle reduces the ability o the chamber to f ll during diastole, resulting in a lower-than-normal ventricular EDV. In this circumstance, the stroke
volume will be reduced while the ESV remains unchanged.
Alterations in Afterload
I preload and contractility are held constant and a terload is augmented (e.g., in highimpedance states such as hypertension or aortic stenosis), the pressure generated by the
le t ventricle during ejection increases. In this situation, more ventricular work is expended
in overcoming the resistance to ejection and there ore less f ber shortening takes place. As
shown in Figure 9-5B, an increase in a terload results in a higher ventricular systolic pressure
and a greater-than-normal LV ESV. Thus, in the setting o increased a terload, the ventricular
stroke volume (EDV-ESV) is reduced.
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Heart Failure
227
H
H
g
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)
)
3
e
e
s
s
s
s
u
u
r
r
e
e
(
(
m
m
m
m
2
P
P
r
r
2
3
Volume (mL)
B
P
r
e
s
s
u
r
e
(
m
m
H
g
)
A
Volume (mL)
Volume mL
C
FIGURE 9-5. The effect of varying preload, afterload, and contractility on the pressure–volume loop.
A. When arterial pressure (afterload) and contractility are held constant, sequential increases (lines 1, 2,
and 3) in preload (measured in this case as end-diastolic volume [EDV]) are associated with loops that have
progressively higher stroke volumes but a constant end-systolic volume (ESV). B. When the preload (EDV) and
contractility are held constant, sequential increases (points 1, 2, and 3) in arterial pressure (afterload) are
associated with loops that have progressively lower stroke volumes and higher end-systolic volumes. There is
a nearly linear relationship between the afterload and ESV, termed the end-systolic pressure–volume relation
(ESPVR). C. A positive inotropic intervention shifts the end-systolic pressure–volume relation upward and
leftward from ESPVR-1 to ESPVR-2, resulting in loop 2, which has a larger stroke volume and a smaller endsystolic volume than the original loop 1.
The dependence of the ESV on afterload is approximately linear: the greater the afterload,
the higher the ESV. This relationship is depicted in Figure 9-5 as the end-systolic pressure–
volume relation (ESPVR) and is analogous to the total tension curve in the isolated muscle
experiments described earlier.
Alterations in Contractility
The slope of the ESPVR line on the pressure–volume loop graph is a function of cardiac contractility. In conditions of increased contractility, the ESPVR slope becomes steeper; that is,
it shifts upward and toward the left. Hence, at any given preload or afterload, the ventricle
empties more completely (the stroke volume increases) and results in a smaller-than-normal
ESV (see Fig. 9-5C). Conversely, in situations of reduced contractility, the ESPVR line shifts
228
Chapter 9
downward, consistent with a decline in stroke volume and a higher ESV. Thus, the ESV is
dependent on the a terload against which the ventricle contracts and the inotropic state, but
is independent o the EDV prior to contraction.
The important physiologic concepts in this section are summarized here:
1. Ventricular stroke volume is a unction o preload, a terload, and contractility. SV rises
when there is an increase in preload, a decrease in a terload, or augmented contractility.
2. Ventricular EDV (or EDP) is used as a representation o preload. The EDV is in uenced by
the chamber’s compliance.
3. Ventricular ESV depends on the a terload and contractility but not on the preload.
PATHOPHYSIOLOGY
Chronic heart ailure may result rom a wide variety o cardiovascular insults. The etiologies
can be grouped into those that (1) impair ventricular contractility, (2) increase a terload,
or (3) impair ventricular relaxation and f lling (Fig. 9-6). Heart ailure that results rom
an abnormality o ventricular emptying (due to impaired contractility or greatly excessive
a terload) is termed systolic dysfun ction , whereas heart ailure caused by abnormalities o
diastolic relaxation or ventricular f lling is termed dia stolic dysfun ction . However, there is
much overlap, and many patients demonstrate both systolic and diastolic abnormalities.
As a result, it is common to categorize heart ailure patients into two general categories
Afte rlo ad
(Chro nic Pre s s ure Ove rlo ad a )
Impaire d Co ntrac tility
1. Adva nce d a ortic s te nos is
1. Corona ry a rte ry dis e a s e
• Myoca rdia l infa rction
• Tra ns ie nt myoca rdia l
is che mia
2. Chronic volume ove rloa d
• Mitra l re gurgita tion
• Aortic re gurgita tion
3. Dila te d ca rdiomyopa thie s
2. Uncontrolle d s eve re
hype rte ns ion
Re duc e d Eje c tio n Frac tio n
(Sys tolic Dys func tion)
He art Failure
Pre s e rve d Eje c tio n Frac tio n
(Dia s tolic Dys func tion)
Impaire d Dias to lic Filling
1. Le ft ve ntricula r hype rtrophy
2. Re s trictive ca rdiomyopa thy
3. Myoca rdia l fibros is
4. Tra ns ie nt myoca rdia l is che mia
5. Pe rica rdia l cons triction or
ta mpona de
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FIGURE 9-6. Conditions that
cause left-sided heart failure
through impairment of ventricular
systolic or diastolic function.
a
Note that in chronic stable stages,
the conditions in this box (aortic
stenosis, hypertension) may instead
result in heart failure with preserved
EF, due to compensatory ventricular
hypertrophy and increased diastolic
stiffness (diastolic dysfunction).
Heart Failure
based on the le t ventricular ejection
(see Table 9-1): (1) heart failure w ith
and (2) heart failure w ith preserved
United States, approximately one hal o
categories.
229
raction (EF), a measure o cardiac per ormance
reduced EF (i.e., primarily systolic dys unction)
EF (i.e., primarily diastolic dys unction). In the
patients with heart ailure all into each o these
Heart Failure with Reduced EF
g
)
In states o systolic dys unction, the a ected ventricle has a diminished capacity to eject
blood because o impaired myocardial contractility or pressure overload (i.e., excessive a terload). Loss o contractility may result rom destruction o myocytes, abnormal myocyte unction, or f brosis. Pressure overload impairs ventricular ejection by signif cantly increasing
resistance to ow.
Figure 9-7A depicts the e ects o systolic dys unction due to impaired contractility on the
pressure–volume loop. The ESPVR is shi ted downward such that systolic emptying ceases
at a higher-than-normal ESV. As a result, the stroke volume alls. When normal pulmonary
venous return is added to the increased ESV that has remained in the ventricle because o
incomplete emptying, the diastolic chamber volume increases, resulting in a higher-thannormal EDV and pressure. While that increase in preload induces a compensatory rise in
stroke volume (via the Frank–Starling mechanism), impaired contractility and the reduced EF
cause the ESV to remain elevated.
During diastole, the persistently elevated LV pressure is transmitted to the le t atrium
(through the open mitral valve) and to the pulmonary veins and capillaries. An elevated pulmonary capillary hydrostatic pressure, when su f ciently high (usually greater than 20 mm Hg),
results in the transudation o uid into the pulmonary interstitium and symptoms o pulmonary congestion.
H
2
P
r
P
e
r
s
e
s
s
u
s
r
u
e
r
(
e
(
m
m
m
m
H
g
)
2
Dia s tolic pre s s ure –
volume curve
Volume (mL)
A
Volume (mL)
B
FIGURE 9-7. The pressure–volume loop in systolic and diastolic dysfunction. A. The normal pressure–
volume loop (solid line) is compared with one demonstrating systolic dys unction (dashed blue line). In
systolic dys unction caused by decreased cardiac contractility, the end-systolic pressure–volume relation is
shi ted downward and rightward ( rom line 1 to line 2). As a result, the end-systolic volume (ESV) is increased
(arrow). As normal venous return is added to that greater-than-normal ESV, there is an obligatory increase
in the end-diastolic volume (EDV) and pressure (preload), which serves a compensatory unction by partially
elevating stroke volume toward normal via the Frank–Starling mechanism. B. The pressure–volume loop
o diastolic dys unction resulting rom increased sti ness o the ventricle (dashed blue line). The passive
diastolic pressure–volume curve is shi ted upward ( rom line 1 to line 2) such that at any diastolic volume, the
ventricular pressure is higher than normal. The result is a decreased EDV (arrow) because o reduced f lling o
the sti ened ventricle at a higher-than-normal end-diastolic pressure.
230
Chapter 9
Heart Failure with Preserved EF
Patients who exhibit heart ailure with preserved EF requently demonstrate abnormalities o
ventricular diastolic unction: impaired early diastolic relaxation (an active, energy-dependent
process), increased sti ness o the ventricular wall (a passive property), or both. Acute myocardial ischemia is an example o a condition that transiently inhibits energy delivery and
diastolic relaxation. Conversely, le t ventricular hypertrophy, f brosis, or restrictive cardiomyopathy (see Chapter 10) causes the LV walls to become chronically sti ened. Certain pericardial
diseases (cardiac tamponade and pericardial constriction, as described in Chapter 14) present
an external orce that limits ventricular f lling and represent potentially reversible orms o diastolic dys unction. The e ect o impaired diastolic unction is re ected in the pressure–volume
loop (see Fig. 9-7B): in diastole, f lling o the ventricle occurs at higher-than-normal pressures
because the lower part o the loop is shi ted upward as a result o reduced chamber compliance. Patients with diastolic dys unction o ten mani est signs o vascular congestion because
the elevated diastolic pressure is transmitted retrograde to the pulmonary and systemic veins.
Right-Sided Heart Failure
Whereas the physiologic principles described above may be applied to both right-sided and
le t-sided heart ailure, there are distinct di erences in unction between the two ventricles.
Compared with the le t ventricle, the right ventricle (RV) is a thin-walled, highly compliant
chamber that accepts its blood volume at low pressures and ejects against a low pulmonary
vascular resistance. As a result o its high compliance, the RV has little di f culty accepting a
wide range o f lling volumes without marked changes in its f lling pressure. Conversely, the
RV is quite susceptible to ailure in situations that present a sudden increase in a terload, such
as acute pulmonary embolism.
The most common cause o right-sided heart ailure is actually the presence o le t-sided
heart ailure (Table 9-2). In this situation, excessive a terload con ronts the RV because o the
elevated pulmonary vascular pressures that result rom LV dys unction. Isolated right heart
ailure is less common and usually re ects increased RV a terload owing to diseases o the
lung parenchyma or pulmonary vasculature. Right-sided heart disease that results rom a
primary pulmonary process is known as cor pulmonale, which may lead to symptoms o right
heart ailure.
When the RV ails, the elevated diastolic pressure is transmitted retrograde to the right
atrium with subsequent congestion o the systemic veins, accompanied by signs o right-sided
heart ailure as described below. Indirectly, isolated right heart ailure may also in uence le t
heart unction: the decreased right ventricular output reduces blood return to the LV (i.e.,
diminished preload), causing le t ventricular stroke volume to decline.
TABLE 9-2 Examples of Conditions That Cause Right-Sided Heart Failure
Cardiac causes
Left-sided heart failure
Pulmonic valve stenosis
Right ventricular infarction
Pulmonary parenchymal diseases
Chronic obstructive pulmonary disease
Interstitial lung disease (e.g., sarcoidosis)
Chronic lung infection or bronchiectasis
Pulmonary vascular diseases
Pulmonary embolism
Pulmonary arteriolar hypertension
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Heart Failure
231
COMPENSATORY MECHANISMS
Several natural compensatory mechanisms are called into action in patients with heart ailure
that bu er the all in cardiac output and help preserve su f cient blood pressure (BP) to per use
vital organs. These compensations include (1) the Frank–Starling mechanism, (2) neurohormonal alterations, and (3) the development o ventricular hypertrophy and remodeling (Fig. 9-8).
Frank–Starling Mechanism
As shown in Figure 9-3, heart ailure caused by impaired le t ventricular contractile unction
causes a downward shi t o the ventricular per ormance curve. Consequently, at a given preload, stroke volume is decreased compared with normal. The reduced stroke volume results
in incomplete chamber emptying, so that the volume o blood that accumulates in the ventricle during diastole is higher than normal (see Fig. 9-3, point b). This increased stretch on
the myof bers, acting via the Frank–Starling mechanism, induces a greater stroke volume on
subsequent contraction, which helps to empty the enlarged le t ventricle and preserve orward cardiac output (see Fig. 9-8).
This benef cial compensatory mechanism has its limits, however. In the case o severe
heart ailure with marked depression o contractility, the curve may be nearly at at higher
diastolic volumes, reducing the augmentation o cardiac output achieved by the increased
chamber f lling. Concurrently in such a circumstance, marked elevation o the EDV and pressure (which is transmitted retrograde to the le t atrium, pulmonary veins, and capillaries)
may result in pulmonary congestion and edema (see Fig. 9-3, point c).
Neurohormonal Alterations
Several important neurohormonal compensatory mechanisms are activated in heart ailure
in response to the decreased cardiac output (Fig. 9-9). Three o the most important involve
(1) the adrenergic nervous system, (2) the renin–angiotensin–aldosterone system, and (3)
increased production o antidiuretic hormone (ADH). In part, these mechanisms serve to
increase systemic vascular resistance, which helps to maintain arterial per usion to vital
an
r
F
ta r
S
k
lin g m e c h a
n is
m
+
↓ S troke
Volume
+
tric u
n
e
↓V
la r
yin g
t
p
em
↑ Wa
ll
n e u r s tre s s &
ohor
a c tiv m o n a l
a tio n
↑C
o n tra
c
c tile fo r
↑ Ve ntricula r
e nd-dia s tolic volume
↑ Atria l
pre s s ure
Myoca rdia l
hype rtrophy
e
FIGURE 9-8. Compensatory mechanisms in heart failure. Both the Frank–Starling mechanism (which is
invoked by the rise in ventricular end-diastolic volume) and increased contractile force (due to myocardial
hypertrophy from augmented wall stress and neurohormonal activation) serve to maintain forward stroke
volume (dashed green arrows). However, the chronic rise in end-diastolic volume and myocardial hypertrophy
passively augment atrial pressure (red arrows), which may in turn contribute to symptoms of heart failure
(e.g., pulmonary congestion in the case of left-sided heart failure).
232
Chapter 9
De c re as e d Cardiac Output
Re nin–a ngiote ns in
sys te m
Sympa the tic
ne rvous sys te m
Contra ctility
He a rt
rate
Circula ting
volume
Va s ocons triction
Ve nous
Arte riola r
Ve nous re turn to
he a rt
( pre loa d)
Maintain
Blo o d
Pre s s ure
+
Cardiac
Output
Antidiure tic
hormone
–
Pe riphe ra l e de ma
a nd pulmona ry
conge s tion
+
S troke
volume
FIGURE 9-9. Compensatory neurohormonal stimulation develops in response to the reduced forward
cardiac output and blood pressure of heart failure. Increased activity o the sympathetic nervous system,
renin–angiotensin–aldosterone system, and antidiuretic hormone serves to support the cardiac output and
blood pressure (boxes). However, adverse consequences o these activations (red lines) include an increase in
a terload rom excessive vasoconstriction (which may then impede cardiac output) and excess f uid retention,
which contributes to peripheral edema and pulmonary congestion.
organs, even in the setting o a reduced cardiac output. That is, because blood pressure (BP)
is equal to the product o cardiac output (CO) and total peripheral resistance (TPR),
BP = CO × TPR
a rise in TPR induced by these compensatory mechanisms can nearly balance the all in CO
and, in the early stages o heart ailure, maintain airly normal BP. In addition, neurohormonal
activation results in salt and water retention, which in turn increases intravascular volume
and le t ventricular preload, maximizing stroke volume via the Frank–Starling mechanism.
Although the acute e ects o neurohormonal stimulation are compensatory and benef cial,
chronic activation o these mechanisms o ten ultimately proves deleterious to the ailing heart
and contributes to a progressive downhill course, as described later.
Adrenergic Nervous System
The all in cardiac output in heart ailure is sensed by baroreceptors in the carotid sinus and
aortic arch. These receptors decrease their rate o f ring in proportion to the all in BP, and
the signal is transmitted by the 9th and 10th cranial nerves to the cardiovascular control
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Heart Failure
233
center in the medulla. As a consequence, sympathetic out ow to the heart and peripheral
circulation is enhanced, and parasympathetic tone is diminished. There are three immediate
consequences (see Fig. 9-9): (1) an increase in heart rate, (2) augmentation o ventricular
contractility, and (3) vasoconstriction caused by stimulation o α-receptors on the systemic
veins and arteries.
The increased heart rate and ventricular contractility directly augment cardiac output (see
Fig. 9-2). Vasoconstriction o the venous and arterial circulations is also initially benef cial.
Venous constriction augments blood return to the heart, which increases preload and raises
stroke volume through the Frank–Starling mechanism, as long as the ventricle is operating on
the ascending portion o its ventricular per ormance curve. Arteriolar constriction increases
the peripheral vascular resistance and there ore helps to maintain blood pressure (BP = CO ×
TPR). The regional distribution o α-receptors is such that during sympathetic stimulation,
blood ow is redistributed to vital organs (e.g., heart and brain) at the expense o the skin,
splanchnic viscera, and kidneys.
Renin–Angiotensin–Aldosterone System
This system is also activated early in patients with heart ailure (see Fig. 9-9), mediated by
increased renin release. The main stimuli or renin secretion rom the juxtaglomerular cells
o the kidney in heart ailure patients include (1) decreased renal artery per usion pressure
secondary to low cardiac output, (2) decreased salt delivery to the macula densa o the kidney
owing to alterations in intrarenal hemodynamics, and (3) direct stimulation o juxtaglomerular β-receptors by the activated adrenergic nervous system.
Renin is an enzyme that cleaves circulating angiotensinogen to orm angiotensin I,
which is then rapidly cleaved by endothelial cell–bound angiotensin-converting enzyme
(ACE) to orm angiotensin II (AII), a potent vasoconstrictor (see Chapter 13). Increased AII
constricts arterioles and raises total peripheral resistance, thereby serving to maintain systemic blood pressure. In addition, AII acts to increase intravascular volume by two mechanisms: (1) at the hypothalamus, it stimulates thirst and there ore water intake, and (2) at
the adrenal cortex, it acts to increase aldosterone secretion. The latter hormone promotes
sodium reabsorption rom the distal convoluted tubule o the kidney into the circulation
(see Chapter 17), serving to augment intravascular volume. The rise in intravascular volume increases le t ventricular preload and thereby augments cardiac output via the Frank–
Starling mechanism in patients on the ascending portion o the ventricular per ormance
curve (see Fig. 9-3).
Antidiuretic Hormone
Secretion o this hormone (also termed vasopressin) by the posterior pituitary is increased
in many patients with heart ailure, presumably mediated through arterial baroreceptors,
and by increased levels o AII. ADH contributes to increased intravascular volume because
it promotes water retention in the distal nephron. The increased intravascular volume serves
to augment le t ventricular preload and cardiac output. ADH also appears to contribute to
systemic vasoconstriction.
Although each o these neurohormonal alterations in heart ailure is in itia lly benef cial,
continued activation ultimately proves harm ul. For example, the increased circulating volume and augmented venous return to the heart may eventually worsen engorgement o the
lung vasculature, exacerbating congestive pulmonary symptoms. Furthermore, the elevated
arteriolar resistance increases the a terload against which the ailing le t ventricle contracts and may there ore ultimately impa ir stroke volume and reduce cardiac output (see
Fig. 9-9). In addition, the increased heart rate augments metabolic demand and can thereore urther reduce the per ormance o the ailing heart. Continuous sympathetic activation
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results in down-regulation o cardiac β-adrenergic receptors and up-regulation o inhibitory
G proteins, contributing to a decrease in the myocardium’s sensitivity to circulating catecholamines and a reduced inotropic response.
Chronically elevated levels o AII and aldosterone have additional detrimental e ects. They
provoke the production o cytokines (small proteins that mediate cell–cell communication
and immune responses), activate macrophages, and stimulate f broblasts, resulting in f brosis
and adverse remodeling o the ailing heart.
Because the undesired consequences o chronic neurohormonal activation eventually outweigh the benef ts, much o today’s pharmacologic therapy o heart ailure is designed to
moderate these “compensatory” mechanisms, as examined later in the chapter.
Natriuretic Peptides
In contrast to the ultimately adverse consequences o the neurohormonal alterations
described in the previous section, the natriuretic peptides are natural “benef cial” hormones
secreted in heart ailure in response to increased intracardiac pressures. The best studied o
these are atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is stored
in atrial cells and is released in response to atrial distention. BNP is not detected in normal
hearts but is produced when ventricular myocardium is subjected to hemodynamic stress
(e.g., in heart ailure or during myocardial in arction). Clinical studies have shown a close
relationship between serum BNP levels and the severity o heart ailure.
Actions o the natriuretic peptides are mediated by specif c natriuretic receptors and are
largely opposite to those o the other hormone systems activated in heart ailure. They result
in excretion o sodium and water, vasodilatation, inhibition o renin secretion, and antagonism o the e ects o AII on aldosterone and vasopressin levels. Although these e ects are
benef cial to patients with heart ailure, they are usually not su f cient to ully counteract the
vasoconstriction and volume-retaining e ects o the other activated hormonal systems.
Other Peptides
Among other peptides that are generated in heart ailure is endothelin-1, a potent vasoconstrictor, derived rom endothelial cells lining the vasculature (see Chapter 6). In patients
with heart ailure, the plasma concentration o endothelin-1 correlates with disease severity
and adverse outcomes. Drugs designed to inhibit endothelin receptors (and there ore blunt
adverse vasoconstriction) improve LV unction, but long-term clinical benef ts have not been
demonstrated in heart ailure patients.
Ventricular Hypertrophy and Remodeling
Ventricular hypertrophy and remodeling are important compensatory processes that
develop over time in response to hemodynamic burdens. Wall stress (as def ned earlier)
is o ten increased in developing heart ailure because o either LV dilatation (increased
chamber radius) or the need to generate high systolic pressures to overcome excessive
a terload (e.g., in aortic stenosis or hypertension). A sustained increase in wall stress
(along with neurohormonal and cytokine alterations) stimulates the development o myocardial hypertrophy and deposition o extracellular matrix. This increased mass o muscle f bers serves as a compensatory mechanism that helps to maintain contractile orce
and coun tera cts the elevated ventricular wall stress (recall that wall thickness is in the
denominator o the Laplace wall stress ormula). However, because o the increased sti ness o the hypertrophied wall, these benef ts come at the expense o higher-than-normal
diastolic ventricular pressures, which are transmitted to the le t atrium and pulmonary
vasculature (see Fig. 9-8).
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Heart Failure
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The pattern o compensatory hypertrophy and remodeling that develops depends on
whether the ventricle is subjected to chronic volume or pressure overload. Chronic chamber
dilatation owing to volume overload (e.g., chronic mitral or aortic regurgitation) results in the
synthesis o new sarcomeres in series with the old, causing the myocytes to elongate. The
radius o the ventricular chamber there ore enlarges, doing so in proportion to the increase in
wall thickness, and is termed eccentric hypertrophy. Chronic pressure overload (e.g., caused
by hypertension or aortic stenosis) results in the synthesis o new sarcomeres in parallel with
the old (i.e., the myocytes thicken), termed concentric hypertrophy. In this situation, the
wall thickness increases without proportional chamber dilatation, and wall stress may thereore be reduced substantially.
Such hypertrophy and remodeling help to reduce wall stress and maintain contractile orce,
but ultimately, ventricular unction may decline urther, allowing the chamber to dilate out
o proportion to wall thickness. When this occurs, the excessive hemodynamic burden on the
contractile units produces a downward spiral o deterioration with progressive heart ailure
symptomatology.
MYOCYTE LOSS AND CELLULAR DYSFUNCTION
Impairment o ventricular unction in heart ailure may result rom the actual loss o myocytes
and/ or impaired unction o living myocytes. The loss o myocytes may result rom cellular
necrosis (e.g., rom myocardial in arction or exposure to cardiotoxic drugs such as doxorubicin) or apoptosis (programmed cell death). In apoptosis, genetic instructions activate intracellular pathways that cause the cell to ragment and undergo phagocytosis by other cells,
without an in ammatory response. Implicated triggers o apoptosis in heart ailure include
elevated catecholamines, AII, in ammatory cytokines, and mechanical strain on the myocytes
owing to the augmented wall stress.
Even viable myocardium in heart ailure is abnormal at the ultrastructural and molecular
levels. Mechanical wall stress, neurohormonal activation, and in ammatory cytokines, such
as tumor necrosis actor (TNF), are believed to alter the genetic expression o contractile
proteins, ion channels, catalytic enzymes, sur ace receptors, and secondary messengers
in the myocyte. Experimental evidence has demonstrated such changes at the subcellular level that a ect intracellular calcium handling by the sarcoplasmic reticulum, decrease
the responsiveness o the myof laments to calcium, impair excitation–contraction coupling,
and alter cellular energy production. Cellular mechanisms currently considered the most
important contributors to dys unction in heart ailure include (1) a reduced cellular ability
to maintain calcium homeostasis and/ or (2) changes in the production, availability, and
utilization o high-energy phosphates. However, the exact subcellular alterations that result
in heart ailure have not yet been unraveled, and this is an active area o cardiovascular
research.
PRECIPITATING FACTORS
Many patients with heart ailure remain asymptomatic or extended periods either because the
impairment is mild or because cardiac dys unction is balanced by the compensatory mechanisms described earlier. O ten, clinical mani estations are precipitated by circumstances that
increase the cardiac workload and tip the balanced state into one o decompensation.
Common precipitating actors are listed in Table 9-3. For example, conditions o increased
metabolic demand such as ever or in ection may not be matched by a su f cient increase
in output by the ailing heart, so that symptoms o cardiac insu f ciency are precipitated.
Tachyarrhythmias precipitate heart ailure by decreasing diastolic ventricular f lling time and
by increasing myocardial oxygen demand. Excessively low heart rates directly cause a drop in
cardiac output (remember, cardiac output = stroke volume × heart rate). An increase in salt
236
Chapter 9
TABLE 9-3
Factors That May Precipitate Symptoms in Patients with
Chronic Compensated Heart Failure
Increased metabolic demands
Fever
In ection
Anemia
Tachycardia
Hyperthyroidism
Pregnancy
Increased circulating volume ( increased preload)
Excessive sodium content in diet
Excessive f uid administration
Renal ailure
Conditions that increase afterload
Uncontrolled hypertension
Pulmonary embolism (increased right ventricular a terload)
Conditions that impair contractility
Negative inotropic medications
Myocardial ischemia or in arction
Excessive ethanol ingestion
Failure to take prescribed heart failure medications
Excessively slow heart rate
ingestion, renal dys unction, or ailure to take prescribed diuretic medications may increase
the circulating volume, thus promoting systemic and pulmonary congestion. Uncontrolled
hypertension depresses systolic unction because o excessive a terload. A large pulmonary
embolism results in both hypoxemia (and there ore decreased myocardial oxygen supply) and
augmented right ventricular a terload. Ischemic insults (i.e., myocardial ischemia or in arction), ethanol ingestion, or negative inotropic medications (e.g., large doses o β-blockers) can
all depress myocardial contractility and precipitate symptoms in the otherwise compensated
congestive heart ailure patient.
CLINICAL MANIFESTATIONS
The clinical mani estations o heart ailure result rom impaired orward cardiac output and/
or elevated venous pressures and relate to the ventricle that has ailed (Table 9-4). A patient
may present with the chronic progressive symptoms o heart ailure described here or, in certain cases, with sudden decompensation o le t-sided heart unction (e.g., acute pulmonary
edema, as described later in the chapter).
Symptoms
The most prominent mani estation o chronic le t ventricular ailure is dyspnea (breathlessness) on exertion. Controversy regarding the cause o this symptom has centered on whether
it results primarily rom pulmonary venous congestion or rom decreased orward cardiac
output. A pulmonary venous pressure that exceeds approximately 20 mm Hg leads to transudation o f uid into the pulmonary interstitium and congestion o the lung parenchyma.
The resulting reduced pulmonary compliance increases the work o breathing to move the
same volume o air. Moreover, the excess f uid in the interstitium compresses the walls o
the bronchioles and alveoli, increasing the resistance to airf ow and requiring greater e ort
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Heart Failure
237
TABLE 9-4 Common Symptoms and Physical Findings in Heart Failure
Symptoms
Left sided
Dyspnea
Orthopnea
Paroxysmal nocturnal dyspnea
Fatigue
Right sided
Peripheral edema
Right upper quadrant discomfort
(because of hepatic enlargement)
Physical Findings
Diaphoresis (sweating)
Tachycardia, tachypnea
Pulmonary rales
Loud P2
S3 gallop (in systolic dysfunction)
S4 gallop (in diastolic dysfunction)
Jugular venous distention
Hepatomegaly
Peripheral edema
o respiration. In addition, juxtacapillary receptors (J receptors) are stimulated and mediate
rapid shallow breathing. The heart ailure patient can also su er rom dyspnea even in the
absence o pulmonary congestion, because reduced blood ow to overworked respiratory
muscles and accumulation o lactic acid may also contribute to that sensation. Heart ailure
may initially cause dyspnea only on exertion, but more severe dys unction results in symptoms at rest as well.
Other mani estations o low orward output in heart ailure may include dulled mental status because o reduced cerebral per usion and impaired urine output during the day because
o decreased renal per usion. The latter o ten gives way to increased urinary requency at
night (nocturia) when, while supine, blood ow is redistributed to the kidney, promoting
renal per usion and diuresis. Reduced skeletal muscle per usion may result in fatigue and
weakness.
Other congestive mani estations o heart ailure include orthopnea, paroxysmal nocturnal
dyspnea (PND), and nocturnal cough. Orthopnea is the sensation o labored breathing while
lying at and is relieved by sitting upright. It results rom the redistribution o intravascular
blood rom the gravity-dependent portions o the body (abdomen and lower extremities)
toward the lungs a ter lying down. The degree o orthopnea is generally assessed by the number o pillows on which the patient sleeps to avoid breathlessness. Sometimes, orthopnea is
so signif cant that the patient may try to sleep upright in a chair.
PND is severe breathlessness that awakens the patient rom sleep 2 to 3 hours a ter
retiring to bed. This rightening symptom results rom the gradual reabsorption into the
circulation o lower extremity interstitial edema a ter lying down, with subsequent expansion o intravascular volume and increased venous return to the heart and lungs. A nocturnal cough is another symptom o pulmonary congestion and is produced by a mechanism
similar to orthopnea. Hemoptysis (coughing up blood) may result rom rupture o engorged
bronchial veins.
In right-sided heart ailure, the elevated systemic venous pressures can result in abdominal
discomfort because the liver becomes engorged and its capsule stretched. Similarly, anorexia
(decreased appetite) and nausea may result rom edema within the gastrointestinal tract.
Peripheral edema, especially in the ankles and eet, also re ects increased hydrostatic venous
pressures. Because o the e ects o gravity, it tends to worsen while the patient is upright
during the day and is o ten improved by morning a ter lying supine at night. Even be ore
peripheral edema develops, the patient may note an unexpected weight gain resulting rom
the accumulation o interstitial uid.
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Chapter 9
TABLE 9-5
New York Heart Association Classif cation o Chronic Heart
Failure
Class
Def nition
I
II
No limitation of physical activity
Slight limitation of activity. Dyspnea and fatigue with moderate exertion
(e.g., walking up stairs quickly)
Marked limitation of activity. Dyspnea with minimal exertion (e.g., slowly walking
up stairs)
Severe limitation of activity. Symptoms are present even at rest.
III
IV
The symptoms o heart ailure are commonly graded according to the New York Heart
Association (NYHA) classif cation (Table 9-5), and patients may shi t rom one class to
another, in either direction, over time. A newer system classif es patients according to their
stage in the temporal course o heart ailure (Table 9-6). In this system, progression is in only
one direction, rom Stage A to Stage D, re ecting the typical sequence o heart ailure maniestations in clinical practice.
Physical Signs
The physical signs o heart ailure depend on the severity and chronicity o the condition
and can be divided into those associated with le t or right heart dys unction (see Table 9-4).
Patients with only mild impairment may appear well. However, a patient with severe chronic
heart ailure may demonstrate cachexia (a rail, wasted appearance) owing in part to poor
appetite and to the metabolic demands o the increased e ort in breathing. In decompensated
le t-sided heart ailure, the patient may appear dusky (decreased cardiac output) and diaphoretic (sweating because o increased sympathetic nervous activity), and the extremities are
cool because o peripheral arterial vasoconstriction. Tachypnea (rapid breathing) is common.
The pattern o Cheyne–Stokes respiration may also be present in advanced heart ailure,
characterized by periods o hyperventilation separated by intervals o apnea (absent breathing). This pattern is related to the prolonged circulation time between the lungs and respiratory center o the brain in heart ailure that inter eres with the normal eedback mechanism
TABLE 9-6
Stages o Chronic Heart Failure
Stage
Description
A
The patient is at risk of developing heart failure but has not yet developed structural
cardiac dysfunction (e.g., patient with coronary artery disease, hypertension, or
family history of cardiomyopathy).
The patient with structural heart disease associated with heart failure but has not
yet developed symptoms
The patient with current or prior symptoms of heart failure associated with structural
heart disease
The patient with structural heart disease and refractory heart failure symptoms
despite maximal medical therapy who requires advanced interventions (e.g.,
cardiac transplantation)
B
C
D
Derived from Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA Guideline for the Management of Heart Failure:
Executive Summary A Report of the American College of Cardiology Foundation/ American heart Association Task Force
on Practice Guidelines. Circulation. 2013;128:1810–1852.
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Heart Failure
239
o systemic oxygenation. Sinus tachycardia (resulting rom increased sympathetic nervous
system activity) is also common. Pulsus alternans (alternating strong and weak contractions
detected in the peripheral pulse) may be present as a sign o advanced ventricular dys unction.
In le t-sided heart ailure, the auscultatory f nding o pulmonary rales (“crackles”) is created by the “popping open” o small airways during inspiration that had been closed o by
edema uid. This f nding is initially apparent at the lung bases, where hydrostatic orces
are greatest; however, more severe pulmonary congestion is associated with additional rales
higher in the lung f elds. Compression o conduction airways by pulmonary congestion may
produce coarse rhonchi and wheezing; the latter f nding in heart ailure is termed cardiac
asthma.
Depending on the cause o heart ailure, palpation o the heart may show that the le t ventricular impulse is not ocal but di use (in dilated cardiomyopathy), sustained (in pressure
overload states such as aortic stenosis or hypertension), or li ting in quality (in volume overload states such as mitral regurgitation). Because elevated le t heart f lling pressures result in
increased pulmonary vascular pressures, the pulmonic component o the second heart sound
is o ten louder than normal. An early diastolic sound (S3) is requently heard in adults with
systolic heart ailure and is caused by abnormal f lling o the dilated chamber (see Chapter 2).
A late diastolic sound (S4) results rom orce ul atrial contraction into a sti ened ventricle and
is common in states o decreased LV compliance (diastolic dys unction). The murmur o mitral
regurgitation is sometimes auscultated in le t-sided heart ailure i LV dilatation has stretched
the valve annulus and spread the papillary muscles apart rom one another, thus preventing
proper closure o the mitral lea ets in systole.
In right-sided heart ailure, di erent physical f ndings may be present. Cardiac examination may reveal a palpable parasternal right ventricular heave, representing RV enlargement,
or a right-sided S3 or S4 gallop. The murmur o tricuspid regurgitation may be auscultated and
is due to right ventricular enlargement, analogous to mitral regurgitation that develops in
patients with LV dilatation. The elevated systemic venous pressure produced by right heart
ailure is mani ested by distention of the jugular veins as well as hepatic enlargement with
abdominal right upper quadrant tenderness. Edema accumulates in the dependent portions o
the body, beginning in the ankles and eet o ambulatory patients and in the presacral regions
o those who are bedridden.
Pleural e usions may develop in either le t- or right-sided heart ailure, because the pleural veins drain into both the systemic and pulmonary venous beds. The presence o pleural
e usions is suggested on physical examination by dullness to percussion over the posterior
lung bases.
Diagnostic Studies
A normal mean le t atrial (LA) pressure is ≤ 10 mm Hg (see Fig. 3-13). I the LA pressure
exceeds approximately 15 mm Hg, the chest radiograph shows upper-zone vascular redistribution, such that the vessels supplying the upper lobes o the lung are larger than those
supplying the lower lobes (see Fig. 3-5). This is explained as ollows: when a patient is in the
upright position, blood ow is normally greater to the lung bases than to the apices because
o the e ect o gravity. Redistribution o ow occurs with the development o interstitial and
perivascular edema, because such edema is most prominent at the lung bases (where the
hydrostatic pressure is the highest), such that the blood vessels in the bases are compressed,
whereas ow into the upper lung zones is less a ected.
When the LA pressure surpasses 20 mm Hg, interstitial edema is usually mani ested on
the chest radiograph as indistinctness o the vessels and the presence o Kerley B lines (short
linear markings at the periphery o the lower lung f elds indicating interlobular edema—
see Fig. 3-5C). I the LA pressure exceeds 25 to 30 mm Hg, alveolar pulmonary edema may
develop, with opacif cation o the air spaces. The relationship between LA pressure and chest
240
Chapter 9
radiograph f ndings is modif ed in patients with chronic heart ailure because o enhanced lymphatic drainage, such that higher pressures can be accommodated with ewer radiologic signs.
Depending on the cause o heart ailure, the chest radiograph may show cardiomegaly, def ned
as a cardiothoracic ratio greater than 0.5 on the posteroanterior image. A high right atrial pressure also causes enlargement o the azygous vein silhouette. Pleural e usions may be present.
Assays or BNP, described earlier in the chapter, correlate well with the degree o LV dysunction and prognosis. Furthermore, an elevated serum level o BNP can help distinguish
heart ailure rom other causes o dyspnea, such as pulmonary parenchymal diseases.
The cause o heart ailure is o ten evident rom the history, such as a patient who has
sustained a large myocardial in arction, or by physical examination, as in a patient with a
murmur o valvular heart disease. When the cause is not clear rom clinical evaluation, the
f rst step is to determine whether systolic ventricular unction is normal or depressed (see
Fig. 9-6). O the several noninvasive tests that can help make this determination, echocardiography is especially use ul and readily available.
PROGNOSIS
The prognosis o heart ailure is dismal in the absence o a correctable underlying cause. The
5-year mortality rate ollowing the diagnosis ranges between 45% and 60% , with men having worse outcomes than women. Patients with severe symptoms (i.e., NYHA class III or IV)
are the least well, having a 1-year survival rate o only 40% . The greatest mortality is due
to re ractory heart ailure, but many patients die suddenly, presumably because o associated
ventricular arrhythmias. Heart ailure patients with preserved EF have similar rates o hospitalization, in-hospital complications, and mortality as those with reduced EF.
Ventricular dys unction usually begins with an inciting insult, but is a progressive process,
contributed to by the maladaptive activation o neurohormones, cytokines, and continuous
ventricular remodeling. Thus, it should not be surprising that measures o neurohormonal
and cytokine stimulation predict survival in heart ailure patients. For example, adverse prognosis correlates with the serum norepinephrine level (marker o sympathetic nervous system
activity), serum sodium (reduced level re ects activation o renin–angiotensin–aldosterone
system and alterations in intrarenal hemodynamics), endothelin-1, BNP, and TNF levels.
Despite the generally bleak prognosis, a heart ailure patient’s outlook can be substantially
improved by specif c interventions, as discussed in the ollowing sections.
TREATMENT OF HEART FAILURE WITH REDUCED EJECTION FRACTION
There are f ve main goals o therapy in patients with chronic heart ailure and a reduced EF:
1. Identif cation and correction o the underlying condition causing heart ailure. In some
patients, this may require surgical repair or replacement o dys unctional cardiac valves,
coronary artery revascularization, aggressive treatment o hypertension, or cessation o
alcohol consumption.
2. Elimination o the acute precipitating cause o symptoms in a patient with heart ailure who
was previously in a compensated state. This may include, or example, treating acute in ections
or arrhythmias, removing sources o excessive salt intake, or eliminating drugs that can aggravate symptomatology (e.g., certain calcium channel blockers, which have a negative inotropic
e ect, or nonsteroidal anti-in ammatory drugs, which can contribute to volume retention).
3. Management o heart ailure symptoms:
a. Treatment o pulmonary and systemic vascular congestion. This is most readily accomplished by dietary sodium restriction and diuretic medications.
b. Measures to increase orward cardiac output and per usion o vital organs through the
use o vasodilators and positive inotropic drugs.
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Heart Failure
241
4. Modulation of the neurohormonal response to prevent adverse ventricular remodeling in
order to slow the progression o LV dys unction.
5. Prolongation of long-term survival. There is strong evidence rom clinical trials that longevity is enhanced by specif c therapies, as described below.
Diuretics
t
m
p
e
u
t
)
The mechanisms o action o diuretic drugs are summarized in Chapter 17. By promoting the
elimination o sodium and water through the kidney, diuretics reduce intravascular volume
and thus venous return to the heart. As a result, the preload o the le t ventricle is decreased,
and its diastolic pressure alls out o the range that promotes pulmonary congestion (Fig. 9-10,
point b). The intent is to reduce the EDP (and there ore hydrostatic orces contributing to pulmonary congestion) without a signif cant all in stroke volume. The judicious use o diuretics does not signif cantly reduce stroke volume and cardiac output in this setting, because
the ailing ventricle is operating on the “ at” portion o a depressed Frank–Starling curve.
However, overly vigorous diuresis can lower LV f lling pressures into the steep portion o the
ventricular per ormance curve, resulting in an undesired all in cardiac output (see Fig. 9-10,
point b′). Thus, diuretics should be used only i there is evidence o pulmonary congestion
(rales) or peripheral interstitial uid accumulation (edema).
Agents that act primarily at the renal loop o Henle (e.g., urosemide, torsemide,
and bumetanide) are the most potent diuretics in heart ailure. Thiazide diuretics (e.g.,
o
r
S
t
c
r
a
o
r
k
d
e
i
a
v
c
o
l
o
u
u
Norma l
(
e
c
b´
b
He a rt fa ilure
a
H
yp
o
t
e
n
s
i
o
n
d
Pulmona ry conge s tion
Le ft ve ntricula r e nd-dia s tolic pre s s ure
(or e nd-dia s tolic volume )
FIGURE 9-10. The effect of treatment on the left ventricular ( LV) Frank–Starling curve in patients who
have heart failure with reduced EF. Point a represents the ailing heart on a curve that is shi ted downward
compared with normal. The stroke volume is reduced (with blood pressure bordering on hypotension), and the
LV end-diastolic pressure (LVEDP) is increased, resulting in symptoms o pulmonary congestion. Therapy with
a diuretic or pure venous vasodilator (point b on the same Frank–Starling curve) reduces LV pressure without
much change in stroke volume (SV). However, excessive diuresis or venous vasodilatation may result in an
undesired all in SV with hypotension (point b′). Inotropic drug therapy (point c) and arteriolar (or “balanced”)
vasodilator therapy (point d) augment SV, and because o improved LV emptying during contraction, the LVEDP
lessens. Point e represents the potential added benef t o combining an inotrope and vasodilator together.
