LSS Cardiovascular System
Alexandra Burke-Smith
Chambers, valves, conduction system and
coronary circulation
CVS 1 - Karen McCarthy (k.mccarthy@imperial.ac.uk)
1. Describe the circulatory pathway through the heart and be able to identify and name the vessels that
enter the heart and the vessels that leave the heart
2. Explain the spatial relationships of left heart chambers relative to right heart chambers, the differences
between atria and ventricles and the structural differences between right and left ventricles
3. Identify and label the components of septum (atrial septum, ventricular septum, membranous septum)
4. Identify and label the heart valves and their locations, and state the structural similarities and differences
5. Describe the components of the conduction system
6. Outline the coronary circulation and be able to identify the main coronary arteries and cardiac veins
Cardiac Position and Borders




The long axis of the heart is at an angle to the long axis (midline) of the body, with the apex (formed by the
INFEROLATERAL part of the left ventricle- the bottom part furthest away from the midline of the body) in the
left side of the body (Approx 2/3rds of the heart lies in the left side of the body)
The heart lies between the STERNUM and the SPINE
o The sternum is ANTERIOR to the right ventricle
o The spine is POSTERIOR to the left atrium
Functionally consists of two pumps separated by a partition. Each pump consists of an atrium, ventricle
separated by a valve.
o The right pump receives deoxygenated blood from the body and sends it to the lungs, and the left
pump receives oxygenated blood from the lungs and sends it to the body
The heart can be thought of as having 5 surfaces:
o Posterior surface (which is the base of the heart)
o Anterior surface (which also then forms the apex)
o Right pulmonary surface (facing the right lung)
o Left pulmonary surface (facing the left lung)
o Diaphragmatic surface (facing the diaphragm)
The posterior surface
The posterior surface consists of:
 left atrium
 Small portion of the right atrium
 PROXIMAL (beginning) parts of the great veins:
o Superior vena cava (enters top right atrium- delivering blood from body). Also known as superior
caval vein
o Inferior vena cava (enters bottom right atrium- delivering blood from body). Also known as inferior
caval vein.
o Coronary sinus (enters right atrium medial to the inferior vena cava opening delivering
deoxygenated blood draining from the coronary veins, i.e. from the heart
itself)
o Pulmonary veins (enter either side of left atrium- delivering blood from lungs)
 There are four pulmonary veins:
o Right upper
1
LSS Cardiovascular System
o
o
o
Alexandra Burke-Smith
Right lower
Left upper
Left lower
The anterior surface


The anterior surface consists of:
o Mainly the right ventricle
o Some of right atrium
o Some of left ventricle
The pulmonary trunk emerges from the right ventricle, and divided into the left and right pulmonary artery
o The pulmonary trunk has a central position, and a spiral relationship with the aorta, which emerges
from the left atrium
Cardiac Chambers
The four chambers of the heart are separated by interatrial, interventricular and atrioventricular septa:
Atrial Chambers
 Right Atrium
- Venous Sinus: superior vena cava, inferior vena cava and coronary sinus
o The inferior vena cava is guarded by the EUSTACHIAN VALVE, and the coronary sinus is also guarded
by a valve
- The right atrium can be divided into two continuous spaces, divided by the TERMINAL CREST (also known as
CRISTA TERMINALS)
- Characteristic PECTINATE muscle bundles cover the walls of the atrium on the triangular appendage in the
space anterior to the crest, known as the RIGHT AURICLE
- In the space posterior to the crest has smooth, thin walls and both venae cavae and the coronary sinus
empty into this space
 Interatrial septum
- The right and left atriums are separated by the interatrial septum
- A depression/infolding rim in the septum (just above the ORIFICE of the inferior vena cava in the RIGHT
ATRIUM) is clear – this is the OVAL FOSSA
o The oval fossa effectively is a flat valve, which prevents blood flow directly between the atrial
chambers
o The oval fossa marks a location important for foetal circulation as it allows oxygenated blood to
bypass the non-functioning lungs and enter the right atrium passing directly to the left atrium
o however when the lungs begin to function, this hole in the septum is supposed to close, however a
defect in this closure often occurs which leads to shunting of the blood between atrial chambers
o the ARTERY TO THE SINUS NODE can course within the depression/infolding between the two
chambers
 Left Atrium
- Posterior half is smooth and receives blood from the four pulmonary veins
- Anterior half is contiuous with the LEFT AURICLE, and contains pectinate muscles. However in the left
atrium, there is no distinct separation (like the terminal crest) between these two halves
2
LSS Cardiovascular System
-
Alexandra Burke-Smith
The crescent shape of the oval fossa is apparent in the anterior wall of left atrium, and is known as the
VALVE OF FORAMEN OVALE (which prevents blood flow from left to right atrium)
o However this valve may not completely fuse with the oval fossa in adults, which may leave a passage
between the two atrial chambers, leaving a PATENT FORAMEN OVALE (effectively a hole in the
septum, leading to shunting of blood between the atria)
Ventricular Chambers
Both ventricular chambers have an INLET, APICAL and OUTLET components, and constant apical TRABECULATIONS.
 Right Ventricle
- Forms most of the anterior surface of the heart, and a portion of the diaphragmatic surface
o Inlet component – the tricuspid valve and the atrioventricular septum
o Apical component – trabecular portion
o Outlet component - infidulum
- It is to the right of the right atrium, and in front of and left of the RIGHT ATRIVENTRICULAR ORIFICE; blood
therefore enters the ventricle moving in a horizontal and forward direction
- Outflow portion: PULMONARY INFIDIBULUM– leads to the pulmonary trunk – has smooth walls
- Inflow portion wall has substantial complex muscle structures called COURSE TRABECULATIONS; these are
either attached continuously to the walls forming ridges, or attached at both ends forming bridges
- Trabeculations which are only attached at one end to the ventricular surface and the other end are attached
to CHORDAE TENDONAEA (fibrous tendon-like chords which connect to the free edges of the tricuspid
valve), are also known as PAPILLARY muscles. There are 3 types of papillary muscles in the right ventricle
depending on their point of origin
o ANTERIOR – largest, arises from the anterior wall
o POSTERIOR – arise from the posterior wall
o SEPTAL (medial)– most inconsistent as either small or absent, but allow chorea tendineae to emerge
directly from the interventricular septum
- The SEPTOMARGINAL TRABECULA/MODERATOR BAND: single trabecula which forms a bridge between the
lower portion of the IV septum and the base of the anterior papillary muscle, carrying the right
atrioventricular bundle to the anterior wall of the right ventricle during cardiac conduction
o SEPTOPARIETAL Trabeculations extend from the anterior surface of the moderator band to the wall
of the ventricle
- any of the individual muscle structures within the right ventricle have the potential to become atrophied, or
necrose following a myocardial infarction
 Interventricular Septum
- The left ventricle is some-what posterior to the right ventricle, so the interventricular septum forms some of
the posterior wall of the right ventricle (and is to the left).
- The septum is described as having two parts:
o Muscular
o Membranous
- The muscular part is thick and forms the major part
- The membranous part is thin and forms the upper part of the septum
- A third part of the septum may be considered to be atrioventricular as its superior location places it between
the left ventricle and the right atrium
 Left Ventricle
- Contributes to the anterior, diaphragmatic and left pulmonary surfaces of the heart
- Forms the apex of the heart
3
LSS Cardiovascular System
-
Alexandra Burke-Smith
Blood enters from the left atrium through the LEFT ATRIVENTRICULAR ORIFICE; flows in a left forward
direction to the apex
Chamber is conical, longer than the right ventricle and has a thicker layer of MYOCARIUM
Inlet – holds the atrioventricular valve
Outflow tract (AORTIC VESTIBULE) is posterior to the infidibulum of the right ventricle and leads to the
AORTA
Apical component: Trabeculations are fine/delicate in comparison with right ventricle
Papillary muscles are larger than those of the right ventricle, and consist of only ANTERIOR (anterolateral)
and POSTERIOR (postero-medial) muscles
Cardiac Valves





All cardiac valve leaflets are composed of highly organised connective tissue fibres.
The connective tissues (collagen and elastic) are arranged in layers along fibroblasts. This organisation
provides strength to the leaflet.
The entire valve is surrounded by a layer of endothelial cells. The free edges are thicker allowing cushioning
of the leaflets.
Atrioventricular valves
o MITRAL valve
o TRICUSPID valve
o At the atrioventricular junctions
o Separated from each other by the interventricular septum
Arterial valves
o AORTIC valve
o SEMI-LUNAR PULMONARY valve
o Formed from the cushions of tissue within the developing outflow tracts from each ventricle
o Have TRI-LEAFLET structures; each leaflet is separated by an inter-leaflet triangle of fibrous tissue
o There is then a cross-over/spiralling of the great arteries: aorta and pulmonary trunk
On the right side

-
Tricuspid Valve
Atrioventricular valve- at the right atrioventricular orifice
Closed during ventricular contraction
Consists of three CUSPS; the base of each is secured to a fibrous ring that surrounds the orifice
o The cusps are continuous with each other near their bases; these sites are termed COMMISSURES
- The free margins of each cusp are attached to the chordate tendineae which arise from the tips of the
papillary muscles
o Tendinaea from TWO papillary muscles attach to each cusp, which ensures proper closing of the
valve during contraction – therefore blood exits the right ventricle and enters the pulmonary trunk
and is prevented from moving back into the right atrium
- The cusps are named based on their relative position in the right ventricle
o ANTEROSUPERIOR cusp
o MURAL (posterior) cusp
o SEPTAL cusp
- During the filling of the right ventricle (ATRIAL SYSTOLE), the tricuspid valve is open, and the 3 cusps project
into the right ventricle
 Pulmonary valve
- Arterial valve – at the opening of the pulmonary trunk
4
LSS Cardiovascular System
-
-
Alexandra Burke-Smith
At the apex of the SUBPUMLONARY INFUNDIBULUM (muscle sleeve within the right ventricle which supports
the valve)
Consists of 3 SEMILUNAR CUSPS with free edges projecting upwards into the lumen of the pulmonary trunk
o LEFT cusp
o RIGHT cusp
o ANTERIOR cusp
Between the cusps, there are interleaflet triangles which make sure there are no gaps between the cusps
Acts as SINUTUBULAR JUNCTION: junction between myocardium and arterial tissue
Prevents flow of blood back into the right ventricle during VENTRICULAR DIASTOLE
On the left side

-
Mitral Valve
Atrio-ventricular valve – at left atrioventricular orifice
Closed during ventricular systole
Also known as BICUSPID VALVE – consists of two cusps:
o ANTERIOR (aortic) cusp – this has FIBROUS CONTINUITY with the aorta
o POSTERIOR (mural) cusp
- Bases of the cusps secured at commissures, and are coordinated by the action of two papillary muscles
attached by tendinuous chords:
o ANTERO-LATERAL muscle
o POSTERO-MEDIAL muscle
 Aortic Valve
- Arterial valve – central location compared to other cardiac valves
- Similar in structure to pulmonary valve; 3 semilunar cusps with free edge projecting upwards into aortic
lumen
- Between the semilunar cusps and the wall of the ASCENDING aorta are:
o RIGHT aortic sinus – origin of right CORONARY ARTERY
o LEFT aortic sinus – origin of left CORONARY ARTERY
o POSTERIOR aortic sinus – also known as the NON-CORONARY sinus
- Membranous septum is situated between the right aortic and non-coronary sinus
- Function: similar to pulmonary valve; in addition as blood recoils during VENTRICULAR DIASTOLE, the blood
fills the aortic sinuses, forcing blood into the coronary arteries
The Coronary Arteries:

-
Right Coronary Artery
Originates from the right aortic sinus
Located along right atrioventricular groove
Gives rise to the POSTERIOR DESCENDING ARTERY (PDA) – also known as the inferior interventricular artery
 Left Coronary Artery
- Originates from left aortic sinus
- Divides into the:
o CIRCUMFLEX ARTERY – located in the left atrioventricular groove
o LEFT ANTERIOIR DESCENDING (LAD) – also known as the superior interventricular artery
 Septum perforator – supplies the septum, feeding the conduction system
Conduction System & Membranous Septum
5
LSS Cardiovascular System



Alexandra Burke-Smith
SAN is located at the junction of the Superior Vena Cava and the right atrium – cells histologically distinct
from surrounding myocardium, but not insulated. Origin of electrical impulse
Conduction of impulse from SAN does not run in CONDUCTION TRACTS, but the orientation of the normal
myocardial fibres within the right atrium directs the impulse towards the atrioventricular node
The atrioventricular node within the right atrium is situated between in the tricuspid valve, Eustachian valve
and the Right coronary sinus
o Is at the apex of the TRIANGLE OF KOCH – surrounded by central fibrous body adjacent to the
membranous septum
o Specialised myocardium known as the BUNDLE OF HIS – which separates into right and left bundle
branches.
o Conduction passes down the bundles through the membranous septum to the PURKINJE FIBRES
6
LSS Cardiovascular System
Alexandra Burke-Smith
7
LSS Cardiovascular System
Alexandra Burke-Smith
Mechanical Properties of the Heart I
CVS 2 - Dr Ken MacLeod (k.macleod@imperial.ac.uk)
1. Describe the relationship between ventricular wall tension, chamber radius, and chamber pressure (Law of
Laplace)
2. List the sequence of events from excitation that bring about contraction then relaxation of a ventricular cell
3. State Starling’s Law of the Heart
4. Explain the mechanisms underlying Starling’s Law of the Heart
5. Use a graph to compare the length-tension relationships for cardiac and skeletal muscle
6. Explain the concepts of preload and afterload
Importance of Calcium with regards to contraction of the whole heart
Single cell structure







Described by Sidney Ringer
Ventricular cells 100 μm long and 15 μm wide
T-tubules (transverse tubules) are finger-like invaginations from the cell surface
T-tubule openings up to 200 nm in diameter
Carry surface depolarisation deep into the cell and are spaced (approx. 2 μm apart) so that a T-tubule lies
alongside each Z line of every myofibril.
Lace-like structure; sarcoplasmic reticulum surround the T-tubules and myofibrils, also store Ca
Major components of Myocytes are myofibrils and mitochondria
Excitation-Contraction coupling




On excitation; influx of Ca into the myocate vie L-TYPE CA CHANNELS occurs
Ca then binds to intracellular SR-Ca release channels, causing them to change conformation
o This change in conformation leads to INDUCED CALCIUM RELEASE from the sarcoplasmic reticulum
Ca release then causes contraction of the myocyte. This is completely dependent on the presence of
extracellular Ca
Relaxation:
o Intracellular Ca is taken up into the SR by Ca-ATPase (also known as SERCA) ready to be released
again
o Ca is also removed from the myocyte by Na/Ca exchanger, which uses the energy gradient from
sodium to expel Ca into the extracellular matrix
Contraction Force
Force production and Intracellular Calcium

There is a SIGNOIDAL relationship between Log of the cytoplasmic
Ca concentration and the % of maximum force produced
Length-tension Relation


Consider Isometric (no shortening) contraction
At a stretched length, a larger contraction is produced which leads
to an increased force production (this is true up to a certain point, after which further stretching reduces the
force produced) – ACTIVE FORCE production
8
LSS Cardiovascular System


Alexandra Burke-Smith
When stretched, muscle exerts a PASSIVE force which is indicated by the indicated by the increase in the
BASELINE force before contraction
Comparison with Skeletal muscle
o Cardiac muscle more resistant to stretch, therefore the PASSIVE force is reduced
o Less compliant than skeletal muscle due to properties of the extracellular matrix and cytoskeleton
o Cardiac muscle is very unlikely to be over-stretched, as PERICARDIUM limits stretch, therefore only
the ascending limb of the length-tension relation is important for cardiac muscle
Concepts of Pre-load and After-load






Pre-load: weight that stretches muscle before it is stimulated to contract
After-load: weight not apparent to muscle in resting state, and only encounteres when the muscle has
started to contract
Isotonic (shortening) contraction
Inverse linear relationship between afterload and shortening
Almost linear inverse relationship between afterload and velocity of shortening
If pre-load increases, there is an initial enhanced stretch, which increases the ability of the muscle to
produce more force by shifting the graph to the right, i.e. a greater afterload will result in more shortening
than before
In-vivo correlates of pre-load





As blood fills the ventricles during the relaxation phase (or diastole) of the cardiac cycle it stretches the
resting ventricular walls
The stretch or filling determines the preload on the ventricles before ejection
Preload is dependent upon venous return to the heart
Exercise increases pre-load
Measures of preload: end-diastolic volume, end diastolic pressure, right atrial pressure
In-vivo correlates of after-load




Definition: The load against which the left ventricle ejects blood after opening of the aortic valve
A simple measure of afterload is the diastolic arterial blood pressure
Any increase in afterload decreases the amount of isotonic shortening that occurs and decreases the velocity
of shortening
I.e. small ventricular filling leads to a smaller contraction as the ventricular cardiac muscle responds less
effectively to the afterload of the arteriol blood pressure
9
LSS Cardiovascular System
Alexandra Burke-Smith
Ways to alter contraction of the heart


Intrinsic Mechanisms
o Frank-Starling Relationship
o Rate-induced regulation
Extrinsic Mechanisms
o Autonomic Nervous System
o Endocrine System
o Blood gases & pH
Intrinsic Mechanisms
 Frank-Starling relationship
- Definition: increased diastolic fibre length increases ventricular contraction
- Consequence: ventricles pump greater stroke volume so that, at equilibrium, cardiac output exactly balances
the augmented (increased) venous return
- Two influencing factors:
o Changes in the number of myofilament cross bridges that attach
o Changes in the Ca sensitivity of the myofilaments
- Changes in the number of cross bridges
o At optimum sarcomere length: maximum INTERDIGITATION between thick and thin filaments
o At shorter lengths than optimal, the actin filaments overlap on themselves therefore reducing the
number of myosin cross bridges that can be made
o At increased lengths than optimal, there is reduced
overlap between myosin and actin, therefore reducing
the number of cross-bridges that can form
- Ca Sensitivity
o Changes with change in sarcomere length
o At longer sarcomere lengths, the affinity of Troponin C
for Ca is increased
o Therefore less Ca is required for the same amount of
force produced
WORK DONE



Stroke work: work done by the heart to eject blood under pressure into the aorta and pulmonary artery
Stroke volume (SV): volume of blood ejected during each stroke by each ventricle
o This is greatly influenced by afterload
Pressure (P): pressure at which blood is ejected
o Greatly influenced by strcture
Stroke Work = SV x P
10
LSS Cardiovascular System
Alexandra Burke-Smith
Law of Laplace

States: when the pressure within a cylinder is held constant, the tension on its walls increases with
increasing radius.
o Therefore if pressure and tension (wall stress) are to remain constant, wall thickness must be
increased or radius of the cylinder must be decreased
T = PR/h
o
o
o
o
T = wall tension
P = internal pressure
R = cylindrical radius
h = height/length of cylinder
Physiological relevance:
 Radius of curvature of walls of Left ventricle less than that of Right ventricle allowing LV to generate higher
pressures with similar wall stress to combat the higher aortic blood pressure than pulmonary bp
 Facilitates late ejection
 Wall stress kept low in giraffe by long, narrow, thick-walled ventricle
 In frog, where pressures are low the ventricle is almost spherical
 Failing hearts often become dilated which decreases pressure generation and ejection of blood and
increases wall stress by increasing the radius
11
LSS Cardiovascular System
Alexandra Burke-Smith
Cardiac Electrophysiology I: Electrical Activity
of the Heart
CVS 3 - Dr Frank Harrison (f.harrison@imperial.ac.uk)
1. Describe the main structures of the human heart.
2. Describe the structure of a typical cardiac ventricular myocyte.
3. Briefly describe the pathways of the heart that subserve the normal orderly passage of electrical activity through
it.
4. Sketch an intracellular action potential for a) a sino-atrial node cell b) an atrial cell c) a ventricular cell.
5. State that the sino-atrial (SA) node is the normal pacemaker and explain why and how this is so.
6. Describe how activity in the SA node spreads to both atria.
7. Explain why transmission of electrical activity from the atria to the ventricles normally only occurs at the atrioventricular (A-V) node.
8. Describe how electrical activity is transmitted to all parts of the ventricles through the Bundle of His and the
Purkinje fibres.
9. Explain why the ventricular action potential has a long duration and relate this to the function of the ventricles.
10. Describe the ECG waveforms using the conventional PQRST nomenclature, and state the electrical events that
each represents.
Structure of the human heart
Cardiac myocytes



Small cells attached to adjacent ones by end-to-end junctions known as INTERCALATED DISCS
o Also small gap junctions with LOW electrical resistance
Action potentials spread between cells and then the cells act together – SYNCYTIUM
Contain actin and myosin as contractile proteins
The conduction system
(NB: numbers on diagram indicate time at which
depolarisation occurs)
5 principle components:
 Sino-Atrial Node (SAN):
- strip of modified muscle cells on
the posterior wall of the right
atrium which is the site of
excitation signal generation
 Atrio-Ventricular Node (AVN):
- Collection of specialised cells which
forms a bridge of conducting tissue
over the non-conductive ring within
the atrio-ventricular septum
 Bundle of His:
- Also known as the atrio-ventricular bundle. It is a direct continuation of the AVN – a bundle of rapidly
conduction tissue which follows along the lower border of the membranous part of the interventricular
septum – conveying electrical activity from the AVN down the septum.
12
LSS Cardiovascular System
Alexandra Burke-Smith
 Bundle Branches:
- RIGHT bundle branch – continues on the right side of the interventricular septum towards the apex of the
right ventricle
- LEFT bundle branch – passes to the left side of the muscular interventricular septum and descends to the
apex of the left ventricle
 Purkinje Fibres:
- Subendocardial plexus of conduction cells – fibres located on the endocardium which penetrate the muscle
walls of the ventricles including the papillary muscles
NB: the conduction system ensures ventricular mass conducts as simultaneously as possible to maximise force
production – i.e. maximise the systolic ventricular blood pressure. Contraction is spontaneous – this is different to
skeletal muscle which requires electrical activity in the motor nerve supplying it.
Depolarisation of the heart


-
Atrial depolarisation
Excitation signal is generated at the SAN, and spread across the atria (right to left)
The atria contract
Wave of depolarisation meets the AVN, depolarising it
There is a delay between atrial depolarisation and ventricular depolarisation – this is due to the AVN
Ventricular depolarisation
Wave of depolarisation flows from the AVN down the bundle of His and the two bundle branches to the
purkinje fibres
This leads to complete ventricular depolarisation, which causes the ventricles to contract
Action Potentials Generated
Pacemaker Cells (SAN)