The middle curve shows one example o how the Frank–Starling relationship shi ts upward during inotropic/
vasodilator therapy but does not achieve the level o a normal ventricle.
242
Chapter 9
hydrochlorothiazide and metolazone) are also use ul but are less e ective in the setting o
decreased renal per usion, which is o ten present in this condition.
The potential adverse e ects o diuretics are described in Chapter 17. The most important
in heart ailure patients include overly vigorous diuresis resulting in a all in cardiac output
and electrolyte disturbances (particularly hypokalemia and hypomagnesemia), which may
contribute to arrhythmias. In patients with acute heart ailure exacerbations, diuretics should
be administered intravenously (either by bolus injections or continuous in usion) because
venous congestion can limit the absorption o oral diuretics rom the gut.
Vasodilators
One o the most important cardiac advances in the late twentieth century was the introduction o vasodilator therapy or the treatment o heart ailure, particularly ACE inhibitors.
As indicated earlier, neurohormonal compensatory mechanisms in heart ailure o ten lead
to excessive vasoconstriction, volume retention, and ventricular remodeling, with progressive deterioration o cardiac unction. Vasodilator drugs help to reverse these adverse
consequences. Moreover, multiple studies have shown that certain vasodilator regimens signif cantly extend survival in patients with heart ailure. The pharmacology o these drugs is
described in Chapter 17.
Ven ous va sodilators (e.g., nitrates) increase venous capacitance and thereby decrease
venous return to the heart and le t ventricular preload. Consequently, LV diastolic pressures
all and the pulmonary capillary hydrostatic pressure declines, similar to the hemodynamic
e ects o diuretic therapy. As a result, pulmonary congestion improves, and as long as the
heart ailure patient is on the relatively “ at” part o the depressed Frank–Starling curve (see
Fig. 9-10), the cardiac output does not all despite the reduction in ventricular f lling pressure. However, venous vasodilatation in a patient who is operating on the steeper part o the
curve may result in an undesired all in stroke volume, cardiac output, and blood pressure.
Pure arteriolar vasodilators (e.g., hydralazine) reduce systemic vascular resistance and
there ore LV a terload, which in turn permits increased ventricular muscle f ber shortening
during systole (see Fig. 9-5B). This results in an augmented stroke volume and is represented
on the Frank–Starling diagram as a shi t in an upward direction (see Fig. 9-10, point d).
Although an arterial vasodilator might be expected to reduce blood pressure—an undesired
e ect in patients with heart ailure who may already be hypotensive—this generally does
not happen. As resistance is reduced by arteriolar vasodilatation, a concurrent rise in cardiac
output usually occurs, such that blood pressure remains constant or decreases only mildly.
Some groups o drugs result in vasodilatation o both the venous and arteriolar circuits
(“balanced” vasodilators). O these, the most important are agents that inhibit the renin–
angiotensin–aldosterone system. ACE inhibitors (described in Chapters 13 and 17) interrupt
the production o AII, thereby modulating the vasoconstriction incited by that hormone in heart
ailure patients. In addition, because aldosterone levels all in response to ACE inhibitor therapy,
sodium elimination is acilitated, resulting in reduced intravascular volume and improvement o
systemic and pulmonary vascular congestion. ACE inhibitors also augment circulating levels o
bradykinin (see Chapter 17), which is thought to contribute to benef cial vasodilatation in heart
ailure. As a result o these e ects, ACE inhibitors limit maladaptive ventricular remodeling in
patients with chronic heart ailure and ollowing acute myocardial in arction (see Chapter 7).
Supporting the benef cial hemodynamic and neurohormonal blocking e ects o ACE inhibitors, many large clinical trials have shown that these drugs reduce heart ailure symptoms,
reduce the need or hospitalization, and most importantly, extend survival in patients with
heart ailure with reduced EF. Thus, ACE inhibitors are standard f rst-line chronic therapy or
patients with LV systolic dys unction.
The renin–angiotensin–aldosterone system can also be therapeutically inhibited by angiotensin II receptor blockers (ARBs), as described in Chapters 13 and 17. Since AII can be
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Heart Failure
243
ormed by pathways other than ACE, ARBs provide a more complete inhibition o the system
than ACE inhibitors, through blockade o the actual AII receptor (see Fig. 17.6). Conversely,
ARBs do not cause the potentially benef cial rise in serum bradykinin. The net result is that the
hemodynamic e ects and mortality benef t o ARBs in heart ailure are similar to those o ACE
inhibitors. Thus, they are prescribed to heart ailure patients mainly when ACE inhibitors are
not tolerated (e.g., because o bradykinin-mediated side e ects such as cough or angioedema).
Chronic therapy using the combination o the venous dilator isosorbide dinitrate plus the
arteriolar dilator hydralazine has also been shown to improve survival in patients with moderate symptoms o heart ailure. However, when the ACE inhibitor enalapril was compared with
the hydralazine–isosorbide dinitrate (H-ISDN) combination, the ACE inhibitor was shown to
produce the greater improvement in survival. Thus, H-ISDN is generally substituted when a
patient cannot tolerate ACE inhibitor or ARB therapy (e.g., because o renal insu f ciency or
hyperkalemia). O note, the A rican American Heart Failure trial demonstrated that the addition
o H-ISDN to standard heart ailure therapy (including a diuretic, β-blocker, and ACE inhibitor
or ARB) in black patients with heart ailure urther improved unctional status and survival.
Nesiritide (human recombinant BNP) is an intravenous vasodilator drug available or
hospitalized patients with decompensated heart ailure. It causes rapid and potent vasodilatation, reduces elevated intracardiac pressures, and augments orward cardiac output. However,
it is an expensive drug that does not improve outcomes and may worsen renal unction, so
its use should be restricted to patients who have not responded to, or cannot tolerate, other
intravenous vasodilators, such as intravenous nitroglycerin or nitroprusside (see Chapter 17).
Positive Inotropic Drugs
Inotropic drugs include β-adrenergic agonists, digitalis glycosides, and phosphodiesterase type 3
inhibitors (see Chapter 17). By increasing the availability o intracellular calcium, each o these
drug groups enhances the orce o ventricular contraction and there ore shi ts the Frank–Starling
curve in an upward direction (see Fig. 9-10). As a result, stroke volume and cardiac output are
augmented at any given ventricular EDV. There ore, these agents may be use ul in treating
patients with systolic dys unction, but typically not those with heart ailure with preserved EF.
β-Adrenergic agonists (e.g., dobutamine and dopamine) are administered intravenously
or temporary hemodynamic support in acutely ill, hospitalized patients. Their long-term
use is limited by the lack o an oral orm o administration and by the development o drug
tolerance. The latter re ers to the progressive decline in e ectiveness during continued administration o the drug, possibly owing to down-regulation o myocardial adrenergic receptors.
Likewise, the role o phosphodiesterase 3 inhibitors (e.g., milrinone) is limited to the intravenous treatment o congestive heart ailure in acutely ill patients. Despite the initial promise
o e ective oral phosphodiesterase 3 inhibitors, studies thus ar actually demonstrate reduced
survival among patients receiving this orm o treatment.
One o the oldest orms o inotropic therapy is digitalis (see Chapter 17), which can be
administered intravenously or orally. Digitalis preparations enhance contractility, reduce cardiac enlargement, improve symptoms, and augment cardiac output in patients with systolic
heart ailure. Digitalis also increases the sensitivity o the baroreceptors, so that the compensatory sympathetic drive in heart ailure is blunted, a desired e ect that reduces le t ventricular a terload. By slowing AV nodal conduction and thereby reducing the rate o ventricular
contractions, digitalis has an added benef t in patients with congestive heart ailure who have
concurrent atrial f brillation. Although digitalis can improve symptomatology and reduce the
rate o hospitalizations in heart ailure patients, it has not been shown to improve long-term
survival. Thus, its use is limited to patients who remain symptomatic despite other standard
therapies or to help slow the ventricular rate i atrial f brillation is also present. Digitalis is
not use ul in the treatment o heart ailure with preserved EF because it does not improve
ventricular relaxation properties.
244
Chapter 9
β-Blockers
Historically, β-blockers were thought to be contraindicated in patients with systolic dys unction because their negative inotropic e ect would be expected to worsen symptomatology.
However, clinical trials have actually shown that long-term β-blocker therapy has important
benef ts in patients with stable chronic heart ailure with reduced EF, including augmented
cardiac output, reduced hemodynamic deterioration, the need or ewer hospitalizations, and
improved survival. The explanation or these desired e ects remains conjectural but may
relate to the drugs’ e ects on reducing heart rate and blunting chronic sympathetic activation
or to their anti-ischemic properties.
The three β-blockers that have been shown to be benef cial in randomized clinical trials o
heart ailure include carvedilol (a nonselective β-blocker with weak α-blocking properties—
see Chapter 17) and the β1-selective agents metoprolol succinate and bisoprolol. These drugs
are well tolerated in stable patients (i.e., those without recent deterioration o heart ailure
symptoms or active volume overload). Nonetheless, β-blockers should always be used cautiously in heart ailure to prevent acute deterioration related to their negative inotropic e ect.
Regimens should be started at low dosage and augmented gradually.
Aldosterone Antagonist Therapy
There is evidence that chronic excess o aldosterone in heart ailure contributes to cardiac
f brosis and adverse ventricular remodeling. Antagonists o this hormone (which have been
used historically as mild diuretics—see Chapter 17) have shown clinical benef t in heart
ailure patients. For example, in a clinical trial o patients with advanced heart ailure (i.e.,
NYHA Class III to IV) who were already taking an ACE inhibitor and diuretics, the aldosterone receptor antagonist spironolactone substantially reduced mortality rates and improved
heart ailure symptoms. Eplerenone, a more specif c aldosterone receptor inhibitor, has been
shown to improve survival o patients with congestive heart ailure a ter acute myocardial
in arction (see Chapter 7) as well as patients with more mild orms o chronic heart ailure
(i.e., NYHA Class II to III). Although aldosterone antagonists have been well tolerated in careully controlled studies, the serum potassium level must be monitored to prevent hyperkalemia, especially i there is renal impairment or concomitant ACE inhibitor therapy.
In summary, standard therapy o chronic heart ailure with reduced EF should include
several drugs, the cornerstones o which are an ACE inhibitor and a β-blocker. An accepted
sequence o therapy is to start with an ACE inhibitor as well as a diuretic i pulmonary or
systemic congestive symptoms are present. I the patient is unable to tolerate the ACE inhibitor, then an ARB (or hydralazine plus isosorbide dinitrate) may be substituted. For patients
without recent clinical deterioration or volume overload, a β-blocker should be added. Those
with persistent symptomatic heart ailure may benef t rom the addition o an aldosterone
antagonist. For re ractory symptoms, digoxin can be prescribed or its hemodynamic benef t.
Additional Therapies
Arrhythmia Management
Atrial and ventricular arrhythmias requently accompany chronic heart ailure. For example, atrial f brillation is very common in this setting and conversion back to sinus rhythm
(see Chapter 11) can substantially improve cardiac output. Ventricular arrhythmias are
also requent in heart ailure and may lead to sudden death. The antiarrhythmic drug that
is most e ective at suppressing arrhythmias and least likely to provoke other dangerous
rhythm disorders in heart ailure patients is amiodarone. However, studies o amiodarone
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Heart Failure
245
or the treatment o asymptomatic ventricular arrhythmias in heart ailure have not shown
a consistent survival benef t. In addition, heart ailure patients with symptomatic or sustained ventricular arrhythmias, or those with inducible ventricular tachycardia during
electrophysiologic testing, benef t more rom the insertion o an impla n ta ble ca rdioverter–
def brilla tor (ICD; see Chapter 11). Based on the results o large-scale randomized trials,
ICD implantation is indicated or many patients with heart ailure and at least moderately reduced systolic unction (e.g., LVEF ≤ 35% ), regardless o the presence o ventricular
arrhythmias, because this approach reduces the likelihood o sudden cardiac death in this
population.
Cardiac Resynchronization Therapy
Intraventricular conduction abnormalities with widened QRS complexes (especially le t bundle branch block) are common in patients with advanced heart ailure. Such abnormalities
can actually contribute to cardiac symptoms because o the resultant uncoordinated pattern
o right and le t ventricular contraction. Advanced pacemakers have been developed that
stimulate both ventricles simultaneously, thus resynchronizing the contractile e ort. This
technique o biventricular pacing, also termed cardiac resynchronization therapy (CRT), has
been shown to augment le t ventricular systolic unction, improve exercise capacity, and
reduce the requency o heart ailure exacerbations and mortality. Thus, CRT is appropriate
or selected patients with advanced systolic dys unction (LV EF ≤ 35% ), a prolonged QRS
duration (> 120 ms) and continued symptoms o heart ailure despite appropriate pharmacologic therapies. Since patients who receive CRT are typically also candidates or an ICD,
modern devices combine both unctions in a single, small implantable unit.
Cardiac Mechanical Circulatory Support and Replacement Therapy
A patient with severe LV dys unction whose condition remains re ractory to maximal medical
management may be a candidate or cardiac transplantation. However, only approximately
4,000 transplants are per ormed worldwide each year because o a shortage o donor hearts,
many ewer than the number o patients with re ractory heart ailure symptoms. For certain
patients who are too ill to wait or a heart donor, or who are not eligible or a transplant,
alternative mechanical therapies are in selected use. Ventricular assist devices (VADs) and
implantable total artif cial hearts can be used to support cardiac pump unction in such
patients. Recent technological advances in continuous- ow le t-sided VADs have resulted in
1-year survival rates greater than 70% , compared to less than 25% survival rates in similar
groups o advanced heart ailure patients treated with medical therapy alone.
TREATMENT OF HEART FAILURE WITH PRESERVED EJECTION FRACTION
The goals o therapy in heart ailure with preserved EF include (1) the relie o pulmonary and
systemic congestion and (2) addressing correctable causes o the impaired diastolic unction
(e.g., hypertension, coronary artery disease). Diuretics reduce pulmonary congestion and
peripheral edema but must be used cautiously to avoid under f lling o the le t ventricle. A
sti ened le t ventricle relies on higher-than-normal pressures to achieve adequate diastolic
f lling (see Fig. 9-7B), and excessive diuresis could reduce f lling and there ore impair stroke
volume and cardiac output (see Fig. 9-10, point b′).
Unlike patients with impaired systolic unction, β-blockers, ACE inhibitors, and ARBs
have no demonstrated mortality benef t in patients with heart ailure with preserved EF.
The aldosterone antagonist spironolactone was recently shown to reduce the requency o
hospitalizations or heart ailure in this population, but did not improve the survival rate. Since
contractile unction is preserved, inotropic drugs have no therapeutic role in this syndrome.
246
Chapter 9
ACUTE HEART FAILURE
R
e
a
d
n
u
d
c
e
V
a
d
s
C
o
a
c
r
o
d
n
i
s
a
t
c
r
i
c
O
t
i
u
o
t
n
p
u
t
In contrast to the f ndings o chronic heart ailure described to this point, patients with acute
heart ailure are those who present with urgent and o ten li e-threatening symptomatology.
Acute heart ailure may develop in a previously asymptomatic patient (e.g., resulting rom an
acute coronary syndrome [Chapter 7], severe hypertension [Chapter 13], or acute valvular
regurgitation [Chapter 8]), or it may complicate chronic compensated heart ailure ollowing
a precipitating trigger (see Table 9-3). Management o acute heart ailure typically requires
hospitalization and prompt interventions.
The classif cation o patients with acute heart ailure, and the approach to therapy, can be
tailored based on the presence or absence o two major f ndings at the bedside: (1) volume
overload (i.e., “wet” vs. “dry”) as a re ection o elevated LV f lling pressures and (2) signs
o decreased cardiac output with reduced tissue per usion (“cold” vs. “warm” extremities).
Examples o a “wet” prof le, indicative o volume overload, include pulmonary rales, jugular
venous distension, and edema o the lower extremities. Figure 9-11 shows how patients with
acute heart ailure can be divided into our prof les based on observations o these parameters.
Prof le A indicates normal hemodynamics. Cardiopulmonary symptoms in such patients
would be due to actors other than heart ailure, such as parenchymal lung disease or transient myocardial ischemia. Prof les B and C are typical o patients with acute pulmonary
edema (described below). Those with Prof le B have “wet” lungs but preserved (“warm”) tissue per usion. Prof le C is more serious; in addition to congestive f ndings, impaired orward
cardiac output results in marked systemic vasoconstriction (e.g., activation o the sympathetic
nervous system) and there ore “cold” extremities. Patients with Prof le C have a prognosis
worse than those with Prof le B, who in turn have poorer outcomes than those with Prof le A.
Patients with Prof le L do not represent an extension o this continuum. Rather, they display “cold” extremities due to low output (hence the label “L”) but no signs o vascular congestion. This prof le may arise in patients who are actually volume deplete, or those with very
limited cardiac reserve in the absence o volume overload (e.g., a patient with a dilated le t
ventricle and mitral regurgitation who becomes short o breath with activity because o the
inability to generate adequate orward cardiac output). These prof les o acute heart ailure
should not be con used with the classif cation o chronic heart ailure (Stages A through D)
presented in Table 9-6.
The goals o therapy in acute heart ailure are to (1) normalize ventricular f lling pressures
and (2) restore adequate tissue per usion. Identif cation o the patient’s prof le type guides
therapeutic interventions. For example, a
patient with Prof le B would require diuretic
LV filling Pre s s ure s
(Pulmona ry a nd/or Sys te mic Conge s tion)
and/ or vasodilator therapy or pulmonary
edema (described in the next section),
No
Ye s
and those with Prof le C may additionally
require intravenous inotropic medications
Profile A
Profile B
to strengthen cardiac output. Patients with
No
“Wa rm a nd Dry”
“Wa rm a nd We t”
Prof le L may require volume expansion.
The presence o prof le A would prompt
a search or contributions to the patient’s
Profile L
Profile C
symptoms other than heart ailure.
Ye s
“Cold a nd Dry”
“Cold a nd We t”
Acute Pulmonary Edema
A common mani estation o acute le tsided heart ailure (e.g., typical o Prof les
B and C) is cardiogenic pulmonary edema,
in which elevated capillary hydrostatic
FIGURE 9-11. Hemodynamic prof les in acute heart
ailure. (Derived rom Nohria A, Tsang SW, Fang JC,
et al. Clinical assessment identif es hemodynamic
prof les that predict outcomes in patients admitted with
heart ailure. J Am Coll Cardiol. 2003;41:1797–1804.)
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Heart Failure
247
pressure causes rapid accumulation o uid within the interstitium and alveolar spaces o
the lung. In the presence o normal plasma oncotic pressure, pulmonary edema develops
when the pulmonary capillary wedge pressure, which re ects LV diastolic pressure, exceeds
approximately 25 mm Hg.
This condition is requently accompanied by hypoxemia because o shunting o pulmonary
blood ow through regions o hypoventilated alveoli. Like other mani estations o acute heart
ailure, pulmonary edema may appear suddenly in a previously asymptomatic person (e.g.,
in the setting o an acute myocardial in arction) or in a patient with chronic compensated
congestive heart ailure ollowing a precipitating event (see Table 9-3). Pulmonary edema is a
horri ying experience or the patient, resulting in severe dyspnea and anxiety while struggling
to breathe.
On examination, the patient is tachycardic and may demonstrate cold, clammy skin owing
to peripheral vasoconstriction in response to increased sympathetic out ow (i.e., Prof le C).
Tachypnea and coughing o “ rothy” sputum represent transudation o uid into the alveoli.
Rales are present initially at the bases and later throughout the lung f elds, sometimes accompanied by wheezing because o edema within the conductance airways.
Pulmonary edema is a li e-threatening emergency that requires immediate improvement o
systemic oxygenation and elimination o the underlying cause. The patient should be seated
upright to permit pooling o blood within the systemic veins o the lower body, thereby reducing
venous return to the heart. Supplemental oxygen is provided by a ace mask. Morphine sul ate
is administered intravenously to reduce anxiety and also acts as a venous dilator to acilitate
pooling o blood peripherally. A rapidly acting diuretic, such as intravenous urosemide, is
administered to urther reduce LV preload and pulmonary capillary hydrostatic pressure. Other
means o reducing preload include administration o nitrates (o ten intravenously). Intravenous
inotropic drugs (e.g., dopamine) may increase orward CO and are used primarily in patients
with Prof le C. During resolution o the pulmonary congestion and hypoxemia, attention should
be directed at identi ying and treating the underlying precipitating cause.
An easy-to-remember mnemonic or the principal components o management o pulmonary edema is the alphabetic sequence LMNOP:
Lasix (trade name or urosemide)
Morphine
Nitrates
Oxygen
Position (sit upright)
SUMMARY
• Ventricular stroke volume (SV) is a unction o preload, a terload, and contractility;
SV rises when there is an increase in preload, a decrease in a terload, or augmented
contractility.
• Cardiac output = heart rate × stroke volume.
• Ventricular EDV (or EDP) represents preload and is in uenced by the chamber’s compliance.
• Ventricular ESV depends on the a terload and contractility but not on the preload.
• Heart ailure is a clinical syndrome in which cardiac output (CO) ails to meet the metabolic
demands o the body or meets those demands only i cardiac f lling pressures are abnormally
high.
• Chronic heart ailure may be classif ed into two categories: (1) heart ailure with reduced EF
owing to impaired le t ventricular systolic unction and (2) heart ailure with preserved EF
(e.g., diastolic dys unction).
• Compensatory mechanisms in heart ailure that initially maintain circulatory unction
include (1) preload augmentation with increased stroke volume via the Frank–Starling
248
Chapter 9
•
•
•
•
•
•
•
•
mechanism, (2) activation o neurohormonal systems, and (3) ventricular hypertrophy; however, these compensations eventually become maladaptive, contributing to adverse ventricular remodeling and progressive deterioration o ventricular unction.
Symptoms o heart ailure may be exacerbated by precipitating actors that increase metabolic demand (e.g., tachycardia), increase circulating volume, augment a terload, or decrease
contractility.
Treatment o heart ailure includes addressing the underlying cause o the condition, eliminating precipitating actors, and modulating detrimental neurohormonal activations.
Standard therapy o symptomatic heart ailure with reduced EF includes an ACE inhibitor,
β-blocker, and sometimes an aldosterone antagonist; or patients who do not tolerate an
ACE inhibitor, an AII receptor blocker or the combination o hydralazine plus nitrates can be
substituted.
Diuretics should be used to treat volume overload, and inotropic drugs are typically reserved
or acute “rescue” management o low CO states.
For patients with heart ailure with reduced EF who meet specif c criteria, an implantable
cardioverter–def brillator and/ or cardiac resynchronization therapy (biventricular pacing)
may be indicated.
For re ractory end-stage heart ailure, cardiac transplantation and/ or mechanical circulatory
support should be considered in care ully selected patients.
Therapy or heart ailure with preserved EF relies primarily on diuretics to relieve pulmonary
congestion, but such therapy must be administered cautiously to avoid excess reduction o
preload and hypotension.
Acute heart ailure can be prof led by, and treatment decisions based on, the presence or
absence o (1) elevated le t heart f lling pressures (wet vs. dry) and (2) reduced systemic tissue per usion with elevated systemic vascular resistance (i.e., cold vs. warm).
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Neal Anjan Chatterjee; Ravi V. Shah,
MD; George S. M. Dyer, MD; Stephen K. Frankel, MD; Arthur Coday Jr., MD; and Vikram
Janakiraman, MD.
Ad d i t i o n a l Rea d i n g
Braunwald E. Heart ailure. JACC: Hea rt Fa ilure. 2013;1:
1–20.
Hsich EM, Pina IL. Heart ailure in women. J Am Coll Cardiol.
2009;54:491–498.
Maeder MT, Kaye DM. Heart ailure with normal le t ventricular ejection raction. J Am Coll Ca rdiol. 2009;53:
905–918.
Maron BA, Leopold JA. Aldosterone receptor antagonists:
e ective but o ten orgotten. Circula tion . 2010;121:
934–939.
McMurray JJV. Systolic heart ailure. N Engl J Med. 2010;362:
228–238.
Stewart G, Givertz M. Mechanical circulatory support or
advanced heart ailure: patients and technology in evolution.
Circulation. 2012;125:1304–1315.
Triposkiadis F, Karayannis G, Giamouzis G, et al. The sympathetic nervous system in heart ailure: physiology, pathophysiology, and clinical implications. J Am Coll Cardiol.
2009;54:1747–1762.
Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline
or the management o heart ailure: executive summary a
report o the American College o Cardiology Foundation/
American Heart Association Task Force on Practice
Guidelines. Circulation. 2013;128:1810–1852.
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The Cardiomyopathies
P. Connor Johnson
G. Willia m Dec
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Dilated Cardiomyopathy
Etiology
Pathology
Pathophysiology
Clinical Findings
Physical Examination
Diagnostic Studies
Treatment
Hypertrophic Cardiomyopathy
Etiology
Pathology
Pathophysiology
Clinical Findings
Physical Examination
Diagnostic Studies
Treatment
Prognosis
Restrictive Cardiomyopathy
Pathophysiology
Clinical Findings
Physical Examination
Diagnostic Studies
Treatment
Other Forms of Cardiomyopathy
Le t Ventricular Noncompaction
Arrhythmogenic Right
Ventricular Cardiomyopathy
10
C
ardiomyopathies are a diverse set o heart muscle disorders that cause mechanical and/ or electrical dys unction
o the myocardium. Excluded rom the def nition o this group
o diseases is heart muscle impairment resulting rom other
specif c cardiovascular disorders such as hypertension, valvular
abnormalities, or congenital heart disease. Cardiomyopathies
o ten result in inappropriate ventricular hypertrophy or dilatation, and progressive heart ailure and cardiovascular death are
common end mani estations. These conditions can involve the
heart alone or may be a component o a systemic syndrome.
Cardiomyopathies can be classif ed into three main types
based on the anatomic appearance and abnormal physiology
o the le t ventricle (LV) (Fig. 10-1). Dilated cardiomyopathy
(DCM) is characterized by ventricular chamber enlargement
with impaired systolic contractile unction; hypertrophic cardiomyopathy (HCM), by an abnormally thickened ventricular wall
with abnormal diastolic relaxation but usually intact systolic
unction; and restrictive cardiomyopathy, by an abnormally
sti ened myocardium (because o f brosis or an inf ltrative
process) leading to impaired diastolic relaxation, but systolic
contractile unction is typically normal or near normal.
DILATED CARDIOMYOPATHY
Etiology
Myocyte damage and cardiac enlargement in DCM result
rom a wide spectrum o genetic, in ammatory, toxic, and
metabolic causes (Table 10-1). Although many cases are
currently classif ed as idiopathic (i.e., the cause is undetermined), examples o def ned conditions associated with
DCM include viral myocarditis, chronic excessive alcohol
249
Aorta
LA
Dila te d LV
with minima l
hype rtrophy
LV
No rmal
A
B
Dilate d
c ardio myo pathy
Infiltra te d or
fibrotic LV
Ma rke d LV
hype rtrophy
C
Hype rtro phic
c ardio myo pathy
D
Re s tric tive
c ardio myo pathy
FIGURE 10-1. Anatomic appearance o the cardiomyopathies ( CMPs) . A. Normal heart demonstrating le t
ventricle (LV) and le t atrium (LA). B. Dilated CMP is characterized by ventricular enlargement with only mildly
increased thickness. C. Hypertrophic CMP demonstrates marked ventricular hypertrophy, either asymmetrically,
or symmetrically (as drawn here). D. Restrictive CMP is caused by inf ltration or f brosis o the ventricles,
usually without chamber enlargement. LA enlargement is common to all three types o CMP.
TABLE 10-1
Examples o Dilated Cardiomyopathies
Idiopathic
Familial ( genetic)
Inf ammatory
In ectious (especially viral)
Nonin ectious
Connective tissue diseases
Peripartum cardiomyopathy
Sarcoidosis
Toxic
Chronic alcohol ingestion
Chemotherapeutic agents (e.g., doxorubicin, trastuzumab)
Metabolic
Hypothyroidism
Chronic hypocalcemia or hypophosphatemia
Neuromuscular
Muscular or myotonic dystrophy
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The Cardiomyopathies
251
ingestion, the peripartum state, specif c gene mutations, and exposure to potentially cardiotoxic antineoplastic agents, such as doxorubicin.
Acute viral myocarditis generally a icts young, previously healthy people. Common responsible in ecting organisms include coxsackievirus group B, parvovirus B19, and adenovirus,
among many others. Viral myocarditis is usually a sel -limited illness with ull recovery, but or
unknown reasons, some patients progress to DCM. It is hypothesized that myocardial destruction
and f brosis result rom immune-mediated injury triggered by viral constituents. Nonetheless,
immunosuppressive drugs have not been shown to improve the prognosis o this condition.
Transvenous ventricular biopsy during acute myocarditis may demonstrate active in ammation,
but specif c viral genomic sequences have been demonstrated in only a minority o patients.
DCM develops in a small number o people who consume alcoholic beverages excessively
and chronically. Although the pathogenesis o the condition is unknown, ethanol is thought
to impair cellular unction by impacting mitochondrial oxidative unction, myof lament protein synthesis, cytosolic calcium levels, and myocyte apoptosis. While its clinical presentation
and histologic eatures are similar to those o other dilated cardiomyopathies, alcoholic cardiomyopathy is important to identi y because it is potentially reversible; cessation o ethanol
consumption can lead to dramatic recovery o ventricular unction.
Peripartum cardiomyopathy is a orm o DCM that presents with heart ailure symptoms
between the last month o pregnancy and up to 6 months postpartum. Risk actors include
older maternal age, being A rican American, and having multiple pregnancies. A uni ying
etiology o this condition has not yet been identif ed. Ventricular unction returns to normal
in approximately 50% o a ected women in the months ollowing pregnancy, but recurrences
o DCM with subsequent pregnancies have been reported.
Other potentially reversible causes o DCM include toxic drug exposures, metabolic abnormalities (such as hypothyroidism), and certain in ammatory etiologies, including sarcoidosis
and connective tissue diseases.
Several amilial orms o DCM have been identif ed and are believed to be responsible or
20% to 30% o what were once classif ed as idiopathic DCM. Autosomal dominant, autosomal
recessive, X-linked, and mitochondrial patterns o inheritance have been described, leading
to de ects in contractile orce generation, orce transmission, energy production, and myocyte
viability. Identif ed mutations occur in genes that code or cardiac cytoskeletal, myof brillar,
and nuclear membrane proteins (Table 10-2).
TABLE 10-2
Familial Forms o Dilated and Hypertrophic Cardiomyopathies
Protein
Cytoskeletal proteins
Desmin
Dystrophin
Myosin-binding protein C
Sarcoglycans
Titin
Myof brillar proteins
β-Myosin heavy chain
Cardiac troponin T
Cardiac troponin I
Cardiac troponin C
α-Tropomyosin
Essential myosin light chain
Cardiac actin
Nuclear membrane protein
Lamin A/ C
Mutations Identif ed in DCM
√
√
√
√
√
√
√
√
√
√
√
√
Mutations Identif ed in HCM
√
√
√
√
√
√
√
√
√
252
Chapter 10
Pathology
Marked enlargement o all our cardiac
chambers is typical o DCM (Fig. 10-2),
although sometimes the disease is limited
to the le t or right side o the heart. The
thickness o the ventricular walls may be
increased, but chamber dilatation is out o
proportion to any concentric hypertrophy.
Microscopically, there is evidence o myocyte degeneration with irregular hypertrophy and atrophy o myof bers. Interstitial
and perivascular f brosis is o ten extensive.
Pathophysiology
FIGURE 10-2. Transverse sections of a normal heart
( right) and a heart from a patient with dilated
cardiomyopathy ( DCM) . In the DCM specimen, there is
biventricular dilatation without a proportional increase
in wall thickness. LV, le t ventricle; RV, right ventricle.
(Modif ed rom Emmanouilides GC, ed. Moss and Adams’
Heart Disease in Infants, Children, and Adolescents.
5th ed. Baltimore, MD: Lippincott Williams & Wilkins;
1995:86.)
The hallmark o DCM is ventricular dilatation with decreased contractile unction
(Fig. 10-3). Most o ten in DCM, both ventricles are impaired, but sometimes dys unction is limited to the LV and even less commonly
to the right ventricle (RV).
As ventricular stroke volume and cardiac output decline because o impaired myocyte
contractility, two compensatory e ects are activated: (1) the Frank–Starling mechanism,
in which the elevated ventricular diastolic volume increases the stretch o the myof bers,
thereby increasing the subsequent stroke volume; and (2) neurohormonal activation, initially
mediated by the sympathetic nervous system (see Chapter 9). The latter contributes to an
increased heart rate and contractility, which help to bu er the all in cardiac output. These
compensations may render the patient asymptomatic during the early stages o ventricular
dys unction; however, as progressive myocyte degeneration and volume overload ensue, clinical symptoms o heart ailure develop.
Myo c yte injury
↓ Co ntrac tility
↓ S tro ke vo lume
↑ Ve ntric ular filling pre s s ure s
LV dilatatio n
↓ Fo rward c ardiac o utput
• Fa tigue
• We a kne s s
Pulmo nary
c o ng e s tio n
Sys te mic
c o ng e s tio n
• Dys pne a
• Orthopne a
• Ra le s
• J VD
• He pa tome ga ly
• Ede ma
Mitral
re g urg itatio n
FIGURE 10-3. Pathophysiology of dilated cardiomyopathy. The reduced ventricular stroke volume results in
decreased orward cardiac output and increased ventricular f lling pressures. The listed clinical mani estations
ollow. JVD, jugular venous distention.
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With a persistent reduction o cardiac output, the decline in renal blood ow prompts the
kidneys to increase secretion o renin. This activation o the renin–angiotensin–aldosterone
axis increases peripheral vascular resistance (mediated through angiotensin II) and intravascular volume (because o increased aldosterone). As described in Chapter 9, these e ects are
also initially help ul in bu ering the all in cardiac output.
Ultimately, however, the “compensatory” e ects o neurohormonal activation prove
detrimental. Arteriolar vasoconstriction and increased systemic resistance render it more di f cult or the LV to eject blood in the orward direction, and the rise in intravascular volume
urther burdens the ventricles, resulting in pulmonary and systemic congestion. In addition,
chronically elevated levels o angiotensin II and aldosterone directly contribute to pathologic
myocardial remodeling and f brosis.
As the cardiomyopathic process causes the ventricles to enlarge over time, the mitral and
tricuspid valves may ail to coapt properly in systole, and valvular regurgitation ensues. This
regurgitation has three detrimental consequences: (1) excessive volume and pressure loads
are placed on the atria, causing them to dilate, o ten leading to atrial f brillation; (2) regurgitation o blood into the le t atrium urther decreases orward stroke volume into the aorta
and systemic circulation; and (3) when the regurgitant volume returns to the LV during each
diastole, an even greater volume load is presented to the dilated LV.
Clinical Findings
The clinical mani estations o DCM are those o congestive heart ailure. The most common symptoms o low orward cardiac output include atigue, light-headedness, and exertional dyspnea associated with decreased tissue per usion. Pulmonary congestion results in
dyspnea, orthopnea, and paroxysmal nocturnal dyspnea, whereas chronic systemic venous
congestion causes ascites and peripheral edema. Because these symptoms may develop insidiously, the patient may complain only o recent weight gain (because o interstitial edema)
and shortness o breath on exertion.
Physical Examination
Signs o decreased cardiac output are o ten present and include cool extremities (owing to
peripheral vasoconstriction) and low arterial pressure. Pulmonary venous congestion results
in auscultatory rales (crackles), and basilar chest dullness to percussion may be present
because o pleural e usions. Cardiac examination shows an enlarged heart with le tward
displacement o the apical impulse. On auscultation, a third heart sound (S3) is common as a
sign o poor systolic unction. The murmur o mitral valve regurgitation is o ten present as a
result o the signif cant le t ventricular dilatation (see Chapter 8). I right ventricular heart ailure has developed, signs o systemic venous congestion may include jugular vein distention,
hepatomegaly, ascites, and peripheral edema. Right ventricular enlargement and contractile
dys unction are o ten accompanied by the murmur o tricuspid valve regurgitation.
Diagnostic Studies
The chest radiograph shows an enlarged cardiac silhouette. I heart ailure has developed,
then pulmonary vascular redistribution, interstitial and alveolar edema, and pleural e usions
are evident (see Fig. 3-5).
The electrocardiogram (ECG) usually demonstrates atrial and ventricular enlargement.
Patchy f brosis o the myof bers results in a variety o arrhythmias, most importantly atrial
f brillation and ventricular tachycardia. Conduction de ects (le t or right bundle branch
block) are common. In addition, regions o dense myocardial f brosis may produce localized
Q waves, resembling the pattern o previous transmural myocardial in arction.
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Chapter 10
Echocardiography in DCM typically demonstrates enlargement o the a ected ventricle(s)
with little concentric hypertrophy, and global reduction o systolic ventricular unction. Mitral
and/ or tricuspid regurgitation is requently detected due to ventricular dilatation.
Cardiac catheterization or CT angiography is o ten per ormed to determine whether coexistent coronary artery disease is contributing to the impaired ventricular unction. This is most
use ul diagnostically in patients who have symptoms o angina or evidence o prior myocardial in arction on the ECG. Typically, hemodynamic measurements show elevated right- and
le t-sided diastolic pressures and diminished cardiac output. A transvenous biopsy o the RV
is sometimes per ormed in the catheterization laboratory, in an attempt to clari y the etiology
o the cardiomyopathy.
Cardiac magnetic resonance imaging (MRI) (described in Chapter 3) is o ten help ul in
the evaluation o DCM, particularly to assess or contributory myocardial in ammation
(myocarditis).
Treatment
The goal o therapy in DCM is to promote reverse remodeling o dilated ventricles, enhance
myocardial unction, relieve symptoms, prevent complications, and improve long-term
survival. Thus, in addition to treating any identif ed underlying cause o DCM, therapeutic
considerations include those described in the ollowing sections.
Medical Treatment of Heart Failure Symptoms
Approaches or the relie o vascular congestion and improvement in orward cardiac output
are the same as standard therapies or heart ailure (see Chapter 9). Initial therapy typically
includes salt restriction and diuretics i volume overload is present, vasodilator therapy with
an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB),
and a β-blocker in hemodynamically stable patients. For patients with persistent symptoms,
the addition o an aldosterone antagonist should be considered. These measures have been
shown to improve symptoms and reduce mortality in patients with DCM.
Prevention and Treatment of Arrhythmias
Atrial and ventricular arrhythmias are common in advanced DCM, and approximately 40%
o deaths in this condition result rom ventricular tachycardia or f brillation. It is important to
maintain serum electrolytes (notably, potassium and magnesium) within their normal ranges,
especially during diuretic therapy, to avoid provoking serious arrhythmias. Studies have
shown that available antiarrhythmic drugs do not prevent death rom ventricular arrhythmias
in DCM. In act, when used in patients with poor LV unction, many antiarrhythmic drugs
may worsen the rhythm disturbance. Amiodarone is the antiarrhythmic drug studied most
extensively in patients with DCM. Whereas there is no convincing evidence that it reduces
mortality rom ventricular arrhythmias in DCM, it is the sa est antiarrhythmic or treating
atrial f brillation and other supraventricular arrhythmias in this population. In contrast to
antiarrhythmic drugs, the placement o an implantable cardioverter–def brillator (ICD) does
reduce arrhythmic deaths in patients with DCM. There ore, based on large-scale randomized trials, an ICD is recommended or patients with chronic symptomatic DCM and at least
moderately reduced systolic unction (e.g., LV ejection raction ≤ 35% ), regardless o whether
ventricular arrhythmias have been detected.
Many patients with DCM have electrical conduction abnormalities that contribute to dyssynchronous ventricular contraction and there ore reduced cardiac output. Electronic pacemakers
capable o stimulating both ventricles simultaneously have been devised to better coordinate systolic contraction as an adjunct to medical therapy (termed cardiac resynchronization
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255
therapy, as described in Chapter 9). Demonstrated benef ts o this approach include improved
quality o li e and exercise tolerance, ewer hospitalizations or heart ailure, and reduced
mortality, particularly in those with pretreatment le t bundle branch block or other conduction abnormalities with a markedly prolonged QRS duration.
Prevention of Thromboembolic Events
Patients with DCM are at increased risk o thromboembolic complications or reasons that include
(1) blood stasis in the ventricles resulting rom poor systolic unction, (2) stasis in the atria due to
chamber enlargement or atrial f brillation, and (3) systemic venous stasis because o poor circulatory ow. Peripheral venous or right ventricular thrombi may lead to pulmonary emboli, whereas
thromboemboli o le t ventricular origin may lodge in a systemic artery, resulting in, or example,
cerebral, myocardial, or renal in arctions. In DCM with heart ailure, systemic anticoagulation
should be considered or patients with a history o venous or systemic thromboembolism, atrial
f brillation, or those with le t ventricular thrombi identif ed by cardiac imaging, especially those
that are mobile or protrude into the LV cavity (and are there ore more likely to embolize).
Cardiac Transplantation
In suitable highly symptomatic patients, cardiac transplantation o ers a substantially better
5-year prognosis than do standard therapies or DCM described above. The 5- and 10-year
survival rates a ter transplantation are 74% and 55% , respectively. However, the scarcity o
donor hearts greatly limits the availability o this technique. As a result, other mechanical
options have been explored and continue to undergo experimental ref nements, including
ventricular assist devices and completely implanted artif cial hearts.
HYPERTROPHIC CARDIOMYOPATHY
With an incidence o about 1 o 500 in the general population, HCM is characterized by
le t ventricular hypertrophy that is not caused by chronic pressure overload (i.e., not the
result o hypertension or aortic stenosis [AS]). Other terms used to describe this disease are
“hypertrophic obstructive cardiomyopathy” and “idiopathic hypertrophic subaortic stenosis.”
In this condition, systolic LV contractile unction is vigorous but the thickened muscle is sti ,
resulting in impaired ventricular relaxation and high diastolic pressures. HCM has received
notoriety in the lay press because it is the most common cardiac abnormality ound in young
athletes in the United States who die suddenly during vigorous physical exertion.
Etiology
HCM is a amilial disease in which inheritance ollows an autosomal dominant pattern with
variable penetrance, and hundreds o mutations in several di erent genes have been implicated. The proteins encoded by the responsible genes are all part o the sarcomere complex
and include β-myosin heavy chain (β-MHC), cardiac troponins, and myosin-binding protein C
(see Table 10-2). The incorporation o these mutated peptides into the sarcomere is thought to
cause impaired contractile unction. The resultant increase in myocyte stress is then hypothesized to lead to compensatory hypertrophy and proli eration o f broblasts.
The pathophysiology and natural history o amilial HCM are variable and appear related to
particular mutations within the disease-causing gene, rather than the actual gene involved. In
act, it has been shown that the precise genetic mutation determines the age o onset o hypertrophy, the extent and pattern o cardiac remodeling, and the person’s risk o developing symptomatic heart ailure or sudden death. For example, mutations in the β-MHC gene that alter electrical
charge in the encoded protein are associated with worse prognoses than other mutations.
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Chapter 10
Pathology
Although hypertrophy in HCM may involve
any portion o the ventricles, a symmetric hypertrophy o the ventricular septum (Fig. 10-4) is most commonly ound
(approximately 90% o cases). Less o ten,
the hypertrophy involves the ventricular
walls symmetrically or is localized to the
apex or mid-region o the LV.
Unlike ventricular hypertrophy resulting
rom hypertension in which the myocytes
enlarge uni ormly and remain orderly, the
histology o HCM is unusual. The myocardial
f bers are in a pattern o extensive disarray
(Fig. 10-5). Short, wide, hypertrophied f bers
are oriented in chaotic directions and are surrounded by numerous cardiac f broblasts and
extracellular matrix. This myocyte disarray
and f brosis are characteristic o HCM and
play a role in the abnormal diastolic sti ness
and the arrhythmias common to this disorder.
IVS
Pathophysiology
FIGURE 10-4. Postmortem heart specimen from a
patient with hypertrophic cardiomyopathy. Marked
le t ventricular hypertrophy is present, especially o the
interventricular septum (IVS).
The predominant eature o HCM is marked
ventricular hypertrophy that reduces the
compliance and diastolic relaxation properties o the chamber, such that f lling
becomes impaired (Fig. 10-6). Patients who have asymmetric hypertrophy o the proximal
interventricular septum may display additional f ndings related to transient obstruction o le t
ventricular out ow during systole. It is use ul to consider the pathophysiology o HCM based
on whether such systolic out ow tract obstruction is present.
A
B
C
FIGURE 10-5. Light microscopy of hypertrophic myocardium. A. Normal myocardium. B. Hypertrophied
myocytes in a patient with valvular heart disease. C. Myocyte disarray with f brosis in a patient with
hypertrophic cardiomyopathy.
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The Cardiomyopathies
Myo c yte
hype rtro phy
Myofibe rs
in
dis a rray
Ve ntricula r
a rrhythmia s
Dynamic LV o utflow
o bs truc tio n
LVH
Impa ire d
re la xa tion
(dia s tolic
dys function)
257
↑ Sys tolic
pre s s ure
Mitra l
re gurgita tion
Fa ilure to
↑ CO
with
exe rtion
↑ MVO 2
↑ LVEDP
S udde n de ath
Sync o pe
Dys pne a
Ang ina
FIGURE 10-6. Pathophysiology o hypertrophic cardiomyopathy. The disarrayed and hypertrophied myocytes
may lead to ventricular arrhythmias (which can cause syncope or sudden death) and impaired diastolic le t
ventricular (LV) relaxation (which causes elevated LV lling pressures and dyspnea). I dynamic LV outf ow
obstruction is present, mitral regurgitation o ten accompanies it (which contributes to dyspnea), and the
impaired ability to raise cardiac output with exertion can lead to exertional syncope. The thickened LV wall,
and increased systolic pressure associated with outf ow tract obstruction, each contribute to increased
myocardial oxygen consumption (MVO2) and can precipitate angina. CO, cardiac output; LVEDP, LV end-diastolic
pressure; LVH, LV hypertrophy.
HCM without Outf ow Tract Obstruction
Although systolic contraction o the LV is usually vigorous in HCM, hypertrophy o the walls
results in increased sti ness and impaired relaxation o the chamber. The reduced ventricular
compliance alters the normal pressure–volume relationship, causing the passive diastolic f lling curve to shi t upward (see Fig. 9-7B). The associated rise in diastolic LV pressure is transmitted backward, leading to elevated le t atrial, pulmonary venous, and pulmonary capillary
pressures. Dyspnea, especially during exertion, is thus a common symptom in this disorder.
HCM with Outf ow Obstruction
Approximately one third o patients with HCM mani est systolic out ow tract obstruction.
The mechanism o systolic obstruction involves abnormal motion o the anterior mitral valve
lea et toward the LV out ow tract where the thickened septum protrudes (Fig. 10-7). The
process is explained as ollows: (1) during ventricular contraction, ejection o blood toward
the aortic valve is more rapid than usual, because it must ow through an out ow tract that is
narrowed by the thickened septum; (2) this rapid ow creates Venturi orces that abnormally
draw the anterior mitral lea et toward the septum during contraction; and (3) the anterior
mitral lea et approaches and abuts the hypertrophied septum, causing transient obstruction
o blood ow into the aorta.
In patients with out ow obstruction, elevated le t atrial and pulmonary capillary wedge
pressures result rom both the decreased ventricular compliance and the out ow obstruction during contraction. During systolic obstruction, a pressure gradient develops between
the main body o the LV and the out ow tract distal to the obstruction (see Fig. 10-7).
258
Chapter 10
Aorta
LA
MR
AML
S e ptum
LV
Early s ys to le
Mid-to -late
s ys to le
FIGURE 10-7. Pathophysiology o le t ventricular ( LV) outf ow obstruction and mitral regurgitation
( MR) in hypertrophic cardiomyopathy. Le t panel. The LV outf ow tract is abnormally narrowed between the
hypertrophied interventricular septum and the anterior leaf et o the mitral valve (AML). It is thought that the
rapid ejection velocity through the narrowed tract in early systole draws the AML toward the septum (short red
arrow). Right panel. As the mitral valve anterior leaf et abnormally moves toward, and contacts, the septum,
outf ow into the aorta is transiently obstructed. Because the mitral leaf ets do not coapt normally in systole,
MR also results (long red arrow).
The elevated ventricular systolic pressure increases wall stress and myocardial oxygen consumption, which can result in angina (see Fig. 10-6). In addition, because obstruction is
caused by abnormal motion o the anterior mitral lea et toward the septum (and there ore
away rom the posterior mitral lea et), the mitral valve does not close properly during systole,
and mitral regurgitation may result. Such regurgitation urther elevates le t atrial and pulmonary venous pressures and may worsen symptoms o dyspnea, as well as contribute to the
development o atrial f brillation.
The systolic pressure gradient observed in obstructive HCM is dynamic in that its magnitude varies during contraction and depends, at any given time, on the distance between the
anterior lea et o the mitral valve and the hypertrophied septum. Situations that decrease
LV cavity size (e.g., reduced venous return owing to intravascular volume depletion) bring
the mitral lea et and septum into closer proximity and promote obstruction. Conversely,
conditions that enlarge the LV (e.g., augmented intravascular volume) increase the distance
between the anterior mitral lea et and septum and reduce the obstruction. Positive inotropic
drugs (which augment the orce o contraction; see Chapter 17) also orce the mitral lea et
and septum into closer proximity and contribute to obstruction, whereas negative inotropic
drugs (e.g., β-blockers, verapamil) have the opposite e ect.
Although dynamic systolic out ow tract obstruction creates an impressive murmur and
receives great attention, the symptoms o obstructive HCM appear to primarily stem rom
the increased LV sti ness and diastolic dys unction that are also present in the nonobstructive orm.
Clinical Findings
The symptoms o HCM vary widely in a ected individuals, rom none to marked physical
limitations (see Fig. 10-6). The average age o presentation is the mid-20s.
The most requent symptom is dyspnea owing to elevated diastolic LV (and there ore
pulmonary capillary) pressure. This symptom is urther exacerbated by the high systolic LV
pressure and mitral regurgitation ound in patients with out ow tract obstruction.
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Angina is o ten described by patients with HCM, even in the absence o obstructive
coronary artery disease. Myocardial ischemia may be contributed to by (1) the high oxygen
demand o the increased muscle mass and (2) the narrowed small branches o the coronary
arteries within the hypertrophied ventricular wall. I out ow tract obstruction is present,
the high systolic ventricular pressure increases myocardial oxygen demand because o the
increased wall stress and contributes to ischemia.
Syncope in HCM may result rom cardiac arrhythmias that arise because o the structurally
abnormal myof bers. In patients with out ow tract obstruction, syncope may also be induced
by exertion, when the pressure gradient is made worse by the increased orce o contraction,
thereby causing a transient all in cardiac output. Orthostatic light-headedness is also common in patients with out ow tract obstruction. This occurs because venous return to the
heart is reduced on standing by the gravitational pooling o blood in the lower extremities.
The LV thus decreases in size and out ow tract obstruction intensif es, transiently reducing
cardiac output and cerebral per usion.
When arrhythmias occur, symptoms o HCM may be exacerbated. For example, atrial
f brillation is not well tolerated because the loss o the normal atrial “kick” urther impairs
diastolic f lling and can there ore worsen symptoms o pulmonary congestion. O greatest concern, the f rst clinical mani estation o HCM may be ventricular f brillation, resulting in sudden cardiac death, particularly in young adults with HCM during strenuous physical exertion.
Risk actors or sudden death among patients with HCM include a history o syncope, a amily
history o sudden death, certain high-risk HCM mutations, and extreme hypertrophy o the LV
wall (> 30 mm in thickness).
Physical Examination
A patient with a mild orm o HCM may have a normal cardiac examination. Otherwise, a
common f nding is a ourth heart sound (S4), generated by le t atrial contraction into the
sti ened LV (see Chapter 2). The orce ul atrial contraction may also result in a palpable presystolic impulse over the cardiac apex (a “double apical impulse”).
Other f ndings are typical in patients with systolic out ow obstruction. The carotid
pulse rises briskly in early systole but then quickly declines as obstruction to cardiac outow appears. The characteristic systolic murmur o LV out ow obstruction is rough and
crescendo–decrescendo in shape, heard best at the le t lower sternal border (in proximity to
the turbulent ow through the narrowed out ow tract), and unlike AS, does not typically
radiate to the carotid arteries. In addition, as the stethoscope is moved toward the apex,
the holosystolic blowing murmur o accompanying mitral regurgitation may be auscultated.
Although the LV out ow obstruction murmur may be so t at rest, bedside maneuvers that
alter preload and a terload can dramatically increase its intensity and help di erentiate this
murmur rom other conditions, such as AS (Table 10-3).
A commonly used technique in this regard is the Valsalva maneuver, produced by asking the patient to “bear down” (technically def ned as orce ul exhalation with the nose,
mouth, and glottis closed). The Valsalva maneuver increases intrathoracic pressure, which
decreases venous return to the heart and transiently reduces LV size. This action brings the
TABLE 10-3
HCM murmur
AS murmur
Effect of Maneuvers on Murmurs of AS and HCM
Valsalva
Squatting
Standing
↑
↓
↓
↑
↑
↓
HCM, hypertrophic cardiomyopathy; AS, aortic stenosis.
260
Chapter 10
hypertrophied septum and anterior lea et o the mitral valve into closer proximity, creating
greater obstruction to orward ow. Thus, during Valsalva, the murmur o HCM increases in
intensity. In contrast, the murmur o AS decreases in intensity during Valsalva because o the
reduced ow across the stenotic valve.
Conversely, a change rom standing to a squatting position suddenly augments venous
return to the heart (which increases preload) while simultaneously increasing the systemic
vascular resistance. The increased preload raises the stroke volume and there ore causes the
murmur o AS to become louder. In contrast, the transient increase in LV size during squatting
reduces the LV out ow tract obstruction in HCM and so tens the intensity o that murmur.
Sudden standing rom a squatting position has the opposite e ect on each o these murmurs
(see Table 10-3).
Diagnostic Studies
The ECG typically shows le t ventricular hypertrophy and le t atrial enlargement. Prominent
Q waves are common in the in erior and lateral leads, representing amplif ed orces o initial
depolarization o the hypertrophied septum directed away rom those leads. In some patients,
di use T wave inversions are present, which can predate clinical, echocardiographic, or other
electrocardiographic mani estations o HCM. Atrial and ventricular arrhythmias are requent,
especially atrial f brillation. Ventricular arrhythmias are particularly ominous because they
may herald ventricular f brillation and sudden death, even in previously asymptomatic
patients.
Echocardiography is very help ul in the evaluation o HCM. The degree o LV hypertrophy
can be measured and regions o asymmetrical wall thickness readily identif ed. Signs o le t
ventricular out ow obstruction may also be demonstrated and include abnormal anterior
motion o the mitral valve as it is drawn toward the hypertrophied septum during systole,
and partial closure o the aortic valve in midsystole as ow across it is transiently obstructed.
Doppler recordings during echocardiography accurately measure the out ow pressure gradient and quanti y any associated mitral regurgitation. Children and adolescents with apparently mild HCM should undergo serial echocardiographic assessment over time, because the
degree o hypertrophy may increase during puberty and early adulthood.
Ca rdia c ca theteriza tion is reserved or patients or whom the diagnosis is uncertain or
i percutaneous septal ablation (described in the “Treatment” section) is planned. The
major eature in patients with obstruction is the f nding o a pressure gradient within the
out ow portion o the LV, either at rest or during maneuvers that transiently reduce LV size
and promote out ow tract obstruction. Myocardial biopsy at the time o catheterization
is not necessary because histologic f ndings do not predict disease severity or long-term
prognosis.
Finally, genetic testing can be help ul in establishing, or excluding, the diagnosis o HCM
in amily members o an a ected patient when a specif c mutation in that amily has been
identif ed.
Treatment
β-Blockers are standard therapy or HCM because they (1) reduce myocardial oxygen demand
by slowing the heart rate and the orce o contraction (and there ore diminish angina and dyspnea); (2) lessen any LV out ow gradient during exercise by reducing the orce o contraction
(allowing the chamber size to increase, thus separating the anterior lea et o the mitral valve
rom the ventricular septum); (3) increase passive diastolic ventricular f lling time owing to
the decreased heart rate; and (4) decrease the requency o ventricular ectopic beats. Despite
their antiarrhythmic e ect, β-blockers do not prevent sudden arrhythmic death in this condition, nor have they been shown to slow disease progression.
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Certain calcium cha n n el a n ta gon ists (e.g., verapamil) may have benef cial e ects on
ventricular relaxation and f lling and are sometimes use ul in improving exercise capacity in
patients who ail to respond to β-blockers. Patients who develop pulmonary congestion may
benef t rom mild diuretic therapy, but these drugs must be administered cautiously to avoid
volume depletion; reduced intravascular volume decreases LV size and could exacerbate outow tract obstruction. Vasodilators (including nitrates) similarly reduce LV size and should
be avoided.
Atrial f brillation is poorly tolerated in HCM and should be controlled aggressively, most
commonly with antiarrhythmic drugs. E ective and use ul antiarrhythmic drugs or atrial
f brillation in HCM include amiodarone and disopyramide (a class IA antiarrhythmic drug that
also possesses negative inotropic properties that may help reduce LV out ow tract obstruction; see Chapter 17). Digitalis should be avoided in HCM because its positive inotropic e ect
increases the orce o contraction and can worsen LV out ow tract obstruction.
Sudden cardiac death has a propensity to occur in patients with HCM in association with
physical exertion; there ore, strenuous exercise and competitive sports should be avoided.
Sudden death in this syndrome is almost always caused by ventricular tachycardia or f brillation. Although amiodarone may reduce the requency o ventricular arrhythmias, HCM
patients who are at high risk (i.e., a amily history o sudden death, extreme hypertrophy
with ventricular wall thickness > 30 mm, unexplained prior syncopal episodes, history o
high-grade ventricular tachyarrythmias) should receive an ICD. ICD therapy is li e saving or
both primary prevention in such patients, and or HCM patients who have already survived
a cardiac arrest.
Some studies have shown clinical improvement when patients with the obstructive orm
o HCM are treated with a dual-chamber permanent pacemaker, the two electrodes o which
are placed in the right atrium and RV. The LV out ow gradient may become reduced by this
procedure, possibly by altering the normal sequence o ventricular contraction, such that
septal–mitral valve apposition becomes less prominent. However, this technique seems to be
use ul or only a small percentage o markedly symptomatic patients.
Surgical therapy (myomectomy) is considered or patients whose symptoms do not respond
adequately to pharmacologic therapy. This procedure involves excision o portions o the
hypertrophied septal muscle mass and usually improves out ow tract obstruction, symptoms,
and exercise capacity. Myomectomy is the “gold standard” approach to treatment o re ractory
symptoms in this condition. A less invasive alternative in select patients is percutaneous septal ablation, per ormed in the cardiac catheterization laboratory, in which ethanol is injected
directly into the f rst major septal coronary artery (a branch o the le t anterior descending
artery), causing a small, controlled myocardial in arction. The desired and o ten achieved
result is reduction o septal thickness and improvement in out ow tract obstruction.
Theoretically, in ective endocarditis could develop in patients with the obstructive orm o
HCM because o turbulent blood ow through the LV out ow tract and the associated mitral
regurgitation. However, that is rare and routine antibiotic prophylaxis or prevention o endocarditis prior to invasive dental work is not recommended in this condition by current U.S.
guidelines (see Chapter 8).
Finally, genetic counseling should be provided to all patients with HCM. Because it is an
autosomal dominant disease, children o a ected persons have a 50% chance o inheriting
the abnormal gene. First-degree relatives o patients with HCM should be screened by physical examination, electrocardiography, echocardiography, and sometimes genetic testing. Even
asymptomatic HCM patients are at risk o complications, including sudden death.
Prognosis
The incidence o sudden death in HCM is 2% to 4% per year in adults and 4% to 6%
in children and adolescents. It has become clear that di erent mutations produce vastly
262
Chapter 10
di erent phenotypes. Some cause extreme hypertrophy in childhood without any clinical
symptoms until the occurrence o sudden death; others present later in li e with heart ailure symptoms. Most mutations produce only mild hypertrophy and are associated with a
normal li e expectancy.
RESTRICTIVE CARDIOMYOPATHY
The restrictive cardiomyopathies are less common than DCM and HCM. They are characterized by abnormally rigid (but not necessarily thickened) ventricles with impaired diastolic
f lling but usually normal, or near normal, systolic unction. This condition results rom either
(1) f brosis or scarring o the endomyocardium or (2) inf ltration o the myocardium by an
abnormal substance (Table 10-4).
The most common recognized cause o restrictive cardiomyopathy in nontropical countries
is amyloidosis. In this systemic disease, insoluble mis olded amyloid f brils deposit within
tissues, including the heart, causing organ dys unction. Amyloid deposition is diagnosed histologically by the Congo red stain, which displays amyloid f brils with a characteristic green
bire ringence under polarized light.
Amyloid f brils can develop rom several di erent proteins that distinguish the categories
o disease. Primary amyloidosis is caused by deposition o immunoglobulin light chain AL
ragments secreted by a plasma cell tumor (usually, multiple myeloma). In contrast, secondary amyloidosis is characterized by the presence o AA amyloid (derived rom the in ammatory marker serum amyloid A) in a variety o chronic in ammatory conditions, such as
rheumatoid arthritis. Less common is hereditary amyloidosis, an autosomal dominant condition in which amyloid f brils orm rom point mutations in the protein transthyretin. Senile
amyloidosis re ers to a condition in the elderly, in which amyloid deposits, derived rom
transthyretin or other proteins, are ound scattered throughout the vascular system, muscles,
kidney, and lung. In each orm o amyloidosis, cardiac involvement is marked by deposition
o extracellular amyloid between myocardial f bers in the atria and ventricles, in the coronary
arteries and veins, and in the heart valves.
Clinical mani estations o cardiac involvement are most common in the primary (AL) orm
o amyloidosis and typically relate to the development o restrictive cardiomyopathy because
o the inf ltrating amyloid protein. Diastolic dys unction is the prominent cardiac abnormality; systolic dys unction may also develop later in the disease. Orthostatic hypotension is
TABLE 10-4
Examples o Restrictive Cardiomyopathy
Noninf ltrative
Idiopathic
Scleroderma
Inf ltrative
Amyloidosis
Sarcoidosis
Storage diseases
Hemochromatosis
Glycogen storage diseases
Endomyocardial disease
Endomyocardial f brosis
Hypereosinophilic syndrome
Metastatic tumors
Radiation therapy
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The Cardiomyopathies
263
present in about 10% o patients, likely contributed to by amyloid deposition in the autonomic nervous system and peripheral blood vessels. Inf ltration o amyloid into the cardiac
conduction system can cause arrhythmias and conduction impairments, which can result in
syncope or sudden death.
Pathophysiology
Reduced compliance o the ventricles in restrictive cardiomyopathy, whether due to inf ltration or f brosis, results in an upward shi t o the passive ventricular f lling curve (see
Fig. 9-7B), leading to abnormally high diastolic pressures. This has two major consequences:
(1) elevated systemic and pulmonary venous pressures, with signs o right- and le t-sided
vascular congestion, and (2) reduced ventricular cavity size with decreased f lling, stroke
volume, and cardiac output.
Clinical Findings
It ollows rom the underlying pathophysiology that signs o le t- and right-sided heart ailure
are expected (Fig. 10-8). Decreased cardiac output is mani ested by atigue and decreased
exercise tolerance. Systemic congestion (o ten more prominent than pulmonary congestion
in this syndrome) leads to jugular venous distention, peripheral edema, and ascites with a
large, tender liver. Arrhythmias, including atrial f brillation, are common. Inf ltrative etiologies that involve the cardiac conduction system can cause conduction blocks (described in
Chapter 12).
Physical Examination
Signs o congestive heart ailure are o ten present, including pulmonary rales, distended neck
veins, ascites, and peripheral edema. Similar to constrictive pericarditis (see Chapter 14),
jugular venous distention may paradoxically worsen with inspiration (the Kussmaul sign)
because the sti ened RV cannot accommodate the increased venous return.
Diagnostic Studies
The chest radiograph usually shows a normal-sized heart with signs o pulmonary congestion.
The ECG o ten displays nonspecif c ST and T wave abnormalities; conduction disturbances
such as atrioventricular block or a bundle branch block may be present.
↑ Dia s tolic
ve ntricula r
pre s s ure
Ve nous
conge s tion
↓ Ve ntricula r
filling
↓ CO
• Jugula r ve in dis te ntion
• He pa tome ga ly a nd a s cite s
• Pe riphe ra l e de ma
Rig id
myo c ardium
• We a kne s s
• Fa tigue
FIGURE 10-8. Pathophysiology of restrictive cardiomyopathy. The rigid myocardium results in elevated
ventricular diastolic pressures and decreased ventricular f lling. The resultant symptoms can be predicted rom
these abnormalities. CO, cardiac output.
264
Chapter 10
The restrictive cardiomyopathies share nearly identical symptoms, physical signs, and
hemodynamic prof les with constrictive pericarditis, as described in Chapter 14. However, it
is important to distinguish these two entities because constrictive pericarditis is o ten correctable, whereas interventions or the restrictive cardiomyopathies are more limited.
The most use ul diagnostic tools to di erentiate restrictive cardiomyopathy rom constrictive pericarditis are transvenous endomyocardial biopsy, computed tomography (CT),
and MRI. For example, in restrictive cardiomyopathies, transvenous endomyocardial biopsy
may demonstrate the cause o the condition (e.g., the presence o amyloid f brils in amyloidosis, or iron deposits in patients with hemochromatosis [a condition o iron overload]).
CT or MRI scans accurately identi y the thickened pericardium present in most patients
with constrictive pericarditis, a f nding that is not present in states causing restrictive
cardiomyopathy.
Treatment
Restrictive cardiomyopathy typically has a very poor prognosis, except when treatment can
target an underlying cause. For example, phlebotomy and iron chelation therapy may be helpul in the early stages o hemochromatosis. Symptomatic therapy or all etiologies includes
salt restriction and cautious use o diuretics to improve symptoms o systemic and pulmonary
congestion. Unlike the dilated cardiomyopathies, vasodilators are not help ul because systolic
unction is usually preserved. Maintenance o sinus rhythm (e.g., converting atrial f brillation i it occurs) is important to maximize diastolic f lling and orward cardiac output. Some
restrictive cardiomyopathies are prone to intraventricular thrombus ormation, thus warranting chronic oral anticoagulant therapy. In the case o primary (AL) amyloidosis, chemotherapy ollowed by autologous bone marrow stem cell transplantation has proved e ective in
selected patients with early cardiac involvement.
OTHER FORMS OF CARDIOMYOPATHY
Not all orms o cardiac muscle disease f t into the traditional categories o cardiomyopathy
described in this chapter. Examples o exceptions include (1) le t ventricular noncompaction
(LVNC), and (2) arrhythmogenic right ventricular cardiomyopathy (ARVC).
Left Ventricular Noncompaction
LVNC is a rare condition with eatures that overlap with hypertrophic, restrictive and dilated
cardiomyopathies. It is mani est by a thickened myocardium with very prominent trabeculae and deep recesses that extend rom the LV cavity into the intertrabecular spaces. The
abnormal regions o myocardium typically contract poorly, o ten demonstrate characteristics
o impaired diastolic relaxation, and predispose to rhythm disturbances and thrombus ormation. Patients with this condition may present in childhood or adulthood with symptoms
o heart ailure (due to systolic and/ or diastolic dys unction), ventricular arrhythmias, or
thromboembolism.
LVNC appears to result rom arrested development o the myocardium during etal
development, though the exact mechanism has not been ully elucidated. Up to 50% o
patients with this condition have a ected amily members, and autosomal dominant, autosomal recessive and X-linked patterns o inheritance have been ound. Mutations in at
least nine genes encoding sarcomere proteins have been identif ed in patients with LVNC
(including mutations that have also been associated with hypertrophic and dilated cardiomyopathies), resulting in either the isolated disorder or a syndrome with other orms o
congenital heart disease.
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The Cardiomyopathies
265
The diagnosis is usu ally established by typical eatures on 2-dim ensional and color
Doppler ech ocardiography or by cardiac MRI. Th e progn osis is variable, bu t is worse
amon g sym ptom atic patien ts com pared to th ose ou n d to h ave th e disorder in ciden tally
by im agin g stu dies. On e series in dicated th at 60% o patien ts h ad died or requ ired cardiac transplantation w ithin 6 years o diagn osis, but oth er studies have reported less
dire ou tcom es.
Management is aimed at treating the symptoms and complications o LVNC as there is
no corrective therapy or the underlying condition itsel . Depending on the clinical maniestations, approaches may include standard treatment o heart ailure (Chapter 9), ICD
implantation or management o li e-threatening ventricular arrhythmias, chronic anticoagulation or those with accompanying atrial f brillation or signif cant contractile dys unction to
prevent thromboembolism, and cardiac transplantation or those with advanced, re ractory
heart ailure.
Arrhythmogenic Right Ventricular Cardiomyopathy
ARVC, also termed arrhythmogenic right ventricular dysplasia, is another genetic orm o
cardiomyopathy. It is characterized by replacement o right ventricular (and occasionally le t
ventricular) myocardium with adipose and f brous tissue, resulting in rhythm disturbances
and contractile dys unction. Ventricular arrhythmias originating rom the abnormal ventricle are common and may result in palpitations, syncope, and even sudden cardiac death.
Symptoms o ten begin in the teen years, and ARVC is another cause o sudden death among
young athletes.
Both autosomal dominant and recessive inheritance orms o ARVC have been identif ed. The majority o mutations occur in genes that encode components o desmosomes, cell
membrane structures responsible or cell-to-cell adhesion, leading to f brosis and aberrant
signaling with proli eration o adipose tissue in the myocardium. Transvenous endomyocardial biopsy o the RV may demonstrate atty or f bro atty replacement o the myocardium, but
has a high alse negative rate or identi ying the disorder. Thus, diagnostic criteria also rely
on amily history, ECG abnormalities (see Chapter 12, Box 12-1), the presence o arrhythmias emanating rom the RV, morphologic abnormalities detected by imaging studies (especially cardiac MRI), and genetic testing or specif c mutations. Management o ARVC typically
includes ICD implantation because the disease is progressive and li e-threatening ventricular
tachycardia is common.
SUMMARY
• Cardiomyopathies are a group o heart muscle disorders that cause mechanical and/ or
electrical dys unction o the myocardium, and o ten result in inappropriate ventricular
hypertrophy or dilatation (Table 10-5); heart ailure and cardiovascular death are common
end mani estations.
• DCM is characterized by progressive ventricular chamber enlargement with impaired systolic
contractile unction, o ten leading to symptomatic heart ailure, ventricular arrhythmias,
and/ or embolic complications.
• HCM is characterized by an abnormally thickened ventricular wall with abnormal diastolic
relaxation but usually intact systolic unction; dynamic LV out ow tract obstruction during
systole may be present, and the most common symptoms are dyspnea and exertional angina.
• Ventricular arrhythmias in HCM may lead to sudden cardiac death.
• Restrictive cardiomyopathies are uncommon and are characterized by an abnormally sti ened myocardium (because o f brosis or an inf ltrative process) leading to impaired diastolic
relaxation, but systolic contractile unction is typically normal or near normal; symptoms o
heart ailure are typical.
266
Chapter 10
TABLE 10-5
Summary of the Cardiomyopathies
Ventricular
morphology
Dilated Cardiomyopathy
Hypertrophic
Cardiomyopathy
Restrictive
Cardiomyopathy
Dilated LV with little
concentric hypertrophy
Marked hypertrophy, o ten
asymmetric
Fibrotic or in ltrated
myocardium
Amyloidosis, hemochromatosis, scleroderma,
radiation therapy
Dyspnea, atigue
LA
LV
Etiologies
Genetic, in ectious,
alcoholic, peripartum
Genetic
Symptoms
Fatigue, weakness,
dyspnea, orthopnea, PND
Pulmonary rales, S3; i RV
ailure present: JVD,
hepatomegaly, peripheral
edema
Dyspnea, angina, syncope
Physical exam
Pathophysiology
Impaired systolic
contraction
Cardiac size on
chest radiograph
Echocardiogram
Enlarged
Dilated, poorly contractile
LV
S4; i outf ow obstruction
present: systolic murmur
loudest at le t sternal
border, accompanied by
mitral regurgitation
Impaired diastolic
relaxation; LV systolic
unction vigorous, o ten
with dynamic obstruction
Normal or enlarged
Predominantly signs o RV
ailure: JVD, hepatomegaly, peripheral edema
LV hypertrophy, o ten more
pronounced at septum;
systolic anterior movement o MV with mitral
regurgitation
Usually normal systolic
contraction; “speckled”
appearance in in ltrative
disorders
“Sti ” LV with impaired
diastolic relaxation but
usually normal systolic
unction
Usually normal
LV, le t ventricle; PND, paroxysmal nocturnal dyspnea; RV, right ventricle; JVD, jugular venous distension; MV, mitral valve.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Christopher T. Lee, MD; Marc N. Wein,
MD; Yi-Bin Chen, MD; David Grayzel, MD; and Kay Fang, MD.
Ad d i t i o n a l Rea d i n g
Arbustini E, Narula J, Tavazzi J, et al. The MOGE(S) classif cation o cardiomyopathy or clinicians. J Am Coll Cardiol.
2014;64:304–318.
Bhatia NL, Tajik AJ, Wilansky S, et al. Isolated noncompaction
o the le t ventricular myocardium in adults: A systematic
overview. J Card Fail. 2011;17:771–778.
Elkayam U. Clinical characteristics o peripartum cardiomyopathy in the United States: Diagnosis, prognosis, and management. J Am Coll Cardiol. 2011;58:659–670.
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/ AHA guideline
or the diagnosis and treatment o hypertrophic cardiomyopathy: Executive summary. J Am Coll Cardiol. 2011;58:2703–2738.
Guan J, Mishra S, Falk RH, et al. Current perspectives on
cardiac amyloidosis. Am J Physiol Heart Circ Physiol.
2012;302:H544–H552.
Maron BJ, Ommen SR, Semsarian C, et al. Hypertrophic cardiomyopathy: Present and uture, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64:83–99.
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The Cardiomyopathies
Maron BJ, Towbin JA, Thiene G, et al. Contemporary
def nitions and classif cation o the cardiomyopathies:
An American Heart Association scientif c statement
rom the Council on Clinical Cardiology, Heart Failure
and Transplantation Committee; Quality o Care and
Outcomes Research and Functional Genomics and
Translational Biology Interdisciplinary Working Groups;
267
and Council on Epidemiology and Prevention. Circulation.
2006;113:1807–1816.
Murray B. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/ C): A review o molecular and clinical
literature. J Genet Couns. 2012;21:494–504.
Sturm AC. Genetic testing in the contemporary diagnosis o
cardiomyopathy. Curr Heart Fail Rep. 2013;10:63–72.
Mechanisms of
Cardiac Arrhythmias
11
Morga n J. Prust
Willia m G. Stevenson
Ga ry R. Stricha rtz
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Normal Impulse Formation
Ionic Basis o Automaticity
Native and Latent Pacemakers
Overdrive Suppression
Electrotonic Interactions
Altered Impulse Formation
Alterations in Sinus Node
Automaticity
Escape Rhythms
Enhanced Automaticity o
Latent Pacemakers
Abnormal Automaticity
Triggered Activity
Altered impulse conduction
Conduction Block
Unidirectional Block and
Reentry
Physiologic Basis of Antiarrhythmic
Therapy
Bradyarrhythmias
Tachyarrhythmias
N
ormal cardiac unction relies on the ow o electric impulses
through the heart in an exquisitely coordinated ashion.
Abnormalities o the electric rhythm are known as arrhythmias
(also termed dysrhythmias) and are among the most common
clinical problems encountered. The presentations o arrhythmias range rom common benign palpitations to severe symptoms o low cardiac output and death. There ore, a thorough
understanding o these disorders is important to the daily
practice o medicine.
Abnormally slow heart rhythms are termed bradycardias
(or bradyarrhythmias). Fast rhythms are known as tachycardias (or tachyarrhythmias). Tachycardias are urther characterized as supraventricular when they involve the atrium
or atrioventricular (AV) node and designated ventricular
when they originate rom the His–Purkinje system or ventricles. This chapter extends the description o basic cardiac
electrophysiology presented in Chapter 1 and explains the
mechanisms by which arrhythmias develop, ollowed by a
general approach to their management. Chapter 12 describes
specif c rhythm disorders, including how to recognize and
treat them.
Disorders o heart rhythm result rom alterations o
impulse formation, impulse conduction, or both. The chapter f rst addresses how abnormalities o impulse ormation
and conduction occur and under what circumstances they
cause arrhythmias. Figure 11-1 provides an organizational
schema or this presentation.
While studying the concepts in this chapter, it is important
to recall that cardiac tissue is composed o cells that are electrically coupled and operate as a syncytium. As myocytes depolarize and ionic currents result in individual action potentials,
268
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Mechanisms of Cardiac Arrhythmias
269
the electrical activity rapidly propagates from one cell to the next with minimal resistance, spreading through
a large mass of tissue. As a result, the leading edge of a depolarization may be located several centimeters
ahead of its trailing edge, and this property plays an important role in the genesis of certain arrhythmias, as
will be described.
NORMAL IMPULSE FORMATION
As described in Chapter 1, electric impulse ormation in the heart arises rom the intrinsic
automaticity o specialized cardiac cells. Automaticity re ers to a cell’s ability to spontaneously depolarize to a threshold voltage to generate an action potential. Although atrial
and ventricular myocytes do not have this property under normal conditions, the cells o
the specialized conducting system do possess natural automaticity and are there ore termed
pacemaker cells. The specialized conducting system includes the sinoatrial (SA) node, the
AV nodal region, and the ventricular conducting system. The latter is composed o the bundle
o His, the bundle branches, and the Purkinje bers. In pathologic situations, myocardial cells
outside the conducting system may also acquire automaticity.
Ionic Basis of Automaticity
Cells with natural automaticity do not have a static resting voltage. Rather, they inherently
display gradual depolarization during phase 4 o the action potential (Fig. 11-2). I this spontaneous diastolic depolarization reaches the threshold condition, an action potential upstroke
is generated. An important ionic current largely responsible or phase 4 spontaneous depolarization is known as the pacemaker current (If). The channels that carry this current are
activated by hyperpolarization (increasingly negative voltages) and mainly conduct sodium
ions. I channels begin to open when the membrane voltage becomes more negative than
approximately − 50 mV and are different entities than the ast sodium channels responsible
or rapid phase 0 depolarization in ventricular and atrial myocytes. The inward f ow o Na +
through these slow channels, driven by its concentration gradient and the negative intracellular potential, depolarizes the membrane toward threshold.
Tac hyarrhythmias (incre a s e d firing ra te )
Automa ticity
of SA node
Automa ticity
of la te nt
pa ce ma ke rs
Abnorma l
a utoma ticity
Trigge re d
a ctivity
Unidire ctiona l
block
a nd re e ntry
Enha nce d
a utoma ticity
Alte re d
impuls e
fo rmatio n
Alte re d
impuls e
c o nduc tio n
Automa ticity
of SA node
Conduction
block
Bradyarrhythmias (de cre a s e d firing ra te )
FIGURE 11-1. Arrhythmias result from alterations in impulse formation and/ or impulse conduction.
Tachyarrhythmias result from enhanced automaticity, unidirectional block with reentry, or triggered activity.
Bradyarrhythmias result from decreased automaticity or conduction block. SA, sinoatrial.
270
Chapter 11
FIGURE 11-2. The action potential ( AP) of
a pacemaker cell ( e.g., the sinus node) . The
slow phase 4 depolarization is largely caused
by the I (pacemaker) inward current, which
drives the cell to threshold (approximately − 40
mV). The upstroke o the AP is caused by the
slow inward current o Ca+ + ions. Reduction
o the Ca+ + current (due to inactivation o
calcium channels) and progressive K+ e f ux
through voltage-gated potassium channels are
responsible or repolarization. MDP, maximum
negative diastolic potential; TP, threshold
potential.
If
influx
In the pacemaker cells o the SA node, three other ionic currents also contribute to phase
4 gradual depolarization: (1) a slowly increasing inward calcium current, carried mostly by
L-type Ca + + channels that become activated at voltages reached near the end o phase 4;
(2) a progressively declining outward potassium current; and (3) an additional inward sodium
current mediated by activation o the electrogenic sodium–calcium exchanger by calcium
release rom the sarcoplasmic reticulum.
When the membrane potential o a pacemaker cell reaches the threshold condition, the
upstroke o the action potential is generated. In contrast to the phase 0 upstroke o cells in the
Purkinje system, that o cells in the sinus and AV nodes is much slower (see Fig. 11-2). The reason or the di erence is that the membrane potential determines the proportion o ast sodium
channels that are in a resting state capable o depolarization, compared with an inactivated
state. The number o available (or resting-state) ast sodium channels decreases as the resting
(diastolic) membrane potential becomes less negative. Because sinus and AV nodal cells have
less negative maximum diastolic membrane voltages (− 50 to − 60 mV) than do Purkinje cells
(− 90 mV), the large majority o ast sodium channels is inactivated in these pacemaker cells.
Thus, the action potential upstroke relies to a great extent on a smaller calcium current (through
the relatively slower opening o L-type Ca + + channels) and has a less rapid rate o rise than
do cells o the Purkinje system or ventricular myocardium. The repolarization phase o pacemaker cells results rom both the inactivation o the open calcium channels and the opening o
voltage-gated potassium channels that permit e f ux o potassium rom the cells (see Fig. 11-2).
Native and Latent Pacemakers
The distinct populations o automatic cells in the specialized conduction pathway have di erent intrinsic rates o ring. These rates are determined by three variables that inf uence
how ast the membrane potential reaches the threshold condition: (1) the rate (i.e., the slope)
o phase 4 spontaneous depolarization, (2) the maximum negative diastolic potential, and
(3) the threshold potential. A more negative maximum diastolic potential, or a less negative
threshold potential, slows the rate o impulse initiation because it takes longer to reach the
threshold value (Fig. 11-3). Conversely, the greater the I , the steeper the slope o phase 4 and
the aster the cell depolarizes. The size o I depends on the number and opening kinetics o
the individual pacemaker channels through which this current f ows.
Since all healthy myocardial cells are electrically connected by gap junctions, an action
potential generated in one part o the myocardium will ultimately spread to all other regions.
When an impulse arrives at a cell that is not yet close to threshold, current rom the depolarized
cell will bring the adjacent cell’s membrane potential to the threshold level so that it will re
(regardless o how close its intrinsic I has brought it to threshold). Thus, the pacemaker cells
with the astest rate o depolarization set the heart rate. In the normal heart, the dominant
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a
FIGURE 11-3. Determinants o cell f ring
rates. A. Alterations in the pacemaker current
(I ) and in the magnitude o the maximum
diastolic potential (MDP) alter the cell f ring
rate. (a) The normal action potential (AP) o
a pacemaker cell. (b) Reduced I renders the
slope o phase 4 less steep; thus, the time
required to reach threshold potential (TP)
is increased. (c) The MDP is more negative;
there ore, the time required to reach TP is
increased. B. Alterations in TP change the
f ring rate o the cell. Compared with the
normal TP (a), the TP in b is less negative;
thus, the duration o time to achieve
threshold is increased, and the f ring rate
decreases.
271
b c
A
a
b
B
pacemaker is the sinoatrial node, which at rest initiates impulses at a rate o 60 to 100 bpm.
Because the sinus node rate is aster than that o the other tissues that possess automaticity,
its repeated discharges prevent spontaneous ring o other potential pacemaker sites.
The SA node is known as the native pacemaker because it normally sets the heart rate.
Other cells within the specialized conduction system harbor the potential to act as pacemakers
i necessary and are there ore called latent pacemakers (or ectopic pacemakers). In contrast
to the SA node, the AV node and the bundle o His have intrinsic ring rates o 50 to 60 bpm,
and cells o the Purkinje system have rates o approximately 30 to 40 bpm. These latent sites
may initiate impulses and take over the pacemaker unction i the SA node slows or ails to re
or i conduction abnormalities block the normal wave o depolarization rom reaching them.
Overdrive Suppression
Not only does the cell population with the astest intrinsic rhythm preempt all other automatic cells
rom spontaneously ring but it also directly suppresses their automaticity. This phenomenon is
called overdrive suppression. Cells maintain their transsarcolemmal ion distributions because o
the continuously active Na + K+ -ATPase that extrudes three Na+ ions rom the cell in exchange or
two K+ ions transported in (Fig. 11-4). Because its net transport e ect is one positive charge in the
outward direction, Na + K+ -ATPase creates a hyperpolarizing current (i.e., it tends to make the inside
o the cell more negative). As the cell potential becomes increasingly negative, additional time is
required or spontaneous phase 4 depolarization to reach the threshold voltage (see Fig. 11-3A),
and there ore, the rate o spontaneous ring is decreased. Although the hyperpolarizing current
moves the membrane voltage away rom threshold, pacemaker cells ring at their own intrinsic
rate have an I current su ciently large to overcome this hyperpolarizing inf uence (see Fig. 11-4).