Pacemaker cells have a natural rhythm of approx 70
action potentials (and hence heartbeats) per minute
They have a resting potential of approx -65mV, but
this is not stable therefore becomes MORE negative.
This is known as the PRE-POTENTIAL, and is seen on
the graph as the slope as the potential increases
towards -50mV
o At -50mV, a full action potential is generated
o Cause of the pre-potential: there is a special
inward Na+ current into pacemaker cells,
along with a decrease in the membrane
permeability to K+, i.e. increase Na+ influx, decreased K+ efflux
Influence of the Sympathetic Nervous System, e.g. ADRENALINE
o Increases Na+ influx
o Seen by an increase in the pre-potential slope, therefore the threshold potential is reached more
rapidly – therefore heart rate is increased
Influence of the Parasympathetic Nervous System, e.g. ACTEYLCHOLINE
o Reduces Na+ influx
o Seen by a decrease in the pre-potential slope, therefore the threshold is reached more slowly and
heart rate is decreased
13
LSS Cardiovascular System
Alexandra Burke-Smith
Atrial Cells



Resting potential is stable at -100mV
Duration of action potential approx 100ms
PLATEAU phase is seen as curve of repolarisation
Ventricular Cells



Resting potential stable – approx -90mV
Duration – approx 250 ms (> Atrial cells)
The plateau phase of the action potential is very
long (200 ms)
o this is due to a Ca2+ influx through
ventricular voltage-gated channels
o at approx -35mV, the channels open
leading to a Ca2+ influx, which delays
repolarisation
AV Nodal Cells


Similar to ventricular cells, but pre-potential slopes
seen
Under “heart-block”, the AV nodal cells become
pacemaker cells, as the normal action potential
spread from atria to ventricles does not occur
Timing of Ventricular cell action potential and isometric force



Due to the Ca2+ influx leading to a long plateau phase (and
hence long membrane refractory period where another
action potential cannot be generated), the contractile force
starts to relax during the refractory period
This prevents the production of a FUSED tetanus
This is designed for the pumping action of the heart –
pumping requires regular relaxation –activation, not
continuous activation
Ca2+ Excitatory Action Potential Coupling




Caused by the influx of Ca2+ into ventricular cells, thus
delaying repolarisation
This increases the strength of contraction
Therefore a possible treatment for heart failure – drug that increases the ventricular intracellular Ca2+
concentration, leading to more powerful contractions – DIGOXIN
Angina treatment:
o Angina – vascular supply to cardiac muscle decreases, oxygen supply reduced
o Treatment – Ca2+ ion blockers, e.g. berapamil
14
LSS Cardiovascular System
Alexandra Burke-Smith
ECG Introduction
Depolarisation Waves




Detected as a change in the potential difference between two electrodes
When a wave of depolarisation is moving TOWARDS the POSITIVE electrode, it is seen as an UPWARD
deflection
When a wave of depolarisation is moving AWAY from the POSITIVE electrode, it is seen as a DOWNWARD
deflection
If the wave of depolarisation is at right angles to the axis of the two electrodes, there should be no
deflection – however the sensitivity of ECG measurements means often a BIPHASIC EQUIPOTENTIAL is seen
instead of a stable potential with no deflection
EGC Waveform
 Atrial Depolarisation – P WAVE
- Depolarisation wave spreads across
the atrial myocytes from the SAN
- Mean direction of spread is right to
left, this causes an electric field
- Seen as small upward deflection
 Ventricular Depolarisation – QRS
Complex
- Wave of depolarisation reaches the
AVN
- The AVN is surrounded by junctional
fibres with a lower conduction
velocity – leads to delay between
atrial depolarisation and ventricular
depolarisation (approx 100ms)
o During this delay, the atria contract and expel blood into the ventricles
- Septum depolarisation of the bundle of his spreads towards the apex of the heart and then along the
purkinje fibres
o The depolarisation has a mean direction – known as the MEAN FRONTAL PLANE AXIS OF THE
VENTRICLES (towards the left apex)
o The endocardium depolarises before the epicardium
- The apex of the heart then contracts slightly before the base, but the whole ventricular depolarisation lasts
about 40ms
- Atrial repolarisation also occurs during this time, but it is negligible in comparison to ventricular
depolarisation
 Ventricular Repolarisation – T wave
Note: the mean direction of the ventricular depolarisation along the MFPA is because the stroke volume of the
ventricles is the same, but the systolic blood pressures are different.
 The right ventricle has a thinner wall and has a systolic blood pressure of about 25/12mmHg
 The left ventricle has a thicker wall and works against a larger pressure gradient, therefore needs to
do more work and hence requires more electrical activity. Its systolic blood pressure is about
120/80mmHg
15
LSS Cardiovascular System
Alexandra Burke-Smith
Cardiac Electrophysiology II: Understanding
the ECG
CVS 4 - Dr Frank Harrison (f.harrison@imperial.ac.uk)
1. Describe how the recordings of the six standard limb leads are obtained from the four electrodes attached to the
limbs
2. Explain briefly the principles underlying the concept of Einthoven's Triangle
3. Appreciate why the magnitude and direction of components of the ECG vary from lead to lead
4. Know the normal physiological range of the mean frontal plane axis
5. Understand what is meant by the terms left and right axis deviation, and how these conditions may occur
6. Describe how the recordings of the six pre-cordial (chest) leads are obtained
7. State how the information obtained from the chest leads is different from that derived from the limb leads
8. Explain why the magnitude and direction of the components of the ECG vary as the recording electrode is moved
across the chest from V1 to V6
Attachment of Electrodes


Right foot – zero reference point
o Point of comparison so that potentials can be generated
o Also removes effect of background electrical noise
Left foot, right and left arm – positions available for recording signals from other electrodes
Standard Limb Leads





An equilateral triangle is considered between the right arm, left arm and the left foot, where the heart lies in
the centre – this is known as EINTHOVEN’S TRIANGLE
There are three leads; each denoted using ROMAN NUMERALS:
o Lead I – comparison between RIGHT ARM and LEFT ARM (where
the left arm is considered to be the positive electrode)
o Lead II – comparison between RIGHT ARM and LEFT FOOT (where
the left foot is considered to be the positive electrode)
o Lead III – comparison between the LEFT ARM and LEFT FOOT
(where the left foot is considered to be the positive electrode)
Lead I is then considered to be at 0°
The positive pole of Lead II is therefore considered to be +60° to the positive pole of Lead I
The positive pole of Lead III is therefore considered to be +120° to the positive pole of Lead I
+ve
NB: angles BELOW the 0° line are considered POSITIVE
0°
+ve
+ve
Augmented Limb Leads


Couple the standard limb leads to form augmented vectors – aV
120°
60°
3 augmented leads, denoted by letters:
o aV-R: the right arm is considered the positive electrode, and the negative electrode is considered to
be half way between the left arm and left foot
16
LSS Cardiovascular System
Alexandra Burke-Smith
o


aV-L: the left arm is considered the positive
electrode, and the negative electrode is considered
to be half way between the right arm and left foot
o aV-F: the left foot is considered the positive
electrode, and the negative electrode is considered
to be half way between the right and left arm
the readings from these leads will be > standard limb lead
readings as they are coupled
considering einthoven’s triangle, where Lead I is 0°
o aV-R is at -150° (150° above the 0° line)
o aV-L is at -30° (30° above the 0° line)
o aV-F is at +90° (90° below the 0° line, i.e.
perpendicular)
Combining Limb Leads  Hexagonal Reference System


Diagrammatic representation of the 6 limb leads
Arranged in 3 pairs of 2 leads which are at right angles to
each other:
o Lead I and AVF
o Lead II and AVL
o Lead III and AVR
The Mean Frontal Plane Axis



The mean vector/direction of wave depolarisation in
the ventricles is towards the apex of the LEFT ventricle
This may be:
o along the axis of lead I, i.e. at 0°
o in the direction of AVF, i.e. at +90°
Remember, when a wave of depolarisation is
moving TOWARDS the positive electrode it causes
an UPWARD deflection. When it is moving AWAY
from the positive electrode it causes a
DOWNWARD deflection.
Waveforms recorded in the leads


0 indicates no deflection, i.e. the wave of
depolarisation is at 90° to the MFPA
+ indicates upward deflection, i.e. the wave of
depolarisation is towards the positive electrode
of the MFPA (++ is larger deflection)
- indicates downward deflection,
i.e. the wave of depolarisation is
away from the positive electrode
of the MFPA
17
LSS Cardiovascular System
MFPA
0°
90°
Lead I
++
0
Alexandra Burke-Smith
Lead II
+
+
Lead III
+
Lead AVL
+
-
Lead AVR
-
Lead AVF
0
++
Why do waveforms vary in size?



Consider SOH CAH TOA
If lead is exactly on MFPA, the signal will be max size (i.e. the angle between the lead and MFPA is 0, and
cos0 = 1 = max)
The fraction of the max signal obtained in each lead can be calculated using SOH CAH TOA (if right angled
triangles are drawn)
Equipotential and Negative Waves


The value of cos 90o is zero.
o Hence the value of (MPFA cos 90o) is also zero.
o This explains why a lead with its axis at right angles to the MFPA show no signal (or a small
equipotential).
Cosines of angles between 90o and 270o are negative.
o Thus when a lead is more than 90o to MFPA the ECG will show downward (negative) rather than
upward deflections.
Range of MFPA



The normal range of the MFPA is between -30° and +90°, and may vary between patients
o This depends on the orientation of the heart in the chest
If a patient has an MFPA that is more negative than -30°, they are exhibiting LEFT AXIS DEVIATION (enlarged
left ventricle e.g. aortic stenosis)
If a patient has an MFPA that is more positive than +90°, they are exhibiting RIGHT AXIS DEVIATION
(enlarged right ventricle which could be pulmonary
disease)
Location of Chest Electrodes







Designation as V1 – V6 (Arabic numberals)
V1 on one right side of sternum, V2 – V6
All electrodes are positive
Septum depolarisation occurs first, and is from left to right
MFPA is then in the right to left direction
QRS complex
o V6 records small wave of depolarisation AWAY
from the electrode, then large wave TOWARDS (qR
wave seen in diagram)
o V1 records a small wave of depolarisation
TOWARDS the electrode, then a large wave AWAY
(rS wave seen in diagram)
o These combine to form the QRS complex seen on an ECG
V3 records a BIPHASIC (both direction) wave known as the TRANSITION ZONE
The ECG then combines the recordings at the 6 chest electrodes, with the hexagonal reference system for the 6
leads (standard + augmented)
18
LSS Cardiovascular System
Alexandra Burke-Smith
The Microcirculation
CVS 5 - Dr Chris John (c.john@imperial.ac.uk)
1. Describe the branching structure of the microvasculature
2. List the three types of capillary and order them in terms of their permeability to water and small lipophobic
solutes
3. Describe the factors controlling capillary blood flow
4. Explain the functional importance of capillary density
5. Identify the different mechanisms by which solute is transported between blood and tissue (depending on size
and lipid solubility).
6. Explain how the “Starling forces” influence fluid transfer across the capillary wall
7. Describe the origin of lymph fluid.
8. Understand how clinical oedema arises
Introduction



Microcirculation: the circulation for every individual tissue/organ in the body
Consists of:
o 1st order arterioles
o Terminal arterioles
o Capillary
o Pericytic (post-capillary) venule
o Venule
Surrounded by large amounts of smooth muscle within the blood vessel walls
Blood Flow