The hyperpolarizing current increases when a cell is caused to re more requently than its
intrinsic pacemaker rate. The more o ten the cell is depolarized, the greater the quantity o Na+ ions
that enter the cell per unit time. As a result o the increased intracellular Na + content, Na+ K+ -ATPase
becomes more active, thereby tending to restore the normal transmembrane Na+ gradient. This
272
Chapter 11
increased pump activity provides a larger hyperpolarizing current, opposing the depolarizing current I ,
and urther decreases the rate o spontaneous depolarization. Thus, overdrive suppression decreases a
cell’s automaticity when that cell is driven to depolarize aster than its intrinsic discharge rate.
Electrotonic Interactions
FIGURE 11-4. Competition between the
depolarizing pacemaker current (If) and Na+ K+ ATPase, which produces a hyperpolarizing
current. Na+ K+ -ATPase transports three Na+ ions
outside the cell in exchange or two K+ ions
transported inward. The hyperpolarizing current
acts to suppress automaticity by antagonizing
I and contributes to overdrive suppression in
cells that are stimulated more rapidly than their
intrinsic f ring rate.
In addition to overdrive suppression, anatomic connections between pacemaker and nonpacemaker
cells are important in determining how adjacent
cells suppress latent pacemaker oci. Myocardial
cells in the ventricle and Purkinje system repolarize to a resting potential o approximately − 90 mV,
whereas pacemaker cells in the sinus and AV nodes
repolarize to a maximum diastolic potential o about
− 60 mV. When these two cell types are adjacent to
one another, they are electrically coupled through low-resistance gap junctions concentrated
in their intercalated discs. This coupling results in a compromise o electric potentials owing
to electrotonic current f ow between the cells, causing relative hyperpolarization o the pacemaker cell and relative depolarization o the nonpacemaker cell (Fig. 11-5). Hyperpolarization
Myo c ardial c e ll
Pac e make r c e ll
RP = –90 mV
MDP = –60 mV
Pac e make r ac tio n po te ntial
TP
MDP
If
Time
A
Te nds to
de pola rize
(le s s ne ga tive
volta ge )
Te nds to
hype rpola rize
(more ne ga tive
volta ge )
TP
↓ MDP
Inte rce llula r curre nt
If
Time
B
FIGURE 11-5. Electrotonic interaction between pacemaker ( e.g., AV nodal) and nonpacemaker ( myocardial)
cells. A. Pacemaker cells that are not coupled to myocardial cells have a maximum diastolic potential (MDP) o
approximately − 60 mV, whereas myocardial cells have a resting potential (RP) o approximately − 90 mV.
B. When pacemaker cells and myocytes are neighbors, they may be connected electrically by gap junctions at
their intercalated discs (e.g., at the AV node). In this situation, electric current ows between the pacemaker cell
and the myocardial cell, tending to hyperpolarize the ormer and depolarize the latter, driving their membrane
potentials closer to one another. The hyperpolarizing current renders the MDP more negative, causing it to take
longer or spontaneous depolarization to reach the threshold value, thereby suppressing automaticity. I a disease
state impairs coupling between cells, the in uence o surrounding myocytes on the pacemaker cell is reduced,
allowing I to depolarize to threshold more readily and enhancing automaticity. TP, threshold potential.
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Mechanisms o Cardiac Arrhythmias
273
moves the diastolic potential urther rom threshold and thus slows the heart rate (as shown in
Fig. 11-3A). Electrotonic e ects may be particularly important in suppressing automaticity in
the AV node (via connections between atrial myocytes and AV nodal cells) and in the distal
Purkinje bers (which are coupled to ventricular myocardial cells). In contrast, cells in the
center o the SA node are less tightly coupled to atrial myocytes; thus, their automaticity is less
subject to electrotonic interactions.
Decoupling o normally suppressed cells, such as those in the AV node (e.g., by ischemic
damage), may reduce the inhibitory electrotonic inf uence and enhance automaticity, producing ectopic rhythms by the latent pacemaker tissue.
ALTERED IMPULSE FORMATION
Arrhythmias may arise rom altered impulse ormation at the SA node or rom other sites,
including the specialized conduction pathways or regions o cardiac muscle. The main abnormalities o impulse initiation that lead to arrhythmias are (1) altered automaticity (o the
sinus node or latent pacemakers within the specialized conduction pathway), (2) abnormal
automaticity in atrial or ventricular myocytes, and (3) triggered activity.
Alterations in Sinus Node Automaticity
The rate o impulse initiation by the sinus node,
as well as by the latent pacemakers o the specialized conducting system, is regulated primarily by
neurohumoral actors.
C
A
B
Increased Sinus Node Automaticity
The most important modulator o normal sinus
node automaticity is the autonomic nervous system. Sympathetic stimulation, acting through
β1-adrenergic receptors, increases the open probability o the pacemaker channels (Fig. 11-6),
through which I can f ow. The increase in I
leads to a steeper slope o phase 4 depolarization, causing the SA node to reach threshold
and re earlier than normal and the heart rate
to increase.
In addition, sympathetic stimulation shi ts
the action potential threshold to more negative voltages by increasing the probability that
voltage-sensitive Ca + + channels are capable o
opening (recall that calcium carries the current
o phase 0 depolarization in pacemaker cells).
There ore, phase 4 depolarization reaches the
threshold potential earlier. Sympathetic activity
thus increases sinus node automaticity both by
increasing the rate o pacemaker depolarization
via I and by causing the action potential threshold to become more negative. Examples o this
normal physiologic e ect occur during physical
exercise or emotional stress, when sympathetic
stimulation appropriately increases the heart rate.
FIGURE 11-6. Effect of sympathetic and
parasympathetic ( cholinergic) stimulation
on pacemaker current channels. The channels
through which the pacemaker current (I ) ows
are voltage gated, opening at more negative
membrane potentials. At any given voltage,
there exists a probability between 0 and 1 that
a specif c channel will be open. Compared with
normal baseline behavior (curve A), sympathetic
stimulation (curve B) or treatment with
anticholinergic drugs shi ts this probability to
a higher value or any given level o membrane
voltage, thus increasing the number o open
channels and the rate at which the cell will f re.
Curve C shows that parasympathetic cholinergic
stimulation (or treatment with a β-blocker,
which antagonizes sympathetic stimulation) has
the opposite e ect, decreasing the probability
o a channel being open and there ore inhibiting
depolarization.
274
Chapter 11
Decreased Sinus Node Automaticity
Normal decreases in SA node automaticity are mediated by reduced sympathetic stimulation
and by increased activity o the parasympathetic nervous system. Whereas activation o the
sympathetic nervous system has a major role in increasing the heart rate during times o
stress, the parasympathetic nervous system is the major controller o the heart rate at rest.
Cholinergic (i.e., parasympathetic) stimulation via the vagus nerve acts at the SA node
to reduce the probability o pacemaker channels being open (see Fig. 11-6). Thus, I and the
slope o phase 4 depolarization are reduced, and the intrinsic ring rate o the cell is slowed.
In addition, the probability o the Ca + + channels being open is decreased, such that the action
potential threshold increases to a less negative potential. Furthermore, cholinergic stimulation
increases the probability o acetylcholine-sensitive K+ channels being open at rest. Positively
charged K+ ions exit through these “inward recti er” channels, which di er rom the K+
channels that are active in phase 3 repolarization (see Chapter 1), producing an outward current that drives the diastolic potential more negative. The overall e ect o reduced I , a more
negative maximum diastolic potential, and a less negative threshold level is a slowing o the
intrinsic ring rate and there ore a reduced heart rate.
It ollows that the use o pharmacologic agents that modi y these e ects o the autonomic nervous system will also a ect the ring rate o the SA node. For example, β-receptor
blocking drugs (“β-blockers”) antagonize the β-adrenergic sympathetic e ect; there ore,
they decrease the rate o phase 4 depolarization o the SA node and slow the heart rate.
Conversely, atropine, an anticholinergic (antimuscarinic) drug, has the opposite e ect: by
blocking parasympathetic activity, the rate o phase 4 depolarization increases and the heart
rate accelerates.
Escape Rhythms
I the sinus node becomes suppressed and res much less requently than normal, the site o
impulse ormation may shi t to a latent pacemaker within the specialized conduction pathway. An impulse initiated by a latent pacemaker because the SA node rate has slowed is called
an escape beat. Persistent impairment o the SA node will allow a continued series o escape
beats, termed an escape rhythm. Escape rhythms are protective in that they prevent the heart
rate rom becoming pathologically slow when SA node ring is impaired.
As discussed in the previous section, suppression o sinus node activity may occur because
o increased parasympathetic tone. Di erent regions o the heart have varied sensitivities to
parasympathetic (vagal) stimulation. The SA node and the AV node are most sensitive to
such an inf uence, ollowed by atrial tissue. The ventricular conducting system is the least
sensitive. There ore, moderate parasympathetic stimulation slows the sinus rate and allows
the pacemaker to shi t to the AV node. However, very strong parasympathetic stimulation
suppresses excitability at both the SA node and AV node and may there ore result in the emergence o a ventricular escape pacemaker.
Enhanced Automaticity of Latent Pacemakers
Another means by which a latent pacemaker can assume control o impulse ormation is i
it develops an intrinsic rate o depolarization faster than that o the sinus node. Termed an
ectopic beat, such an impulse is premature relative to the normal rhythm, whereas an escape
beat is late and terminates a pause caused by a slowed sinus rhythm. A sequence o similar
ectopic beats is called an ectopic rhythm.
Ectopic beats may arise in several circumstances. For example, high catecholamine concentrations can enhance the automaticity o latent pacemakers, and i the resulting rate o
depolarization exceeds that o the sinus node, then an ectopic rhythm will develop. Ectopic
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beats are also commonly induced by hypoxemia, ischemia, electrolyte disturbances, and
certain drug toxicities (such as digitalis, as described in Chapter 17).
Abnormal Automaticity
Cardiac tissue injury may lead to pathologic changes in impulse ormation whereby myocardial cells outside the specialized conduction system acquire automaticity and spontaneously
depolarize. Although such activity may appear similar to impulses originating rom latent
pacemakers within the specialized conduction pathways, these ectopic beats arise rom cells
that do not usually possess automaticity. I the rate o depolarization o such cells exceeds
that o the sinus node, they transiently take over the pacemaker unction and become the
source o an abnormal ectopic rhythm.
Because these myocardial cells have ew or no activated pacemaker channels, they do
not normally carry I . How injury allows such cells to spontaneously depolarize has not
been ully elucidated. However, when cardiac tissue becomes injured, its cellular membranes
become “leaky.” As such, they are unable to maintain the concentration gradients o ions,
and the resting potential becomes less negative (i.e., the cell partially depolarizes). When a
cell’s membrane potential is reduced to a value less negative than − 60 mV, gradual phase
4 depolarization can be demonstrated even among nonpacemaker cells. This spontaneous
depolarization probably results rom a very slowly inactivating calcium current, a decrease
in the outward potassium current that normally acts to repolarize the cell, and less e ect o
the inward rectif er K+ current that normally holds cells at a more negative potential range.
Triggered Activity
Under certain conditions, an action potential can “trigger” abnormal depolarizations that result
in extra heart beats or tachyarrhythmias. This process may occur when the f rst action potential
leads to oscillations o the membrane voltage known as afterdepolarizations. Unlike the spontaneous activity seen when enhanced automaticity occurs, this type o automaticity is stimulated
by a preceding action potential. As illustrated in Figures 11-7 and 11-8, there are two types o
a terdepolarizations depending on their timing a ter the inciting action potential: early a terdepolarizations occur during the repolarization phase o the inciting beat, whereas delayed a terdepolarizations occur shortly a ter repolarization has been completed. In either case, abnormal
action potentials are triggered i the a terdepolarization reaches a threshold voltage.
Early afterdepolarizations are changes o the membrane potential in the positive direction
that interrupt normal repolarization (see Fig. 11-7). They can occur either during the plateau
o the action potential (phase 2) or during rapid repolarization (phase 3). Early a terdepolarizations are more likely to develop in conditions that prolong the action potential duration
(and there ore the electrocardiographic QT interval), as may occur during therapy with certain drugs (see Chapter 17) and in the inherited long QT syndromes (see Chapter 12).
FIGURE 11-7. Triggered activity. An early
afterdepolarization (arrow) occurs before the action
potential (AP) has fully repolarized. Repetitive
afterdepolarizations (dashed curve) may produce a
rapid sequence of triggered action potentials and
hence a tachyarrhythmia.
276
Chapter 11
FIGURE 11-8. Triggered activity. A
delayed afterdepolarization (arrow) arises
after the cell has fully repolarized. If the
delayed afterdepolarization reaches the
threshold voltage, a propagated action
potential (AP) is triggered (dashed curve).
The ionic current responsible or an early a terdepolarization depends on the membrane
voltage at which the triggered event occurs. I the early a terdepolarization occurs during
phase 2 o the action potential, when most o the Na + channels are still in an inactivated state,
the upstroke o the triggered beat relies mostly on an inward Ca + + current. I , however, the
a terdepolarization occurs during phase 3 (when the membrane voltage is more negative),
there is partial recovery o the inactivated Na + channels, which then contribute more to the
current underlying the triggered beat.
An early a terdepolarization-triggered action potential can be sel -perpetuating and lead to
a series o depolarizations and there ore a tachyarrhythmia (see Fig. 11-7). Early a terdepolarizations appear to be the initiating mechanism o the polymorphic ventricular tachycardia
known as torsades de pointes, which is described in Chapter 12.
Delayed afterdepolarizations may appear shortly a ter repolarization is complete (see
Fig. 11-8). They most commonly develop in states o high intracellular calcium, as may be
present with digitalis intoxication (see Chapter 17), or during marked catecholamine stimulation. It is thought that intracellular Ca + + accumulation causes the activation o chloride
currents, or o the Na + –Ca + + exchanger, that results in brie inward currents that generate the
delayed a terdepolarization.
As with early a terdepolarizations, i the amplitude o the delayed a terdepolarization
reaches a threshold voltage, an action potential will be generated. Such action potentials can
be sel -perpetuating and lead to tachyarrhythmias. Some idiopathic ventricular tachycardias
that occur in otherwise structurally normal hearts are likely due to this mechanism, as are
atrial and ventricular tachycardias associated with digitalis toxicity (see Chapter 17).
ALTERED IMPULSE CONDUCTION
Alterations in impulse conduction also lead to arrhythmias. Conduction blocks generally slow
the heart rate (bradyarrhythmias); however, under certain circumstances, the process o reentry (described later) can ensue and produce abnormal ast rhythms (tachyarrhythmias).
Conduction Block
A propagating impulse is blocked when it encounters a region o the heart that is electrically
unexcitable. Conduction block can be either transient or permanent and may be unidirectional
(i.e., conduction proceeds when the involved region is stimulated rom one direction but
not when stimulated rom the opposite direction) or bidirectional (conduction is blocked in
both directions). Various conditions may cause conduction block, including ischemia, brosis, inf ammation, and certain drugs. When conduction block occurs because a propagating
impulse encounters cardiac cells that are still re ractory rom a previous depolarization, the
block is said to be functional. A propagating impulse that arrives a short time later, when the
tissue is no longer re ractory, may be conducted appropriately. For example, antiarrhythmic
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Mechanisms of Cardiac Arrhythmias
277
drugs that prolong the action potential duration (described in Chapter 17) tend to produce
unctional conduction blocks. Conversely, when conduction block is caused by a barrier
imposed by brosis or scarring that replaces myocytes, the block is said to be f xed.
Conduction block within the specialized conducting system o the AV node or the His–
Purkinje system prevents normal propagation o the cardiac impulse rom the sinus node to
more distal sites. This atrioventricular block (AV block) removes the normal overdrive suppression that keeps latent pacemakers in the His–Purkinje system in check. Thus, conduction
block usually results in emergence o escape beats or escape rhythms, as the more distal sites
assume the pacemaker unction.
AV block is common and a major reason or implantation o a permanent pacemaker, as
discussed in Chapter 12.
Unidirectional Block and Reentry
A common mechanism by which altered impulse conduction leads to tachyarrhythmias is
termed reentry. During such a rhythm, an electric impulse circulates repeatedly around a
reentry path, recurrently depolarizing a region o cardiac tissue.
During normal cardiac conduction, each electric impulse that originates in the SA node
travels in an orderly, sequential ashion through the rest o the heart, ultimately depolarizing
all the myocardial bers. The re ractory period o each cell prevents immediate reexcitation
rom adjacent depolarized cells, so that the impulse stops when all o the heart muscle has
been excited. However, conduction blocks that prevent rapid depolarization o parts o the
myocardium can create an environment conducive to continued impulse propagation and
reentry, as illustrated in Figure 11-9.
The gure depicts electric activity as it f ows through a branch point anywhere within the
conduction pathways. Panel A shows propagation o a normal action potential. At point x,
the impulse branches into two pathways (α and β) and travels down each into the more
distal conduction tissue. In the normal heart, the α and β pathways have similar conduction
velocities and re ractory periods such that portions o the wave ronts that pass through
them may collide in the distal conduction tissue and extinguish each other, as shown by the
red line.
Panel B shows what happens i conduction is blocked in one limb o the pathways. In
this example, the action potential is obstructed when it encounters the β pathway rom
above and there ore propagates only down the α tract into the distal tissue. As the impulse
continues to spread, it encounters the distal end o the β pathway (at point y). I the tissue
in the distal β tract is also unable to conduct, the impulse simply continues to propagate
into the deeper tissues and reentry does not occur. However, i the impulse at point y is able
to propagate retrogradely (backward) into pathway β, one o the necessary conditions or
reentry is met.
When an action potential can conduct in a retrograde direction in a conduction pathway,
whereas it had been prevented rom doing so in the orward direction, unidirectional block is
said to be present. Unidirectional block tends to occur in regions where the re ractory periods
o adjacent cells are heterogeneous, such that some cells recover be ore others. In addition,
unidirectional block may occur in states o cellular dys unction and in regions where brosis
has altered the myocardial structure.
As shown in panel C o Figure 11-9, i the impulse is able to propagate retrogradely up the
β pathway, it will again arrive at point x. At that time, i the α pathway has not yet repolarized
rom the previous action potential that had occurred moments earlier, that limb is re ractory
to repeat stimulation and the returning impulse simply stops there.
However, panel D illustrates what happens i the velocity o retrograde conduction in the
diseased β path is not normal but slower than normal. In that case, su cient time may elapse
or the α pathway to repolarize be ore the returning impulse reaches point x rom the β limb.
278
Chapter 11
Action
potential
No rmal
x
Dis ta l conduction tis s ue
A
Unidire c tio nal
blo ck
x
y
B
Norma l
re trogra de
conduction
ve locity
S lowe d
re trogra de
conduction
ve locity
x
x
y
y
C
D
FIGURE 11-9. Mechanism of reentry. A. Normal conduction. When an action potential (AP) reaches a branch
in the conduction pathway (point x), the impulse travels down both f bers (α and β) to excite distal conduction
tissue. B. Unidirectional block. Forward passage o the impulse is blocked in the β pathway but proceeds
normally down the α pathway. When the impulse reaches point y, i retrograde conduction o the β pathway is
intact, the AP can enter β rom below and conduct in a retrograde ashion. C. When point x is reached again,
i the α pathway has not had su f cient time to repolarize, then the impulse stops. D. However, i conduction
through the retrograde pathway is su f ciently slow (jagged line), it reaches point x a ter the α pathway has
recovered. In that circumstance, the impulse is able to excite the α pathway again and a reentrant loop is
ormed.
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Mechanisms of Cardiac Arrhythmias
279
Then, the invading impulse is able to stimulate the α pathway once again, and the cycle
repeats itsel . This circular stimulation can continue inde nitely, and each pass o the impulse
through the loop excites cells o the distal conduction tissue, which propagates to the rest o
the myocardium, at an abnormally high rate, resulting in a tachyarrhythmia.
For the mechanism o reentry to occur, the propagating impulse must continuously
encounter excitable tissue. Thus, the time it takes or the impulse to travel around the reentrant loop must be greater than the time required or recovery (the re ractory period) o the
tissue, and this must be true or each point in the circuit. I the conduction time is shorter
than the recovery time, the impulse will encounter re ractory tissue and stop. Because normal conduction velocity in ventricular muscle is approximately 50 cm/ s and the average
e ective re ractory period is about 0.2 seconds, a reentry path circuit would need to be at
least 10 cm long or reentry to occur in a normal ventricle. However, with slower conduction
velocities, a shorter reentry circuit is possible. Most clinical cases o reentry occur within
small regions o tissue because the conduction velocity within the reentrant loop is, in act,
abnormally slow.
In summary, the two critical conditions or reentry are (1) unidirectional block and
(2) slowed conduction through the reentry path. These conditions commonly occur in
regions where brosis has developed, such as in arction scars. In some cases, reentry occurs
over an anatomically xed circuit or path, such as AV reentry using an accessory pathway
(as discussed in the ollowing section). Reentry around distinct anatomic pathways usually appears as a monomorphic tachycardia on the electrocardiogram (ECG); that is, in the
case o ventricular tachycardia, each QRS has the same appearance as the preceding and
subsequent QRS complexes. This is because the reentry path is the same rom beat to beat,
producing a stable, regular tachycardia. This is the most common mechanism o ventricular
tachycardia associated with areas o ventricular scar, as may result rom a prior myocardial
in arction.
Other types o reentry do not require a stable, xed path. For example, one orm can
occur in electrically heterogeneous myocardium, in which waves o reentrant excitation spiral through the tissue, continually changing direction. These so-called “spiral waves” can be
initiated when a wave ront o depolarization encounters a broad region o unctional block,
which could be re ractory rom a preceding wave ront, be poorly excitable tissue due to myocardial ischemia, or be under the inf uence o certain antiarrhythmic medications. Forward
propagation o the wave ront is asymmetrically blocked by this region, as the remainder o
the ront proceeds around the block. As the region repolarizes and becomes excitable again,
parts o the wave ront then spread retrogradely through it and continue in a spiral path ollowing in the wake o the depolarization that had just passed. Unlike an anatomically xed
reentrant tract, the center o the spiral wave can move through the myocardium and even split
into two or more reentry waves. In the ventricles, the resulting tachycardia has a continually
changing QRS appearance, producing polymorphic ventricular tachycardia. I such activation
is rapid and very disorganized, no distinct QRS complexes will be discernable and the rhythm
is ventricular f brillation (as described in Chapter 12).
Accessory Pathways and the Wolff–Parkinson–White Syndrome
The mechanism o reentry is dramatically illustrated by the Wolff–Parkinson–White (WPW)
syndrome. In the normal heart, an impulse generated by the SA node propagates through
atrial tissue to the AV node, where expected slower conduction causes a short delay be ore
continuing on to the ventricles. However, approximately 1 in 1,500 people has the WPW syndrome and is born with an additional connection between an atrium and ventricle. Termed
an accessory pathway (or bypass tract), this connection allows conduction between the atria
and ventricles to bypass the AV node. The most common type o accessory pathway consists
280
Chapter 11
AV node
No rm a l ECG
QRS
SA node
P
Bypa s s tra ct
T
ECG with byp a s s tra c t
Wide ne d
QRS
Right
bundle
bra nch
De lta wave
Le ft bundle
bra nch
S horte ne d P R
FIGURE 11-10. Accessory pathway ( also termed a bypass tract) . Example of an atrioventricular bypass tract
(bundle of Kent), shown schematically, which can conduct impulses from the atrium directly to the ventricles,
bypassing the AV node. The ECG demonstrates a shortened PR interval and a “delta wave” caused by early
excitation of the ventricles via the accessory pathway. ECG, electrocardiogram; SA, sinoatrial.
o microscopic f bers (known as a bundle of Kent) that span the AV groove somewhere along
the mitral or tricuspid annuli, as shown in Figure 11-10.
Because accessory pathway tissue conducts impulses aster than the AV node, stimulation o the ventricles during sinus rhythm begins earlier than normal and the PR interval o
the ECG is there ore shortened (usually < 0.12 seconds, or < 3 small boxes). In this situation,
the ventricles are said to be “preexcited.” However, the accessory pathway connects to ventricular myocardium rather than to the Purkinje system, such that the subsequent spread o
the impulse through the ventricles rom that site is slower than usual. In addition, because
normal conduction over the AV node proceeds concurrently, ventricular depolarization represents a combination o the electric impulse traveling via the accessory tract and that conducted through the normal Purkinje system. As a result, the QRS complex in patients with
WPW is wider than normal and demonstrates an abnormally slurred initial upstroke, known
as a delta wave (Fig. 11-10).
During sinus rhythm, simultaneous conduction through the accessory pathway and AV node
results in this interesting ECG appearance but causes no symptoms. The presence o the abnormal pathway, however, creates an ideal condition or reentry because the re ractory period o the
pathway is usually di erent rom that o the AV node. An appropriately timed abnormal impulse
(e.g., a premature beat) may encounter block in the accessory pathway but conduct through the
AV node or vice versa. I the propagating impulse then f nds that the initially blocked pathway
has recovered (unidirectional block), it can conduct in a retrograde direction up to the atrium
and then down the other pathway back to the ventricles. Thus, a large anatomic loop is established, with the accessory pathway serving as one limb and the normal conduction pathway
through the AV node as the other. The clinical characteristics o the WPW syndrome, including
the types o reentrant tachycardia associated with it, are described in Chapter 12.
The mechanisms o altered impulse ormation and conduction orm the basis o all common arrhythmias, both abnormally slow rhythms (bradyarrhythmias) and abnormally ast
ones (tachyarrhythmias). Table 11-1 lists the underlying mechanisms and examples o their
commonly associated rhythm disturbances.
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Mechanisms o Cardiac Arrhythmias
TABLE 11-1
Mechanisms of Arrhythmia Development
Abnormality
Bradyarrhythmias
Altered impulse formation
• Decreased automaticity
Altered impulse conduction
• Conduction blocks
Tachyarrhythmias
Altered impulse formation
• Enhanced automaticity
Sinus node
AV node
Ectopic ocus
• Triggered activity
Early a terdepolarization
Delayed
a terdepolarization
Altered impulse conduction
• Reentry
Anatomical
Functional
281
Mechanism
Examples
Decreased phase 4 depolarization
(e.g., parasympathetic
stimulation)
Sinus bradycardia
Ischemic, anatomic, or drug-induced
impaired conduction
First-, second-, and third-degree AV
blocks
Increased phase 4 depolarization
(e.g., sympathetic stimulation)
Sinus tachycardia
Acquires phase 4 depolarization
AV junctional tachycardia
Ectopic atrial tachycardia and some
orms o VT
Prolonged action potential duration
Intracellular calcium overload
(e.g., digitalis toxicity)
Torsades de pointes
APBs, VPBs, digitalis-induced
arrhythmias, “idiopathic” VT
Unidirectional block plus slowed
conduction
Atrial utter, AV nodal reentrant
tachycardia, VT related to ventricular
scar tissue
Atrial f brillation, polymorphic VT,
ventricular f brillation
AV, atrioventricular; APB, atrial premature beat; VPB, ventricular premature beat; VT, ventricular tachycardia.
PHYSIOLOGIC BASIS OF ANTIARRHYTHMIC THERAPY
Appropriate treatment o a rhythm disorder depends on its severity and its likely mechanism.
When an arrhythmia produces severe hypotension or cardiac arrest, it must be immediately
terminated to restore e ective cardiac unction. Therapy or termination may include electrical cardioversion (an electric “shock”) or tachycardias, cardiac pacing or bradycardias, or
administration o medications.
Additional therapy to prevent recurrences is guided by the etiology o the rhythm disturbance.
Correctable actors that contribute to abnormal impulse ormation and conduction (such as ischemia or electrolyte abnormalities) should be corrected. I there is a risk o recurrent arrhythmia,
medications that alter automaticity, conduction, and/ or re ractoriness may be administered,
or catheter or surgical ablation o conduction pathways is undertaken to physically disrupt the
region responsible or the arrhythmia. Other advanced options include implantation o a permanent pacemaker or serious bradyarrhythmias or an internal cardioverter–def brillator (ICD) to
automatically terminate malignant tachyarrhythmias should they recur. The ollowing sections
summarize the common therapeutic modalities, and Chapter 12 describes how they are used to
address specif c rhythm disorders.
282
Chapter 11
Bradyarrhythmias
Not all slow heart rhythms require specif c treatment. For those that do, pharmacologic therapy can increase the heart rate acutely, but the e ect is transient. Electronic pacemakers are
used when more sustained therapy is needed.
Pharmacologic Therapy
Pharmacologic therapy o bradyarrhythmias modif es the autonomic input to the heart in one
o two ways:
1. Anticholinergic drugs (i.e., antimuscarinic agents such as atropine). Vagal stimulation
reduces the rate o sinus node depolarization (which slows the heart rate) and decreases
conduction through the AV node, through the release o acetylcholine onto muscarinic
receptors. Anticholinergic drugs competitively bind to muscarinic receptors and thereby
reduce the vagal e ect. This results in an increased heart rate and enhanced AV nodal
conduction.
2. β1-Receptor agonists (e.g., isoproterenol). Mimicking the e ect o endogenous catecholamines, these drugs increase heart rate and speed AV nodal conduction.
Atropine and isoproterenol are administered intravenously. Although these drugs are useul in managing certain slow heart rhythms emergently, it is not practical to continue them
over the long term to treat persistent bradyarrhythmias.
Electronic Pacemakers
Electronic pacemakers apply repeated electric stimulation to the heart to initiate depolarizations at a desired rate, thereby assuming control o the rhythm. Pacemakers may be installed
on a temporary or a permanent basis. Temporary units are used to stabilize patients who are
awaiting implantation o a permanent pacemaker or to treat transient bradyarrhythmias, such
as those caused by reversible drug toxicities.
There are two types o temporary pacemakers. External transthoracic pacemakers deliver
electric pulses to the patient’s chest through large adhesive electrodes placed on the skin. The
advantage o this technique is that it can be applied rapidly. Un ortunately, because the current used must be su f cient to initiate a cardiac depolarization, it stimulates thoracic nerves
and skeletal muscle, which can be quite uncom ortable. There ore, this orm o pacing is
usually used only on an emergency basis until another means o treating the arrhythmia can
be implemented.
The other option or temporary pacing is a transvenous unit. In this case, an electrodetipped catheter is inserted percutaneously into the venous system, passed into the heart, and
connected to an external power source (termed a pulse generator). Electric pulses are applied
directly to the heart through the electrode catheter, which is typically placed in the right ventricle or right atrium. This type o pacing is not pain ul and can be e ective or days. There is,
however, a risk o in ection and/ or thrombosis associated with the catheter.
Permanent pacemakers are more sophisticated than the temporary variety. Various conf gurations can sense and capture the electric activity o the atria and/ or ventricles. One or
more wires (known as leads) with pacing electrodes are passed through an axillary or subclavian vein into the right ventricle or right atrium, or through the coronary sinus into a cardiac
vein (to stimulate the le t ventricle). The pulse generator, similar in size to two silver dollars
stacked on top o one another, is connected to the leads and then implanted under the skin,
typically in the in raclavicular region. The pacemaker battery typically lasts about 10 years.
Modern permanent pacemakers sense cardiac activity and pace only when needed. They
incorporate complex unctions to track the patient’s normal heart rate and can stimulate beats
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automatically in response to activity. They can also record use ul data, such as whether ast
rates have been sensed (that might indicate a tachyarrhythmia), the amount o pacing that
has been required, and other parameters o pacemaker unction. An external radio requency
programming device is used to “interrogate” the pacemaker to obtain the recorded in ormation and to adjust the pacing unctions.
Although the most common indications or permanent pacemakers are bradyarrhythmias,
pacemakers that incorporate a le t ventricular pacing lead are also used to improve cardiac perormance in some patients with heart ailure (cardiac resynchronization therapy—see Chapter 9).
Tachyarrhythmias
The treatment o tachyarrhythmias is directed at (1) protection o the patient rom the consequences o the arrhythmia and (2) the specif c mechanism responsible or the abnormal rhythm. Pharmacologic agents and cardioversion/ def brillation are commonly used
approaches, but innovative electronic devices and transvenous catheter–based techniques
to intentionally damage (ablate) arrhythmia-causing tissue have revolutionized treatment o
these disorders.
Pharmacologic Therapy
Pharmacologic management o tachyarrhythmias is directed against the underlying mechanism (abnormal automaticity, reentrant circuits, or triggered activity). Many antiarrhythmic
drugs are available, and the choice o which to use relies on the cause o the specif c arrhythmia. From consideration o the arrhythmia mechanisms presented in this chapter, the ollowing strategies emerge:
Desired Drug Effects to Eliminate Rhythms Caused by Increased Automaticity:
1. Reduce the slope o phase 4 spontaneous depolarization o the automatic cells
2. Make the diastolic potential more negative (hyperpolarize)
3. Make the threshold potential less negative
Desired Antiarrhythmic Effects to Interrupt Reentrant Circuits:
1. Inhibit conduction in the reentry circuit to the point that conduction ails, thus stopping
the reentry impulse
2. Increase the re ractory period within the reentrant circuit so that a propagating impulse
f nds tissue within the loop unexcitable and the impulse stops
3. Suppress premature beats that can initiate reentry
Desired Drug Effects to Eliminate Triggered Activity:
1. Shorten the action potential duration (to prevent early a terdepolarizations)
2. Correct conditions o calcium overload (to prevent delayed a terdepolarizations)
Drugs used to achieve these goals modulate the action potential through interactions with
ion channels, sur ace receptors, and transport pumps. Many drugs have multiple e ects and
may attack arrhythmias through more than one mechanism. The commonly used antiarrhythmic drugs and their actions are described in Chapter 17.
It is important to recognize that although these drugs suppress arrhythmias, they also
have the potential to aggravate or provoke certain rhythm disturbances. This undesired consequence is re erred to as proarrhythmia and is a major limitation o contemporary antiarrhythmic drug therapy. For example, antiarrhythmic agents that act therapeutically to prolong
the action potential duration can, as an undesired e ect, cause early a terdepolarizations,
the mechanism underlying the polymorphic ventricular tachycardia torsades de pointes (see
284
Chapter 11
Chapter 12). In addition, most agents used to treat tachyarrhythmias have the potential to
aggravate bradyarrhythmias, and all antiarrhythmics have potentially toxic noncardiac side
e ects. These shortcomings have led to an increased reliance on nonpharmacologic treatment
options, as described in the ollowing sections.
Vagotonic Maneuvers
Many tachycardias involve transmission o impulses through the AV node, a structure that is
sensitive to vagal modulation. Vagal tone can be transiently increased by a number o bedside
maneuvers, and per orming these may slow conduction, which terminates some reentrant
tachyarrhythmias. For example, carotid sinus massage is per ormed by rubbing rmly or
a ew seconds over the carotid sinus, located at the bi urcation o the internal and external
carotid arteries on either side o the neck. This maneuver stimulates the baroreceptor ref ex
(see Chapter 13), which elicits the desired increase in vagal tone and withdrawal o sympathetic tone. This maneuver should be per ormed on only one carotid sinus at a time (to prevent inter erence with brain per usion) and is best avoided in patients with known advanced
atherosclerosis involving the carotid arteries.
Electric Cardioversion and Def brillation
Cardioversion and de brillation involve the application o an electric shock to terminate a
tachycardia. A shock with su cient energy depolarizes the bulk o excitable myocardial tissue, interrupts reentrant circuits, establishes electric homogeneity, and allows the sinus node
(the site o astest spontaneous discharge) to regain pacemaker control. Tachyarrhythmias
that are caused by reentry can usually be terminated by this procedure, whereas arrhythmias
due to abnormal automaticity may simply persist.
External cardioversion is used to terminate supraventricular tachycardias or organized
ventricular tachycardias. It is per ormed by brief y sedating the patient and then placing
two large electrode paddles (or adhesive electrodes) against the chest on either side o the
heart. The electric discharge is electronically synchronized to occur at the time o a QRS complex (i.e., when ventricular depolarization occurs). This prevents the possibility o discharge
during the T wave, when a shock could induce reentry (leading to ventricular brillation)
because regions o myocardium are in di erent phases o depolarization and recovery.
External def brillation is per ormed to terminate ventricular brillation, employing the
same equipment as that used or cardioversion. However, during brillation, there is no organized QRS complex on which to synchronize the electric discharge, so it is delivered using the
“asynchronous” mode o the device.
Implantable Cardioverter–Def brillators
ICDs automatically terminate dangerous ventricular arrhythmias using internal cardioversion/
de brillation or by way o a special type o arti cial pacing. These devices are implanted, in
a manner similar to that o permanent pacemakers, in patients at high risk o sudden cardiac
death rom ventricular arrhythmias. The device continuously monitors cardiac activity, and i
the heart rate exceeds a certain programmable threshold or a speci ed time, the ICD delivers
an appropriate intervention, such as an electric shock. Internal cardioversion or de brillation
requires substantially less energy than does external de brillation but is still pain ul i the
patient is conscious.
The majority o monomorphic ventricular tachycardias can be terminated by an ICD with
a rapid burst o electric impulses, termed antitachycardia pacing (ATP), rather than a shock.
The goal is to arti cially pace the heart at a rate aster than the tachycardia to prematurely
depolarize a portion o a reentrant circuit, thereby rendering it re ractory to urther immediate
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Mechanisms of Cardiac Arrhythmias
285
stimulation. Consequently, when a reentrant impulse returns to the zone that has already
been depolarized by the device, it encounters unexcitable tissue, it cannot propagate urther,
and the circuit is broken. An advantage o the ATP technique is that, unlike internal cardioversion, it is painless. However, ATP is not e ective or terminating ventricular f brillation, a
situation in which the device is programmed to deliver an electric shock instead.
Catheter Ablation
I an arrhythmia originates rom a distinct anatomical reentry circuit or an automatic ocus,
electrophysiologic mapping techniques can be used to localize the region o myocardium or
conduction tissue responsible or the disturbance. It is then o ten possible to ablate the site
via a catheter that applies radio requency current to heat and destroy the tissue. Such procedures have revolutionized the management o patients with many types o tachycardias,
because they o ten o er a permanent therapeutic solution that spares patients rom prolonged
antiarrhythmic drug therapy. Additionally, or patients with ICDs and recurrent ventricular
tachycardias causing def brillator shocks, ablation is o ten e ective in reducing the requency
o episodes.
SUMMARY
• Arrhythmias result rom disorders o impulse ormation, impulse conduction, or both.
• Bradyarrhythmias (abnormally slow heart rhythms) develop because o decreased impulse
ormation (e.g., sinus bradycardia) or decreased impulse conduction (e.g., AV nodal conduction blocks).
• Tachyarrhythmias (abnormally ast rhythms) result rom increased automaticity (o the SA
node, latent pacemakers, or abnormal myocardial sites), triggered activity, or reentry.
• The two critical conditions or reentry are (1) unidirectional block and (2) slowed conduction
through the reentry path; these conditions commonly occur in regions where f brosis has
developed, such as in arction scars.
• Bradyarrhythmias are usually treated acutely with drugs that accelerate the rate o sinus
node discharge and enhance AV nodal conduction (atropine, isoproterenol) or with temporary electronic pacemakers.
• Permanent electronic pacemakers are implanted when more sustained therapy or
bradyarrhythmias is needed.
• Pharmacologic therapy or tachyarrhythmias is directed at the mechanism responsible or the
rhythm disturbance.
• For re ractory tachyarrhythmias, or in emergency situations, electrical cardioversion or
def brillation is utilized.
• Catheter-based ablative techniques are use ul or long-term control o certain
tachyarrhythmias.
• ICDs are li esaving devices implanted in patients at high risk o sudden cardiac death.
• For patients with ICDs and recurrent ventricular tachycardias causing def brillator shocks,
ablation techniques are o ten e ective in reducing the requency o episodes.
Chapter 12 describes the diagnosis and management o the most common arrhythmias.
Chapter 17 describes commonly used antiarrhythmic drugs.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Ranliang Hu, MD; Hillary K. Rolls, MD;
Jenni er E. Ho, MD; Mark S. Sabatine, MD; Wendy Armstrong, MD; Nicholas Boulis, MD; Elliott
M. Antman, MD; and Leonard I. Ganz, MD.
286
Chapter 11
Ad d i t i o n a l Rea d i n g
Chen PS, Joung B, Shinohara T, et al. The initiation of the
heart beat. Circ J. 2010;74:221–225.
DiFrancesco D. The role of the funny current in pacemaker
activity. Circ Res. 2010;106:434–446.
Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol.
2009;2:185–194.
Katritsis DG, Camm AJ. Atrioventricular nodal reentrant tachycardia. Circulation. 2010;122:831–840.
Spector P. Principles of cardiac electric propagation and their
implications for re-entrant arrhythmias. Circ Arrhythm
Electrophysiol. 2013;6:655–661.
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Clinical Aspects of
Cardiac Arrhythmias
12
Morga n J. Prust
Willia m G. Stevenson
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Bradyarrhythmias
Sinoatrial Node
Escape Rhythms
Atrioventricular Conduction
System
Tachyarrhythmias
Supraventricular Arrhythmias
Ventricular Arrhythmias
C
hapter 11 presented the mechanisms by which abnormal
heart rhythms develop. This chapter describes how to recognize and treat specif c arrhythmias. Table 12-1 categorizes
the common rhythm disorders considered in this chapter.
There are f ve basic questions to consider when con ronted
with a patient with an abnormal heart rhythm, as detailed in
the sections that ollow:
1. Identif cation: What is arrhythmia?
2. Pathogenesis: What is the underlying mechanism?
3. Precipitating actors: What conditions provoke it?
4. Clinical presentation: What symptoms and signs accompany
the arrhythmia?
5. Treatment: What to do about it?
BRADYARRHYTHMIAS
The normal resting heart rate, resulting rom repetitive depolarization o the sinus node, ranges rom 60 to 100 bpm.
Bradyarrhythmias are rhythms in which the heart rate is less
than 60 bpm. They arise rom disorders o impulse ormation
or impaired impulse conduction, as described in Chapter 11.
Sinoatrial Node
Sinus Bradycardia
Sinus bradycardia (Fig. 12-1) is a slowing o the normal
heart rhythm, as a result o decreased f ring o the sinoatrial
(SA) node, to a rate less than 60 bpm. Sinus bradycardia at
rest or during sleep is normal and a benign f nding in many
people. Conversely, pathologic sinus bradycardia can result
rom either intrinsic SA node disease or extrinsic actors
that a ect the node. Depressed intrinsic automaticity can
be caused by aging or any disease process that a ects the
287
288
Chapter 12
TABLE 12-1
Common Arrhythmias
Location
Bradyarrhythmias
Tachyarrhythmias
SA node
Sinus bradycardia
Sick sinus syndrome
Sinus tachycardia
Atria
AV node
Ventricles
Conduction blocks
Junctional escape rhythm
Ventricular escape rhythm
Atrial premature beats
Atrial f utter
Atrial brillation
Paroxysmal supraventricular tachycardias
Focal atrial tachycardia
Multi ocal atrial tachycardia
Paroxysmal reentrant tachycardias
(AV or AV nodal)
Ventricular premature beats
Ventricular tachycardia
Torsades de pointes
Ventricular brillation
AV, atrioventricular; SA, sinoatrial.
atrium, including ischemic heart disease or cardiomyopathy. Extrinsic actors that suppress
SA nodal activity include medications (e.g., β-blockers and certain calcium channel blockers)
and metabolic causes (e.g., hypothyroidism).
Trained athletes o ten have elevated vagal tone, which results in physiologic and
asymptomatic resting sinus bradycardia. Transient periods o high vagal tone can also
occur in individuals as a ref ex response to pain or ear, resulting in inappropriate sinus
bradycardia.
Mild sinus bradycardia is usually asymptomatic and does not require treatment.
However, a pronounced reduction o the heart rate can produce a all in cardiac output
with atigue, light-headedness, con usion, or syncope. In such cases, any extrinsic provocative actors should be corrected, and speci c therapy, as described in the next section,
may be needed.
Sick Sinus Syndrome
Intrinsic SA node dys unction that causes periods o inappropriate bradycardia is known as
sick sinus syndrome (SSS). This condition o ten produces symptoms o dizziness, con usion,
or syncope. Patients with this syndrome (or any cause o symptomatic sinus bradycardia) can
be treated acutely with intravenous anticholinergic drugs (e.g., atropine) or β-adrenergic agents
(e.g., isoproterenol), which transiently accelerate the heart rate. I the problem is chronic and not
corrected by removal o aggravating actors, placement o a permanent pacemaker is required.
FIGURE 12-1. Sinus bradycardia. The P wave and QRS complexes are normal, but the rate is less than 60 bpm.
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289
FIGURE 12-2. Bradycardia–tachycardia syndrome. A brief irregular tachycardia is followed by slow sinus
node discharge.
SSS is common in elderly patients, who are also susceptible to supraventricular tachycardias (SVTs), most commonly atrial brillation (AF). This combination o slow and ast dysrhythmias is known as the bradycardia–tachycardia syndrome (Fig. 12-2) and is thought
to result rom atrial brosis that impairs unction o the SA node and predisposes to AF and
atrial f utter. During the tachyarrhythmia, overdrive suppression o the SA node occurs (as
described in Chapter 11), and when the tachycardia terminates, a period o pro ound sinus
bradycardia may ensue. Treatment generally requires the combination o antiarrhythmic
drug therapy to suppress the tachyarrhythmias plus a permanent pacemaker to prevent
bradycardia.
Escape Rhythms
Cells in the atrioventricular (AV) node and His–Purkinje system are capable o automaticity
but typically have slower ring rates than do those in the sinus node and are there ore suppressed during normal sinus rhythm. However, i SA node activity becomes impaired or i
there is conduction block o the impulse rom the SA node, escape rhythms can emerge rom
the more distal latent pacemakers (Fig. 12-3).
Junctional escape beats arise rom the AV node or proximal bundle o His. They are
characterized by a normal, narrow QRS complex, and when they occur in sequence
(termed a junctional escape rhythm), appear at a rate o 40 to 60 bpm. The QRS complexes are not preceded by normal P waves because the impulse originates below the
A
B
FIGURE 12-3 Escape rhythms. No P waves are evident. A. Junctional escape rhythm with normal-width QRS
complexes. B. Wide QRS complexes typical of a ventricular escape rhythm.
290
Chapter 12
atria. However, retrogra de P waves may be observed as an impulse propagates rom the
more distal pacemaker backward to the atrium. Retrograde P waves typically follow the
QRS complex and are abnormally in verted (negative def ection on the electrocardiogram
[ECG]) in limb leads II, III, and aVF, indicating activation o the atria rom the in erior
direction.
Ventricular escape rhythms are characterized by even slower rates (30 to 40 bpm) and
abnormally widened QRS complexes. The complexes are wide because the ventricles are
not depolarized by the normal rapid simultaneous conduction over the right and le t bundle
branches but rather rom a more distal point in the conduction system. The morphology that
the QRS shows depends on the site o origin o the escape rhythm. For example, an escape
rhythm originating rom the le t bundle branch will cause a right bundle branch block QRS
pattern, because the impulse depolarizes the le t ventricle rst and then spreads more slowly
through the right ventricle (RV). Conversely, an escape rhythm originating in the right bundle branch causes the QRS to appear with a le t bundle branch block con guration. Escape
rhythms that originate more distally, in the ventricular myocardium itsel , are characterized
by even wider QRS complexes because such impulses are conducted outside the rapidly
propagating Purkinje bers.
Junctional and ventricular escape rhythms are protective backup mechanisms that maintain a heartbeat and cardiac output when the sinus node or normal AV conduction ails. The
clinical ndings and treatment o bradycardia associated with escape rhythms are identical to
those o SSS described earlier.
Atrioventricular Conduction System
The AV conduction system includes the AV node, bundle o His, and the le t and right bundle
branches. Impaired conduction between the atria and ventricles can result in three degrees
(types) o AV conduction block.
First-Degree AV Block
First-degree AV block, shown in Figure 12-4, indicates prolongation o the normal delay
between atrial and ventricular depolarization, such that the PR interval is lengthened (> 0.2
seconds, which is > 5 small boxes on the ECG). In this situation, the 1:1 relationship between
P waves and QRS complexes is preserved. The impairment o conduction is usually within
the AV node itsel and can be caused by a transient reversible inf uence or a structural de ect.
Reversible causes include heightened vagal tone, transient AV nodal ischemia, and drugs
that depress conduction through the AV node, including β-blockers, certain calcium channel
antagonists, digitalis, and other antiarrhythmic medications. Structural causes o rst-degree
AV block include myocardial in arction and chronic degenerative diseases o the conduction
system, which commonly occur with aging.
P
P
P
FIGURE 12-4. First-degree AV block. The PR interval is prolonged.
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P
P
Clinical Aspects of Cardiac Arrhythmias
P
P
P
P
P
291
P
FIGURE 12-5. Second-degree AV block: type I ( Wenckebach) . The P-wave rate is constant, but the PR
interval progressively lengthens until a QRS is completely blocked (after the fourth P wave).
Generally, f rst-degree AV block is a benign, asymptomatic condition that does not
require treatment. However, it can indicate disease in the AV node associated with susceptibility to higher degrees o AV block i drugs are administered that urther impair AV
conduction or i the conduction disease progresses.
Second-Degree AV Block
Second-degree AV block is characterized by in termitten t fa ilure o AV conduction, resulting
in some P waves that are not ollowed by a QRS complex. There are two orms o seconddegree AV block. In type I block (also termed Wenckebach block), shown in Figure 12-5,
the degree o AV delay gradually increases with each beat until an impulse is completely
blocked, such that there is no QRS a ter the P wave or a single beat. There ore, the ECG
shows a progressive increase in the PR interval rom one beat to the next until a single QRS
complex is absent, a ter which the PR interval shortens to its initial length, and the cycle
starts anew. Type I block almost always results rom impaired conduction in the AV node
(rather than more distally in the conduction system). It is usually benign and may be seen
in children, trained athletes, and people with high vagal tone, particularly during sleep. It
may also occur during an acute myocardial in arction because o increased vagal tone or
ischemia o the AV node, but the block is usually temporary. Treatment o type I block is
typically not necessary, but in symptomatic cases, administration o intravenous atropine
or isoproterenol usually improves AV conduction transiently. Occasionally, placement o a
permanent pacemaker is required or symptomatic block that does not resolve spontaneously or persists despite the correction o aggravating actors.
In contrast, type II second-degree AV block is a more dangerous condition. It is characterized by the sudden intermittent loss o AV conduction, without preceding gradual lengthening
o the PR interval (Fig. 12-6). The block may persist or two or more beats (i.e., two sequential P waves not ollowed by QRS complexes), in which case it is known as high-grade AV
P
P
P
P
P
FIGURE 12-6. Second-degree AV block: type II. A QRS complex is blocked (after the fourth P wave) without
gradual lengthening of the preceding PR intervals. While the QRS width in this example is normal, it is often
widened in patients with type II block.
292
Chapter 12
P
P
P
P
P
P
FIGURE 12-7. High-grade AV block. Sequential QRS complexes are blocked (after the second and third
P waves).
block (Fig. 12-7). Type II block is usually caused by conduction block distal to the AV node
(in the bundle of His or more distally in the Purkinje system), and the QRS pattern often is
widened in a pattern of right or left bundle branch block. This type of block may arise from
extensive myocardial infarction involving the septum or from chronic degeneration of the
His–Purkinje system. It usually indicates severe disease and may progress to complete heart
block without warning; therefore, a pacemaker is usually warranted, even in asymptomatic
patients.
Third-Degree AV Block
Third-degree AV block, also termed complete heart block (Fig. 12-8), is present when
there is complete failure of conduction between the atria and ventricles. In adults, the
most common causes are acute myocardial infarction and chronic degeneration of the
conduction pathways with advanced age. Third-degree AV block electrically disconnects
the atria and ventricles; there is no relationship between the P waves and QRS complexes
because the atria depolarize in response to SA node activity, while a more distal escape
rhythm drives the ventricles independently. Thus, the P waves “march out” at a rate that
is not related to the intervals at which QRS complexes appear. Depending on the site of
the escape rhythm, the QRS complexes may be of normal width and occur at 40 to 60 bpm
(originating from the AV node) or may be widened and occur at slower rates (originating
from the His–Purkinje system). As a result of the slow rate, patients frequently experience light-headedness or syncope. Permanent pacemaker implantation is almost always
necessary.
The term AV dissociation is a general description that refers to any situation in which the
atria and ventricles beat independently, without any direct relationship between P waves and
QRS complexes. Third-degree AV block is one example of AV dissociation.
P
P
P
P
P
P
P
P
FIGURE 12-8. Third-degree AV block. The P wave and QRS rhythms are independent of one another. The QRS
complexes are widened as they originate within the distal ventricular conduction system, not at the bundle of
His. The second and fourth P waves are superimposed on normal T waves.
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TACHYARRHYTHMIAS
When the heart rate is greater than 100 bpm for three beats or more, a tachyarrhythmia is
present. Tachyarrhythmias result from one of the three mechanisms described in Chapter 11:
enhanced automaticity, reentry, or triggered activity. Tachyarrhythmias are categorized into
those that arise above the ventricles (supraventricular) and those that arise within the ventricles.
Supraventricular Arrhythmias
Figure 12-9 presents a schema to help organize the common supraventricular tachyarrhythmias presented in this section.
Sinus Tachycardia
Sinus tachycardia is characterized by an SA node discharge rate greater than 100 bpm (typically 100 to 180 bpm) with normal P waves and QRS complexes (Fig. 12-10). This rhythm
most often results from increased sympathetic and/ or decreased vagal tone. Sinus tachycardia is an appropriate physiologic response to exercise. However, it may also result from
sympathetic stimulation in pathologic conditions, including fever, hypoxemia, hyperthyroidism, hypovolemia, and anemia. In disease states, sinus tachycardia is usually a sign of the
severity of the primary pathophysiologic process, and treatment should be directed at the
underlying cause.
S uprave ntricula r
Ta chya rrhythmia s
Re gula r rhythm
(cons ta nt P –P inte rva l)
Irre gula r rhythm
≥ 3 P wave
s ha p e s
No d is tinc t
P wave s
Multifo c al atrial
tachyc ardia
Atrial
fibrillatio n
Atria l
ra te (b p m)
P-wave
morp hology
Re s p ons e to ca rotid
s inus ma s s a g e
S inus tachyc ardia
100–180
Norma l
Atria l ra te
may s low
Re e ntrant SVTs
(e .g ., AVNRT, ARVT)
140–250
Hidde n or
re trogra de
May a bruptly
te rmina te
Fo c al atrial
tac hyc ardia
130–250
Diffe rs from
norma l P
AV block may
incre a s e ; doe s n’t
us ua lly reve rt
Atrial flutte r
180–350
“Saw-toothe d”
AV block may
incre a s e
FIGURE 12-9. Differentiation of common supraventricular tachyarrhythmias.
294
Chapter 12
FIGURE 12-10. Sinus tachycardia. The P wave and QRS complexes are normal, but the rate is greater than
100 bpm.
Atrial Premature Beats
Atrial premature beats (APBs) are common in healthy as well as diseased hearts (Fig. 12-11).
They originate rom automaticity or reentry in an atrial ocus outside the SA node and are
o ten exacerbated by sympathetic stimulation. APBs are usually asymptomatic but may cause
palpitations. On the ECG, an APB appears as an earlier-than-expected P wave with an abnormal shape (the impulse does not arise rom the SA node, resulting in an abnormal sequence
o conduction through the atria). The QRS complex that ollows the P wave is usually normal,
resembling the QRS during sinus rhythm, because ventricular conduction is not impaired.
However, i the abnormal atrial ocus res very soon a ter the previous beat, the impulse may
encounter an AV node that is still re ractory to excitation, resulting in a blocked impulse that
does not conduct to the ventricles. In that case, the premature P wave is not ollowed by a
QRS complex and is termed a blocked APB. Similarly, i the ectopic ocus res just a bit later
in diastole, it may conduct through the AV node but encounter portions o the His–Purkinje
system (typically the right or le t bundle branch) that are still re ractory. As a result o ailure
o conduction in one o the bundle branches, the impulse is conducted through a portion o
the ventricles more slowly than normal, producing QRS complexes that are abnormally wide
(termed an APB with aberrant conduction).
APBs require treatment only i they are symptomatic. Because ca eine, alcohol, and adrenergic stimulation (e.g., emotional stress) can all predispose to APBs, it is important to address
these actors. β-Blockers are the initial pre erred pharmacologic treatment i needed.
Atrial Flutter
Atrial f utter is characterized by rapid, regular atrial activity at a rate o 180 to 350 bpm
(Fig. 12-12). Many o these ast impulses reach the AV node during its re ractory period and
do not conduct to the ventricles, resulting in a slower ventricular rate, o ten an even raction o the atrial rate. Thus, i the atrial rate is 300 bpm and 2:1 block occurs at the AV node
(i.e., every other atrial impulse nds the AV node re ractory), the ventricular rate is 150 bpm.
Because vagal maneuvers (e.g., carotid sinus massage) decrease AV nodal conduction, they
increase the degree o block, temporarily slowing the ventricular rate, which allows better
visualization o the underlying atrial activity. In general, atrial f utter is caused by reentry
over a large anatomically xed circuit. In the common orm o atrial f utter, this circuit is the
APB
FIGURE 12-11. Atrial premature beat (APB). The P wave occurs earlier than expected, and its shape is abnormal.
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FIGURE 12-12. Atrial utter is typif ed by rapid “saw-toothed” atrial activity ( arrows) .
atrial tissue along the tricuspid valve annulus: the circulating depolarization wave propagates
up the interatrial septum, across the roo and down the ree wall o the right atrium, and
nally along the f oor o the right atrium between the tricuspid valve annulus and in erior
vena cava. Because large parts o the atrium are depolarized throughout the cycle, P waves
o ten have a sinusoidal or “sawtooth” appearance. Large f utter circuits can occur in other
parts o the right or le t atrium as well, usually associated with areas o atrial scarring rom
disease, prior heart surgery, or ablation procedures.
Atrial f utter generally occurs in patients with preexisting heart disease. It may be paroxysmal
and transient, persistent (lasting or days or weeks), or permanent. Symptoms o atrial f utter depend on the accompanying ventricular rate. I the rate is less than 100 bpm, the patient
may be asymptomatic. Conversely, aster rates o ten cause palpitations, dyspnea, or weakness.
Paradoxically, antiarrhythmic medications that reduce the rate o atrial f utter by slowing conduction in the atrium may make the rhythm more dangerous by allowing the AV node more
time to recover between impulses. In this situation, the AV node may begin to conduct in a 1:1
ashion, producing very rapid ventricular rates. For example, a patient with atrial f utter at a rate
o 280 bpm and 2:1 conduction block at the AV node would have a ventricular rate o 140 bpm.
I the atrial rate then slows to 220 bpm, the AV node may be able to recover su ciently between
depolarizations to conduct every atrial impulse, causing the ventricular rate to accelerate to 220
bpm. In patients with limited cardiac reserve, this acceleration may result in a pro ound reduction o cardiac output and hypotension. Atrial f utter also predisposes to atrial thrombus ormation, and anticoagulation therapy is o ten appropriate, as described below or atrial brillation.
Several approaches or the conversion o atrial f utter to sinus rhythm are available:
1. For symptomatic patients with recent-onset atrial f utter, the most expeditious therapy
is electrical cardioversion to restore sinus rhythm. This technique is also used to revert
chronic atrial f utter that has not responded to other approaches.
2. Flutter can be terminated by rapid atrial stimulation (burst pacing) using a temporary or
permanent pacemaker (see Chapter 11). This procedure can be used when temporary atrial
pacing wires are already present, as in the days ollowing cardiac surgery. In addition,
certain types o permanent pacemakers and implanted de brillators can be programmed to
per orm burst pacing automatically when atrial f utter occurs.
3. Patients without an immediate need or cardioversion can begin pharmacologic therapy.
First, the ventricular rate is slowed by drugs that increase AV block: β-blockers, certain calcium channel blockers (e.g., verapamil, diltiazem), or digoxin. Once the rate is e ectively
slowed, attempts can be made to restore sinus rhythm using antiarrhythmic drugs that slow
conduction or prolong the re ractory period o the atrial myocardium (usually class IC or
class III agents; see Chapter 17). Should these drugs ail to convert the rhythm, electrical
cardioversion can be undertaken. Once sinus rhythm has been restored, antiarrhythmic
drugs may be administered chronically to prevent recurrences.
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Chapter 12
4. When chronic therapy is required to prevent recurrences, catheter ablation is o ten a better alternative than pharmacologic approaches. In this method, an electrode catheter is
inserted into the emoral vein, passed via the in erior vena cava to the right atrium, and
used to localize and cauterize (ablate) part o the reentrant loop to permanently interrupt
the f utter circuit.
Atrial Fibrillation
AF is a chaotic rhythm with an atrial rate so ast (350 to 600 discharges/ min) that distinct P
waves are not discernible on the ECG (Fig. 12-13). As with atrial f utter, many o the atrial
impulses encounter re ractory tissue at the AV node, allowing only some o the depolarizations to be conducted to the ventricles in a very irregular ashion (indicated by a characteristic
“irregularly irregular” rhythm). The average ventricular rate in untreated AF is approximately
140 to 160 bpm. Because discrete P waves are not visible on the ECG, the baseline shows
low-amplitude undulations punctuated by QRS complexes and T waves.
The mechanism o AF likely involves multiple wandering reentrant circuits within the
atria, and in some patients, the rhythm repetitively shi ts between brillation and atrial f utter. When brillation is paroxysmal (i.e., sudden, unpredictable episodes), it is o ten initiated
by rapid ring o oci in sleeves o atrial muscle that extend into the pulmonary veins. To sustain AF, a minimum number o reentrant circuits is needed, and an enlarged atrium increases
the potential or this to occur. Thus, AF is o ten associated with right or le t atrial enlargement. Accordingly, diseases that increase atrial pressure and size promote AF, including heart
ailure, hypertension, coronary artery disease, and pulmonary disease. Thyrotoxicosis and
alcohol consumption can also precipitate AF in some individuals. In addition, AF is a common rhythm disturbance in the elderly.
As with atrial f utter, when the ventricular rate is less than 100 beats/ min, AF may be
asymptomatic. When the rate is aster, as may occur be ore treatment is instituted and when
AV nodal conduction is acilitated by elevated sympathetic tone during illness, the rapid
ventricular rate may compromise cardiac output, resulting in hypotension and pulmonary
congestion (especially in patients with a hypertrophied or “sti ” le t ventricle in whom the
loss o normal atrial contraction can signi cantly reduce le t ventricular lling and stroke
volume). AF is also an important cause o stroke. The absence o organized atrial contraction promotes blood stasis in the atria, increasing the risk o thrombus ormation in the le t
atrial appendage (LAA), which can embolize to the cerebral circulation and other systemic
sites. Thus, treatment o AF is directed at three aspects o the arrhythmia: (1) ventricular rate
control, (2) assessment o the need or anticoagulation to prevent thromboembolism, and (3)
consideration o methods to restore sinus rhythm.
Antiarrhythmic drug treatment o AF is similar to that o atrial f utter. β-Blockers or certain
Ca + + channel antagonists (diltiazem, verapamil) are administered to promote block at the AV
node so as to reduce the ventricular rate. Digitalis is less e ective or this purpose, although
it may be use ul in patients with accompanying impairment o ventricular contractile unction. For those who remain symptomatic despite adequate rate control, conversion to sinus
rhythm is usually attempted, as described in the next paragraph. AF that has been present
FIGURE 12-13. Atrial f brillation is characterized by chaotic atrial activity without organized P waves
and by irregularity o the ventricular ( QRS) rate.
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or more than 48 hours may predispose to atrial thrombus ormation, and systemic anticoagulation ( or at least 3 weeks) is usually warranted prior to cardioversion to reduce the risk
o thromboembolism. Alternatively, a transesophageal echocardiogram can be per ormed to
evaluate or the presence o thrombus; i none is ound, cardioversion may proceed directly,
with minimum thromboembolic risk, provided that anticoagulation is instituted or several
weeks therea ter (since recovery o normal atrial contraction may be delayed or a period o
time ollowing cardioversion). Anticoagulant drugs are described in Chapter 17.
Cardioversion to sinus rhythm can be attempted chemically by administration o class IC,
IA, or III antiarrhythmic drugs (see Chapter 17 or descriptions o these classes). Alternatively,
electrical cardioversion can be undertaken. Following success ul conversion to sinus rhythm,
antiarrhythmic drugs are o ten continued in an attempt to prevent recurrences. Note that
these drugs have the capacity to cause serious, sometimes lethal, side e ects (see Chapter
17). Thus, in patients with asymptomatic AF, it is o ten appropriate to simply control the ventricular rate and continue anticoagulation therapy chronically, rather than to pursue cardioversion. Such an approach is supported by clinical trials o AF that have assessed long-term
clinical outcomes.
Because the e f cacies and toxicities o antiarrhythmic drugs have been disappointing,
nonpharmacologic options or the management o AF have been devised. For example, the
surgical maze procedure places multiple incisions in the le t and right atria to prevent the ormation o reentry circuits and is sometimes per ormed in patients undergoing cardiac surgery
or coronary artery or valve disease who also have AF. A less invasive approach is percutaneous catheter ablation. In this approach, areas o the le t atrium around the pulmonary veins
are cauterized to interrupt potential reentry circuits and oci that initiate AF. Doing so requires
extensive catheter manipulation and ablation in the le t atrium, and risks o the procedure
includes stroke rom systemic thromboembolism and cardiac per oration that can cause pericardial tamponade. Thus, catheter ablation or AF is usually reserved or patients who remain
symptomatic despite pharmacologic approaches. When sinus rhythm cannot be maintained
and the heart rate cannot be controlled adequately with medications, catheter ablation of the
AV node is another available procedure. This method intentionally creates complete heart
block as a means to permanently slow the ventricular rate. Permanent ventricular pacemaker
placement is then also required to generate an adequate ventricular rate.
Left atrial appendage (LAA) ligation or occlusion, which can be per ormed through open
surgical or percutaneous techniques, excludes the LAA rom the circulation, removing it as
a source o thrombi that can embolize to cause strokes. The advantages and risks o such
approaches to prevent stroke in AF are still being def ned.
Paroxysmal Supraventricular Tachycardias
Paroxysmal supraventricular tachycardias (PSVTs) are mani ested by (1) sudden onset and termination, (2) atrial rates between 140 and 250 bpm, and (3) narrow (normal) QRS complexes
(Fig. 12-14), unless aberrant conduction is present, as summarized later. The mechanism o
FIGURE 12-14. Paroxysmal supraventricular tachycardia caused by AV nodal reentry. Retrograde P waves in
this example occur simultaneously with, and are “hidden” in, the QRS complexes.
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Chapter 12
PSVTs is most o ten reentry involving the AV node, atrium, or an accessory pathway between
an atrium and a ventricle. Enhanced automaticity and triggered activity in the atrium or AV
node are less common causes.
AV Nodal Reentrant Tachycardia
Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common orm o PSVT in
adults. In the normal heart, the AV node is a lobulated structure that consists o a compact
portion and several atrial extensions. The latter constitute two (or more) potential pathways
or conduction through the AV node (Fig. 12-15). In some people, these extensions have di erent conduction times, providing both slow- and ast-conducting pathways. The ast pathway is characterized by a rapid conduction velocity, whereas the slow pathway demonstrates
slower conduction but typically has a shorter re ractory period than does the ast pathway.
Thus, although the ast pathway conducts rapidly, it takes longer to recover between impulses
compared with the slow pathway. Normally, a stimulus arriving at the AV node travels down
both pathways, but the impulse traveling down the ast pathway reaches the bundle o His
rst. By the time the impulse traversing the slow pathway reaches the bundle o His, it
encounters re ractory tissue and is extinguished. Thus, under normal conditions, only the ast
pathway impulse makes its way orward to the ventricles (see Fig. 12-15A).
In contrast, consider what happens when an APB spontaneously occurs (Fig. 12-15B).
Because the re ractory period o the ast pathway is relatively long, an APB would nd that
pathway unexcitable and unable to conduct the impulse. However, the impulse is able to
conduct over the slow pathway (which is excitable because it has a shorter re ractory period
than does the ast pathway and has already repolarized when the APB arrives). By the time
this impulse travels down the slowly conducting pathway and reaches the compact portion
o the AV node, the distal end o the ast pathway may have had time to repolarize, and the
impulse is able to propagate both distally (to the bundle o His and ventricles) and backward
to the atria, up the ast pathway in a retrograde direction. On reaching the atria, the impulse
can then circulate back down the slow pathway, completing the reentrant loop and initiating
tachycardia as this sequence repeats. Thus, the undamental conditions or reentry in AVNRT
in this example are transient unidirectional block in the ast pathway (an APB encountering
re ractory tissue) and relatively slow conduction through the other pathway.
The ECG in AVNRT shows a regular tachycardia with normal-width QRS complexes. P
waves may not be apparent, because retrograde atrial depolarization typically occurs simultaneously with ventricular depolarization (see Fig. 12-14). Thus, the retrograde P wave and
QRS are inscribed at the same time, and the P is typically “hidden” in the QRS complex. When
P waves are visible, they are superimposed on the terminal portion o the QRS complex and
inverted (negative def ection) in limb leads II, III, and aVF, because o the caudocranial direction o atrial activation.
Rarely, the reentrant loop revolves in the reverse direction, with anterograde conduction
down the ast pathway and retrograde conduction up the slow pathway. This is known as
uncommon AVNRT and, unlike the more common rhythm, typically results in clearly visible
retrograde P waves ollowing the QRS complex on the ECG.
AVNRT o ten presents in teenagers or young adults. It is usually well tolerated but causes
palpitations that many patients nd rightening, and rapid tachycardias can cause lightheadedness or shortness o breath. In elderly patients or those with underlying heart disease,
more severe symptoms may result, such as syncope, angina, or pulmonary edema.
Acute treatment o AVNRT is aimed at terminating reentry by impairing conduction in the
AV node. Transient increases in vagal tone produced by the Valsalva maneuver or carotid
sinus massage (see Chapter 11) may block AV conduction, stopping the tachycardia. The
most rapidly e ective pharmacologic treatment is intravenous adenosine, which impairs AV
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Clinical Aspects o Cardiac Arrhythmias
299
Compa ct
AV node
Fa s t pa thway
Bundle of His
Right a trium
IVS
Impuls e from
SA node
S low pa thway
Tricus pid va lve
A
Re tro g ra d e
c o n d u c tio n
Un id ire c tio n a l
b lo ck
Bundle of His
Atria l
pre ma ture
be a t
B
FIGURE 12-15. Common mechanism of AV nodal reentry. In most patients, the AV node is a lobulated
structure consisting proximally o several atrial extensions and distally o a compact node portion. A. In
patients with AV nodal reentry, two unctionally distinct tracts exist within the AV node (termed the slow and
ast pathways). The slow pathway conducts slowly and has a short re ractory period, whereas the ast pathway
conducts more rapidly but has a long re ractory period. Impulses rom above conduct down both pathways;
because the ast pathway impulse reaches the distal common pathway f rst, it continues to the bundle o His.
Conversely, the slow pathway impulse arrives later and encounters re ractory tissue. B. An atrial premature beat
arrives at the entrance o the two pathways. The ast pathway is still re ractory rom the preceding beat and the
impulse is blocked, but the slow pathway has repolarized and is able to conduct. When the impulse reaches the
distal portion o the ast pathway a ter traveling down the slower pathway, the ast pathway has repolarized and
is able to conduct the impulse in a retrograde direction (exempli ying unidirectional block) as shown by the green
pathway. The impulse can then travel back to the slow pathway, and a reentrant loop is initiated.
nodal conduction and o ten aborts the reentrant rhythm (see Chapter 17). Other drug options
include intravenous calcium channel antagonists (verapamil and diltiazem) or β-blockers.
Most patients with AVNRT have in requent episodes that terminate with vagal maneuvers and
do not require other specif c interventions. Frequent symptomatic episodes, particularly when
requiring visits to the emergency department or treatment, warrant preventive therapy: oral
300
Chapter 12
β-blockers, calcium channel blockers, or digoxin is o ten success ul or this purpose. Catheter
ablation o the slow AV nodal pathway is usually curative and recommended when pharmacologic therapy ails or is not desired by the patient, but has a small risk (< 2% ) o heart block owing
to unintended damage to the ast AV nodal pathway, a complication that requires permanent
pacemaker implantation. Chronic class IC or IA antiarrhythmic drugs are also e ective but are
o ten less desirable than catheter ablation, because o associated potential drug toxicities.
Atrioventricular Reentrant Tachycardias
Atrioventricular reentrant tachycardias (AVRTs) are similar to AVNRTs except that in the ormer, one limb o the reentrant loop is constituted by an accessory pathway (bypass tract),
rather than by separate ast and slow pathways within the AV node itsel . As described in
Chapter 11, an accessory pathway is an abnormal band o myocytes that spans the AV groove
and connects atrial to ventricular tissue separately rom the normal conduction system (see
Fig. 11-10). Approximately 1 in 1,500 people has such a pathway.
Accessory pathways allow an impulse to conduct rom atrium to ventricle (anterograde conduction), rom ventricle to atrium (retrograde conduction), or in both directions. Depending
on the characteristics o the pathway, one o two characteristic entities can result: (1) the ventricular preexcitation syndrome or (2) PSVT resulting rom a concealed accessory pathway.
Some pathways do not conduct impulses at rates su f cient to cause tachycardias and cause
no symptoms at all.
Ventricular Preexcitation Syndrome
In patients with ventricular preexcitation (also termed Wol –Parkinson–White [WPW] syndrome; see Chapter 11), atrial impulses can pass in an anterograde direction to the ventricles
through both the AV node and the accessory pathway. Because conduction through the accessory pathway is usually aster than that via the AV node, the ventricles are stimulated earlier
than by normal conduction over the AV node. During sinus rhythm, activation o the ventricle
rom the accessory pathway causes a characteristic ECG appearance: (1) the PR interval is
shortened (less than 0.12 seconds) because ventricular stimulation begins earlier than normal through the accessory pathway, (2) the QRS has a slurred rather than a sharp upstroke
(re erred to as a delta wave) because the initial ventricular activation by the accessory pathway is slower than activation over the Purkinje system, and (3) the QRS complex is widened
because it represents usion o two excitation wave ronts through the ventricles, one rom
the accessory pathway and one rom the normal His–Purkinje system (Figs. 12-16 and 12-17).
Patients with WPW syndrome are predisposed to PSVTs because the accessory pathway
provides a potential limb o a reentrant loop. The most common PSVT in these patients is orthodromic AVRT. During this tachycardia, an impulse travels anterogradely down the AV node to
the ventricles and then retrogradely up the accessory tract back to the atria (see Fig. 12-17B).
FIGURE 12-16. Wolff–Parkinson–White syndrome. The delta wave (arrow) indicates preexcitation of the
ventricles. Note the shortened PR interval.
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A
B
S inus Rhythm
Orthodromic
Atrio ventric ular
Reentrant
Tac hycardia
C
301
Antidro mic
Atrio ve ntricular
Re entrant
Tachycardia
AP
FIGURE 12-17. Wolff–Parkinson–White syndrome. A. During normal sinus rhythm, the shortened PR
interval, delta wave, and widened QRS complex indicate fusion of ventricular activation via the AV node and
accessory pathway (AP). B. An atrial premature beat can trigger an orthodromic atrioventricular reentrant
tachycardia, in which impulses are conducted anterogradely down the AV node and retrogradely up the
accessory pathway. Retrograde P waves are visible immediately after the QRS complex. There is no delta
wave because anterograde ventricular stimulation passes exclusively through the AV node. C. Antidromic
atrioventricular reentrant tachycardia in which impulses are conducted anterogradely down the accessory tract
and retrogradely up the AV node. The QRS complex is greatly widened because the ventricles are stimulated by
abnormal conduction through the accessory pathway rather than via the His-Purkinje system. SA, sinoatrial.
Because the ventricles in this situation are depolarized exclusively via the normal conduction
system (through the AV node and the bundle o His), there is no delta wave during the tachycardia and the width o the QRS is usually normal. Retrograde P waves are o ten visible soon
a ter each QRS complex because the atria are stimulated rom below via retrograde conduction
through the accessory pathway.
In ewer than 10% o patients with AVRT involving an accessory pathway, the reentrant
arrhythmia travels in the opposite direction. Impulses travel anterogradely down the accessory pathway and retrogradely up the AV node (see Fig. 12-17C). Termed antidromic AVRT,
its ECG pattern is characterized by a wide QRS complex because the ventricles are activated
entirely rom anterograde conduction over the accessory pathway. From the ECG alone, such
antidromic tachycardia is di cult to distinguish rom ventricular tachycardia (described later
in the chapter).
A third type o arrhythmia encountered in patients with WPW syndrome is anterograde
conduction over the accessory pathway when AF or atrial f utter is present. Some accessory
pathways have short re ractory periods that allow aster rates o ventricular stimulation than
does the AV node. Thus, during AF or atrial f utter, ventricular rates as ast as 300 bpm may
result. Such rates are poorly tolerated and can lead to ventricular brillation and cardiac
arrest, even in a young, otherwise healthy patient.
Pharmacologic management o arrhythmias in patients with the WPW syndrome requires
greater caution than that o those with AVNRTs. Although digitalis, β-blockers, and certain
302
Chapter 12
calcium channel blockers are e ective at blocking conduction through the AV node, they do
not slow conduction over most accessory pathways. Sometimes these drugs actually shorten
the re ractory period o the accessory pathway, thus speeding conduction. There ore, the drugs
could precipitate even aster ventricular rates (and hemodynamic collapse) when administered to patients with WPW syndrome who develop AF or f utter. In contrast, sodium channel blockers (speci cally, class IA and IC antiarrhythmics) and some class III antiarrhythmic
drugs slow conduction and prolong the re ractory period o accessory pathways as well as the
AV node; there ore, these are the pre erred pharmacologic agents or this condition.
When a patient with WPW presents with a wide QRS tachycardia, acute therapy depends
on the patient’s tolerance o the arrhythmia. I accompanied by hemodynamic collapse,
immediate cardioversion is required. Conversely, i the patient is hemodynamically stable,
intravenous administration o procainamide (a class IA agent that slows conduction in the
accessory pathway) or ibutilide (a class III agent that prolongs re ractoriness in the accessory
pathway) will o ten terminate the arrhythmia.
Patients who have WPW with symptomatic arrhythmias should generally undergo an invasive electrophysiologic study with radio requency ablation o the accessory pathway. Ablation
abolishes conduction over the pathway, curing the condition. I this procedure is not an
option, chronic oral therapy should include a drug that slows accessory pathway conduction
(i.e., a class IA, IC, or III agent).
The Low n–Ganong–Levine syndrome is also characterized by a short PR interval but a
normal, narrow QRS complex (i.e., no delta wave during sinus rhythm). It used to be considered a orm o preexcitation, but most patients just have enhanced conduction through the
normal AV node, thus shortening the PR interval. When PSVT occurs in these patients, it is
usually simply due to AV nodal reentry.
Concealed Accessory Pathways
Accessory pathways do not always result in ECG ndings o ventricular preexcitation (i.e.,
short PR, delta wave). Many are capable o only retrograde conduction. In this case, during
sinus rhythm, the ventricles are depolarized normally through the AV node alone and the ECG
is normal (i.e., the accessory pathway is concealed). However, because the accessory pathway
is capable o retrograde conduction, it can orm a limb o a reentrant circuit under appropriate
circumstances and result in orthodromic AVRT.
Management o patients with tachycardia involving a concealed accessory pathway is the
same as or patients with AVNRT. Because the reentrant circuit travels anterogradely down the AV
node, vagal maneuvers and drugs that interrupt conduction over the AV node (e.g., adenosine,
verapamil, diltiazem, and β-blockers) can terminate the tachycardia. Another option or recurrent episodes is catheter ablation o the accessory pathway, which is curative in most patients.
Focal Atrial Tachycardia
Focal atrial tachycardia (AT) results rom either automaticity o an atrial ectopic site or reentry.
The ECG has the appearance o sinus tachycardia, with a P wave be ore each QRS complex,
but the P-wave morphology is di erent rom that o sinus rhythm, indicating depolarization
o the atrium rom an abnormal location. The arrhythmia can be paroxysmal and o limited
duration, or it can persist. Short, asymptomatic bursts o AT are commonly observed on
24-hour ECG recordings, even in otherwise healthy people.
AT can be caused by digitalis toxicity and is also aggravated by elevated sympathetic
tone (e.g., during exertion or periods o illness). Initial treatment includes correction o any
contributing actors. Unlike AVNRT or AVRT, vagal maneuvers (such as carotid sinus massage) may have no e ect on atrial discharges rom an ectopic pacemaker ocus. However,
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P
P
P
P
P
P
P
P
P
303
P
FIGURE 12-18. Multifocal atrial tachycardia. The rhythm is irregular, and each QRS is preceded by a P wave
of varying morphology.
β-blockers, calcium channel blockers, and class IC, IA, and III antiarrhythmic drugs can be
e ective. Catheter ablation is also a use ul option or symptomatic patients.
Multifocal Atrial Tachycardia
In multi ocal atrial tachycardia (MAT), the ECG shows an irregular rhythm with multiple (at
least three di erent) P-wave morphologies, and the average atrial rate is greater than 100 bpm
(Fig. 12-18). An isoelectric (i.e., “f at”) baseline between P waves distinguishes MAT rom the chaotic
baseline o AF. This rhythm is likely caused by either abnormal automaticity in several oci within
the atria or triggered activity and occurs most o ten in the setting o severe pulmonary disease and
hypoxemia. Because patients with this rhythm are o ten critically ill rom the underlying disease,
the mortality rate is high, and treatment is aimed at the causative disorder. The calcium channel blocker verapamil is o ten e ective at slowing the ventricular rate as a temporizing measure.
Ventricular Arrhythmias
Ventricular arrhythmias include (1) ventricular premature beats (VPBs), (2) ventricular
tachycardia (VT), and (3) ventricular brillation (VF). Ventricular arrhythmias are usually
more dangerous than supraventricular rhythm disorders and are responsible or many o the
approximately 300,000 sudden cardiac deaths that occur every year in the United States.
Ventricular Premature Beats
A VPB arises when an ectopic ventricular ocus res an action potential. On the ECG, a VPB
appears as a widened QRS complex, because the impulse travels rom its ectopic site through the
ventricles via slow cell-to-cell connections rather than through the normal rapidly conducting His–
Purkinje system (Fig. 12-19). Furthermore, the ectopic beat is not related to a preceding P wave.
VPBs can also occur in repeating patterns. When every alternate beat is a VPB, the rhythm
is termed bigeminy. When two normal beats precede every VPB, trigeminy is present.
Consecutive VPBs are re erred to as couplets (two in a row) or triplets (three in a row).
Similar to APBs, VPBs are common even among healthy people and are o ten asymptomatic and benign. Speci c precipitants o VPBs include medications (e.g., β-adrenergic receptor
FIGURE 12-19. Ventricular premature beats ( arrows) .
304
Chapter 12
FIGURE 12-20. Monomorphic ventricular tachycardia.
agonists), ca eine, electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), and
hypoxia. VPBs are not dangerous by themselves, and in patients without heart disease, they
con er no added risk o a li e-threatening arrhythmia. They can, however, be an indication o
an underlying cardiac disorder and take on added signif cance in that case. For example, in
patients with structural heart disease, VPBs generally increase in requency in relation to the
severity o depressed ventricular contractility. They have been associated with an increased
risk o sudden death in patients with heart ailure or prior myocardial in arction.
In otherwise healthy persons, treatment o VPBs mainly involves reassurance and, i
needed, symptomatic control using β-blockers. In patients with advanced structural heart
disease with eatures that place them at risk o li e-threatening ventricular arrhythmias, placement o an implantable cardioverter–def brillator (ICD) is typically recommended.
Ventricular Tachycardia
VT is a series o three or more consecutive VPBs (Fig. 12-20). VT is divided arbitrarily into
two categories. I it persists or more than 30 seconds, produces severe symptoms, such as
syncope, or requires termination by cardioversion or administration o an antiarrhythmic
drug, it is designated as sustained VT; shorter, sel -terminating episodes are termed nonsustained VT. Both orms o VT are ound most commonly in patients with structural heart
disease, including myocardial ischemia and in arction, heart ailure, ventricular hypertrophy,
primary electrical diseases (e.g., long-QT syndromes [LQTS]; see Box 12-1), valvular heart
diseases, and congenital cardiac abnormalities.