The overall aim of the cardiovascular system is to achieve adequate blood flow through the capillaries
Blood flow rate: volume of blood passing through a vessel per unit time
o F = ΔP / R
o ΔP = pressure gradient
o R = vascular resistance
ΔP = pressure gradient
o The pressure at the beginning of arterioles vs. Pressure at the beginning of capillaries determines
blood flow rate through tissues
o Increase ΔP, increase blood flow rate
R = vascular resistance
o Hindrance to blood flow due to friction between moving fluid and stationary vascular walls
o Influencing factors:
 Blood viscosity – is relatively constant though
 Vessel length – increased length, increased resistance (although length is relatively constant)
 Vessel radius – variable (R α 1/r4, therefore if the radius is halved, the resistance is increased
16x)
Summary
o Increased blood pressure in major arteries  increased blood flow rate, increased pressure
gradient, decreased vascular resistance
o Arteriolar vasoconstriction  decreased blood flow rate, decreased pressure gradient, increased
vascular resistance
19
LSS Cardiovascular System
Alexandra Burke-Smith
Microvessels - Arterioles



Major resistance vessels
Pressure gradient = 93mmHg (mean arteriole pressure=MAP)  37mmHg
F = ΔP / R
o If 93mmHg is the mean arteriole pressure, as blood flows through an organ, by the time it reaches
the end of the venule, the pressure is considered 0
o without this pressure difference, blood would not reach the capillary beds and would accumulate in
the arterioles
o therefore FORGAN = MAP/ RORGAN
Vasoconstriction/Vasodilation



the STATE OF TONE of the arterioles within that tissue also determine flow:
o VASOCONSTRICTION – decreases the radius, increases vascular resistance therefore decreases flow
rate
o VASODILATION – increases the radius, decreases the resistance therefore increases flow rate
o State of tone is usually a state of PARTIAL CONSTRICTION at rest
Vasoconstriction and vasodilation can happen simultaneously in different tissues
The radii of arterioles are adjusted independently to accomplish two functions:
o Match blood flow to the metabolic needs of specific tissues – regulated by local INTRINSIC controls
o Help regulate arterial blood pressure – regulated by EXTRINSIC controls
1. Matching blood flow to the metabolic needs of specific tissues (depending on the body’s momentary
needs)
 Chemical response:
- ACTIVE HYPEREMIA
- E.g. skeletal muscle during initial exercise
- Increase metabolism therefore increase glucose requirement and oxygen consumption
- This is sensed by tissue, i.e. if oxygen concentration falls, REFLEX VASODILATION occurs
 Physical response:
- E.g. Reduced blood temperature on superficial structures, e.g. the skin
o Sensed locally, then in order to decrease blood flow to tissue REBOUND VASOCONSTRICTION occurs
to divert blood from the tissue
- E.g. 2. Physical stretch
o AUTOREGULATORY response to physical stretch of arterioles
o MYOGENIC VASOCONSTRICTION occurs (e.g. the gut during exercise) – this increases the vascular
resistance hence reducing blood flow
2. Help regulate arterial blood pressure
 Apply F = ΔP / R to the entire circulation
o Cardiac Output (CO) can be seen as F
o Mean Arterial Pressure (MAP) can be seen as ΔP
o Total Peripheral Resistance (TRP) can be seen as R
 CO = MAP/TRP , therefore MAP = CO x TRP
o Hence if you control resistance in all tissues, you can control and maintain the MAP
 Neural Control
- Cardiovascular Control Center (CCC) in the Medulla (part of brain stem) sends a profound
VASOCONSTRICTION SIGNAL which decreases blood flow to all organs
20
LSS Cardiovascular System
-
Alexandra Burke-Smith
This can be used after significant blood loss, as it preserves the MAP but is not a good long term system, as it
leads to dysfunction and infarction
α receptors within the periphery and β receptors within the heart respond to this neural signal
o β receptors especially important as they can result in an increase in heart rate
 Hormonal Control
- Vasoconstrictors:
o Vasopressin – Posterior Pituitary Gland
o Angiotensin II – Lungs
- Hormones which act on α and β receptors to increase sympathetic activity
o Adrenaline
o Noradrenaline – both from adrenal glands
Microvessels – Capillaries




Capillary exchange – delivery of metabolic substrate to the cells of the organism
Design is specific – accentuates function:
o Single cell wall (1 micrometer diameter)
o Diameter of lumen (7 micrometers)
o Extensive branching increases surface area
Therefore capillaries are ideally suited to enhance diffusion (via FICK’S LAW):
o Minimise diffusion distance
o Maximum diffusion time
o Maximise surface area
Capillary Network depends on:
o Highly metabolically active tissues – denser capillary networks
o E.g. skeletal muscle, myocardium, brain, lung
o However not all capillaries dilated at once, e.g. at rest only 10% of capillaries are dilated in skeletal
muscle
Structure
 Continuous
- Most common – continuous flattened endothelial cells with water-filled gap junctions
- As blood flows through the capillary:
o Nutrients diffuse across junctions
o LIPO molecules diffuse across cells
o Transport proteins present to transport larger molecules into tissues
- BLOOD BRAIN BARRIER: modified continuous capillary – very tight gap junctions reduce capacity for a large
number of small molecules diffusing into the brain tissue – more selective control of transport of substances
into tissues
 Fenestrated
- Circular FENESTRAE (circular holes approx 80 nm large) allow slightly larger molecules to leave the blood and
enter the tissues
- E.g. in the glomerulus in kidney nephron
 Discontinuous
- Very large gap junctions, therefore large molecules i.e. White blood cells can leave blood and enter tissues
(and vice versa)
- E.g. in bone marrow
21
LSS Cardiovascular System
Alexandra Burke-Smith
Fluid movement





BULK FLOW – a volume of protein free plasma filters out of the capillary, mixes with the surrounding
interstitial fluid (IF) and is reabsorbed
Two important forces affect the bulk flow: the STARLING FORCES:
o HYDROSTATIC PRESSURE – derived from the heart, and drives fluid into surrounding tissues
o ONCOTIC PRESSURE – derived from the fact there is an increased concentration of plasma proteins
in the blood, but not in the surrounding IF. This generates an osmotic force pulling water back into
the capillaries
Starling’s Hypothesis:
o "... there must be a balance between the hydrostatic pressure of the blood in the capillaries and the
osmotic attraction of the blood for the surrounding fluids. "
o " ... and whereas capillary pressure determines transudation, the osmotic pressure of the proteins of
the serum determines absorption."
The oncotic pressure along the capillary remains relatively constant, but there are changes in the hydrostatic
pressure:
o The hydrostatic pressure at the venous end of the capillary is < the arterial end
o ULTRAFILTRATION - When the pressure inside the capillary > in the IF, there is a net loss of fluid into
the surrounding tissues (Hydrostatic pressure > Oncotic pressure) – this occurs at the arterial end
o REABSORPTION - When the oncotic pressure > hydrostatic pressure, there is a net reabsorption of
fluid back into the capillary. This occurs at the venous end.
There is a net loss of fluid from the capillaries, as the oncotic pressure is never great enough to reabsorb all
the fluid lost by ultrafiltration
o Therefore a mechanism is required for the return of this loss of fluid to the capillaries – this is the
role of the LYMPHATIC SYSTEM
The Lymphatic System
Initial Lymphatics
 LYMPHATIC CAPILLARIES are interwoven with capillaries
 These are blind-ended, therefore do not form complete loop therefore fluid which enters cannot leave
 The excess fluid in the capillaries is then drained back into the blood
 All excess fluid is eventually drained into the blood by the lymphatic system
Lymph Nodes
 Important for immune surveillance
 Filled with immune cells; excess fluid passes through the lymph nodes before draining into the blood
 SPLEEN – organ acts as giant lymph node
Lymph Flow
 No heart – relies on skeletal muscle contraction etc
 Areas where lymphatic system returns fluid, i.e. drainage ducts:
o Right lymphatic duct
o Thoracic duct
o Right & left subclavian veins
 3L/day returned from the lymphatic system into the blood
 If the rate of production of fluid > rate of return, this leads to the accumulation of fluid within the tissues =
OEDEMA
 Parasitic blockage of lymph nodes may also lead to Oedema, e.g. ELEPHANTIASIS
22
LSS Cardiovascular System
Alexandra Burke-Smith
ECG: Identifying some basic disturbances of
cardiac rhythm
CVS 6 - Dr Sanjay Prasad (s.prasad@imperial.ac.uk)
1.
2.
3.
4.
5.
State the normal duration and amplitude of the components of the ECG waveform
Recognize normal sinus rhythm and bradycardia and tachycardia on the ECG
Recognize common abnormalities of cardiac conduction
Recognize common patterns suggesting acute myocardial infarction on the ECG
Adopt a systematic approach to ECG interpretation
The ECG Waveform




1 big square = 5mm, and represents a time interval of 0.2seconds, and a potential of 0.5mV
I little square = 1mm, and represents a time interval of 0.04seconds, and a potential of 0.1mV
Normal heart rate = 60-100bpm
To calculate heart rate:
o Count number of squares between each QRS complex and divide 300 by this number
o Count number of QRS complexes in 10 seconds, and multiply this number by 6
 P wave – represents atrial depolarisation
- Duration: <0.11 s
- Amplitude: <2.5 mm in Lead II (Right Arm  Left foot)
 PR interval – represents time taken for the wave of depolarisation to migrate from one side of the AVN to
the other (the AVN acts like a safety valve to separate atrial and ventricular systole)
- Duration: from 0.12-0.20s
 QRS complex/interval – represents ventricular depolarisation
o Duration: < 0.12s
o Amplitude: R wave is recorded in chest electrode V6 - <25mm (MFPA range -30 - +90 degrees)
23
LSS Cardiovascular System
Alexandra Burke-Smith
 Q Wave
o Duration: <0.04s
o Amplitude: 25% of total QRS complex amplitude, but in OPPOSITE DIRECTION; downward deflection
indicates depolarisation wave moving away from the recording positive electrode
 QT interval
o Duration: from 0.38-0.42s
 ST segment
o Roughly the same as the PR interval
 T wave – represents ventricular repolarisation
o May appear inverted in Lead III, Lead AVR, or chest electrodes V1 &V2 – but this does not mean
abnormal
Checking an ECG
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Is it the correct recording – i.e. the right patient
Identify leads
Check calibration and speed of paper
Identify the rhythm
Look at QRS axis
Look at P wave
Look at PR interval
Look at QRS complex
Determine position of ST segment
Calculate the QT interval
Look at T wave
Check
Common Arrhythmias