BOX 12-1
Genetic Mutations and Ventricular Arrhythmias
Genetic causes o arrhythmias occur either in association with various types o structural heart
disease or as isolated conditions. Examples o inherited structural disease that can be complicated
by li e-threatening ventricular arrhythmias include hypertrophic cardiomyopathy, the familial
dilated cardiomyopathies, and arrhythmogenic right ventricular cardiomyopathy (ARVC),
which are all described in Chapter 10. ARVC may be suspected on
routine ECG by the presence o inverted T waves in leads V1 through V1
Eps ilon wave
V3 and occasionally an epsilon wave, a terminal notch o the QRS
complex in lead V1 (see arrow in the adjacent gure), which ref ects
abnormal RV activation.
Several other inherited arrhythmic disorders occur in the
absence o structural cardiac disease. These occur in requently but
are important because they can cause li e-threatening polymorphic VT or VF in young, otherwise
healthy people without prior warning. The most common o these conditions are (1) the Brugada
syndrome, (2) the congenital LQTS, and (3) amilial catecholaminergic polymorphic VT.
The Brugada syndrome is inherited in an autosomal dominant ashion and has been linked in
some (but not all) amilies to mutations in a sodium channel subunit gene (SCN5A). A clue to the
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Clinical Aspects o Cardiac Arrhythmias
BOX 12-1
Genetic Mutations and Ventricular Arrhythmias
305
( continued)
presence o this syndrome is a speci c ECG nding o prominent ST elevation in leads V1 through
V3 (see adjacent gure). This pattern may be present chronically or intermittently; in the latter
case, the syndrome may be unmasked by administering sodium channel blocking antiarrhythmic
drugs (e.g., f ecainide, procainamide, which are described in Chapter 17). Brugada syndrome
is a potentially lethal condition, and ICD implantation is the most e ective way to prevent an
arrhythmic death.
The congenital long QT syndromes are associated with
V1
prolonged ventricular repolarization (hence the long QT interval),
which can lead to li e-threatening polymorphic VT (i.e., torsades
de pointes). Mutations in a number o di erent genes result in
LQTS (the three most common are listed in the table below) by
prolonging the action potential duration. Most identi ed mutations
alter ion channel unction to either enhance the depolarizing
Na+ current or impair the repolarizing K+ current. Autosomal dominant and recessive patterns o
inheritance occur.
Gene penetrance and symptomatology o patients with LQTS is highly variable, even or
individuals with the same mutation. The degree o QT prolongation and, in some cases, the patient’s
gender are predictors o arrhythmic risk when a mutation is present. An a ected patient may be
asymptomatic and come to medical attention only as a result o the abnormal ECG or because o a
amily member who died suddenly. Others present with syncope or sudden death caused by torsades
de pointes. The most common orms (LQT1 and LQT2) are associated with ventricular arrhythmias
during physical exercise (particularly swimming) or emotional stress. Conversely, those with LQT3 are
much more likely to experience cardiac events at rest or during sleep.
Other acquired conditions that urther prolong the QT interval can trigger li e-threatening
arrhythmias in patients with LQTS, including hypokalemia, hypomagnesemia, hypocalcemia,
and several medications (including many antiarrhythmic drugs). Conversely, β-blockers reduce
the risk o arrhythmias in many orms o congenital LQTS, even though they do not shorten
the QT interval. For patients at high risk o li e-threatening arrhythmias, ICD implantation is
warranted.
Familial catecholaminergic polymorphic VT, inherited in autosomal dominant and recessive
patterns, is marked by VT and/ or VF during exercise or emotional arousal. The mechanism is
thought to be triggered activity resulting rom delayed a terdepolarizations (described in Chapter
11). Mutations in a ected amilies have been demonstrated in at least two genes involved
in intracellular calcium handling, including a missense mutation in the locus that codes or
the cardiac ryanodine receptor (see Chapter 1). Treatment with a β-blocker, calcium channel
blocker, and/ or drug that inhibits ryanodine receptor–mediated calcium release (e.g., the class
IC antiarrhythmic f ecainide has this additional attribute) may be e ective; an ICD is also o ten
recommended.
Genetic Basis of the Three Most Common Congenital Long QT Syndromes
Type
Gene
( Location)
Protein
Mechanism of Prolonged
Repolarization
Inheritance
LQT1
KCNQ1 (11p15)
↓ Outward K+ current
AD and AR
LQT2
KCNH2 (7q35)
KvLQT1 (α subunit o
I Ks K+ channel)
HERG (α subunit o IKr
K+ channel)
↓ Outward K+ current
AD
LQT3
SCN5A (3p21)
Nav 1.5 (Na+ channel)
↑ Inward Na+ current
AD
AD, autosomal dominant; AR, autosomal recessive.
306
Chapter 12
The QRS complexes o VT are typically wide (greater than 0.12 seconds) and occur at a rate
o 100 to 200 bpm or sometimes aster. VT is urther categorized according to its QRS morphology. When every QRS complex appears the same and the rate is regular, it is re erred to as
monomorphic VT (see Fig. 12-20). Sustained monomorphic VT usually indicates a structural
abnormality that supports a reentry circuit, most commonly a region o myocardial scar rom an
old in arction or cardiomyopathy. Occasionally, sustained monomorphic VT occurs as a result
o an ectopic ventricular ocus in an otherwise healthy person (re erred to as idiopathic VT).
When the QRS complexes continually change in shape and the rate varies rom beat to beat,
the VT is re erred to as polymorphic. Multiple ectopic oci or a continually changing reentry
circuit is the cause. Torsades de pointes (discussed later in the chapter) and acute myocardial ischemia or in arction are the most common causes o polymorphic VT. Rare, inherited
predispositions to polymorphic VT and sudden death arise rom abnormalities o cardiac ion
channels or calcium handling (e.g., the long QT syndromes, the Brugada syndrome, amilial
catecholaminergic polymorphic VT), as described in Box 12-1. Sustained polymorphic VT
usually degenerates to VF.
The symptoms o VT vary depending on the rate o the tachycardia, its duration, and the
underlying condition o the heart. Sustained VT can cause low cardiac output resulting in loss
o consciousness (syncope), pulmonary edema, or progress to cardiac arrest. These severe
consequences o VT are most likely in patients who have underlying depressed contractile
unction. Conversely, i sustained VT is at a relatively slow rate (e.g., less than 130 bpm), it
may be well tolerated and cause only palpitations.
Distinguishing Monomorphic VT from Supraventricular Tachycardia
VT can usually be distinguished rom SVT by the width o the QRS complex: it is routinely
wide in the ormer and narrow (i.e., normal) in the latter. However, under certain circumstances, arrhythmias that originate rom sites above the ventricles ca n result in wide QRS
complexes and may appear similar to monomorphic VT. This situation is termed SVT with
aberra n t ven tricula r con duction , or simply SVT with a berra n cy, and may arise in three
scenarios: (1) a patient has an underlying conduction abnormality (e.g., a bundle branch
block), such that the QRS is abnormally wide even when in normal sinus rhythm; (2)
repetitive rapid ventricular stimulation during SVT nds one o the bundle branches re ractory (because o insu cient time to recover rom the previous depolarization), such that
the impulse propagates abnormally through the ventricles, causing the QRS to be distorted
and wide; or (3) a patient develops antidromic tachycardia through an accessory pathway
(described earlier).
Certain clinical and electrocardiographic eatures can help to distinguish wide QRS complexes o monomorphic VT rom those o supraventricular rhythms with aberrant conduction.
In patients with a history o prior myocardial in arction, congestive heart ailure, or le t ventricular dys unction, a wide complex tachycardia is more likely to be VT rather than SVT with
aberrancy. At the bedside, SVT is more probable i vagal maneuvers (such as carotid sinus
massage) a ect the rhythm (see Fig. 12-9).
Electrocardiographically, a supraventricular tachyarrhythmia is more likely i the morphology o the QRS at the rapid rate is similar to that on the patient’s ECG tracing obtained while
in sinus rhythm (i.e., the complex is widened because o an underlying bundle branch block).
Conversely, VT is more likely i (1) there is no relationship between the QRS complexes and
any observed P waves (AV dissociation) or (2) the QRS complexes in each o the chest leads
(V1 through V6) have a similar appearance, with a dominant positive or negative def ection
(i.e., there is “concordance” o the precordial QRS complexes). These eatures are summarized in Table 12-2. Other morphologic ECG eatures have been used to distinguish VT rom
SVT with aberrancy, but the distinction is o ten very di cult. Most patients with wide QRS
tachycardia should be managed as though they have VT until proven otherwise.
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Clinical Aspects of Cardiac Arrhythmias
TABLE 12-2
307
Differentiation of Wide Complex Tachycardias
Supports SVT with Aberrant Conduction
Supports Ventricular Tachycardia
QRS morphology same as when in sinus
rhythm
History of prior MI or heart failure
No relationship between P waves and QRS complexes
Concordance of QRS complexes in the chest leads
(V1–V6)
Rhythm responds to vagal maneuvers
(see Fig. 12-9)
MI, myocardial infarction; SVT, supraventricular tachycardia.
Management of Patients with VT
Sustained episodes o VT are dangerous because they can produce syncope or deteriorate into
VF, which is atal i not quickly corrected. Acute treatment usually consists o electrical cardioversion. Intravenous administration o certain antiarrhythmic drugs, such as amiodarone,
procainamide, or lidocaine, can be considered i the patient is hemodynamically stable.
A ter sinus rhythm is restored, a patient who has had sustained VT requires care ul evaluation to de ne whether underlying structural heart disease is present and to correct any
aggravating actors, such as myocardial ischemia, electrolyte disturbances, or drug toxicities.
Patients who have su ered VT in the setting o structural heart disease have a high risk o
recurrence and sudden cardiac death; implantation o an ICD is usually warranted to automatically and promptly terminate uture episodes.
Patients who experience VT in the absence o underlying structural heart disease are usually ound to have idiopathic VT. This type o arrhythmia tends to originate rom oci in the
right ventricular outf ow tract or in the septal portion o the le t ventricle. It is rarely li e
threatening. β-Blockers, calcium channel blockers, or catheter ablation is commonly e ective
to control symptomatic episodes o idiopathic VT.
Torsades de Pointes
Torsades de pointes (“twisting o the points”) is a orm o polymorphic VT that presents
as varying amplitudes o the QRS, as i the complexes were “twisting” about the baseline
(Fig. 12-21). It can result rom early a terdepolarizations (triggered activity), particularly
in patients who have a prolon ged QT in terva l. QT prolongation (which indicates a lengthened action potential duration) can result rom electrolyte disturbances (hypokalemia
or hypomagnesemia), persistent bradycardia, and drugs that block cardiac potassium
currents, including many antiarrhythmic agents (particularly the class III drugs sotalol,
ibutilide, and do etilide and some class I drugs, including quinidine, procainamide, and
disopyramide). Many medications administered or noncardiac illnesses can also prolong
FIGURE 12-21. Torsade de pointes. The widened polymorphic QRS complexes demonstrate a waxing and
waning pattern.
308
Chapter 12
FIGURE 12-22. Ventricular f brillation.
the QT interval and predispose to torsades de pointes, including erythromycin, phenothiazines, haloperidol, and methadone. A rare group o hereditary ion channel abnormalities produces con gen ita l QT prolongation, which can also lead to torsades de pointes
(see Box 12-1).
Torsades de pointes is usually symptomatic, causing light-headedness or syncope, but is
requently sel -limited. Its main danger results rom degeneration into VF. When it is drug or
electrolyte induced, correcting the underlying trigger abolishes recurrences, but measures to
suppress episodes are required to allow time to address the cause. Administration o intravenous magnesium o ten suppresses repeated episodes. Additional preventive strategies are
aimed at shortening the QT interval by increasing the underlying heart rate with intravenous
β-adrenergic stimulating agents (e.g., isoproterenol) or an artif cial pacemaker. When torsades de pointes results rom congenital prolongation o the QT interval (i.e., in the long QT
syndromes), β-blocking drugs are the treatment o choice, because sympathetic stimulation
actually aggravates the arrhythmia.
Ventricular Fibrillation
VF is an immediately li e-threatening arrhythmia (Fig. 12-22). It results in disordered, rapid
stimulation o the ventricles with no coordinated contractions. The result is essentially cessation o cardiac output and death i not quickly reversed. This rhythm most o ten occurs in
patients with severe underlying heart disease and is the major cause o mortality in acute
myocardial in arction.
VF is o ten initiated by an episode o VT, which degenerates, it is believed, by the breakup
o excitation waves into multiple smaller wavelets o reentry that wander through the myocardium. On the ECG, VF is characterized by a chaotic irregular appearance without discrete
QRS wave orms.
Untreated, VF rapidly leads to death. The only e ective therapy is prompt electrical def brillation. As soon as the heart has been converted to a sa e rhythm, the underlying precipitant
o the arrhythmia (e.g., myocardial ischemia, electrolyte imbalances, hypoxemia, or acidosis)
should be sought and corrected to prevent urther episodes. Intravenous antiarrhythmic drug
therapy may be administered to prevent immediate recurrences. I no reversible inciting precipitant is ound, survivors o VF usually receive an ICD.
SUMMARY
• Disorders o impulse ormation and conduction result in bradyarrhythmias (heart rate <60
bpm) and tachyarrhythmias (heart rate > 100 bpm or three beats or more).
• The f ve basic considerations when con ronted with a patient with an abnormal heart
rhythm are (1) identif cation, (2) pathogenesis, (3) precipitating actors, (4) clinical presentation, and (5) treatment.
• When evaluating a patient with a slow heart rhythm, two key questions should be
addressed: (1) are P waves present? and (2) what is the relationship between the P waves
and the QRS complexes?
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Clinical Aspects of Cardiac Arrhythmias
309
• Di erentiation o tachyarrhythmias requires assessment o (1) the width o the QRS complex
(normal or wide), (2) the morphology and rate o the P waves, (3) the relationship between
the P waves and the QRS complexes, and (4) the response to vagal maneuvers.
• The ECG texts listed at the end o Chapter 4 provide multiple examples o arrhythmias and
are suited or practicing the principles described in this chapter.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Ranliang Hu, MD; Hillary K. Rolls, MD;
Wendy Armstrong, MD; Nicholas Boulis, MD; Jenni er E. Ho, MD; Marc S. Sabatine, MD;
Elliott M. Antman, MD; and Leonard I. Ganz, MD.
Ad d i t i o n a l Rea d i n g
January CT, Wann LS, Alpert JS, et al. 2014 AHA/ ACC/ HRS
guideline or the management o patients with atrial f brillation: A report o the American College o Cardiology/
American Heart Association Task Force on Practice
Guidelines and the Heart Rhythm Society. Circulation.
2014;130(23):2071–2104.
Link MS. Clinical practice. Evaluation and initial treatment o supraventricular tachycardia. N Engl J Med.
2012;367:1438–1448.
Pediatric Congenital Electrophysiology Society, Heart Rhythm
Society, American College o Cardiology Foundation,
et al. PACES/ HRS expert consensus statement on the
management o the asymptomatic young patient with
a Wol -Parkinson-White (WPW, ventricular preexcitation) electrocardiographic pattern. Heart Rhythm.
2012;9:1006–1024.
Roden DM. Clinical practice. Long-QT syndrome. N Engl J
Med. 2008;358:169–176.
Stevenson WG. Current treatment o ventricular arrhythmias:
State o the art. Heart Rhythm. 2013;10:1919–1926.
Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/ AHA/ HRS
ocused update o the 2008 guidelines or device-based
therapy o cardiac rhythm abnormalities: A report o the
American College o Cardiology Foundation/ American Heart
Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2012;60:1297–1313.
Hypertension
Joshua Dra go
Gordon H. Willia ms
Leona rd S. Lilly
Ch a p t e r O u t l i n e
What Is Hypertension?
How Is Blood Pressure
Regulated?
Hemodynamic Factors
Blood Pressure Re exes
Essential Hypertension
Genetics and Epidemiology
Experimental Findings
Natural History
Secondary Hypertension
Patient Evaluation
Exogenous Causes
Renal Causes
Mechanical Causes
Endocrine Causes
Consequences of Hypertension
Clinical Signs and Symptoms
Organ Damage Caused by
Hypertension
Hypertensive Crisis
Treatment of Hypertension
Nonpharmacologic Treatment
Pharmacologic Treatment
O
13
ver 70 million Americans, and 1 billion people throughout the world, have hypertension—a blood pressure (BP)
high enough to be a danger to their well-being. This number
will undoubtedly rise; data rom the Framingham Heart Study
indicate that 90% o people over age 55 will develop hypertension during their li etimes. Thus, this condition represents
a great public health concern because it is a major risk actor
or coronary artery disease, stroke, heart ailure, renal disease,
and peripheral vascular disease. Surprisingly, two thirds o
hypertensive persons are either unaware o their elevated BP
or are not treated adequately to minimize the cardiovascular risk. Moreover, because elevated BP is usually asymptomatic until an acute cardiovascular event strikes, screening or
hypertension is a critical aspect o preventive medicine.
Hypertension is also a scientif c problem o unexpected
complexity. In approximately 90% o a ected patients, the
cause o the BP elevation is unknown, a condition termed
primary or essential hypertension ( EH) . Evidence suggests
that the causes o EH are multiple and diverse, but considerable insight into those causes can be achieved by studying the
normal physiology o BP control, as examined in this chapter.
High BP attributed to a def nable cause is termed
secondary hypertension. Although ar less common than
EH, conditions that cause secondary hypertension are important because many are amenable to permanent cure. Notably,
many o the conditions now understood to cause secondary
hypertension were once unknown, and a ected patients were
there ore considered to have EH. As more is learned about the
pathophysiology o high BP, ewer cases o hypertension will
likely be considered to be o the essential type.
Following the descriptions o EH and secondary hypertension, this chapter considers the clinical consequences o
elevated BP and approaches to treatment.
310
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Hypertension
311
WHAT IS HYPERTENSION?
BP values vary widely in the population and
tend to increase with age, as illustrated in
Figure 13-1. The risk o a vascular complication increases progressively and linearly with
higher BP values, so the exact cuto points to
def ne stages o hypertension are somewhat
arbitrary. The currently accepted criteria are
listed in Table 13-1. By this classif cation, a
diastolic pressure consistently ≥ 90 mm Hg or
a systolic pressure ≥ 140 mm Hg establishes
the diagnosis o hypertension. Those with prehyperten sion (systolic 120 to 139 mm Hg or
diastolic 80 to 99 mm Hg) have an increased
risk o developing def nite hypertension over
time. Although the emphasis has historically
been on the level o dia stolic pressure, more
recent evidence suggests that systolic pressure more accurately predicts cardiovascular
complications.
HOW IS BLOOD PRESSURE REGULATED?
Sys tolic
Dia s tolic
FIGURE 13-1. Relationship between blood
pressure and age (n = 1,029). Systolic (upper
curves) and diastolic (lower curves) values are shown.
Notice that by age 60, the average systolic pressure o
women exceeds that o men. (Modif ed rom Kotchen
JM, McKean HE, Kotchen TA. Blood pressure trends
with aging. Hypertension. 1982;4(suppl. 3):111–129.)
Hemodynamic Factors
BP is the product o cardiac output (CO) and total peripheral resistance (TPR):
BP = CO × TPR
And CO is the product o cardiac stroke volume (SV) and heart rate (HR):
CO = SV × HR
As described in Chapter 9, SV is determined by (1) cardiac contractility; (2) the venous
return to the heart (preload); and (3) the resistance the le t ventricle must overcome to eject
blood into the aorta (a terload).
It ollows that at least our systems are directly responsible or BP regulation: the heart,
which supplies the pumping pressure; the blood vessel tone, which largely determines systemic resistance; the kidney, which regulates intravascular volume; and hormones, which
modulate the unctions o the other three systems. Figure 13-2 shows how actors related to
these systems contribute to CO and TPR.
TABLE 13-1
Classif cation o Blood Pressure in Adults
Category
Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension
Systolic Pressure ( mm Hg)
< 120
120–139
140–159
≥ 160
Diastolic Pressure ( mm Hg)
And
Or
Or
Or
< 80
80–89
90–99
≥ 100
Modif ed rom Chobanian AV, Bakris GL, Black HR, et al. The seventh report o the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment o High Blood Pressure. JAMA. 2003;289:2560–2572.
312
Chapter 13
Blood Pre s s ure
Ca rdia c Output
HR
Pe riphe ra l Re s is ta nce
SV
Circula ting
re gula tors
Dire ct
inne rva tion
• Angiote ns in II (↑ ) • α 1 -Re ce ptors (↑ )
• Ca te chola mine s (↑ ) • β 2 -Re ce ptors (↓ )
• P S NS (↓ )
• S NS (↑ )
• Ca te chola mine s (↑ )
Loca l
re gula tors
Blood
vis cos ity
• He ma tocrit (↑ )
• Nitric oxide (↓ )
• [H+] (↓ )
• Ade nos ine (↓ )
• Pros ta gla ndins (↓ )
• Endothe lin (↑ )
• Oxyge n (↑ )
Ve nous
re turn
Contra ctility
• Ca te chola mine s (↑ )
• S NS (↑ )
Blood
volume
Ve nous
tone
• S NS (↑ )
• Ca te chola mine s (↑ )
Re na l
re te ntion
(Na +, H2 O)
• Thirs t (↑ )
• Aldos te rone (↑ )
• ADH (↑ )
• S NS (↑ )
• NP (↓ )
FIGURE 13-2. Regulation of systemic blood pressure. The small arrows indicate whether there is a stimulatory
(↑) or inhibitory (↓) effect on the boxed parameters. ADH, antidiuretic hormone; HR, heart rate; NP, natriuretic
peptides; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system; SV, stroke volume.
The renal component o BP regulation deserves special mention, in light o the temptation to
view hypertension simply as a cardiovascular problem. No matter how high the CO or TPR, renal
excretion has the capacity to completely return BP to normal by reducing intravascular volume.
There ore, the maintenance o chronic hypertension requires renal participation. Transplantation
studies have conf rmed this point: the implantation o a kidney rom a normotensive person into
a hypertensive one typically improves the BP. Similarly, surgical placement o a kidney rom a
genetically hypertensive rat into a previously normotensive one usually leads to hypertension.
In the presence o normally unctioning kidneys, an increase in BP leads to augmented
urine volume and sodium excretion, which then returns the BP to normal. This process,
known as pressure natriuresis, is blunted in the kidneys o hypertensive patients; thus, higher
pressures are required to excrete a given sodium and water load. Current evidence suggests
at least two possible reasons or this blunted response. First, microvascular and tubulointerstitial injury within the kidneys o hypertensive patients impairs sodium excretion. Second,
the de ect may lie with hormonal actors critical to appropriate renal reactions to the sodium
and intravascular volume environment (e.g., the renin–angiotensin system, as described later
in the chapter). In contrast to the f rst possibility, abnormalities o hormonal regulation are
amenable to correction with appropriate therapy.
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Hypertension
313
Blood Pressure Ref exes
The cardiovascular system is endowed with eedback mechanisms that continuously monitor
arterial pressure: they sense when the pressure becomes excessively high or low and then
respond rapidly to those changes. One such mechanism is the baroreceptor ref ex, which is
mediated by receptors in the walls o the aortic arch and the carotid sinuses. The baroreceptors
monitor changes in pressure by sensing the stretch and de ormation o the arteries. I the arterial
pressure rises, the baroreceptors are stimulated, increasing their transmission o impulses to the
central nervous system (i.e., the medulla). Negative eedback signals are then sent back to the
circulation via the autonomic nervous system, causing the BP to all back to its baseline level.
The higher the BP rises, the more the baroreceptors are stretched and the greater the
impulse transmission rate to the medulla. Signals rom the carotid sinus receptors are carried
by the glossopharyngeal nerve (cranial nerve IX), whereas those rom the aortic arch receptors are carried by the vagus nerve (cranial nerve X). These nerve bers converge at the tractus solitarius in the medulla, where the baroreceptor impulses inhibit sympathetic nervous
system outf ow and excite parasympathetic e ects. The net result is (1) a decline in peripheral
vascular resistance (i.e., vasodilation) and (2) a reduction in CO (because o a lower HR and
reduced contractility). Each o these e ects tends to lower arterial pressure back toward its
baseline. Conversely, when a fall in systemic pressure is sensed by the baroreceptors, ewer
impulses are transmitted to the medulla, leading to a ref exive increase in BP.
The main e ect o the baroreceptor mechanism is to modulate moment-by-moment variations in systemic BP. However, the baroreceptor ref ex is not involved in the long-term regulation o BP and does not prevent the development o chronic hypertension. The reason or
this is that the baroreceptors constantly reset themselves. A ter a day or two o exposure to
higher-than-baseline pressures, the baroreceptor- ring rate slows back to its control value,
and a new set point is established.
ESSENTIAL HYPERTENSION
Approximately 90% o hypertensive patients have BPs that are elevated or no readily de nable reason, and are considered to have EH. The diagnosis o EH is one o exclusion; it is the
option le t to the clinician a ter considering the causes o secondary hypertension described
later in this chapter.
EH is more a description than a diagnosis, indicating only that a patient mani ests a speci c
physical nding (high BP) or which no cause has been ound. In all likelihood, di erent underlying de ects are responsible or the elevated pressure in di erent subpopulations o patients.
Because the exact nature o these de ects is unknown, to understand EH is to understand the
possibilities: what could go wrong with normal physiology to produce chronically elevated BP?
This description o EH there ore ref ects what is currently known about its genetics and
epidemiology, experimental ndings, and natural history. The picture that emerges is that EH
likely results rom multiple de ects o BP regulation that interact with environmental stressors. The regulatory de ects may be acquired or genetically determined and may be independent o one another. As a result, EH patients exhibit varied combinations o abnormalities
and, there ore, have various physiologic bases or their elevated BPs.
Genetics and Epidemiology
Strong support or the role o heredity in EH is evident in the higher rate o elevated BP among
rst-degree relatives o hypertensive patients than in the general population. Further, concordance between identical twins is high and signi cantly greater than it is that between dizygotic
twins. However, no singular, consistent genetic marker or hypertension has been identi ed.
Instead, it seems likely that EH is a complex polygenic disorder, involving several loci.
314
Chapter 13
While autosomal dominant contributors to elevated BP have been discovered, such
abnormalities are rare and are thought to represent only a small raction o hypertensive
patients. With respect to loci that a ect hypertension in a polygenic way, genes regulating the
renin–angiotensin–aldosterone axis have been most thoroughly studied because o the central
role o this system in determining intravascular volume and vascular tone. Within this group,
certain polymorphisms in the genes or angiotensinogen, angiotensin-converting enzyme
(ACE), the angiotensin type-1 receptor, and aldosterone synthase con er a small increase in the
risk o developing hypertension. Additionally, polymorphisms in the gene or alpha-adducin,
a cytoskeletal protein, may be involved in a subgroup o EH patients, possibly by increasing renal tubular sodium absorption. Finally, as described later in the chapter, signif cant
associations exist among hypertension and obesity, insulin resistance, and diabetes. These
conditions are all characterized by similar complex inheritance patterns, some o which may
overlap with the genetic underpinnings o hypertension.
As genetics cannot explain the complete basis o hypertension, it stands to reason that the
environment also plays a role. Indeed, hypertension has been epidemiologically linked to low
socioeconomic status, certain dietary and exercise patterns, poor access to health care, and
comorbid medical conditions such as obesity, diabetes, and kidney disease. Thus, the heritable traits described above most likely predispose individuals to develop hypertension a ter
exposure to certain environmental triggers.
Experimental Findings
Systemic Abnormalities
Multiple de ects in BP regulation have been ound in EH patients and their relatives. By themselves, or in conjunction with one another, these abnormalities may contribute to chronic
BP elevation.
The heart can contribute to a high CO-based hypertension owing to sympathetic overactivity. For example, when tested under psychologically stress ul conditions, hypertensive
patients (and their f rst-degree relatives) o ten develop excessive HR acceleration compared
with control subjects, suggesting an excessive sympathetic response.
The blood vessels may contribute to peripheral vascular resistance–based hypertension
by constricting in response to (1) increased sympathetic activity; (2) abnormal regulation o
vascular tone by local actors, including nitric oxide, endothelin, and natriuretic actors; or (3)
ion channel de ects in contractile vascular smooth muscle.
The kidn ey can induce volu me-based hyperten sion by retain in g excessive sodium an d
water as a resu lt o (1) ailu re to regu late renal blood low appropriately; (2) ion ch an nel
de ects (e.g., reduced basolateral Na + K+ -ATPase), wh ich directly cause sodiu m retention ;
or (3) in appropriate h ormon al regu lation . For example, th e ren in –an giotensin–aldosterone axis is an important hormonal regulator o peripheral vascular resistance. Renin
levels in EH patien ts (compared with those in norm oten sive person s) are subnorm al in
25% , n ormal in approxim ately 60% , and h igh in 10% to 15% . Because ren in secretion
should be suppressed by h igh BP, even “n ormal” levels are in appropriate in hyperten sives. Thus, abnormalities o this system’s regulation may play a role in some individuals
with EH.
Figure 13-3 highlights these and other potential mechanisms o EH. Note that although
the heart, blood vessels, and kidneys are the organs ultimately responsible or producing
the pressure, primary de ects may be located elsewhere as well (e.g., the central nervous system, arterial baroreceptors, and adrenal hormone secretion). Yet, although abnormal regulation at these sites can contribute to elevated BP, it is important to remember
that without renal complicity, mal unction o other systems would not produce sustained
hypertension, since the normal kidney is capable o eliminating su f cient volume to return
the BP to normal.
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Hypertension
315
CNS
Blo o d ve s s e l
Func tiona l:
• ↓ Nitric oxide s e cre tion
• ↑ Endothe lin production
• Ca ++ or Na +/K+ cha nne l de fe cts
• Hype rre s pons ive ne s s to
ca te chola mine s
• ↑ Ba s a l s ympa the tic tone
• Abnorma l s tre s s re s pons e
• Abnorma l re s pons e to s igna ls from
ba rore ce ptors a nd volume re ce ptors
Pre s s ure /vo lume re c e pto rs
• De s e ns itiza tion
S truc tura l:
• Exa gge ra te d me dia l
hype rtrophy
Adre nal
• Ca te chola mine le a k
or ma lre gula tion
Kidne y
• RAA dys function
• Ion cha nne l de fe cts (e .g., Na +/K+/2 Cl –
cotra ns porte r, ba s ola te ra l Na +/ K+ ATP a s e ,
Ca ++ ATP a s e )
FIGURE 13-3. Potential primary abnormalities in essential hypertension ( EH) . These de ects are
supported by experimental evidence, but their specif c contributions to EH remain unknown. CNS, central
nervous system; RAA, renin–angiotensin–aldosterone system.
Insulin Resistance, Obesity, and the Metabolic Syndrome
Recent research has suggested that the hormone insulin may play a role in the development o EH. In many people with hypertension, especially those who are obese or have type
2 diabetes, there is impaired insulin-dependent transport o glucose into many tissues (termed
insulin resistance). As a result, serum glucose levels rise, stimulating the pancreas to release
additional insulin. Elevated insulin levels may contribute to hypertension via increased sympathetic activation or by stimulation o vascular smooth muscle cell hypertrophy, which
increases vascular resistance. Smooth muscle cell hypertrophy may be caused by a direct
mitogenic e ect o insulin or through enhanced sensitivity to platelet-derived growth actor.
Obesity itsel has been directly associated with hypertension. Possible explanations or this
relationship include (1) the release o angiotensinogen rom adipocytes as substrate or the
renin–angiotensin system; (2) augmented blood volume related to increased body mass; and
(3) increased blood viscosity caused by adipocyte release o prof brinogen and plasminogen
activator inhibitor 1. The current epidemic o obesity has led to a dramatic increase in the number o people with metabolic syndrome. As described in Chapter 5, this condition represents a
clustering o atherogenic risk actors, including hypertension, hypertriglyceridemia, low serum
high-density lipoprotein (HDL), a tendency toward glucose intolerance, and truncal obesity.
Current evidence suggests that insulin resistance is central to the pathogenesis o this clustering.
Natural History
EH characteristically arises a ter young adulthood. Its prevalence increases with age, and
more than 60% o Americans older than 60 years are hypertensive. In addition, the hemodynamic characteristics o BP elevation in EH tend to change over time. The systolic pressure
increases throughout adult li e, while the diastolic pressure rises until about the age o
Chapter 13
100%
90%
80%
Is ola te d sys tolic
hype rte ns ion
60%
Sys tolic a nd dia s tolic
hype rte ns ion
50%
r
e
q
u
e
n
c
y
70%
F
316
40%
Is ola te d dia s tolic
hype rte ns ion
30%
20%
10%
0%
<40
40–49
50–59
60–69
Age (ye a rs )
70–79
>80
FIGURE 13-4. Categories of blood pressure elevation in untreated hypertensive patients. Isolated
systolic hypertension predominates in patients older than 50 years, primarily as a result o decreased vascular
compliance. (Modif ed rom Franklin SS, Jacobs MJ, Wong ND, et al. Predominance o isolated systolic
hypertension among middle aged and elderly US hypertensives: analysis based on National Health and Nutrition
Examination Survey (NHANES III). Hypertension. 2001;37:869–874.)
50 and then declines slightly therea ter (see Fig. 13-1). Accordingly, diastolic hypertension is
more common in young people, while a substantial number o hypertensive patients over age
50 have isolated systolic hypertension with normal diastolic values (see Fig. 13-4).
In younger persons with hypertension, elevated BP tends to be driven by high CO in the
setting o relatively normal peripheral vascular resistance, termed the hyperkinetic phase o
EH (Fig. 13-5). With advancing age, however, the e ect o CO declines, perhaps because o
the development o le t ventricular hypertrophy (LVH) and its consequent reduced diastolic
f lling (which in turn reduces SV and CO). Conversely, vascular resistance increases with
age due to medial hypertrophy as the vessels adapt to the prolonged pressure stress. Thus,
younger hypertensive patients o ten display augmented CO as the principal abnormality, and
older patients tend to have elevated TPR as the major hemodynamic f nding.
In summary, EH is a syndrome that may arise rom many potential abnormalities, but it
exhibits a characteristic hemodynamic prof le and natural history. It is likely that multiple
de ects, separately inherited or acquired, act together to chronically raise BP. Although we
may not understand the precise underlying mechanisms in individual hypertensive patients,
we can at least describe the kinds o pathophysiology that might be at ault.
CO
Ca rdia c
output (CO)
contribution
to blood
pre s s ure
TP
R
Pe riphe ra l
re s is ta nce (TP R)
contribution
to
blood
pre s s ure
Incre a s ing a ge
FIGURE 13-5. Hemodynamic progression of essential hypertension ( EH) . Schematic representation o the
changing contribution o cardiac output (CO) and total peripheral resistance (TPR) as age increases in many
patients with EH.
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Hypertension
317
SECONDARY HYPERTENSION
Although EH dominates the clinical picture, a de ned structural or hormonal cause or hypertension may be ound in a small percentage o patients. Identi cation o such cases o secondary hypertension is important because the underlying conditions may require therapy
di erent rom that administered or EH, and they are o ten curable. Moreover, i secondary
hypertension is le t uncontrolled, adaptive cardiovascular changes may develop analogous
to those o long-standing EH that could cause the elevated pressures to persist even a ter the
underlying cause is corrected.
Although secondary orms should be considered in the workup o all patients with hypertension, there are clues that a given patient may have one o the correctable conditions (Table 13-2):
1. Age. I a patient develops hypertension be ore age 20 or a ter age 50 (outside the usual
range o EH), secondary hypertension is more likely.
2. Severity. Secondary hypertension o ten causes BP to rise dramatically, whereas most EH
patients usually have mild-to-moderate hypertension.
3. Onset. Secondary orms o hypertension o ten present abruptly in a patient who was previously normotensive, rather than gradually progressing over years as is the usual case in EH.
4. Associated signs and symptoms. The process that induces hypertension may give rise to
other characteristic abnormalities, identi ed by the history and physical examination. For
example, a renal artery bruit (swishing sound caused by turbulent blood f ow through a stenotic artery) may be heard on abdominal examination in a patient with renal artery stenosis.
5. Family history. EH patients o ten have hypertensive rst-degree relatives, whereas secondary hypertension more commonly occurs sporadically.
Patient Evaluation
The usual clinical evaluation o a patient with recently diagnosed hypertension begins with a
care ul history and physical examination, including a search or clues to the secondary orms.
For example, repeated urinary tract in ections may suggest the presence o chronic pyelonephritis
TABLE 13-2
Causes of Hypertension
Type
Essential
Chronic renal disease
Primary aldosteronism
Renovascular
Percent of
Hypertensive Patients
~90%
2%–4%
< 2%–15%
(varies by sensitivity of
screening)
1%
Pheochromocytoma
0.2%
Coarctation of the
aorta
0.1%
Cushing syndrome
0.1%
Clinical Clues
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Age of onset: 20–50 years
Family history of hypertension
Normal serum K+ , urinalysis
↑ Creatinine, abnormal urinalysis
↓ Serum K+
Abdominal bruit
Sudden onset (especially if age > 50 or < 20)
↓ Serum K+
Paroxysms of palpitations, diaphoresis, and headache
Weight loss
Episodic hypertension in one third of patients
Blood pressure in arms > legs, or right arm > left arm
Midsystolic murmur between scapulae
Chest x-ray: aortic indentation, rib notching due to
arterial collaterals
• “Cushingoid” appearance (e.g., central obesity, hirsutism)
318
Chapter 13
with renal damage as the cause o hypertension. Excessive weight loss may be an indicator
o pheochromocytoma, whereas weight gain may point to the presence o Cushing syndrome
(these conditions are described below). The history also should include an assessment o li estyle
behaviors that may contribute to hypertension, such as excessive alcohol consumption, and the
patient’s medications should be reviewed because certain drugs (see next section) may elevate
BP. Obstructive sleep apnea is commonly associated with hypertension and should be considered
particularly in patients who snore and have a history o hypertension re ractory to medications.
Laboratory tests commonly per ormed in the initial evaluation o the hypertensive patient,
including general screening or secondary causes, are (1) urinalysis and measurement o the serum
concentration o creatinine and blood urea nitrogen to evaluate or renal abnormalities; (2) serum
potassium level (abnormally low in renovascular hypertension [RH] or aldosteronism); (3) blood
glucose level (elevated in diabetes, which is strongly associated with hypertension and renal disease); (4) serum cholesterol, HDL cholesterol, and triglyceride levels, as part o the global vascular
risk screen; and (5) an electrocardiogram ( or evidence o LVH caused by chronic hypertension).
I no abnormalities are ound that suggest a secondary orm o hypertension, the patient
is presumed to have EH and treated accordingly. I , however, the patient’s BP continues to
be elevated despite standard treatments, then more detailed diagnostic testing may be undertaken to search or specif c secondary causes.
Exogenous Causes
Several medications can elevate BP. For example, oral contraceptives may cause secondary
hypertension in some women. The mechanism is likely related to increased activity o the
renin–angiotensin system. Estrogens increase the hepatic synthesis o angiotensinogen, leading to greater production o angiotensin II (Fig. 13-6). Angiotensin II raises BP by several
ANGIOTENS INOGEN
(s e cre te d by live r)
RENIN
(s e c re te d by
kid ney)
ANGIOTENS IN I
ANGIOTENS INCONVERTING ENZYME
ANGIOTENS IN II
ANGIOTENS IN II RECEP TORS (AT1 s ubtype )
Arte ria l s mooth mus c le :
Ad re na l g la nd :
Symp a the tic ne rvous
sys te m:
Kid ney:
Bra in:
He a rt:
Va s ocons triction
↑ Aldos te rone (↑ re na l Na + re a bs orption)
Fa cilita te s re le a s e of nore pine phrine
↑ Re na l tubula r Na + re a bs orption
S timula te s thirs t a nd va s opre s s in s e cre tion
Enha nce s contra ctility a nd ve ntricula r hype rtrophy
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FIGURE 13-6. The renin–
angiotensin–aldosterone system.
Liver-derived angiotensinogen
is cleaved in the circulation
by renin (of kidney origin) to
form angiotensin I (AI). AI is
rapidly converted to the potent
vasoconstrictor angiotensin II
(AII) by angiotensin-converting
enzyme. AII also modulates the
release of aldosterone from the
adrenal cortex. Aldosterone in
turn acts to reabsorb Na+ from
the distal nephron, resulting in
increased intravascular volume. The
other listed effects of AII receptor
stimulation may also contribute to
the development and maintenance
of hypertension.
Hypertension
319
mechanisms, most notably by direct vasoconstriction and by stimulating the adrenal release
o aldosterone. The latter hormone causes renal sodium retention and, there ore, increased
intravascular volume.
Other medications that can raise BP include glucocorticoids, cyclosporine (an antirejection
drug used in patients with organ transplants), erythropoietin (a hormone that increases bone
marrow red blood cell ormation and elevates BP by increasing blood viscosity and reversing
local hypoxic vasodilatation), and sympathomimetic drugs (which are common in over-thecounter cold remedies). Nonsteroidal anti-inf ammatory drugs can contribute to hypertension
through dose-related augmentation o renal sodium and water retention.
Two other substances that may contribute to hypertension are ethanol (i.e., chronic excessive consumption) and cocaine. Both o these are associated with increased sympathetic
nervous system activity.
Renal Causes
Given the crucial role o the kidney in the control o BP, it is not surprising that renal
dys unction can lead to hypertension. In act, renal disease contributes to two important
endogenous causes o secondary hypertension: renal parenchymal disease, accounting or
2% to 4% o hypertensive patients, and RH (renal arterial stenosis), which accounts or
approximately 1% .
Renal Parenchymal Disease
Parenchymal damage to the kidney can result rom diverse pathologic processes. The major
mechanism by which injury leads to elevated BP is through increased intravascular volume.
Damaged nephrons are unable to excrete normal amounts o sodium and water, leading to a
rise in intravascular volume, elevated CO, and hence increased BP.
I renal unction is only mildly impaired, BP may stabilize at a level at which the higher
systemic pressure (and there ore renal per usion pressure) enables sodium excretion to balance sodium intake. Conversely, i a patient has end-stage renal ailure, the glomerular ltration rate may be so greatly decreased that the kidneys simply cannot excrete su cient
volume, and malignant-range BP may ollow. Renal parenchymal disease may urther contribute to hypertension even i the glomerular ltration rate is not greatly reduced, through the
excessive elaboration o renin.
Renovascular Hypertension
Stenosis o one or both renal arteries leads to hypertension. Although emboli, vasculitis, and
external compression o the renal arteries can be responsible, the two most common causes o
RH are atherosclerosis and bromuscular dysplasia. Atherosclerotic lesions arise rom extensive plaque ormation either within the renal artery or in the aorta at the origin o the renal
artery. This orm accounts or about two thirds o cases o RH and occurs most commonly in
elderly men. In contrast, f bromuscular lesions consist o discrete regions o brous or muscular proli eration, generally within the arterial media. Fibromuscular dysplasia accounts or
one third o cases o RH and characteristically occurs in young women.
The elevated BP in RH arises rom reduced renal blood f ow to the a ected kidney, which
responds to the lower per usion pressure by secreting renin. The latter raises the BP through
the subsequent actions o angiotensin II (vasoconstriction) and aldosterone (sodium retention), as shown in Figure 13-6.
The diagnosis o RH is suggested by an abdominal bruit, which can be ound in 40% to
60% o patients, or by the presence o unexplained hypokalemia (owing to excessive renal
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Chapter 13
excretion o potassium as a result o an elevated aldosterone level). The diagnosis can be conrmed, when invasive interventions are being considered, by duplex Doppler ultrasonography,
computed tomographic angiography (CTA), or magnetic resonance angiography o the renal
arteries.
Therapy o RH with antihypertensive drugs is o ten e ective, particularly when an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker is included. These
inhibitors o the renin–angiotensin system negate the hypertensive e ects o elevated circulating renin in RH by impeding the ormation or action o angiotensin II (see Chapter 17).
However, these classes o drugs should be avoided, or used cautiously, in patients with
bilateral renal artery stenotic lesions. The inhibition o angiotensin II may excessively reduce
intraglomerular pressure and ltration, and worsen renal unction, in patients with bilateral
disease who already have compromised per usion to both kidneys. In select patients with
RH (e.g., those with recent onset hypertension due to RH, those whose BP remains elevated
despite medical therapy, or those with progressive renal insu ciency due to renal artery stenosis) percutaneous catheter interventions or surgical reconstruction o the stenosed vessel
may be more e ective than continued medical antihypertensive therapy alone.
Mechanical Causes
Coarctation of the Aorta
Coarctation is an in requent congenital narrowing o the aorta typically located just distal to
the origin o the le t subclavian artery (see Chapter 16). As a result o the relative obstruction to f ow, the BP in the aortic arch, head, and arms is higher than that in the descending
aorta and its branches and in the lower extremities. Sometimes the coarctation involves the
origin o the le t subclavian artery, causing lower pressure in the le t arm compared with
the right arm.
Hypertension in this condition arises by two mechanisms. First, reduced blood f ow
to the kidneys stimulates the renin–angiotensin system, resulting in vasoconstriction (via
angiotensin II). Second, high pressures proximal to the coarctation sti en the aortic arch
through medial hyperplasia and accelerated atherosclerosis, blunting the normal baroreceptor
response to elevated intravascular pressure.
Clinical clues to the presence o coarctation include symptoms o inadequate blood f ow
to the legs or le t arm, such as claudication or atigue, or the nding o weakened or absent
emoral pulses. A midsystolic murmur associated with the stenotic segment o the aorta
may be auscultated, especially over the back, between the scapulae. The chest radiograph
may show indentation o the aorta at the level o the coarctation. It may also demonstrate
a notched appearance o the ribs secondary to the enlargement o collateral intercostal
arteries, which shunt blood around the aortic narrowing. Treatment options include angioplasty or surgery to correct the stenosis. However, hypertension may not abate completely
a ter mechanical correction, in part because o persistent desensitization o the arterial
baroreceptors.
Endocrine Causes
Circulating hormones play an important role in the control o normal BP, so it should not be
surprising that endocrine diseases may cause hypertension. When suspected, the presence o
such conditions is evaluated in our ways:
1. History o characteristic signs and symptoms
2. Measurement o hormone levels
3. Assessment o hormone secretion in response to stimulation or inhibition
4. Imaging studies to identi y tumors secreting the excessive hormone
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321
Pheochromocytoma
Pheochromocytomas are catecholamine-secreting tumors o neuroendocrine cells (usually in
the adrenal medulla) that account or approximately 0.2% o cases o hypertension. The
release o epinephrine and norepinephrine by the tumor results in intermittent or chronic
vasoconstriction, tachycardia, and other sympathetic-mediated e ects. A characteristic presentation consists o paroxysmal rises in BP accompanied by “autonomic attacks” caused by
the increased catecholamine levels: severe throbbing headaches, pro use sweating, palpitations, and tachycardia. Although some patients are actually normotensive between attacks,
most have sustained hypertension. Ten percent o pheochromocytomas are malignant.
Determination o plasma catecholamine levels, or urine catecholamines and their metabolites (e.g., vanillylmandelic acid and metanephrine), obtained under controlled circumstances,
are used to identi y this condition. Because some pheochromocytomas secrete only episodically, diagnosis may require measurement o catecholamines immediately ollowing an attack.
Pharmacologic therapy o pheochromocytomas includes the combination o an α-receptor
blocker (e.g., phenoxybenzamine) combined with a β-blocker. However, once the tumor is
localized by computed tomography, magnetic resonance imaging, or angiography, the def nitive
therapy is surgical resection. For patients with inoperable disease, treatment consists o α- and
β-blockade as well as drugs that inhibit catecholamine biosynthesis (e.g., α-methyltyrosine).
Adrenocortical Hormone Excess
Among the hormones produced by the adrenal cortex are mineralocorticoids and glucocorticoids. Excess o either o these can result in hypertension.
Mineralocorticoids, primarily aldosterone, increase blood volume by stimulating reabsorption o sodium into the circulation by the distal portions o the nephron. This occurs in
exchange or potassium excretion into the urine, and the resulting hypokalemia is an important marker o mineralocorticoid excess. Primary aldosteronism results either rom an adrenal
adenoma (termed Conn syndrome) or rom bilateral hyperplasia o the adrenal glands. While
once considered rare, recent data suggest that the requency o primary aldosteronism may be
as high as 10% to 15% among hypertensives, depending on the sensitivity o screening, with
a substantial majority having the bilateral hyperplasia orm. The diagnosis may be suspected
by the presence o hypokalemia and is conf rmed by the f nding o excessive plasma aldosterone and a suppressed renin level. Therapy includes either surgical removal o the responsible
adenoma (i present) or medical management with aldosterone receptor antagonists.
Glucocorticoid-remediable aldosteronism (GRA), an uncommon hereditary (autosomal
dominant) orm o primary aldosteronism, results rom a genetic rearrangement in which
aldosterone synthesis abnormally comes under the regulatory control o adrenocorticotropic
hormone (ACTH). This condition typically presents as severe hypertension in childhood or
young adulthood, as opposed to the more common orms o primary aldosteronism, which
are generally diagnosed in the third through sixth decades. Unlike other orms o hypertension, GRA-related BP elevation responds to glucocorticoid therapy, which suppresses ACTH
release rom the pituitary gland.
Secondary aldosteronism can result rom increased angiotensin II production stimulated by
rare renin-secreting tumors. More commonly, secondary elevation o aldosterone is a result o
augmented circulating angiotensin II in women taking oral contraceptives (which stimulate
hepatic production o angiotensinogen, as described earlier) or because o impaired angiotensin II degradation in chronic liver diseases.
Glucocorticoids, such as cortisol, elevate BP when present in excess amounts, likely via
blood volume expansion and stimulated synthesis o components o the renin–angiotensin
system. In addition, though mineralocorticoids are more potent activators o mineralocorticoid receptors in the renal tubules, excess glucocorticoids may also activate them.
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Chapter 13
Nearly 80% o patients with Cushing syn drome, a disorder o glucocorticoid excess,
have some degree o hypertension. These patients o ten present with classic “cushingoid”
eatures: a characteristic rounded acial appearance, central obesity, proximal muscle weakness, and hirsutism. The cause o the excess glucocorticoids may be either a pituitary
ACTH-secreting adenoma, a peripheral ACTH-secreting tumor (either o which causes
adrenal cortical hyperplasia), or an adrenal cortisol-secreting adenoma. The diagnosis o
Cushing syndrome is con rmed by a 24-hour urine collection or the measurement o cortisol, or by a dexamethasone test, which evaluates whether exogenous glucocorticoids can
suppress cortisol secretion.
Thyroid Hormone Abnormalities
Approximately one third o hyperthyroid and one ourth o hypothyroid patients have signi cant hypertension. Thyroid hormones exert their cardiovascular e ects by (1) inducing
sodium–potassium ATPases in the heart and vessels; (2) increasing blood volume; and (3)
stimulating tissue metabolism and oxygen demand, with secondary accumulation o metabolites that modulate local vascular tone. Hyperthyroid patients develop hypertension through
cardiac hyperactivity with an increase in blood volume. Hypothyroid patients demonstrate
predominantly diastolic hypertension and an increase in peripheral vascular resistance.
Though the precise mechanism is unclear, the latter e ect appears to be mediated by sympathetic and adrenal activation in hypothyroidism.
CONSEQUENCES OF HYPERTENSION
Whatever the cause o BP elevation, the ultimate consequences are similar. High BP itsel is
generally asymptomatic but can result in devastating e ects on many organs.
Clinical Signs and Symptoms
In the past, “classic” symptoms o hypertension were considered to include headache, epistaxis (nose bleeds), and dizziness. However, the use ulness o these symptoms has been
called into question by studies that indicate that they are ound no more requently among
hypertensive patients than in the general population. Other symptoms, such as f ushing,
sweating, and blurred vision, do seem more common in the hypertensive population. In general, however, most hypertensive patients are asymptomatic and are diagnosed simply by BP
measurement during routine physical examinations.
Several physical signs o hypertension discussed in the ollowing sections result directly rom
elevated pressure, including LVH and retinopathy. In addition, hypertension complicated by
atherosclerosis can mani est by arterial bruits, particularly in the carotid and emoral arteries.
Organ Damage Caused by Hypertension
Target organ complications o hypertension ref ect the degree o chronic BP elevation. Such
organ damage can be attributed to (1) the increased workload o the heart and (2) arterial
damage resulting rom the combined e ects o the elevated pressure itsel (weakened vessel walls) and accelerated atherosclerosis (Fig. 13-7). Abnormalities o the vasculature that
result rom elevated pressure include smooth muscle hypertrophy, endothelial cell dys unction, and atigue o elastic bers. Chronic hypertensive trauma to the endothelium promotes
atherosclerosis possibly by disrupting normal protective mechanisms, such as the secretion o
nitric oxide. Arteries lined by atherosclerotic plaque may thrombose or may serve as a source
o cholesterol emboli that occlude distal vessels, causing organ in arction (such as cerebrovascular occlusion, resulting in stroke). In addition, atherosclerosis o large arteries hinders
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323
Hype rte ns ion
↑ Afte rloa d
Sys tolic
dys function
LVH
Arte ria l da ma ge
↑ Myoca rdia l
oxyge n de ma nd
Dia s tolic
dys function
Acce le ra te d
a the ros cle ros is
We a ke ne d
ve s s e l wa ll
(Corona ry) (Ce re bra l/ca rotid)
↓ Myoca rdia l
oxyge n
s upply
(Aorta)
(Ce re bra l
he morrha ge )
(Eye )
Thrombos is
&
a the roe mboli
Ao rtic ane urys m
& dis s e c tio n
He art failure
(Kidney)
Myo c ardial is c he mia
& infarc tio n
Ne phro s cle ro s is
& re nal failure
S tro ke
Re tino pathy
FIGURE 13-7. Pathogenesis of the major consequences of arterial hypertension. LVH, left ventricular
hypertrophy.
their elasticity, resulting in systolic pressure spikes that can further traumatize endothelium
or provoke events such as aneurysm rupture.
The major target organs for the destructive complications of chronic hypertension are the
heart, the cerebrovascular system, the aorta and peripheral vascular system, the kidney, and
the retina (Table 13-3). Left untreated, approximately 50% of hypertensive patients die of
coronary artery disease or congestive heart failure, about 33% succumb to stroke, and 10%
to 15% die from complications of renal failure.
Heart
The major cardiac effects of hypertension relate to the increased afterload against which the
heart must contract and accelerated atherosclerosis within the coronary arteries.
TABLE 13-3
Target Organ Damage in Hypertension
Organ System
Manifestations
Heart
•
•
•
•
•
•
•
•
•
•
Cerebrovascular
Aorta and peripheral vascular
Kidney
Retina
Left ventricular hypertrophy
Heart failure
Myocardial ischemia and infarction
Stroke
Aortic aneurysm and/ or dissection
Arteriosclerosis
Nephrosclerosis
Renal failure
Arterial narrowing
Hemorrhages, exudates, papilledema
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Chapter 13
Left Ventricular Hypertrophy and Diastolic Dysfunction
The high arterial pressure (heightened a terload) increases the wall tension o the le t ventricle, which compensates through hypertrophy. Concentric hypertrophy (without dilatation) is
the normal pattern o compensation, although conditions that elevate BP by virtue o increased
circulating volume (e.g., primary aldosteronism) may instead cause eccentric hypertrophy with
chamber dilatation (see Chapter 9). LVH results in increased sti ness o the le t ventricle with
diastolic dys unction, mani ested by elevation o LV lling pressures that can result in pulmonary congestion (i.e., heart ailure with preserved ejection raction—see Chapter 9).
Physical ndings o LVH may include a heaving LV impulse on chest palpation, indicative
o the increased muscle mass. It is requently accompanied by a ourth heart sound (S4), as
the le t atrium contracts into the sti ened le t ventricle (see Chapter 2).
LVH is one o the strongest predictors o cardiac morbidity in hypertensive patients. The
degree o hypertrophy correlates with the development o congestive heart ailure, angina,
arrhythmias, myocardial in arction, and sudden cardiac death.
Systolic Dysfunction
Although LVH initially serves a compensatory role, later in the course o systemic hypertension, the increased LV mass may be insu cient to balance the high wall tension caused by
the elevated pressure. As LV contractile capacity deteriorates, ndings o systolic dys unction
become evident (i.e., reduced CO and pulmonary congestion). Systolic dys unction is also
provoked by the accelerated development o coronary artery disease with resultant periods o
myocardial ischemia.
Coronary Artery Disease
Chronic hypertension is a major contributor to the development o myocardial ischemia and
in arction. These complications ref ect the combination o accelerated coronary atherosclerosis (decreased myocardial oxygen supply) and the high systolic workload (increased oxygen
demand). In addition, hypertensives have a higher incidence o postmyocardial in arction
complications such as rupture o the ventricular wall, LV aneurysm ormation, and congestive
heart ailure.
Cerebrovascular System
Hypertension is the major modi able risk actor or strokes, also termed cerebrovascular
accidents (CVAs). Although diastolic pressure is important, it is the magnitude o the systolic
pressure that has been most closely linked to CVAs. The presence o isolated systolic hypertension more than doubles a person’s risk or this complication.
Hypertension-induced strokes can be hemorrhagic or, more commonly, atherothrombotic.
Hemorrhagic CVAs result rom rupture o microaneurysms induced in cerebral parenchymal
vessels by longstanding hypertension. Atherothrombotic (also called thromboembolic) CVAs
arise when portions o atherosclerotic plaque within the carotids or major cerebral arteries,
or thrombi that orm on those plaques, break o , and embolize to smaller distal vessels.
Additionally, intracerebral vessels may be directly occluded by local atherosclerotic plaque
rupture and thrombosis.
Occlusion o small penetrating brain arteries can result in multiple tiny in arcts. As these
lesions so ten and are absorbed by phagocytic cells, small (≤ 3 mm diameter) cavities orm,
termed lacunae. These lacunar in arctions are seen almost exclusively in patients with longstanding hypertension and are usually localized to the penetrating branches o the middle and
posterior circulation o the brain.
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Hypertension
325
In addition, the generalized arterial narrowing ound in hypertensive patients reduces
collateral f ow to ischemic tissues and imposes structural requirements or higher per usion
pressure to maintain adequate tissue f ow. This leaves the hypertensive patient vulnerable
to cerebral in arcts in areas supplied by the distal ends o arterial branches (“watershed”
in arcts) i BP should all suddenly.
E ective treatment o hypertension diminishes the risk o stroke and has contributed to a
50% reduction in deaths attributed to cerebrovascular events in recent decades.
Aorta and Peripheral Vasculature
The accelerated atherosclerosis associated with hypertension may result in plaque ormation and narrowing throughout the arterial vasculature. In addition to the coronary arteries,
lesions most commonly appear within the aorta and the major arteries that serve the lower
extremities, neck, and brain.
Chronic hypertension may lead to the development o aneurysms, particularly o the
abdominal aorta. An abdominal aortic aneurysm represents prominent dilatation o the
vessel, usually located below the level o the renal arteries, contributed to by the mechanical stress o the high pressure on an arterial wall already weakened by medial damage and
atherosclerosis (see Chapter 15). Aneurysms greater than 6 cm in diameter have a very high
likelihood o rupture within 2 years i not surgically corrected.
Another li e-threatening vascular consequence o high BP is aortic dissection (see Chapter
15). Elevated BP, especially in the highest ranges, accelerates degenerative changes in the
media o the aorta. When the weakened wall is urther exposed to high pressure, the intima
may tear, allowing blood to dissect into the aortic media and propagate in either direction
within the vessel wall, “clipping o ” and obstructing major branch vessels along the way
(including coronary or carotid arteries). The treatment o aortic dissection requires rigorous
BP control, and urgent surgical repair i the proximal aorta is involved.
Kidney
Hypertension-induced kidney disease (nephrosclerosis) is a leading cause o renal ailure
that results rom damage to the organ’s vasculature. Histologically, the vessel walls become
thickened with a hyaline in ltrate, known as hyaline arteriolosclerosis (Fig. 13-8). Greater
levels o hypertension can induce smooth muscle hypertrophy and necrosis o capillary walls,
termed f brinoid necrosis. These changes result in reduced vascular supply and subsequent
ischemic atrophy o tubules and, to a lesser extent, glomeruli. Because intact nephrons can
usually compensate or those damaged by patchy ischemia, mild hypertension rarely leads to
renal insu ciency in the absence o other insults to the kidney. However, malignant levels o
hypertension can inf ict permanent damage leading to chronic renal ailure.
One o the consequences o hypertensive renal ailure is perpetuation o elevated BP. For
example, progressive renal dys unction compromises the ability o the kidney to regulate
blood volume, which contributes urther to chronic hypertension.
Retina
The retina is the only location where systemic arteries can be directly visualized by physical
examination. High BP induces abnormalities that are collectively termed hypertensive retinopathy. Although vision may be compromised when the damage is extensive, more commonly the
changes serve as an asymptomatic clinical marker or the severity o hypertension and its duration.
Severe hypertension that is acute in onset (e.g., uncontrolled and/ or malignant hypertension) may burst small retinal vessels, causing hemorrhages, exudation o plasma lipids,
and areas o local in arction. I ischemia o the optic nerve develops, patients may describe
326
Chapter 13
FIGURE 13-8. Hypertension-associated kidney injury. The arteriolar walls are thickened by hyaline inf ltrate
(short arrows). The glomeruli (long arrow) appear sclerosed because o reduced vascular supply. (Courtesy o
Dr. Helmut G. Rennke, Brigham and Women’s Hospital, Boston, MA.)
generalized blurred vision. Retinal ischemia caused by hemorrhage leads to more patchy loss
o vision. Papilledema, or swelling o the optic disk with blurring o its margins, may arise
rom high intracranial pressure when the BP reaches malignant levels and cerebrovascular
autoregulation begins to ail.
Chronically elevated BP results in a di erent set o retinal ndings. Papilledema is absent,
but vasoconstriction results in arterial narrowing, and medial hypertrophy thickens the vessel wall, which “nicks” (indents) crossing veins. With more severe chronic hypertension,
arterial sclerosis is evident as an increased ref ection o light through the ophthalmoscope
(termed “copper” or “silver” wiring). Although these changes are not in themselves o major
unctional importance, they indicate that the patient has had long-standing, poorly controlled
hypertension.
HYPERTENSIVE CRISIS
A hypertensive crisis is a medical emergency characterized by a severe elevation o BP. In
the past, this type o elevation was usually a consequence o inadequate BP treatment. Now
a hypertensive crisis is more o ten caused by an acute hemodynamic insult (e.g., acute renal
disease) superimposed on a chronic hypertensive state. As a result o rapid pathologic changes
( brinoid necrosis) within the blood vessels and kidneys, a spiraling increase in BP evolves.
Further volume expansion and vasoconstriction occur as renal per usion drops and serum
renin and angiotensin levels rise.
Severe BP elevation results in increased intracranial pressure, and patients may present
with hypertensive encephalopathy mani ested by headache, blurred vision, con usion,
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Hypertension
327
somnolence, and sometimes coma. When hypertension results in acute damage to retinal
vessels, accelerated-malignant hypertension is said to be present. Funduscopic examination
shows the e ects o the rapid pressure rise as hemorrhages, exudates, and sometimes papilledema, as described earlier. The increased load on the le t ventricle during a hypertensive
crisis may precipitate angina (because o increased myocardial oxygen demand) or pulmonary edema.
A hypertensive crisis requires rapid therapy to prevent permanent vascular complications.
Correction o BP is generally ollowed by reversal o the acute pathologic changes, including
papilledema and retinal exudation, although renal damage o ten persists.
TREATMENT OF HYPERTENSION
The therapeutic approach to the hypertensive patient should be inf uenced by two considerations. First, a single elevated BP measurement does not establish the diagnosis o hypertension
because BP varies considerably rom day to day. Moreover, BP measurement in the hospital or
doctor’s o ce may be a ected by the “white coat” e ect resulting rom patient anxiety. The
average o multiple readings taken at two or three o ce visits and/ or in the home provides a
more reliable basis or labeling a patient as hypertensive. There is also evidence that automatic
ambulatory BP measurements, taken over the course o 24 hours while the patient ollows a daily
routine, are more predictive o cardiovascular mortality than traditional in-clinic measurements.
Second, although even mild hypertension is a major public health problem because o its
high prevalence, or the person with stage 1 hypertension, the risks are small. For example,
the additional risk o a stroke is approximately 1 in 850 per year. Hence, observation over time
to determine whether the low-level hypertension persists, or whether li estyle changes can
reduce the pressure, is o ten a recommended alternative to immediate drug therapy. This is
especially true in the absence o other cardiovascular risk actors such as smoking, diabetes,
or high serum cholesterol. However, or patients with established cardiovascular disease or
or those who have other major atherosclerotic risk actors, a more aggressive approach to
pharmacologic therapy is usually warranted to reduce the risk burden.
For most hypertensive patients, drug therapy is ultimately the most e ective way to prevent uture complications, but that should not deter consideration o other bene cial li estyle
changes.
Nonpharmacologic Treatment
Certain li estyle modi cations have been shown to be e ective in lowering BP and should be
considered in the treatment plan or any patient with hypertension.
Weight Reduction
Studies have consistently ound obesity and hypertension to be highly correlated, especially
when the obesity is o a central (abdominal) distribution. BP reduction ollows weight loss
in a large portion o hypertensive patients who are more than 10% above their ideal weights.
Each 10 kg o weight loss is associated with a 5 to 20 mm Hg all in systolic BP.
Exercise
Sedentary normotensive people have a 20% to 50% higher risk o developing hypertension than
do their more active peers. Regular aerobic exercise, such as walking, jogging, or bicycling, has
been shown to contribute to BP reduction over and above any resulting weight loss. A hypertensive patient who becomes physically conditioned mani ests a lower resting HR and reduced
levels o circulating catecholamines than be ore training, suggesting a all in sympathetic tone.
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Chapter 13
Diet
In addition to caloric restriction or weight loss, changes in the composition o a patient’s diet
may be important or BP reduction. For example, a diet high in ruits, vegetables, and low- at
dairy products has been shown to signif cantly reduce BP.
Sodium
Salt restriction or people with high BP is a controversial issue, but there are several epidemiologic
and clinical trials that support the benef t o moderating sodium intake. In normotensive persons,
excess salt ingestion is simply excreted by the kidneys, but approximately 50% o patients with EH
are ound to have BPs that vary with sodium intake, suggesting a de ect in natriuresis. Sensitivity
to sodium levels is more common in A rican American and elderly hypertensive patients. Because
low-salt diets tend to increase the e ectiveness o antihypertensive medications in general, the
current recommendation is to limit salt intake to less than 6 g o sodium chloride (less than 2.3 g
sodium) per day, which is one third less than the average United States consumption.
Potassium
Total body potassium content tends to decrease when a person eats a diet low in ruits and
vegetables or takes potassium-wasting diuretics. Potassium def ciency has several theoretical
e ects that may raise BP and contribute to adverse cardiovascular outcomes, such that dietary
supplements are routinely recommended to help replete low serum K+ levels. There is no
convincing evidence that prescribing potassium supplements to a normokalemic hypertensive
patient will lower BP.
Alcohol
The chronic excessive intake o alcoholic beverages correlates with high BP and resistance
to antihypertensive medications. Moreover, experimental evidence shows that BP (especially
systolic) may rise acutely ollowing alcohol consumption. The reason or this link remains
incompletely understood, but decreasing chronic alcohol intake has been shown to lower BP.
Other
Low calcium intake and magnesium depletion have been associated with elevated BP, but
the responsible mechanisms and the implications or therapy are unclear. Ca eine ingestion
transiently increases BP (as much as 5 to 15 mm Hg a ter two cups o co ee), but routine use
does not seem to produce chronic pressure elevation.
Smoking Cessation
Cigarette smoking transiently increases BP, likely because o the e ect o nicotine on autonomic ganglia, and is a risk actor or the development o sustained hypertension. In addition,
the atherogenic e ect o smoking may contribute to the development o RH. Cigarette usage
is associated with many other health hazards, and all patients should be discouraged rom
smoking.
Relaxation Therapy
BP requently rises under conditions o stress. In addition, essential hypertensive patients
and their relatives o ten show higher-than-normal basal sympathetic tone and exaggerated
autonomic responses to mental stress. Hence, relaxation techniques have been advocated as
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Hypertension
TABLE 13-4
329
Classes of Antihypertensive Medications
Drug Class
Examples ( See Chapter 17)
Physiologic Action
Diuretics
Thiazides
Potassium-sparing diuretics
Loop diuretics
β-Blockers
↓ Circulating volume
Sympatholytics
Combined α- and β-blockers
Vasodilators
Renin–angiotensin–
aldosterone system
antagonists
Central α2-agonists
Peripheral α1-antagonists
Calcium channel blockers
Direct vasodilators (e.g., hydralazine, minoxidil)
Angiotensin-converting enzyme inhibitors
Angiotensin II receptor blockers
Direct renin inhibitors
↓ Heart rate, cardiac contractility,
and renin secretion
Same as β-blocker plus vascular
smooth muscle relaxation
↓ Sympathetic tone
Vascular smooth muscle relaxation
↓ Peripheral vascular resistance
↓ Peripheral vascular resistance and
↓ Sodium retention
a method to control hypertension. Available methods include bio eedback and meditation.
The e ectiveness o such therapy has not been consistently demonstrated in clinical trials and
seems to depend on the patient’s attitude and long-term compliance.
In summary, nonpharmacologic therapy o ers a wide range o options that do not have the
expense and potential side e ects o prescribed drug use. The e ectiveness o these therapies
should come as no surprise, given the extent to which environmental actors play a role in
hypertension. There ore, behavior-based interventions are recommended as f rst-line therapy
in any patient whose hypertension is not an immediate danger.
Pharmacologic Treatment
Antihypertensive medications are the standard means to lower chronically elevated BP and
are indicated i nonpharmacologic treatment proves inadequate. More than 100 drug preparations are available to treat hypertension, but ortunately the most commonly used medications all into our classes: diuretics, sympatholytics, vasodilators, and drugs that inter ere
with the renin–angiotensin system (Table 13-4). The individual actions o these groups on the
physiologic abnormalities in hypertension are shown in Figure 13-9. The pharmacology and
use o antihypertensive drugs are described in greater detail in Chapter 17.
Diuretics have been in use or many decades to treat hypertension. They reduce circulatory volume, CO, and mean arterial pressure, and are most e ective in patients with mildto-moderate hypertension who have normal renal unction. They are especially e ective in
A rican American or elderly persons, who tend to be salt sensitive. In clinical trials, diuretics have reduced the risk o strokes and cardiovascular events in hypertensive patients and
are inexpensive compared with other agents. Thiazide diuretics (e.g., hydrochlorothiazide)
and pota ssium-sparin g diuretics (e.g., spironolactone) promote Na + excretion in the distal
nephron (see Chapter 17). Loop diuretics (e.g., urosemide) are generally too potent and
their actions too short-lived or use as antihypertensive agents; however, they are use ul in
lowering BP in patients with renal insu f ciency, who o ten do not respond to other diuretics.
Thiazides, the most commonly used diuretics in hypertension, may result in adverse metabolic side e ects, including elevation o serum glucose, cholesterol, and triglyceride levels. In
addition, hypokalemia, hyperuricemia, and decreased sexual unction are potential side e ects.
330
Chapter 13
Blood Pre s s ure
Ca rdia c Output
HR
Pe riphe ra l Re s is ta nce
Circula ting
re gula tors
SV
• β-Blocke rs
• S ome CCB
Contra ctility
Ve nous re turn
Dire ct
inne rva tion
• CCB a nd dire ct
va s odila tors
• RAS blocke rs
• α 1 -Blocke rs
• α 1 -Blocke rs
• Ce ntra l α 2 -a gonis ts
• Ce ntra l α 2 -a gonis ts
• β-Blocke rs
• CCB
Blood volume
Ve nous tone
• Diure tics
• RAS blocke rs
• RAS blocke rs
• CCB
• α 1 -Blocke rs
FIGURE 13-9. Physiologic effects of antihypertensive medications. Notice that some antihypertensive
medications work at multiple sites. CCB, calcium channel blockers; HR, heart rate; RAS blockers, renin–
angiotensin system blockers (i.e., angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers); SV, stroke volume.
However, when diuretics are prescribed in low dosages, it is o ten possible to accrue the
desired antihypertensive e ect while minimizing adverse complications.
Sympatholytic agents include (1) β-blockers, (2) central α-adrenergic agonists, and (3)
systemic α-adrenergic-blocking drugs. β-Blockers are believed to lower BP through several
mechanisms, including (1) reducing CO through a decrease in HR and a mild decline in
contractility and (2) decreasing the secretion o renin (and there ore levels o angiotensin II),
which leads to a reduction in TPR. β-Blockers are less e ective than diuretics in elderly and
A rican American hypertensive patients. Adverse e ects o β-blockers include bronchospasm
(because o bronchiolar β2-receptor blockade), atigue, impotence, and hyperglycemia. They
may also adversely alter lipid metabolism. Most β-blockers cause an increase in serum triglyceride levels and a decrease in “good” HDL cholesterol levels. However, β-blockers with intrinsic sympathomimetic activity (see Chapter 17) or those with combined α- and β-blocking
properties (such as labetalol) do not adversely a ect HDL levels.
Centrally acting α 2-adrenergic agonists, such as methyldopa and clonidine, reduce sympathetic outf ow to the heart, blood vessels, and kidneys. These are now rarely used owing to
their high requency o side e ects (e.g., dry mouth, sedation). Systemic α 1-antagonists, such
as prazosin, terazosin, and doxazosin, cause a decrease in TPR through relaxation o vascular
smooth muscle. They may be use ul or hypertension in some older men because the drugs
also improve symptoms o prostatic enlargement. However, they are otherwise not o ten recommended or treatment o hypertension because a major clinical trial showed that diuretic
therapy is superior to an α1-antagonist in the prevention o adverse cardiovascular events.
Peripheral vasodilators include calcium channel blockers, hydralazine, and minoxidil.
Calcium channel blockers reduce the inf ux o Ca + + responsible or cardiac and vascular
smooth muscle contraction, thus reducing cardiac contractility and TPR (see Chapter 17).
Clinical trials in patients with hypertension have shown that calcium channel blockers reduce
the risk o myocardial in arction and stroke. Thus, long-acting (i.e., sustained-release drugs
taken once a day) members o this group are requently used to treat hypertension. Shorteracting calcium channel blocker preparations are not used or this purpose; they are less convenient and have actually been associated with adverse cardiovascular outcomes (see Chapter 6).
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Hypertension
331
Hydralazine and minoxidil lower BP by directly relaxing vascular smooth muscle o
precapillary resistance vessels. However, the resultant vasodilatation can result in a ref ex
increase in HR, so that combined β-blocker therapy is requently necessary. The use o these
direct vasodilators in treating hypertension has waned with the advent o newer agents with
ewer side e ects.
Drugs that inter ere with the renin–angiotensin–aldosterone system include ACE inhibitors, angiotensin II receptor blockers, and direct renin inhibitors. ACE inhibitors decrease BP
by blocking the conversion o angiotensin I to angiotensin II (see Fig. 17-6), thereby reducing
the vasopressor e ect o angiotensin II and the secretion o aldosterone. As a result, peripheral vascular resistance alls and sodium retention by the kidney declines. An additional
antihypertensive e ect o ACE inhibitors occurs via an increase in the concentration o the circulating vasodilator bradykinin (see Fig. 17-6). ACE inhibitors are important drugs that have
been shown to reduce mortality rates in patients ollowing an acute myocardial in arction, in
patients with chronic heart ailure with reduced ejection raction (see Chapter 9), and even in
people at high risk or developing cardiovascular disease. The drugs also slow the deterioration o renal unction in patients with diabetic nephropathy. The most common side e ect o
ACE inhibitors is the development o a reversible dry cough (likely related to the increased
bradykinin e ect); hyperkalemia and azotemia may also occur, as described in Chapter 17.
Angiotensin II receptor blockers (ARBs) block the binding o angiotensin II to its receptors (i.e., subtype AT1 receptors) in blood vessels and other targets (see Fig. 17-6). By inhibiting the e ects o angiotensin II (and thereby causing vasodilatation and reduced secretion o
aldosterone), BP alls. In clinical trials, the antihypertensive e cacy o this group is similar to
that o ACE inhibitors. They are very well-tolerated drugs, and unlike ACE inhibitors, cough is
not a common side e ect. Like ACE inhibitors, ARBs have been shown to reduce cardiovascular event rates (including myocardial in arction and stroke) in high-risk patients.
The oral direct renin inhibitor aliskiren reduces levels o angiotensin I and angiotensin
II by binding to the proteolytic site o renin, thus inhibiting cleavage o angiotensinogen.
Antihypertensive e ectiveness is no greater than that o other drugs that inhibit the renin–
angiotensin–aldosterone axis and long-term e ects on cardiovascular event rates are not yet
known.
Given the large number o e ective antihypertensive medications that are available, the
choice o which drug to use as initial therapy in an individual patient can seem daunting. Besides the exceptions noted above, clinical trial data reveal little di erence between
antihypertensive agents on cardiovascular outcomes in the average hypertensive subject
as long as equivalent decreases in BP are achieved. As o this writing, national guidelines
recommend the use o either a thiazide diuretic, calcium channel blocker, ACE inhibitor, or
an ARB as equally e ective rst-line treatment options or EH. Thiazide diuretics remain
among the most popular choices by health care providers because o long-proven bene ts
and low cost. In certain circumstances, or i initial therapy with a single agent is not su cient, another type o antihypertensive should be substituted or added (Table 13-5). For
example, an ACE inhibitor would be given prime consideration in patients with hypertension who also have chronic heart ailure, diabetes, or LV dys unction ollowing myocardial
in arction. A β-blocker would be an appropriate choice in a patient with concurrent ischemic heart disease.
There are some other guiding principles. First, the chosen drug regimen should con orm to
the patient’s speci c needs. For example, an anxious young patient in the throes o the hyperkinetic phase o EH might be treated with a β-blocker, whereas a more e ective choice or the
same patient many years later, a ter the pressure becomes more dependent on peripheral vascular resistance, could be a vasodilator (e.g., long-acting calcium channel blocker). Because
therapy is likely to continue or many years, consideration o adverse e ects and impact o
drug therapy on the patient’s quality o li e are very important.
332
Chapter 13
TABLE 13-5
Indications or Specif c Antihypertensive Medications
Concurrent Condition
Initial Therapy Drug Classes
Heart failure
Diuretics
β-Blockers
ACE inhibitors
Angiotensin II receptor blockers
Aldosterone antagonists (e.g., spironolactone—see Chapter 9)
β-Blockers
ACE inhibitors
Angiotensin II receptor blockers
Aldosterone antagonists
ACE inhibitors
Angiotensin II receptor blockers
Calcium channel blockers
ACE inhibitors
Angiotensin II receptor blockers
Postmyocardial infarction
Diabetes
Chronic kidney disease
ACE, angiotensin-converting enzyme.
Another principle o antihypertensive drug therapy concerns the use o multiple agents. The
e ects o one drug, acting at one physiologic control point, can be de eated by natural compensatory mechanisms. For example, the drop in renal per usion by a direct vasodilator can activate the renin–angiotensin system, prompting the kidney to retain volume, thereby blunting
the antihypertensive benef t. Combination drug therapy is aimed at preventing such an action
by using agents acting at di erent complementary sites. In this example, a direct vasodilator is
o ten paired with a low-dose diuretic to avoid the undesired volume expansion e ect.
In conclusion, hypertension emerges as a tremendously important clinical problem because
o its prevalence and potentially devastating consequences. The evaluation and treatment o
a patient with hypertension require methodical consideration o the ways in which normal
cardiovascular physiology may have gone awry. Because most patients still all into the idiopathic category o EH, there is still much room or creative thought and research in this area.
SUMMARY
• Hypertension is def ned as a chronic diastolic BP ≥ 90 mm Hg and/ or systolic BP ≥
140 mm Hg.
• Those with prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 99 mm Hg) have
an increased risk o developing def nite hypertension over time.
• Hypertension is o unknown etiology in the vast majority o patients (termed EH), and is a
diagnosis o exclusion.
• Secondary hypertension may arise rom: (1) renal abnormalities (e.g., renal parenchymal
disease and renal artery stenosis); (2) coarctation o the aorta; and (3) endocrine abnormalities (e.g., pheochromocytoma, primary or secondary aldosteronism, Cushing syndrome, and
thyroid abnormalities).
• Most hypertensive patients remain asymptomatic until complications arise.
• Potential complications include stroke, myocardial in arction, heart ailure, aortic aneurysm
and dissection, renal damage, and retinopathy.
• Treatment o hypertension includes li estyle and dietary improvements and pharmacologic
therapy.
• The most commonly recommended antihypertensive drugs include diuretics, ACE, angiotensin receptor blockers, long-acting calcium channel blockers, and sometimes β-blockers.
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333
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Christopher T. Lee, MD; Payman
Zamani, MD; Rajeev Malhotra, MD; Rahul Deshmukh, MD; Allison McDonough, MD;
Rajesh S. Magrulkar, MD; Peter A. Nigrovic, MD; and Thomas J. Moore, MD.
Ad d i t i o n a l Rea d i n g
Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical
therapy or atherosclerotic renal-artery stenosis. N Engl J
Med. 2014;370:13–22.
Franceschini N, Reiner AP, Heiss G. Recent f ndings in the
genetics o blood pressure and hypertension traits. Am J
Hypertens. 2011;24:392–400.
Go AS, Bauman MA, Coleman King SM, et al. An e ective
approach to high blood pressure control: a science advisory
rom the American Heart Association, the American College
o Cardiology, and the Centers or Disease Control and
Prevention. Hypertension. 2014;63:878–885.
James PA, Oparil S, Carter BL, et al. Evidence-based guideline
or the management o high blood pressure in adults: report
rom the panel members appointed to the Eighth Joint
National Committee (JNC 8). JAMA. 2014;311:507–520.
Raman SV. The hypertensive heart: an integrated understanding in ormed by imaging. J Am Coll Cardiol. 2010;55:91–96.
Weber MA, Schi rin EL, White WB, et al. Clinical practice guidelines or the management o hypertension in
the community: a statement by the American Society o
Hypertension and the International Society o Hypertension.
J Clin Hypertension. 2014;16:14–26.
Diseases of the
Pericardium
14
Leona rd S. Lilly
Ch a p t e r O u t l i n e
Anatomy and Function
Acute Pericarditis
Etiology
Pathology
Clinical Features
Diagnostic Studies
Treatment
Pericardial Effusion
Etiology
Pathophysiology
Clinical Features
Diagnostic Studies
Treatment
Cardiac Tamponade
Etiology
Pathophysiology
Clinical Features
Diagnostic Studies
Treatment
Constrictive Pericarditis
Etiology and Pathogenesis
Pathology
Pathophysiology
Clinical Features
Diagnostic Studies
Treatment
D
iseases of the pericardium form a spectrum that ranges
from benign, self-limited pericarditis to life-threatening
cardiac tamponade. The clinical manifestations of these disorders and approaches to their management can be predicted
from an understanding of pericardial anatomy and pathophysiology, as presented in this chapter.
ANATOMY AND FUNCTION
The pericardium is a two-layered sac that encircles the
heart. The inner serosal layer (visceral pericardium) adheres
to the outer wall o the heart and is re ected back on itsel ,
at the level o the great vessels, to line the tough f brous
outer layer (parietal pericardium). A thin f lm o pericardial uid slightly separates the two layers and decreases the
riction between them.
The pericardium appears to serve three unctions: (1) it
f xes the heart within the mediastinum and limits its motion,
(2) it prevents extreme dilatation o the heart during sudden rises o intracardiac volume, and (3) it may unction
as a barrier to limit the spread o in ection rom the adjacent lungs. However, patients with complete absence o the
pericardium (either congenitally or a ter surgical removal)
are generally asymptomatic, casting doubt on its actual
importance in normal physiology. Yet like the unnecessary
appendix, the pericardium can become diseased and cause
great harm.
In the healthy heart, intrapericardial pressure varies during the respiratory cycle rom − 5 mm Hg (during inspiration) to + 5 mm Hg (during expiration) and nearly equals
the pressure within the pleural space. However, pathologic
changes in pericardial sti ness, or the accumulation o
uid within the pericardial sac, may pro oundly increase
this pressure.
334
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Diseases of the Pericardium 335
ACUTE PERICARDITIS
The most common a iction o the pericardium is acute pericarditis, which re ers to in ammation o its layers. Many disease states and etiologic agents can produce this syndrome
(Table 14-1), the most requent o which are described here.
Etiology
Infectious
Idiopathic and Viral Pericarditis
Acute pericarditis is most o ten o idiopathic origin, meaning that the actual cause is unknown.
However, serologic studies have demonstrated that many such episodes are actually caused
by viral in ection, especially by echovirus or coxsackievirus group B. Although a viral origin
could be conf rmed in in ected patients by comparing antiviral titers o acute and convalescent serum, this is rarely done in the clinical setting because the patient has usually recovered
by the time those results would be available. Thus, idiopathic and viral pericarditis are considered similar clinical entities, and the terms are used interchangeably.