Bradycardia (<60bpm)
Tachycardia (>100bpm)
Cardiac Conduction abnormalities
o Supraventricular arrhythmias (AVN or above)
 Atrial fibrillation
 Atrial flutter
 AVNRT
o Ventricular arrhythmias (Below AVN)
 Ventricular tachycardia
 Ventricular
fibrillation
Sinus Tachycardia
P waves have normal morphology;
towards positive electrode of Lead II (RA
 LF; similar to axis of heart), and
REVERSE direction of Lead AVR
Atrial rate: 100-200bpm
Ventricular rate: 100-200bpm (regular
rhythm)
One P wave precedes every QRS complex
(normal)
24
LSS Cardiovascular System
Alexandra Burke-Smith
Atrial Fibrillation
P waves absent, replaced by oscillating
baseline fibrillation waves
Atrial rate: 350-600bpm – all atrial
myocytes are firing rapidly and irregularly,
therefore atrial systole not completely
efficient therefore blood pools in the atria
– compromises cardiac output and
increases risk of stroke
Ventricular rate: 100-180bpm – rapid
atrial rate means ventricles rapidly
depolarise leading to a narrow QRS
complex (NARROW COMPLEX RHYTHM
DISTURBANCE), but since atrial systole is
irregular, the ventricular rate is also irregular.
Atrial Flutter
P wave morphology abnormal: undulating
saw-toothed baseline flutter waves
“re-entry” circuit develops in right atrium
there atrial systole is irregular and rapid
Atrial rate: 250-350bpm
Characterised by occasional depolarisation
of the AVN, therefore the heartbeat is
variable but rhythm is regular
Ventricular rate: 150bpm (often with a 2:1
AV block, but also sometimes 4:1)
Pre-excitation Syndrome
Abnormal physical pathway develops where
conducting tissue connects the atria and
ventricles via an accessory pathway other
than the AVN
This leads to depolarisation of the ventricles
early
This leads to a slurring of the QRS complex,
and a lack of regulation by the AVN,
therefore electrical activity is conducted
faster leading to an increased heart rate.
25
LSS Cardiovascular System
Alexandra Burke-Smith
Normal ECG Reading from V5 
Heart Block - AV Nodal Block
 1st degree – PR interval is lengthened >0.20s
 2nd degree – one or more of the atrial impulses fail to conduct to the ventricles, i.e. a non-conducted P wave
No QRS
complex
o
Type 1 (Mobitz I/ Wenckebach) – disease of AV node – progressive lengthening of PR interval on
consecutive heartbeats followed by a blocked P wave (i.e. no QRS complex), then the PR interval
resets and the cycle repeats
o
Type 2 (Mobitz II/ Hay) – disease of the His-Pukinje conduction system – intermittently nonconducted P waves not preceded by PR interval lengthening and not followed by PR Interval
shortening
 3rd Degree – complete heart block in which the impulses generated in the SAN does not propagate to the
ventricles; an accessory pacemaker in the ventricles will then cause systole (escape rhythm), resulting in two
independently regular rhythms
Second
o The P waves with a regular P to P interval represents the first rhythm.
o The QRS complexes with a regular R to R interval represent the second rhythm. Rhythm: R-R
intervals
o The PR interval will be variable, as the hallmark of complete heart block is no apparent
relationship
First Rhythm:
between P waves and QRS complexes.
P-P intervals
Normal QRS complex seen in V1 & V2 
26
LSS Cardiovascular System
Alexandra Burke-Smith
Heart Block – Bundle Branch Blocks





Normal Impulse Conduction: SAN – AVN – Bundle of His – BUNDLE BRANCHES – Purkinje fibres
Bundle branch and purkinje fibre depolarisation seen as QRS complex, therefore conduction black
represented by change in the QRS complex
Septum depolarisation usually in left to right direction
The left bundle branch then leads to the anterior and posterior fascicles
Two ECG changes seen:
o QRS complex widens (>0.12s) – when the conduction pathway is blacked, it takes longer for the
electrical signal to pass throughout the ventricles
o QRS morphology changes – depending on which lead, and right vs. Left branch block
 Right BBB
- The left bundle branch depolarizes normally, but
the right bundle has a conduction block
- wide QRS complex assumes a unique, virtually
diagnostic shape in those leads overlying the
right ventricle (V1 and V2)
o this is seen as RSR complex instead of a
QRS complex – like “rabbit ears”
 Left BBB
- The right ventricle depolarises first,
therefore the wide QRS complex assumes
a characteristic change in shape in those
leads opposite the left ventricle (right
ventricular leads - V1 and V2).
- This is seen as broad deep negative S
waves
Ventricular Tachycardia





Medical emergency
Irregular rapid contraction of the ventricles, not as a result of depolarisation through the normal AVN and
rapid conduction system
This leads to a broad QRS complex
Unstable rhythm disturbance; often occurs in the middle/just after MI
May lead to cardiac ischemia
27
LSS Cardiovascular System
Alexandra Burke-Smith
Ventricular Fibrillation
Most commonly identified
arrhythmia in cardiac arrest
patients. This arrhythmia is a
severe derangement of the
heartbeat that usually ends in
death within minutes
The ventricular muscle twitches
randomly, rather than contracting
in a coordinated fashion (from the
apex of the heart to the outflow
of the ventricles), and so
the ventricles fail to pump blood
into the arteries and into systemic
circulation.
Use The ECG made easy, 150 ECG problems, ECG in practice. Author: John Hampton. Published by Churchill
Livingstone for revision
28
LSS Cardiovascular System
Alexandra Burke-Smith
Blood Pressure and Flow
CVS 7 - Professor Alun Hughes (a.hughes@imperial.ac.uk)
1. Understand the role and design of the normal circulation
2. Be able to describe physical factors influencing flow., know ‘Ohms law for the circulation’ and the principles of
the Poiseuille’s equation
3. Be able to describe physical factors acting on blood vessels and know the Laplace equation,
4. Know the basic mechanisms by which flow of blood and transmural pressure influence blood vessel structure and
function
5. Understand how standing (gravity) affects the circulation
6. Understand how the compliance of the aorta and elastic arteries affect the pulse pressure.
The CVS & Circulation
Role of the Circulation
•
•
•
•
To transport blood around the body (gases, nutrients, metabolites, ions, hormones, heat)
Flow is achieved by the action of a muscular pump (heart) propelling blood through a network of tubes
(blood vessels). The pump generates a pressure gradient that drives bulk flow of blood through the network
of blood vessels
The circulation consists of two such pumps (left and right ventricle) which are physically coupled and pump
through the systemic and pulmonary circulations respectively.
At the capillary level gas and nutrient exchanged is accomplished by diffusion. Diffusion is crucial for
movement of materials through tissues, but is only effective over short distances so a capillary needs to be
~10m from every cell. This necessitates a highly branched structure
Structure of the circulation
•
Highly specialised - Consists of different vessel types which have distinct structures highly appropriate for
their function.
o Large ELASTIC arteries – act as conduits and dampening vessels
o Small MUSCULAR arteries
o Arterioles – have extensive smooth muscle in their walls so they can regulate their diameter and
resistance to blood flow
o Capillaries – very numerous and have thin walls to facilitate transport and diffusion
o Venules
o Medium sized & large veins – highly compliant vessels which act as a reservoir for blood volume
Design of the CVS
•
•
•
In essence consists of two pumps and circuits:
o Pulmonary (RV  LA)
o Systemic (LV  RA)
The cardiac output from both ventricles must be the same, despite to different in pressures within the two
circulatory systems
o Otherwise blood will tend to pool
The relative areas and volumes within each circulatory system are also relatively equal
o Relative cross sectional area – primarily capillaries; related to exchange function
o Blood volume (total 5L) – primarily veins and venules; related to reservoir function
29
LSS Cardiovascular System
•
•
Alexandra Burke-Smith
The diameter of the blood vessels changes dramatically from the aorta (25mm in man) to the capillaries
(5m = 0.005mm).
o As a result of the change in diameter and the expansion of components of the vascular system due
to branching there are large changes in the cross-sectional area of the vasculature at different levels.
o There are billions of capillaries and this segments resents by far the largest cross-sectional are of the
circulation. This presents a huge surface area for exchange to take place.
o Although the volume in a single capillary is tiny, the equivalent of the whole cardiac output passes
through the capillary bed every minute.
The majority of blood volume is contained within the venous part of the circulation.
o Regulation of the capacitance of the veins and venules regulates how much blood is stored and
influences venous return to the heart and
ventricular work via the Frank-Starling effect in
the heart.
Why does blood flow?
•
•
•
Blood pressure – the force that drives the circulation
First measured in a horse by STEVEN HALES, where
blood rises 8ft above the crural artery when a brass pipe
is inserted and then the ligature on the artery is
removed
A simplified model of the mare’s circulation in Hales
experiment is used to explain blood pressure
o This is a very simple model of the circulation but
it is useful in understanding how the system works.
o It assumes that the action of the heart (pump) has established a pressure in the tank (the aorta)
equivalent to 8 ft of water (as measured by Hales) – this is P1
o This drives a steady flow (Q) through the circulation.
o The branching vessels of the circulation are simplified into a single long rigid pipe for the purposes of
this model.
o Pressure drops along this pipe due to viscous losses of energy (friction), so that the pressure
measured at the end (P2) is lower than at P1 – this pressure difference drives the flow (Q).
o At the end of the circulation the system empties into the right atrium of the heart which is almost at
atmospheric pressure.
Resistance
•
•
•
Links blood flow and pressure
In its simplest form the circulation can be equated to an electrical circuit:
o The pressure difference (P) is equivalent to the potential difference (V)
o The fluid/volumetric flow (Q) is equivalent to current flow (I)
o The fluid resistance (R) equates to the electrical resistance (R).
Ohm’s law can be used to describe the relationship between V, I and R or P, Q and R:
o V = IR
o Therefore, ΔP = QR (this is DARCY’S LAW)
The hemodynamic determinants of mean blood pressure (MBP)
•
In the circulation (systemic & pulmonary) Ohm’s relationship between pressure, flow and resistance can be
restated in physiological terms as:
o ΔP  MBP
30
LSS Cardiovascular System
o
o
•
•
•
Alexandra Burke-Smith
Q  CO
R  PVR
Therefore MBP = CO x PVR, where:
o MBP = mean blood pressure
o CO = cardiac output (=stroke volume x heart rate)
o PVR = peripheral vascular resistance (like TPR – total peripheral resistance)
This relationship is an approximation since flow is the circulation is not steady (due to the intermittent
pumping of the heart) and blood vessels are not rigid.
o Nevertheless it is a simple and useful relationship which is applicable in many situations.
o The relationship between pressure and flow can be used to estimate the resistance of the circulation
using estimates of cardiac output as bulk flow/unit time and the difference between mean arterial
and venous pressure as the pressure drop across the circulation.
Remember it is pressure drop not absolute pressure itself that drive flow.
o If this is done for the systemic and pulmonary circulation then it is clear that the resistance of the
pulmonary circulation is substantially less than the systemic.
o Physiologically, regulation of flow is achieved by variation in resistance while blood pressure remains
relatively constant.
Pressure
•
•
•
•
•
Pressure is not constant in the circulation - It
falls due to the resistance to blood flow
provided by the blood vessels.
The distribution of pressure throughout the
circulation is illustrated in the figure.
o Both the maximum (systolic) and
minimum (diastolic) pressures are
illustrated.
o It is important to remember that it is the pressure difference between points in the circulation that
drives flow not the absolute pressure.
The magnitude of oscillation in pressure (pulse pressure) is damped in the smaller arteries and arterioles.
The diagram also illustrates that the major site of resistance (i.e. major region of pressure drop) is in small
muscular arteries (<0.5mm internal diameter) and arterioles.
Note that the pulmonary circulation operates at lower pressures but shows a broadly similar distribution of
pressure across the difference components of the circulation.
Why is there resistance to Blood flow?
 LAMINAR FLOW
- In the normal circulation flow is laminar, i.e. the fluid behaves as if it flows in layers or streamlines.
- Laminar flow can be demonstrated by injecting a dye into fluid, showing the existence of a clearly defined
streamline.
 VISCOSITY
- Dynamic Viscosity (µ) is a measure of the resistance of a fluid to deform under shear stress.
- Resistance arises as a result of the resistance due to friction between fluid laminae moving at different
velocities.
 SHEAR
31
LSS Cardiovascular System
-
Alexandra Burke-Smith
A force per unit area (the pressure difference) is needed to move the fluid in opposition to viscosity.
The flow velocity on the surface of the vessel wall is zero (so called NO SLIP CONDITION) but in a flowing
fluid, the velocity of each lamina increases progressively as you move further way from the wall.
o The spatial velocity gradient is called the shear rate (s)
 s = du/dr
 S = shear rate
 U = velocity of blood flow
 R = radial dimension
o The shear rate multiplied by the dynamic viscosity is the shear stress (τ). The shear stress near the
wall is believed to be an important influence on endothelial function in health and disease.
 τ = (du/dr) µ
 µ = is dynamic viscosity
Poiseuille’s law and Vessel calibre
•
•
•
•
Experiments performed by Jean Poiseuille (1797-1869) in long glass tubes elucidated the relationship
between pressure and laminar flow (i.e. resistance) in long straight tubes.
Subsequently the theoretical basis of this relationship was derived by Wiedman, and Neumann and
Hagenbach. The resistance to flow in a long straight rigid tube depends on the viscosity of the fluid (µ), the
length of the tube (L) and the radius of the tube (r) and is described by Poiseuille’s equation:
o µ= fluid viscosity
o L = vessel length
o r = vessel radius
o d= diameter
o ΔP = pressure difference (P1-P2)
o Q = volumetric flow
o ΔP/Q = resistance
This equation emphasizes the importance of arterial diameter as a determinant of resistance. Consequently
relatively small changes in vascular tone (vasoconstriction/vasodilatation) can achieve marked changes in
flow.
Due to the 4th order relationship between diameter and flow, relatively small changes in diameter have
marked effects on flow.
o This explains why active changes in arterial and arteriolar diameter are so important in the
physiological regulation of blood
flow and blood pressure.
Distribution of blood flow to organs
•
•
During exercise, there is a change in the
distribution of blood flow to different
organs
Dilation of the arteries and arterioles
feeding skeletal muscle results in a ~30fold
increase in muscle blood flow.
32
LSS Cardiovascular System
Alexandra Burke-Smith
Blood Pressure
•
•
•
•
Conventionally blood pressure measurements are made in
the arm.
Blood pressure varies over the cardiac cycle with a peak in
systole and a minimum in diastole.
o SYSTOLIC blood pressure (SBP)
o DIASTOLIC blood pressure (DBP)
o PULSE PRESSURE (PP) = SBP – DBP
o MEAN blood pressure = ~ DBP + 1/3 PP
The systolic (SBP) and diastolic pressure (DBP) are usually recorded in clinic as SBP/DBP (e.g. 110/70).
Values of blood pressure vary widely in a community.
o High levels of blood pressure are termed hypertension.
Ventricular vs. Aortic pressure
•
•
•
Shown by Wigger’s diagram
During systole, the aortic valve opens due to the
difference in pressure between the ventricles and the
aorta (marked by AO)
Note the difference in ventricular and aortic pressure
in diastole.
o Once the pressure gradient between the
aorta and ventricles is reversed, the aortic
valve closes
o Once the aortic valve closes ventricular
pressure falls rapidly but aortic pressure only
falls slowly in diastole
o This can be explained by the elasticity of the
aorta and large arteries which act to ‘buffer’
the change in pulse pressure.
Arterial compliance and pulse pressure
•
•
•
The ability of the aorta and the elastic arteries to buffer or damp the oscillation in blood pressure is often
termed a WINDKESSEL (German for air chamber)
In systole more blood is ejected into the aorta and large elastic arteries than leaves them. This distends
these vessels.
o ~40% of the stroke volume is stored by the elastic arteries.
o In effect some of the pressure energy generated in systole is converted to elastic energy in the
artery wall which is stored during systole.
Once the heart ceases ejection and the aortic valve closes, pressure starts to fall. Consequently the walls of
the aorta and elastic arteries recoil and the elastic energy is reconverted into pressure and the stored
volume is discharged.
o This process damps the magnitude of pressure change and accounts (to a large extent) for the
diastolic component of arterial pressure.
33
LSS Cardiovascular System
o
Alexandra Burke-Smith
It also accounts for the maintenance of flow in the microcirculation during diastole. If arterial
compliance is reduced (i.e. arteries get stiffer e.g. with age) then this mechanism is less able to damp
the fluctuation in pressure and pulse pressure increases.
What is the effect of the blood pressure on the vessel wall?
•
•
•
•
Pressure difference between two locations in the circulation is important for flow, but the pressure inside
the vessel (TRANSMURAL pressure) determines the distension of the vessel wall
o This pressure causes a tension in the wall (T)
The relationship between transmural pressure and wall tension is determined by LAPLACE’S LAW:
o T = Pr where P= transmural pressure, r=radius of vessel, T= tension
The CIRCUMFERENTIAL STRESS (σ) is determined by the tension caused by transmural pressure and the wall
thickness:
o σ = Pr / h where h = wall thickness
o Therefore larger arteries which have higher pressures require increased wall thickness
The relationship between the transmural pressure and the vessel volume depends on the ELASTICITY of the
vessel, and is known as COMPLIANCE
o In extreme cases over a prolonged period in a weakened vessel high circumferential stress can cause
a balloon like distension (ANEURYSM) or even rupture.
Aneurysms
•
•
•
When compliance of a vessel fails, and a weakened vessel is exposed to high circumferential stress a balloonlike dilation can occur
This is a tensile-strength failure
Aneurysms are prone to rupture, which could lead to exsanguinations
Compliance properties of arteries and veins
•
•
The elastic properties of blood vessels depend mainly on structural proteins, elastin and collagen.
o Elastin is much more distensible than collagen.
o The combination of elastin and collagen in vessels results in a non-linear relationship between vessel
pressure and volume (i.e. non-linear compliance).
The elastic properties of arteries and veins differ and this is important for their function.
o Veins are highly compliant at low pressures while arteries are compliant over a wider pressure
range.
o This means that relatively small changes in venous pressure distend veins and increase the volume
of blood stored in them. This is important when the pressure in veins changes for example on
standing.
Gravity and venous pressure
•
•
In man (and other bipeds) the venous reservoir is not always at the same level as the heart. On standing
gravity increases pressure in the lower limbs (~80mmHg). Since veins are compliant this increases the
volume of blood in these vessels and (transiently) reduces the venous volume returning to the heart.
o This would reduce cardiac output and blood pressure if there were no compensatory response.
o When at heart level venous pressure = central venous pressure
The effect of gravity and posture affects the transmural pressure in all vessels, but at any particular location
the gradient of pressure from large artery to capillary to vein is maintained so flow still occurs in the same
way.
34
LSS Cardiovascular System
•
•
•
•
•
Alexandra Burke-Smith
The major effect of gravity is on the distensible veins in the leg and the volume of blood contained in them.
Veins act as an important reservoir for blood. This is because despite the low pressures, vein walls are
relatively thin and compliant therefore they accommodate large volumes of blood (~2/3 total blood volume)
at low pressures.
o This reservoir/compliance function is physiologically regulated. Vein walls, although thin, do contain
smooth muscle.
o The role of this muscle is to stiffen the wall i.e. reduce compliance.
A number of mechanisms act to limit the effect of blood pooling in the lower limb veins on the circulation:
o Activation of the sympathetic nervous system to:
 constrict venous smooth muscle and ‘stiffen’ the veins.
 constrict arteries to increase resistance and maintain blood pressure
 increase heart rate + force of contraction and maintain cardiac output
o Myogenic venoconstriction (in response to elevated venous pressure) to ‘stiffen’ veins
o Use of muscle and respiratory ‘pumps’ to improve venous return
Nevertheless cerebral blood flow falls on standing
Failure of these mechanisms causes fainting (SYNCOPE)
Muscle and Respiratory “Pumps”
•
•
•
Return of blood to the heart during upright posture is assisted by the contraction of skeletal muscle in the
lower limb which compresses veins within the muscle and forces blood back to the heart This is called the
muscle pump.
Another mechanism called the respiratory pump also assists venous return.
o During respiration expansion of the chest and diaphragm causes a negative pressure within the
thorax which effectively sucks blood into the central veins by reducing the extra-vascular pressure in
the thorax and increasing it in the abdominal cavity.
Both the skeletal and respiratory pump depend on the presence of valves in the veins outside the chest to
prevent retrograde flow.
o Incompetent valves cause dilated superficial veins in the leg (VARICOSE VEINS)
o Prolonged elevation of venous pressure, even with intact compensatory mechanisms, causes
OEDEMA in feet
35
LSS Cardiovascular System
Alexandra Burke-Smith
Blood vessel order, function, and
specialisation of cells in the CVS
CVS 8 - Dr Adrian H Chester (a.chester@imperial.ac.uk)
1. Appreciate the function of the endothelium as a generator of hormones that regulate vascular and cardiac muscle
form and function
2. Describe ways in which the endothelium can be stimulated and how this results in release of the named
hormones: NO, prostacyclin, endothelin-1.
3. Describe in general terms the renin-angiotension system and know how its major components regulate vascular
function
4. Describe how the following work:
i. low dose aspirin
ii. calcium channel blockers
iii. nitrovasodilators
5. Appreciate why these drugs carry side effect risks along with their therapeutic benefits
CVS Overview
•
•
Consists of the heart, blood and blood vessels
Function - rapid convective transport of:
o Oxygen
o Glucose
o Amino acids
o Fatty acids
o Vitamins
o Water
o As well as removal of:
 Carbon dioxide
 Urea
 Creatine
o Also homeostasis:
 Hormone delivery
 Temperature regulation
 reproduction
Arterial and venous structure