Other viruses known to cause pericarditis include those responsible or in uenza, varicella, mumps, hepatitis B, and in ectious mononucleosis. Pericarditis is the most common
mani estation o cardiovascular disease in patients with AIDS, arising rom HIV in ection
itsel or rom superimposed tuberculous or other bacterial in ections in this immunocompromised population.
Tuberculous Pericarditis
Although tuberculosis remains a worldwide problem, its incidence in the United States is low.
It is, however, an important cause o pericarditis in immunosuppressed patients. Tuberculous
pericarditis arises rom reactivation o the organism in mediastinal lymph nodes, with spread
into the pericardium. It can also extend directly rom a site o tuberculosis within the lungs,
or the organism can arrive at the pericardium by hematogenous dissemination.
Nontuberculous Bacterial Pericarditis (Purulent Pericarditis)
Bacterial pericarditis is a ulminant illness but is rare in otherwise healthy persons; it is
most likely to occur in immunocompromised patients, including those with severe burns
and malignancies. Pneumococci and staphylococci are responsible most requently, whereas
TABLE 14-1
Causes of Acute Pericarditis
Infectious
Viral
Tuberculosis
Pyogenic bacteria
Noninfectious
Postmyocardial infarction or after cardiac surgery
Uremia
Neoplastic disease
Radiation induced
Connective tissue diseases
Drug induced
336
Chapter 14
gram-negative in ection occurs less o ten. Mechanisms by which bacterial invasion o
the pericardium develops include (1) per orating trauma to the chest (e.g., stab wound);
(2) contamination during chest surgery; (3) extension o an intracardiac in ection (i.e.,
in ective endocarditis); (4) extension o pneumonia or a subdiaphragmatic in ection; and
(5) hematogenous spread rom a remote in ection.
Noninfectious
Pericarditis following Myocardial Infarction
There are two orms o pericarditis associated with acute myocardial in arction (MI). The
early type occurs within the f rst ew days a ter an MI. It likely results rom in ammation
extending rom the epicardial sur ace o the injured myocardium to the adjacent pericardium;
there ore, it is more common in patients with transmural (as opposed to subendocardial)
in arctions. The prognosis ollowing acute MI is not a ected by the presence o pericarditis;
its major importance is in distinguishing it rom the pain o recurrent myocardial ischemia.
This orm o pericarditis occurs in ewer than 5% o patients with acute MI who are treated
with acute reper usion strategies (see Chapter 7), but it is more common in those who are not
(and who, there ore, sustain larger in arctions).
The second orm o post-MI pericarditis is known as Dressler syndrome, which can develop
2 weeks to several months ollowing an acute in arction. Its cause is unknown, but it is
thought to be o autoimmune origin, possibly directed against antigens released rom necrotic
myocardial cells. Dressler syndrome has become very rare since the advent o reper usion
therapies or acute MI. A clinically similar orm o pericarditis may occur weeks to months
ollowing heart surgery, termed postpericardiotomy pericarditis.
Uremic Pericarditis
Pericarditis is a potentially serious complication o untreated chronic renal ailure. While its
pathogenesis in this setting is unknown, it has become uncommon with the widespread availability o dialysis. Pericarditis may also appear or the f rst time in patients already treated
with chronic dialysis therapy, and o ten responds to intensif cation o dialysis.
Neoplastic Pericarditis
Tumor involvement o the pericardium most commonly results rom metastatic spread or
local invasion by cancer o the lung, breast, or lymphoma. Primary tumors o the pericardium
are rare. Neoplastic e usions are usually large and hemorrhagic and requently lead to cardiac
tamponade, a li e-threatening complication described later in the chapter.
Radiation-Induced Pericarditis
Pericarditis may complicate radiation therapy to the thorax (e.g., administered or the treatment o certain tumors), especially i the cumulative dose has exceeded 4,000 cGy. Radiationinduced damage causes a local in ammatory response that can result in pericardial e usions
and ultimately f brosis. Cytologic examination o the pericardial uid helps to distinguish
radiation-induced pericardial damage rom that o tumor invasion.
Pericarditis Associated with Connective Tissue Diseases
Pericardial involvement is common in many connective tissue diseases, including systemic
lupus erythematosus (SLE), rheumatoid arthritis, and progressive systemic sclerosis. For
example, 20% to 40% o patients with SLE experience clinically detectable pericarditis during
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Diseases of the Pericardium 337
the course o the disease. Customary treatment o the underlying connective tissue disease
usually ameliorates the pericarditis as well.
Drug-Induced Pericarditis
Several pharmaceutical agents can cause pericarditis as a side e ect, o ten by inducing a
systemic lupus-like syndrome (Table 14-2). These drugs include the antiarrhythmic procainamide and the vasodilator hydralazine. Drug-induced pericarditis usually abates when the
causative agent is discontinued.
Pathogenesis
Similar to other in ammatory processes, pericarditis is characterized by three stages: (1) local
va sodila tion with transudation o protein-poor, cell- ree uid into the pericardial space;
(2) in crea sed va scula r permea bility, with leak o protein into the pericardial space; and
(3) leukocyte exudation, initially by neutrophils, ollowed later by mononuclear cells.
The leukocytes are o critical importance because they help contain or eliminate the o ending in ectious or autoimmune agent. However, metabolic products released by these cells may
prolong in ammation, cause pain and local cellular damage, and mediate somatic symptoms
such as ever. There ore, the immune response to pericardial injury may signif cantly contribute to tissue damage and symptomatology.
Pathology
The pathologic appearance o the pericardium depends on the underlying cause and severity
o in ammation. Serous pericarditis is characterized by scant polymorphonuclear leukocytes, lymphocytes, and histiocytes. The exudate is a thin uid secreted by the mesothelial
cells lining the serosal sur ace o the pericardium. This likely represents the early in ammatory response common to all types o acute pericarditis.
Serof brinous pericarditis is the most commonly observed morphologic pattern in
patients with pericarditis. The pericardial exudate contains plasma proteins, including f brinogen, yielding a grossly rough and shaggy appearance (termed “bread and butter” pericarditis). Portions o the visceral and parietal pericardium may become thickened and used.
Occasionally, this process leads to a dense scar that restricts movement and diastolic f lling o
the cardiac chambers, as described later in the chapter.
Suppurative (or purulent) pericarditis is an intense in ammatory response associated
most commonly with bacterial in ection. The serosal sur aces are erythematous and coated
with purulent exudate. Hemorrhagic pericarditis re ers to a grossly bloody orm o pericardial in ammation and is most o ten caused by tuberculosis or malignancy.
TABLE 14-2
Examples of Drug-Induced Pericarditis
Related to drug-induced SLE-like syndrome
Procainamide
Hydralazine
Methyldopa
Isoniazid
Phenytoin
Not related to drug-induced SLE-like syndrome
Anthracycline antineoplastic agents (doxorubicin, daunorubicin)
Minoxidil
SLE, systemic lupus erythematosus.
338
Chapter 14
TABLE 14-3
Clinical Features of Acute Pericarditis
Pleuritic chest pain
Fever
Pericardial friction rub
ECG abnormalities
ECG, electrocardiogram.
Clinical Features
History
The most requent symptoms o acute pericarditis are chest pain and fever (Table 14-3). The
pain may be severe and usually localizes to the retrosternal area and le t precordium; it may
also radiate to the back and to the ridge o the le t trapezius muscle. What di erentiates it
rom myocardial ischemia or in arction is that the pain o pericarditis is typically sharp, pleuritic (it is aggravated by inspiration and coughing), and positional (e.g., sitting and leaning
orward o ten lessen the discom ort). Dyspnea is common during acute pericarditis but is not
exertional and probably results rom a reluctance o the patient to breathe deeply because o
pleuritic pain.
Patients with idiopathic or viral pericarditis are typically young and previously healthy.
Pericarditis o other causes should be suspected in patients with the underlying conditions
listed in Table 14-1 who develop the typical sharp, pleuritic chest pains and ever.
Physical Examination
A scratchy pericardial friction rub is common in acute pericarditis and is believed to be produced by the movement o the in amed pericardial layers against one another. Auscultation
o the rub is best heard using the diaphragm o the stethoscope with the patient leaning orward while exhaling (which brings the pericardium closer to the chest wall and stethoscope).
In its ull orm, the rub consists o three components, corresponding to the phases o greatest cardiac movement: ventricular contraction, ventricular relaxation, and atrial contraction.
Characteristically, the pericardial rub is evanescent, coming and going rom one examination
to the next.
Diagnostic Studies
The presence o pleuritic, positional chest pain and the characteristic pericardial riction rub
implicate the presence o acute pericarditis. However, certain laboratory studies are help ul to
conf rm the diagnosis and to assess or impending complications.
The electrocardiogram (ECG) is abnormal in 90% o patients with acute pericarditis and
helps to distinguish it rom other orms o cardiac disease, such as an acute coronary syndrome. The most important ECG pattern, which re ects in ammation o the adjacent myocardium, consists o diffuse ST-segment elevation in most o the ECG leads, usually with the
exception o aVR and V1 (Fig. 14-1). In addition, PR-segment depression in several leads is
o ten evident, re ecting abnormal atrial repolarization related to atrial epicardial in ammation. These abnormalities are in contrast to the ECG o acute ST-segment elevation MI, in
which the ST segments are elevated only in the leads overlying the region o in arction, and
PR depression is not expected.
Blood studies typically reveal signs o acute in ammation, including an increased white
blood cell count (usually a mild lymphocytosis in acute viral/ idiopathic pericarditis) and
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Diseases of the Pericardium 339
FIGURE 14-1. Electrocardiogram in acute pericarditis. Diffuse ST-segment elevation is present. Also notice
depression of the PR segment (arrow).
elevation o serum in ammatory markers (e.g., erythrocyte sedimentation rate and C-reactive
protein). Some patients with acute pericarditis also demonstrate elevated serum cardiac biomarkers (e.g., cardiac troponins), suggesting in ammation o the neighboring myocardium.
Further testing in acute pericarditis o ten includes echocardiography to evaluate or the presence and hemodynamic signif cance o a pericardial e usion. Additional studies that may be
use ul in individual cases to def ne the cause o pericarditis include (1) purif ed protein derivative skin test or tuberculosis, (2) serologic tests (antinuclear antibodies and rheumatoid actor) to screen or connective tissue diseases, and (3) a care ul search or malignancy, especially
o the lung and breast (physical examination supplemented by chest radiography and mammography). The yield o diagnostic pericardiocentesis (removal o pericardial uid through a
needle) in uncomplicated acute pericarditis is low and should be reserved or patients with
very large e usions or evidence o cardiac chamber compression, as described below.
Treatment
Idiopathic or viral pericarditis is a sel -limited disease that usually runs its course in 1 to
3 weeks. Management consists o rest, to reduce the interaction o the in amed pericardial
layers, and pain relief by analgesic and anti-in ammatory drugs (aspirin, ibupro en, and other
nonsteroidal anti-in ammatory agents). Colchicine, a drug with anti-in ammatory properties
usually used to treat gout, may be use ul as an additional agent in acute pericarditis. It has
been shown to decrease the recurrence rate a ter an initial episode. Oral corticosteroids are
e ective or severe or recurrent pericardial pain but should not be used in uncomplicated
cases because o potentially signif cant side e ects and because steroid use is associated with
an increased rate o recurrent episodes o pericarditis.
The orms o pericarditis related to MI are treated in a similar ashion, with rest and aspirin. Other nonsteroidal anti-in ammatory agents are o ten avoided immediately ollowing an
MI because o experimental evidence linking them to delayed healing o the in arct.
Purulent pericarditis requires more aggressive treatment, including catheter drainage o
the pericardium and intensive antibiotic therapy. Nevertheless, even with such therapy, the
mortality rate is very high. Tuberculous pericarditis requires prolonged multidrug antituberculous therapy. Pericarditis in the setting o uremia o ten resolves ollowing intensive dialysis.
Neoplastic pericardial disease usually indicates widely metastatic cancer, and therapy is
un ortunately only palliative.
340
Chapter 14
PERICARDIAL EFFUSION
Etiology
The normal pericardial space contains 15 to 50 mL o pericardial uid, a plasma ultraf ltrate
secreted by the mesothelial cells that line the serosal layer. A larger volume o uid may accumulate in association with any o the orms o acute pericarditis previously described.
In addition, nonin ammatory serous e usions may result rom conditions o (1) increased
capillary permeability (e.g., severe hypothyroidism), (2) increased capillary hydrostatic pressure (e.g., congestive heart ailure), or (3) decreased plasma oncotic pressure (e.g., cirrhosis or
the nephrotic syndrome). Chylous e usions may occur in the presence o lymphatic obstruction o pericardial drainage, most commonly caused by neoplasms and tuberculosis.
Pathophysiology
A
B
P
e
r
i
c
a
(
r
(
m
d
i
m
a
m
l
m
p
H
r
g
H
e
)
g
s
)
s
u
r
u
e
Because the pericardium is a relatively sti structure, the relationship between its internal
volume and pressure is not linear, as shown in curve A in Figure 14-2. Notice that the initial
portion o the curve is nearly at, indicating that at the low volumes normally present within
the pericardium, a small increase in volume leads to only a small rise in pressure. However,
when the intrapericardial volume expands beyond a critical level (see Fig. 14-2, arrow), a
dramatic increase in pressure is incited by the nondistensible sac. At that point, even a minor
increase in volume can translate into an enormous compressive orce on the heart.
Three actors determine whether a pericardial e usion remains clinically silent or whether
symptoms o cardiac compression ensue: (1) the volume o uid, (2) the rate at which the
uid accumulates, and (3) the compliance characteristics o the pericardium.
A sudden increase o pericardial volume, as may occur in chest trauma with intrapericardial hemorrhage, results in marked elevation o pericardial pressure (see Fig. 14-2, steep
portion o curve A) and the potential or severe cardiac chamber compression. Even lesser
amounts o uid may cause signif cant elevation o pressure i the pericardium is pathologically
Tota l pe rica rdia l volume (mL)
FIGURE 14-2. Schematic representation of the volume–pressure relationship of normal pericardium.
A. At the very lowest levels, a small rise in volume results in a small rise in pressure. However, when the
limits o pericardial stretch are reached (arrow), the curve becomes very steep, and a urther small rise in
intrapericardial volume results in signif cantly increased pressure. B. Chronic slow accumulation o volume
allows the pericardium to gradually stretch over time; thus, the curve shi ts to the right and much larger
volumes are accommodated at lower pressures. (Modif ed rom Freeman GL, LeWinter MM. Pericardial
adaptations during chronic dilation in dogs. Circ Res. 1984;54:294.)
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Diseases of the Pericardium 341
TABLE 14-4
Clinical Features of Large Pericardial Effusion
Soft heart sounds
Reduced intensity of friction rub
Ewart sign (dullness over posterior left lung)
noncompliant and sti , as may occur in the presence o tumor or f brosis o the sac. In
contrast, i the pericardial e usion accumulates slowly, over weeks to months, the pericardium gradually stretches, such that the volume–pressure relationship curve shi ts toward the
right (see Fig. 14-2, curve B). With this adaptation, the pericardium can accommodate larger
volumes without marked elevation o intrapericardial pressure.
Clinical Features
A spectrum o possible symptoms is associated with pericardial e usions. For example, the
patient with a large e usion may be asymptomatic, may complain o a dull constant ache in
the le t side o the chest, or may present with f ndings o cardiac tamponade, as described
later in the chapter. In addition, the e usion may cause symptoms resulting rom compression o adjacent structures, such as dysphagia (di f culty swallowing because o esophageal
compression), dyspnea (shortness o breath resulting rom lung compression), hoarseness
(due to recurrent laryngeal nerve compression), or hiccups (resulting rom phrenic nerve
stimulation).
On examination (Table 14-4), a large pericardial uid “insulates” the heart rom the chest
wall, and the heart sounds may be mu ed. In act, a riction rub that had been present during the acute phase o pericarditis may disappear i a large e usion develops and separates
the in amed layers rom one another. Dullness to percussion o the le t lung over the angle
o the scapula may be present (known as the Ewart sign) owing to compressive atelectasis by
the enlarged pericardial sac.
Diagnostic Studies
The chest ra diogra ph may be normal i only a small pericardial e usion is present.
However, i more than approximately 250 mL has accumulated, the cardiac silhouette
enlarges in a globular, symmetric ashion. In large e usions, the ECG may demonstrate
reduced voltage o the complexes. In the presence o very large e usions, the height o
the QRS complex may vary rom beat to beat (electrica l a ltern a n s), a result o a constantly
changing electrical axis as the heart swings rom side to side within the large pericardial
volume (Fig. 14-3).
FIGURE 14-3. Electrical alternans. Rhythm strip of lead V1 showing alternating height of the QRS complex
from beat to beat, due to shifting of the cardiac axis as the heart swings within a large pericardial effusion.
342
Chapter 14
One o the most use ul laboratory tests
in the evaluation o an e usion is echocardiography (Fig. 14-4), which can identi y
pericardial collections as small as 20 mL.
This noninvasive technique can quanti y
the volume o pericardial uid, determine
whether ventricular f lling is compromised,
and when necessary, help direct the placement o a pericardiocentesis needle.
PE
LV
Treatment
I the cause o the e usion is known,
therapy is directed toward the underlying
disorder (e.g., intensive dialysis or ureFIGURE 14-4. Two-dimensional echocardiogram
mic e usion). I the cause is not evident,
( parasternal short-axis view) of a pericardial
the clinical state o the patient determines effusion ( PE) surrounding the heart. LV, left
wh eth er pericardiocen tesis (rem oval o
ventricle.
pericardial uid) should be undertaken.
An asymptomatic e usion, even o large volume, can be observed or long periods without
specif c intervention. However, i serial examination demonstrates a precipitous rise in pericardial volume or i hemodynamic compression o the cardiac chambers becomes evident,
then pericardiocentesis should be per ormed or therapeutic drainage and or analysis o
the uid.
CARDIAC TAMPONADE
At the opposite end o the spectrum rom the asymptomatic pericardial e usion is cardiac
tamponade. In this condition, pericardial uid accumulates under high pressure, compresses
the cardiac chambers, and severely limits f lling o the heart. As a result, ventricular stroke
volume and cardiac output decline, potentially leading to hypotensive shock and death.
Etiology
Any etiology o acute pericarditis (see Table 14-1) can progress to cardiac tamponade, but
the most common causes are neoplastic, postviral, and uremic pericarditis. Acute hemorrhage into the pericardium is also an important cause o tamponade, which can result
(1) rom blunt or penetrating chest trauma, (2) rom rupture o the le t ventricular (LV) ree
wall ollowing MI (see Chapter 7), or (3) as a complication o a dissecting aortic aneurysm
(see Chapter 15).
Pathophysiology
As a result o the surrounding tense pericardial uid, the heart is compressed, and the diastolic pressure within each chamber becomes elevated and equal to the pericardial pressure.
The pathophysiologic consequences o this are illustrated in Figure 14-5. Because the compromised cardiac chambers cannot accommodate normal venous return, the systemic and
pulmonary venous pressures rise. The increase o systemic venous pressure results in signs
o right-sided heart ailure (e.g., jugular venous distention), whereas elevated pulmonary
venous pressure leads to pulmonary congestion. In addition, reduced f lling o the ventricles
during diastole decreases the systolic stroke volume, and the cardiac output declines.
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Diseases o the Pericardium 343
Ca rdia c ta mpona de
Cons trictive pe rica rditis
Pe rica rdia l fluid unde r
pre s s ure
S ca rre d, rigid
pe rica rdium
Impa ire d
dia s tolic filling
of ve ntricle s
Eleva te d ve nous
pre s s ure s
Sys te mic ve nous
conge s tion
Impa ire d s troke
volume
Pulmona ry ve nous
conge s tion
De cre a s e d ca rdia c
output
Hypote ns ion
Jugula r ve nous dis te ntion
He pa tome ga ly & a s cite s
Pe riphe ra l e de ma
Pulmona ry
ra le s
Re flex ta chyca rdia
FIGURE 14-5. Pathophysiology of cardiac tamponade and constrictive pericarditis. The symptoms and
signs (orange boxes) arise rom impaired diastolic f lling o the ventricles in both conditions.
These derangements trigger compensatory mechanisms aimed at maintaining tissue per usion, initially through activation o the sympathetic nervous system (e.g., increased heart rate
and contractility). Nonetheless, ailure to evacuate the e usion leads to inadequate per usion
o vital organs, shock, and ultimately death.
Clinical Features
Cardiac tamponade should be suspected in any patient with known pericarditis, pericardial
e usion, or chest trauma who develops signs and symptoms o systemic vascular congestion
and decreased cardiac output (Table 14-5). The key physical f ndings include (1) jugular
venous distention, (2) systemic hypotension, and (3) a “small, quiet heart” on physical examination, a result o the insulating e ects o the e usion. Other signs include sinus tachycardia
and pulsus paradoxus (described later). Dyspnea and tachypnea re ect pulmonary congestion and decreased oxygen delivery to peripheral tissues.
I tamponade develops suddenly, symptoms o pro ound hypotension are evident, including con usion and agitation. However, i the e usion develops more slowly, over a period o
weeks, then atigue (caused by low cardiac output) and peripheral edema (owing to rightsided heart ailure) may be the presenting complaints.
TABLE 14-5
Clinical Features of Cardiac Tamponade
Jugular venous distention
Hypotension with pulsus paradoxus
Quiet precordium on palpation
Sinus tachycardia
344
Chapter 14
BOX 14-1
Measurement of Pulsus Paradoxus at the Bedside
Pulsus paradoxus is an exaggeration o the normal decline in systolic blood pressure that occurs
with inspiration. It can be measured at the bedside using a manual sphygmomanometer. First,
inf ate the sphygmomanometer to a level greater than the patient’s systolic pressure. As the cu is
slowly def ated, care ully listen or the appearance o the rst Korotko sounds. This level marks the
maximum systolic pressure and occurs during expiration. I the pressure is held at that level (i.e.,
i you stop def ating the cu ) in a patient with pulsus paradoxus, the Korotko sounds will dri t in
and out, audible with expiration, and absent with inspiration. That is, the systolic pressure will all
during inspiration to a level below the cu ’s pressure and no sound will be heard during that time.
Next, slowly def ate the cu and continue listening. When the cu pressure alls to the level just
below the patient’s systolic pressure during inspiration, the Korotko sounds stop dri ting in and
out (i.e., they are audible during both inspiration and expiration). Pulsus paradoxus is calculated as
the di erence between the initial systolic pressure (when the intermittent Korotko sounds are rst
heard) and this pressure (when the sounds are rst audible throughout the respiratory cycle). In the
presence o cardiac tamponade, this pressure di erence is greater than 10 mm Hg.
Pulsus paradoxus is an important physical sign in cardiac tamponade that can be recognized at the bedside using a standard blood pressure cu . It re ers to a decrease of systolic
blood pressure (more than 10 mm Hg) during normal inspiration (see Box 14-1).
Pulsus paradoxus is not really “paradoxical”; it is just an exaggeration o appropriate cardiac physiology. Normally, expansion o the thorax during inspiration causes the intrathoracic
pressure to become more negative compared with the expiratory phase. This acilitates systemic venous return to the chest and augments f lling o the right ventricle (RV). The transient
increase in RV size shi ts the interventricular septum toward the le t, which diminishes LV
f lling. As a result, in normal persons, LV stroke volume and systolic blood pressure decline
slightly ollowing inspiration.
In cardiac tamponade, this situation is exaggerated because both ventricles share a reduced,
f xed volume as a result o external compression by the tense pericardial uid. In this case, the
inspiratory increase o RV volume and bulging o the interventricular septum toward the le t
have a proportionally greater e ect on the limitation o LV f lling. Thus, in tamponade, there
is a more substantial reduction o LV stroke volume (and there ore systolic blood pressure)
ollowing inspiration.
Pulsus paradoxus may also be mani ested by other conditions in which inspiration is exaggerated, including severe asthma and chronic obstructive airway disease.
Diagnostic Studies
Echocardiography is the most use ul noninvasive technique to evaluate whether pericardial e usion has led to cardiac tamponade physiology. An important indicator o high-pressure pericardial uid is compression o the RV and right atrium during diastole (see Fig. 3-12). In addition,
echocardiography can di erentiate between cardiac tamponade and other causes o low cardiac
output, such as ventricular contractile dys unction. The def nitive diagnostic procedure or cardiac tamponade is cardiac catheterization with measurement o intracardiac and intrapericardial
pressures, usually combined with therapeutic pericardiocentesis, as described in the next section.
Treatment
Removal o the high-pressure pericardial uid is the only intervention that reverses the li ethreatening physiology o this condition. Pericardiocentesis is best per ormed in the cardiac
catheterization laboratory, where the hemodynamic e ect o uid removal can be assessed.
The patient is positioned head up at a 45-degree angle to promote pooling o the e usion, and
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Diseases o the Pericardium 345
a needle is inserted into the pericardial space through
the skin, usually just below the xiphoid process (which
is the sa est location to avoid piercing a coronary
a
A
artery). A catheter is then threaded into the pericarv
dial space and connected to a transducer or pressure
Norma l
x
y
measurement. Another catheter is threaded through a
systemic vein into the right side o the heart, and simultaneous recordings o intracardiac and intrapericardial
pressures are compared. In tamponade, the pericardial
a
B
pressure is elevated and is equal to the diastolic presv
y
sures within all o the cardiac chambers, re ecting the
x
Ta mpona de
compressive orce o the surrounding e usion.
In addition, the right atrial pressure tracing,
which is equivalent to the jugular venous pulsation
a
observed on physical examination, displays a characC
v
teristic abnormality (Fig. 14-6). During early diastole
Cons trictive
x
y
in a normal person, as the RV pressure alls and the
pe rica rditis
tricuspid valve opens, blood quickly ows rom the
right atrium into the RV, leading to a rapid decline in
the right atrial pressure (the y descent). In tamponTricus pid
ade, however, the pericardial uid compresses the
va lve
RV and prevents its rapid expansion. Thus, the right
ope ns
atrium cannot empty quickly, and the y descent is
FIGURE 14-6. Schematic diagrams of right atrial ( or blunted.
jugular venous) pressure recordings. A. Normal. The
Following success ul pericardiocentesis, the pericarinitial a wave represents atrial contraction. The v wave
dial pressure alls to normal and is no longer equal to
ref ects passive lling o the atrium during systole,
the diastolic pressures within the heart chambers, which
when the tricuspid valve is closed. A ter the tricuspid
also decline to their appropriate levels. A ter initial aspivalve opens, the right atrial pressure alls (y descent)
ration o uid, the pericardial catheter may be le t in
as blood empties into the right ventricle. B. Cardiac
tamponade. High-pressure pericardial f uid compresses
place or 1 to 2 days to allow more complete drainage.
the heart, impairing right ventricular lling, so that
When pericardial uid is obtained or diagnostic
the y descent is blunted. C. Constrictive pericarditis.
purposes, it should be stained and cultured or bacThe earliest phase o diastolic lling is not impaired
teria, ungi, and acid- ast bacilli (tuberculosis), and
so that the y descent is not blunted. The y descent
cytologic examination should be per ormed to evaluappears accentuated because it descends rom a
ate or malignancy. Other common measurements o
higher-than-normal right atrial pressure. The right
pericardial uid include cell counts (e.g., white cell
atrial c wave (described in Chapter 2) is not shown.
count is elevated in bacterial in ections and other
in ammatory conditions) and protein and lactate dehydrogenase levels. I the concentration
ratio o pericardial protein to serum protein is greater than 0.5, or that o pericardial LDH to
serum LDH is greater than 0.6, then the uid is consistent with an exudate; otherwise, it is
more likely a transudate. When tuberculosis is suspected, it is also use ul to measure the level
o adenosine deaminase in the pericardial uid. Studies have indicated that an elevated level
is highly sensitive and specif c or tuberculosis.
I cardiac tamponade recurs ollowing pericardiocentesis, the procedure can be repeated.
In some cases, a more def nitive surgical undertaking (removal o part or all o the pericardium) is required to prevent reaccumulation o the e usion.
ECG
CONSTRICTIVE PERICARDITIS
The other major potential complication o pericardial diseases is constrictive pericarditis.
This is a condition not requently encountered but is important to understand, because it can
masquerade as other more common disorders. In addition, it is an a iction that may cause
pro ound symptoms yet is o ten ully correctable i recognized.
346
Chapter 14
Etiology and Pathogenesis
In the early part o the 20th century, tuberculosis was the major cause o constrictive pericarditis but that is much less common today in industrialized societies. The most requent
cause now is “idiopathic” (i.e., months to years ollowing presumed idiopathic or viral acute
pericarditis). However, any etiology o pericarditis can lead to this complication, including
prior radiation therapy to the le t side o the chest.
Pathology
Following an episode o acute pericarditis, any pericardial e usion that has accumulated
usually undergoes gradual resorption. However, in patients who later develop constrictive
pericarditis, the uid undergoes organization, with subsequent usion o the pericardial layers, ollowed by f brous scar ormation. In some patients, calcif cation o the adherent layers
ensues, urther sti ening the pericardium.
Pathophysiology
The pathophysiologic abnormalities in constrictive pericarditis occur during diastole; systolic
contraction o the ventricles is usually normal. In this condition, a rigid, scarred pericardium
encircles the heart and inhibits normal f lling o the cardiac chambers. For example, as blood
passes rom the right atrium into the RV during diastole, the RV size expands and quickly
reaches the limit imposed by the constricting pericardium. At that point, urther f lling is suddenly arrested, and venous return to the right heart ceases. Thus, systemic venous pressure
rises, and signs o right-sided heart ailure ensue. In addition, the impaired f lling o the le t
ventricle causes a reduction in stroke volume and cardiac output, which leads to lower blood
pressure.
Clinical Features
The symptoms and signs o constrictive pericarditis usually develop over months to years.
They result rom (1) reduced cardiac output ( atigue, hypotension, and re ex tachycardia)
and (2) elevated systemic venous pressures (jugular venous distention, hepatomegaly with
ascites, and peripheral edema). Because the most impressive physical f ndings are o ten the
insidious development o hepatomegaly and ascites, patients may be mistakenly suspected
o having hepatic cirrhosis or an intra-abdominal tumor. However, care ul inspection o the
elevated jugular veins can point to the correct diagnosis o constrictive pericarditis.
On cardiac examination, an early diastolic “knock” may ollow the second heart in patients
with severe calcif c constriction. It represents the sudden cessation o ventricular diastolic f lling imposed by the rigid pericardial sac.
In contrast to cardiac tamponade, pericardial constriction results in pulsus paradoxus
less requently. Recall that in tamponade, this f nding re ects inspiratory augmentation
o RV f lling, at the expense o LV f lling. However, in constrictive pericarditis, the negative intrathoracic pressure generated by inspiration is not easily transmitted through the
rigid pericardial shell to the right-sided heart chambers; there ore, inspiratory augmentation o RV f lling is more limited. Rather, when a patient with severe pericardial constriction inhales, the negative intrathoracic pressure draws blood toward the thorax, where it
cannot be accommodated by the constricted right-sided cardiac chambers. As a result, the
increased venous return accumulates in the intrathoracic systemic veins, causing the jugular
veins to become more distended during inspiration (Kussmaul sign). This is the opposite
o normal physiology, in which inspiration results in a declin e in jugular venous pressure,
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Diseases o the Pericardium 347
as venous return is drawn into the heart. Thus, typical f ndings in pericardial disease can
be summarized as ollows:
Pulsus paradoxus
Kussmaul sign
Constrictive Pericarditis
Cardiac Tamponade
+
+++
+++
–
Diagnostic Studies
The chest radiograph in constrictive pericarditis shows a normal or mildly enlarged cardiac
silhouette. Calcif cation o the pericardium can be detected in some patients with severe
chronic constriction. The ECG generally shows nonspecif c ST and T-wave abnormalities;
atrial arrhythmias are common.
Echocardiographic evidence o constriction is subtle. The pericardium, i well imaged, is thickened. The ventricular cavities are small and contract vigorously, but ventricular f lling terminates
abruptly in early diastole, as the chambers reach the limit imposed by the surrounding rigid shell.
Aberrant diastolic motion o the interventricular septum, and alterations o LV in ow velocities
during respiration assessed by Doppler, also re ect the abnormal pattern o diastolic f lling.
Computed tomography or magnetic resonance imaging is superior to echocardiography in the
assessment o pericardial anatomy and thickness. The presence o normal pericardial thickness
(less than 2 mm) by these modalities makes constrictive pericarditis a much less likely diagnosis.
The diagnosis o constrictive pericarditis can be conf rmed by cardiac catheterization,
which reveals our key eatures:
1. Elevation and equalization o the diastolic pressures in each o the cardiac chambers.
2. An early diastolic “dip and plateau” conf guration in the RV and LV tracings (Fig. 14-7).
This pattern re ects blood ow into the ventricles at the very onset o diastole, just a ter the
tricuspid and mitral valves open, ollowed by sudden cessation o f lling as urther expansion o the ventricles is arrested by the surrounding rigid pericardium.
ECG
ECG
100
100
LV
LV
g
H
m
e
r
e
RV
s
40
P
r
e
RV
P
r
s
u
r
u
s
40
e
s
60
(
m
60
(
m
m
H
g
)
80
)
80
20
P la te a u
20
Ea rly dia s tolic
filling wave
Time
A
Time
B
FIGURE 14-7. Schematic tracings of left ventricular ( LV) and right ventricular ( RV) pressures in a
normal heart ( A) and in constrictive pericarditis ( B) . In the latter situation, early diastolic ventricular
f lling abruptly halts as the volume in each ventricle quickly reaches the limit imposed by the constricting
pericardium. Throughout most o diastole, the LV and RV pressures are abnormally elevated and equal.
348
Chapter 14
3. A prominent y descent in the right atrial pressure tracing (see Fig. 14-6). A ter the tricuspid
valve opens, the right atrium quickly empties into the RV (and its pressure rapidly alls)
during the very brie period be ore f lling is arrested. This is in contrast to cardiac tamponade, in which the external compressive orce throughout the cardiac cycle prevents rapid
ventricular f lling, even in early diastole, such that the y descent is blunted.
4. During the respiratory cycle, there is discordance in the RV and LV systolic pressures (the
RV systolic pressure rises with inspiration, while that o the LV declines). This is explained
as ollows: in normal persons, the negative intrathoracic pressure induced by inspiration
causes the systolic pressure o both ventricles to decline slightly. In contrast, in constrictive
pericarditis, the heart is isolated rom the rest o the thorax by the surrounding rigid shell.
In this circumstance, negative intrathoracic pressure induced by inspiration decreases the
pressure in the pulmonary veins but not in the le t-sided cardiac chambers. This causes a
decline in the pressure gradient driving blood back to the le t side o the heart rom the pulmonary veins, such that le t ventricle f lling is diminished. Less ventricular f lling reduces
the stroke volume and results in a lower LV systolic pressure (and is the likely mechanism o
pulsus paradoxus in some patients with constrictive pericarditis). Simultaneously, because
the two ventricles share a f xed space limited by the rigid pericardium, the reduced LV
volume allows the interventricular septum to shi t toward the le t, which enlarges the RV
(this reciprocal behavior is termed ventricular interdependence). The subsequent increase
in RV f lling augments systolic pressure during inspiration. During expiration, the situation
is reversed, with the RV systolic pressure declining and that o the LV increasing.
The clinical and hemodynamic f ndings o constrictive pericarditis are o ten similar to those
o restrictive cardiomyopathy (see Chapter 10), another uncommon condition. Distinguishing
between these two syndromes is important because pericardial constriction is o ten correctable, whereas most cases o restrictive cardiomyopathy have very limited e ective treatments
(Table 14-6). An endomyocardial biopsy is sometimes necessary to distinguish between these
(the biopsy results are normal in constriction but usually abnormal in restrictive cardiomyopathy; see Chapter 10).
TABLE 14-6
Differences between Constrictive Pericarditis and
Restrictive Cardiomyopathy
Feature
Chest radiography
• Pericardial calcif cations
CT or MRI
• Thickened pericardium
Echocardiography
• Thickened pericardium
• Respiratory cycle e ect on
transvalvular Doppler velocities
Cardiac catheterization
• Equalized LV and RV diastolic
pressures
• Elevated PA systolic pressure
• E ect o inspiration on systolic
pressures
Endomyocardial biopsy
Constrictive Pericarditis
Restrictive Cardiomyopathy
Yes (25%–30% o patients)
Absent
Yes
No
Yes (but di f cult to visualize)
Exaggerated variations
No
Normal
Yes
O ten, LV > RV
Uncommon
Discordant : LV↓, RV↑
Common
Concordant: LV↓, RV↓
Normal
Abnormal (e.g., amyloid)
CT, computed tomography; LV, le t ventricle; MRI, magnetic resonance imaging; PA, pulmonary artery; RV, right
ventricle.
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Diseases of the Pericardium 349
Treatment
The only e ective treatment o severe constrictive pericarditis is surgical removal o the
pericardium. Symptoms and signs o constriction may not resolve immediately a ter surgery
because o the associated sti ness o the neighboring outer walls o the heart, but subsequent
clinical improvement is the rule in patients with otherwise intact cardiac unction. The degree
o improvement depends on the underlying etiology, with the most avorable outcomes in
patients with an idiopathic/ post–viral pericarditis origin, and the least avorable benef t when
prior radiation therapy is the cause.
SUMMARY
• Acute pericarditis is characterized by three stages: (1) local vasodilation with transudation o protein-poor, cell- ree uid into the pericardial space; (2) increased vascular
permeability, with leak o protein into the pericardial space; and (3) leukocyte exudation,
initially by neutrophils, ollowed later by mononuclear cells.
• Acute pericarditis is most o ten o idiopathic or viral cause and is usually a sel -limited
illness.
• Common clinical f ndings in acute pericarditis include pleuritic chest pain, ever, pericardial
riction rub, and di use ST-segment elevation on the ECG, o ten accompanied by PR-segment
depression.
• Treatment o common acute pericarditis (i.e., viral or idiopathic pericarditis) consists o a
nonsteroidal anti-in ammatory drug; the addition o colchicine may reduce the requency o
recurrences and shorten the duration o the acute illness.
• Glucocorticoid drugs should not be used as initial therapy or acute pericarditis as they
increase the likelihood o recurrences.
• Complications o pericarditis include cardiac tamponade (accumulation o pericardial uid
under high pressure, which compresses the cardiac chambers) and constrictive pericarditis
(restricted f lling o the heart because o the surrounding rigid pericardium).
• Distinguishing between constrictive pericarditis and restrictive cardiomyopathy is important
because pericardial constriction is o ten correctable with surgical removal o the pericardium,
whereas most cases o restrictive cardiomyopathy have very limited e ective treatments.
Ack n ow le d gm en t s
Contributors to previous editions o this chapter were Yin Ren, MD; Yanerys Ramos, MD;
Thomas G. Roberts, MD; Angela Fowler, MD; Kathy Glatter, MD; and Alan Braverman, MD.
Ad d i t i o n a l Rea d i n g
ESC Committee or Practice Guidelines. Guidelines on the diagnosis and management o pericardial diseases, executive
summary. Eur Heart J. 2004;25:587–610.
Herzog E, ed. Management of Pericardial Disease. London, UK:
Springer-Verlag; 2014.
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Diseases of the
Peripheral Vasculature
15
Sruthi Rena ti
Ma rk A. Crea ger
Ch a p t e r O u t l i n e
Diseases of the Aorta
Aortic Aneurysms
Aortic Dissection
Peripheral Artery Diseases
Peripheral Atherosclerotic
Vascular Disease
Acute Arterial Occlusion
Vasculitic Syndromes
Vasospasm: Raynaud
Phenomenon
Venous Disease
Varicose Veins
Chronic Venous Insu ciency
Venous Thromboembolism
P
eripheral vascular disease is an umbrella term that includes
a number o diverse pathologic entities that a ect arteries,
veins, and lymphatics. Although this terminology makes a distinction between the “central” coronary and “peripheral” systemic vessels, the vasculature as a whole comprises a dynamic,
integrated, and multi unctional organ system that does not
naturally comply with this semantic division.
Blood vessels serve many critical unctions. First, they
regulate the di erential distribution o blood and delivery
o nutrients and oxygen to tissues. Second, blood vessels
actively synthesize and secrete vasoactive substances that
regulate vascular tone, and antithrombotic substances that
maintain the f uidity o blood and vessel patency (see Chapters 6 and 7). Third, the vessels play an integral role in the
transport and distribution o immune cells to traumatized or
in ected tissues. Disease states o the peripheral vasculature
inter ere with these essential unctions.
Peripheral vascular diseases result rom processes that can
be grouped into three categories: (1) structural changes in the
vessel wall secondary to degenerative conditions, in ection,
or inf ammation that lead to dilatation, aneurysm, dissection, or rupture; (2) narrowing of the vascular lumen caused
by atherosclerosis, thrombosis, or inf ammation; and (3)
spasm o vascular smooth muscle. These processes can occur
in isolation or in combination.
350
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Diseases of the Peripheral Vasculature
351
DISEASES OF THE AORTA
The aorta is the largest conductance vessel o the vascular system. In adults, its diameter is
approximately 3 cm at its origin at the base o the heart. The ascending aorta, 5 to 6 cm in
length, leads to the aortic arch, rom which arise three major branches: the brachiocephalic
(which bi urcates into the right common carotid and subclavian arteries), the le t common
carotid, and the le t subclavian arteries. As the descending aorta continues beyond the arch,
its diameter narrows to approximately 2 to 2.5 cm in healthy adults. As the aorta pierces the
diaphragm, it becomes the abdominal aorta, providing arteries to the abdominal viscera
be ore bi urcating into the le t and right common iliac arteries, which supply the pelvic organs
and lower extremities.
The aorta, like other arteries, is composed o three layers (see Fig. 5-1). At the luminal
sur ace, the intima is composed o endothelial cells overlying the internal elastic lamina. The
endothelial layer is a unctional inter ace between the vasculature and circulating blood cells
and plasma. The media is composed o smooth muscle cells and a matrix that includes collagen and elastic bers. Collagen provides tensile strength that enables the vessels to withstand
high-pressure loads. Elastin is capable o stretching to 250% o its original length and con ers
a distensible quality on vessels that allows them to recoil under pressure. The adventitia is
composed primarily o collagen bers, perivascular nerves, and vasa vasorum, a rich vascular
network that supplies oxygenated blood to the aorta.
The aorta is subject to injury rom mechanical trauma because it is continuously exposed
to high pulsatile pressure and shear stress. The predominance o elastin in the media
(2:1 over collagen) allows the aorta to expand during systole and recoil during diastole. The
recoil o the aorta against the closed aortic valve contributes to the distal propagation o blood
f ow during the phase o le t ventricular relaxation. With advancing age, the elastic component o the aorta and its branches degenerates, and as collagen becomes more prominent, the
arteries sti en. Systolic bl