-
Artery
Regularly shaped lumen
Thick muscular wall consisting of MEDIA and ADEVENTITIA
Lined by endothelium and connective tissue
Vein
Possible irregular shaped lumen
Lined by endothelium and connective tissue
Thin muscular wall; very thin media and thin adventitia
Note: the vascular system forms a continuous circuit between the left and right side of the heart, consisting of
arteries, arterioles, capillaries, venules and veins
36
LSS Cardiovascular System
Alexandra Burke-Smith
The Endothelium
Endothelial mediators of vascular function
•
Mediators target smooth muscle, myocytes, and platelets:
o Nitric oxide
o Prostacyclin
o thromboxane
o Endothelin-1
o Angiotensin II
Effects of Nitric
Oxide (NO)
Effects of
Prostacycline (PGI2)
Effects of
Thromboxane (TXA2)
Effects of
Endothelin-1 (ET-1)
Effects of Angiotensin
II (Ang II)
Smooth muscle –
Relaxation &
Inhibition of
growth
Smooth muscle –
Relaxation &
Inhibition of growth
Smooth muscle –
contraction
Smooth muscle –
contraction & weak
stimulation of
growth
Smooth muscle –
contraction &
stimulation of growth
Myocytes Increased blood
flow & Enhance
contractility
Myocytes Increased blood flow
Platelets – inhibit
aggregation
Myocytes – reduce
blood flow
Platelets –
stimulates
aggregation
Platelets – inhibit
aggregation
Myocytes reduced blood flow
& Enhance
contractility
Myocytes - reduced
blood flow,
remodelling & fibrosis
Platelets – no effect
Platelets – no
effect
Control of Vascular Tone
•
•
•
Balance between vasodilation and vasoconstriction
Vasodilators: NO, PGI2
Vasoconstrictors: ET-1. TXA2, Ang II
Endothelial Hormones
Nitric Oxide
•
•
•
•
•
Release is induced by physical force, as well as by acetylcholine or hormones
Precursor is L-ARGININE, which is cleaved by e-NOS (NITRIC OXIDE SYNTHASE enzyme present in all
endothelial cells, whose function is Ca2+ dependent)
o ACh binding on endothelial receptors activates the phospholipase C 2nd messenger pathway, which
results in an increase in Ca2+ which activates the e-NOS enzyme
The NO then migrates to target (smooth muscle), where is converted to cyclic-GMP by SOLUBLE GUANYLYL
CYCLASE (s-GC)
o The cyclic-GMP activates PROTEIN KINASE G (PKG), which causes vasodilation and a decrease in Ca2+
The c-GMP has a short half life, as it is rapidly broken down by PHOSPHOESTERASES
This is known as FLOW-INDUCED VASODILATION, and is a response to increased sheer stress in blood
vessels. It is important in:
o Thermoregulation
o Penile erection
37
LSS Cardiovascular System
Alexandra Burke-Smith
Prostacyclin & Thromboxane
•
•
•
•
•
Precursor is ARACHIDONIC ACID, and is converted under the influence of CYCLO-OXYGENASE (COX)
There are two ISOFORMS of COX:
o COX 1 – active in a healthy CVS
o COX 2 – active in an unhealthy CVS, e.g. in CVD related to pain and inflammation
COX 1 and COX 2 act on the arachnidonic acid to convert it first into PGG2 and then PGH2
PROSTACYCLIN SYNTHASE then acts on the PGH2 to synthesise the prostaglandins, the most important being
PGI2
o Prostacyclin acts on IP receptors and eventually causes vasodilation and inhibition of platelets – this
can reduce ATHEROSCLEROSIS
THROMBOXANE SYNTHASE acts on the PGH2 to synthesis thromboxane
o TXA2 also is converted to TXB2
o thromboxane acts on TP receptors and causes vasoconstriction and stimulation of platelets – this
increases atherosclerosis
Endothelin-1
•
•
•
•
•
•
•
•
Endothelin-1 is a very potent vasoconstrictor
It has a polypeptide chain consisting of 21 amino acids
specific conformation due to the bods between CYSTEINE molecules
At times of pathophysiological insult, transcription of the PREPRO-ET1 mRNA occurs, which is then translated
to form the precursor PREPRO-ET1
PREPRO-ET1 is then converted to PRO-ET1, which is then finally converted to ET-1 by ECE-1 (endothelin
converting enzyme 1)
Transcriptional control:
o Inhibition –
 Prostacyclin
 Nitric oxide
 ANP, Heparin, HGF & EGF
o Stimulation –
 Adrenaline
 Ang II
 Vasopressin
 Steroids
 IL-1, TGF-β, Endotoxin, endothelin, VECF, tacrolimus, CsA
Endothelin Receptors
o On smooth muscle cells
 ETA – leads to contraction of the smooth muscle
 ETB – leads to contraction of the smooth muscle
o On endothelial cells
 ETB – binding causes NO to be produced, which then in turn acts on the smooth muscle cells
with a vasodilatory effect
Inhibition of ET-1 pathway produces vasodilation, therefore can have therapeutic potential
The Renin-Angiotensin System
•
•
Renin (an enzyme from the kidneys produced in response to a decrease in blood pressure) converts
ANGIOTENSINOGEN (from the liver)  ANGIOTENSIN I
ACE (ace converting enzyme) converts angiotensin I to ANGIOTENSIN II
38
LSS Cardiovascular System
Alexandra Burke-Smith
o
•
Also simultaneously degrades BRADYKININ on epithelial cells (acts on beta-1 receptors to release
valodilators)
Angiotensin II causes vasoconstriction by acting on AT I receptors
o Also causes renal salt absorption
Effects of Angiotensin II
ACE Inhibitors
•
•
E.g. CAPTORIL
Reduce blood pressure by blocking the action of ACE so that no angiotensin II is produced (which acts on AT1 receptors to cause vasoconstriction)
o Also prevents the breakdown on bradykinin into inactive fragments (bradykinin then stimulates the
production of Nitric Oxide involving NOS; this leads to vasodilation via a cyclic GMP pathway)
Aspirin
•
•
Works by balancing the effects of thromboxane and prostacyclin
Effects of 75mg of aspirin over 7 days:
o Prostacyclin production reduction of 10% each day
o Reduction of thromboxane production 10% more each day (i.e. -10%, -20%, -30% etc)
Pharmacology of NO
•
•
•
NO donors – e.g. nitroglycerine, nitroprusside
E-NOS activators – e.g. endothelium-dependent vasodilators
Phosphodiesterase inhibitors – e.g. Viagra, zaprinast
How do Nitro-vasodilators work?
•
•
Increase [NO] within smooth muscle cells, where it is converted to cyclic-GMP by SOLUBLE GUANYLYL
CYCLASE (s-GC)
The cyclic-GMP activates PROTEIN KINASE G (PKG), which causes vasodilation and a decrease in Ca2+
How does Viagra work?
•
•
Phosphodiesterase inhibitor
Phosphodiesterase breaks down cyclic GMP, therefore its inhibition leads to excess cyclic GMP activity 
vasodilation
39
LSS Cardiovascular System
Alexandra Burke-Smith
Calcium Channel Blockers
•
•
•
•
•
•
•
•
•
•
Drugs that do not act by modifuing endogenous receptors or enzymes, but increase or decrease intracellular
Ca2+ by affecting the entry of calcium into the cell
Increase intracellular Ca2+
o Endothelin
o Angiotensin II
o Thromboxane
Decrease intracellular Ca2+
o Nitric oxide
o Prostacyclin
They decrease intracellular calcium levels by blocking the voltage gated calcium channels in cardiac and
blood vessel muscle.
The voltage-gated channels mediate calcium influx in response to membrane depolarisation
o Regulate intracellular processes such as contraction, secretion, neurotransmission and gene
expression
o Activity is essential to couple electrical signals in the cell surface to physiological events in cells
This means that upon stimulation, less calcium flows into cells (negative INOTROPIC effect) and so the
muscles contract less.
o In cardiac muscle, this results in a decrease in cardiac output by decreasing the heart rate and stroke
volume.
o In smooth muscle around vessels, this decreases total peripheral resistance and so results in
vasodilation.
o Overall result is a decrease in blood pressure.
They prevent coronary artery vasospasm, which makes them very useful in the treatment of variant angina
the affinity of the blockers for the channel is directly related to the membrane potential of the target cells
o in smooth muscle, vasodilation occurs at -50mV
o in myocytes, negative inotropic effects are seen at more negative potentials of -80mV
Dihydropyridines – e.g. NIFEDIPINE
o Used to decrease systemic vascular resistance and arterial blood pressure but not in angina as
reduced cardiac output may lead to reflex tachycardia
Phenylalkylamine – e.g. VERAPAMIL
o Selective for myocytes, reducing myocardial oxygen demang
o Used to treat angina but is not a potent vasodilator
Side Effects
•
•
•
•
•
•
•
Our body often uses the same chemical to regulate more than one process
Interaction between different systems in the body
Unfortunately, drugs are not always as selective
Tissue specific distribution of receptors
It is also a fact that two people taking the same medicine can have very different experiences
E.g. 1 Viagra
o There are 5 types of phosphodiesterase enzymes
o Expression varies between tissues therefore different side effects may be observed
E.g. 2 Prostacyclin/thromboxane synthesis
o Arachidonic acid may also be converted to LEUKOTRIENES instead of PGG2 by LIPO-OXYGENASE
o This may cause asthma is 3-5% of patients
40
LSS Cardiovascular System
Alexandra Burke-Smith
Mechanical Properties of the Heart II
CVS 9 - Ken MacLeod (k.macleod@imperial.ac.uk)
1. Describe the mechanical events of the cardiac cycle
2. Use a graph to correlate electrocardiographic events and pressure events of the atria, ventricles, aorta and
pulmonary artery
3. Indicate on the graph the phases of the cardiac cycle and the corresponding pressure changes, valve openings and
closures
4. Define and state normal values for right and left ventricular end-diastolic volume, end-systolic volume, stroke
volume, end-diastolic pressure and peak systolic pressure
5. State the origin of the heart sounds
6. Provide the mathematical equation for ejection fraction
7. Define cardiac output and indicate its determinants
8. Construct simple pressure-volume diagrams from the events during the cardiac cycle and annotate these graphs
appropriately
Introduction




Preload: the stretch or filling of the ventricles before they contract
Afterload: the load/pressure against which the ventricles eject blood after opening of the aortic/pulmonary
valve
The ventricular heart beat is divided into two main phases:
o Diastole: ventricular relaxation during which the ventricles fill with blood
 Split into 4 sub-phases
o Systole: ventricular contraction when blood is pumped into the arteries
 Split into 2 sub-phases
Cardiac cycle: a description of mechanical and electrical events, volume changes and sounds associated with
the heart beat. It consists of:
o Atrial systole (resulting in the end diastolic volume)
o Isovolumetric ventricular contraction
o Ventricular ejection
 Rapid ejection
 Reduced ejection
o Isovolumetric ventricular relaxation
o Late diastole
 Rapid ventricular filling
 Reduced ventricular filling
41
LSS Cardiovascular System
Alexandra Burke-Smith
ATRIAL SYSTOLE
Mechanical events
Changes in pressure & volume
Just prior to atrial systole, blood flows passively
through the open atrioventricular valves (tricuspid
and mitral)
Atrial depolarisation  contraction of atria, which
“tops off” the volume of blood in the ventricles
green – aortic pressure
yellow – atrial pressure
Electrocardiogram
SAN activation  depolarisation of atria (seen as P
wave)
red – ventricular pressure
white – ventricular volume
As atria contract, the “a wave” can be seen on the
yellow graph due to the increase in atrial pressure
Blood is also pushed back into jugular vein, causing a
wave in jugular venous pulse
Heart sounds
No heart sound should be heard, but 4th heart sound
may be heard as an abnormality – occurs in congestive
heart failure, pulmonary embolism or tricuspid
incompetence
42
LSS Cardiovascular System
Alexandra Burke-Smith
ISOVOLUMETRIC CONTRACTION
Mechanical events
Changes in pressure & volume
Occurs just as the ventricles depolarise – is the
interval between AV valve closing and semi-lunar
valve (aortic and pulmonary) opening
green – aortic pressure
yellow – atrial pressure
Electrocardiogram
Ventricular depolarisation marked by QRS
complex
red – ventricular pressure
white – ventricular volume
the AV valves close as the ventricular pressure
exceeds the atrial pressure
Since the AV and semi-lunar valves are closed,
there is no movement of blood out of the
ventricles, just an increase in pressure
approaching the aortic pressure
Heart sounds
Consider the heart sound to be LUB- DUB
Ventricular depolarisation is the 1st heart sound
(lub) – this is due to the closure of the AV valve
with associated vibrations
43
LSS Cardiovascular System
Alexandra Burke-Smith
RAPID EJECTION
Mechanical events
Changes in pressure & volume
Ventricular muscle walls undergo ISOTONIC
contraction, pushing blood out of the ventricles
Semi-lunar valves open
green – aortic pressure
yellow – atrial pressure
red – ventricular pressure
white – ventricular volume
Electrocardiogram
as the ventricles contract, the pressure within
them exceeds the pressure in the aorta and
pulmonary arteries
when the semi-lunar valves open, the volume of
the ventricles decreases
the right ventricular contraction pushes the
tricuspid valve slightly into the atrium, creating a
small wave into the jugular vein – “c wave”
observed in yellow graph
Heart sounds
No changes
No heart sounds
44
LSS Cardiovascular System
Alexandra Burke-Smith
REDUCED EJECTION
Mechanical events
Changes in pressure & volume
Marks the end of ventricular systole
Aortic and pulmonary valves begin to close
green – aortic pressure
yellow – atrial pressure
red – ventricular pressure
white – ventricular volume
Electrocardiogram
as the blood flow from the ventricles decreases,
the ventricular volume decreases more slowly
as the pressure in the ventricles fall blow that in
the arteries, blood begins to flow back causing
the semi-lunar valves to close
Heart sounds
Ventricular repolarisation marked by T wave
No heart sounds
45
LSS Cardiovascular System
Alexandra Burke-Smith
ISOVOLUMETRIC RELAXATION
Mechanical events
Beginning of diastole
Aortic and pulmonary valves shut completely
AV valves remain closed
Atria fill with blood
Electrocardiogram
No changes
Changes in pressure & volume
green – aortic pressure
yellow – atrial pressure
red – ventricular pressure
white – ventricular volume
atrial pressure rises as volume of blood in atria
increases
blood pushing on the tricuspid valve gives a
second jugular pulse (“v wave” on yellow graph)
as the aortic valve shuts, there is a rebound
pressure wave against the valve as the distended
aortic wall relaxes. This recoil reduces the aortic
pressure and is seen as the DICHROTIC NOTCH
on the green graph
Heart sounds
2nd heart sound (dub) occurs when aortic and
pulmonary valves close
46
LSS Cardiovascular System
Alexandra Burke-Smith
RAPID FILLING (late diastole)
Mechanical events
Changes in pressure & volume
AV valves open, and the blood flows rapidly
(although passively) into the ventricles
green – aortic pressure
yellow – atrial pressure
Electrocardiogram
No changes
red – ventricular pressure
white – ventricular volume
the ventricular volume increases, as the atrial
pressure falls
Heart sounds
3rd heart sound abnormal – can signify turbulent
ventricular filling due to severe hypertension or
mitral incompetence
47
LSS Cardiovascular System
Alexandra Burke-Smith
REDUCED FILLING (late diastole)
Mechanical events
Changes in pressure & volume
Called DIASTASIS
Ventricles fill more slowly as pressure difference between
atria and ventricles decreases
Electrocardiogram
green – aortic pressure
yellow – atrial pressure
No changes
red – ventricular pressure
white – ventricular volume
ventricular volume increases more slowly
Heart sounds
No heart sounds
48
LSS Cardiovascular System
Alexandra Burke-Smith
Summary of the Cardiac Cycle – the Wiggers diagram
Pressure Volume Loops
pressures



Typical pressure of the systemic circulation – 120/80mmHg
Typical pressure of the pulmonary circulation – 25/5mmHg
PAWP – pulmonary artery wedge pressure
o Taken from a branch of pulmonary artery when the back pressure has been occluded
o Elevation can indicate left ventricle failure, mitral insufficiency, mitral stenosis
49
LSS Cardiovascular System
Alexandra Burke-Smith
Pressure-volume loop in heart
1
2
3
4



X1 – end diastolic volume, i.e. the preload after max ventricular filling
o Blood filling the ventricle during diastole determines the preload that stretches the resting ventricle
X2- The blood pressures encountered in great vessels (aorta and pulmonary artery) represent the afterload
Between X2 and X3, isotonic contraction of the ventricles occurs
Frank-Starling Relationship
The pressure-volume loop can be fitted into the frankstarling graph



The straight line of the active force is equal to the
end-systolic pressure line
Increasing preload increases stroke volume
(increasing X1 increases the width of the loop)
Increases afterload decreases stroke volume
o There is a greater pressure to overcome in
order to open the aortic valve, therefore X2
increases and less shortening occurs
Cardiac Contractility



Definition: Contractile capability (or strength of
contraction) of the heart
Simple measure of cardiac contractility is ejection
fraction
Contractility is increased by sympathetic stimulation
o Beta-adrenoreceptor activation  increase
cyclic AMP  phosphorylation of key Ca2+
handling proteins  Ca2+ channels open for
longer  increased Ca2+ in cytoplasm 
increased force of contraction
50
LSS Cardiovascular System



Alexandra Burke-Smith
Family of different Frank-Starling relations as cardiac
contractility changes
During exercise contractility is increased due to increased
sympathetic activity
During exercise end diastolic volume is increased due to
changes in the peripheral circulation (venoconstriction
and muscle pump)
51
LSS Cardiovascular System
Alexandra Burke-Smith
The sympathetic nervous system & reninangiotensin system
CVS 10 - Dr Mike Schachter (m.schachter@imperial.ac.uk)
1.
2.
3.
4.
5.
6.
7.
8.
Describe the principles of the organisation of the sympathetic nervous system
Describe the synthesis, release and removal of the neurotransmitter, noradrenaline
Outline the types of adrenoreceptor in the sympathetic nervous system
Evaluate the cardiovascular effects of infusion of some common adrenergic agonists
Describe the principles of the organisation of the renin-angiotensin-aldosterone system
Describe the biosynthetic pathway for angiotensin II synthesis
Evaluate the individual roles the SNS and RAS play in modulating the behaviour of the CVS
Recognize some of the pharmacological concepts involved in how important sympathetic neurotransmitters
interact with receptors to evoke downstream effects
The autonomic nervous system


Consists of the parasympathetic and sympathetic nervous systems
Sympathetic nervous system is organised around the thoracic and lumbar spinal cord
o There is no sympathetic innervation in the bronchi, but practically everywhere else
Cardiovascular control


Baroreceptors in carotid sinus and aortic arch sensitive to stretch (increased stretch  increased frequency
of impulses to hypothalamic autonomic centre)
Increased frequency of impulses  reduced inhibition of sympathetic activity from solitary tract nucleus
increased blood pressure through increased vasoconstriction
o α1 receptors at end of pre-ganglionic neurone
o α2 receptors in arterioles
o β2 receptors in heart via vagus nerve
Effector nerves
 Sympathetic outflow
- Paravertebral sympthatic chain ganglion – neurotransmitter is acetylcholine therefore is a cholinergic
receptor
- Post-ganglionic fibre contains lots of noradrenaline vesicles which are released on depolarisation, binding to
the adrenergic receptor on the effect organ.
o The NA is then either taken up by the neurone and repackages, or taken up by the effector organ
and broken down by COMT
 Parasympathetic outflow
- Parasympathetic ganglia are in or near effector organ, and involve acertylcholine
- Effector organ also has cholinergic receptor, which binds to the acetylcholine released by the postganglionic
neurone.
o This acetylcholine is then recycled
52
LSS Cardiovascular System
Alexandra Burke-Smith
Catecholamines


Noradrenaline and adrenaline are synthesised in the
terminal VARISCOSITY (see neurotransmitter lecture)
They are then removed from the neuroeffector
junctional synapse via uptake systems:
o Neuronal reuptake and recycling, or
degradation into deaminated metabolites by
MAO
o Extraneuronal uptake into effector organ and
degradation by COMT or MAO
Adrenoceptors
Two groups of effects:
 Excitatory effects on smooth muscle (constriction)
o alpha-adrenoceptor-mediated
o lead to an increase in intracellular calcium
 Relaxant effects on smooth muscle, stimulatory effects on heart
o beta-adrenoceptor-mediated
o lead to an increase in cyclic AMP, which causes an increase in Ca2+ in the heart but a decrease in
smooth muscle
β- receptors

β1 adrenoceptors located on:
o cardiac muscle
o smooth muscle of the GI tract

β2 adrenoceptors located on:
o bronchial, vascular and uterine smooth muscle
β3 adrenoceptors located on:
o adipocytes
o smooth muscle of GI tract

α- receptors

α1-adrenoceptors: located post-synaptically i.e. predominantly on effector cells
o important in mediating constriction of resistance vessels
53
LSS Cardiovascular System

Alexandra Burke-Smith
α2 -adrenoceptors: located on presynaptic nerve terminal membrane
o their activation by released transmitter causes negative feedback inhibition of further transmitter
release
o some are post-synaptic on vascular smooth muscle
Receptor coupling
 α1-adrenoceptors
- coupled with G-protein linked receptor which activates the phosphlipase C pathway, which leads to an
increase in free Ca2+ and activated protein kinases (involving IP3 and DAG)
 α2-adrenoceptors
- coupled with beta-receptor
- activates adenyl cyclase, which converts ATP  cyclic AMP leading to a decrease in intracellular Ca2+
Effects of catecholamines on activation of adrenoceptors

-
Natural
Noradrenaline – α1, α2, β1
Adrenaline – α1, α2, β1, β2
Dopamine – weak effects at α1, β1, but has own receptors
 Synthetic
- Isoprenaline - β1, β2 (unselective beta-agonist)
- Phenylephrin - α1 (selective alpha-agonist)
CVS effects (10 g/min infused IV)
Effect on:
Noradrenaline
Systolic BP
↑↑↑
Diastolic BP
↑↑
Mean BP
↑↑
Heart Rate
↓
Adrenaline
↑↑
↓
↑
↑
isoprenaline
↑
↓↓
↓ or →
↑↑
NB: noradrenaline acts on the beta receptors in the heart to increase cardiac output, and the alpha receptors in the
periphery to increase total peripheral resistance
Response of major vascular beds




Skin (alpha receptors)
o Noradrenaline – constriction
o Adrenaline – constriction
o Isoprenaline – no effect
Visceral (alpha receptors)
o Noradrenaline – constriction
o Adrenaline – constriction
o Isoprenaline – no effect (slight dilation)
Renal (alpha & beta receptors) – constriction
o Noradrenaline – constriction
o Adrenaline – constriction
o Isoprenaline – no effect (slight dilation)
Coronary (alpha & beta1 receptors) – dilation
54
LSS Cardiovascular System

Alexandra Burke-Smith
o Noradrenaline – dilation
o Adrenaline – dilation
o Isoprenaline – dilation
Skeletal muscle (alpha & beta2 receptors)
o Noradrenaline – constriction
o Adrenaline – dilation
o Isoprenaline – dilation
The Renin-Angiotensin System
NB: angiotensin II can also be converted to angiotensin III by
aminopeptidase
Stimuli for renin release






A decrease in the renal perfusion pressure, a decrease of blood pressure in the pre-glomerular vessels.
A decrease in arterial blood pressure.
Haemorrhage, salt and water loss,
hypotension (low blood pressure).
A change in Cl- (or Na+) ion
concentration.
β1-receptor activation in the kidney
(sympathetic nervous system).
NaCl reabsorption at the macula densa
(which are a group of cells in the
glomerulus).
55
LSS Cardiovascular System
Alexandra Burke-Smith
What happens when blood pressure decreases?
Pharmacologic manipulation of renin release





Loop diuretics – block NaCl reabsorption at macula densa
NSAIDs – block renin release via inhibition of COX
ACE inhibitors – block the synthesis of Ang II
AT1 blockers (Ang II receptor antagonists) – block vasoconstriction and aldosterone synthesis and secretion
o E.g. losartan, valsartan
Alpha2 and beta1 blockers - block receptor activation in the kidney, inhibiting renin release
AT1 ./ Ang II type I receptors




Are G-protein coupled; Gi and Gq.
It also couples to phospholipase A2.
The AT1 receptors are located in the blood vessels, brain, adrenal glands, the kidneys and the heart.
Activation of the AT1 receptors works to increase the blood pressure, and stimulate aldosterone secretion
Effects of angiotensin II
 Peripheral resistance:
o Direct vasoconstriction.
o There is enhanced action of peripheral noradrenaline.
 Increased norandrenaline release.
 Decreased noradrenaline uptake.
o increased sympathetic discharge (CNS).
o release of catecholamines from the adrenal glands.
- These all act to produce a rapid pressor response.
 Renal Function:
o Direct effects to increase Na+ reabsorption in the proximal tubule.
o Synthesis and release of aldosterone from the adrenal cortex.
o Altered renal haemodynamics.
 Renal vasoconstriction.
 Enhanced noradrenaline effects on the kidney.
56
LSS Cardiovascular System
-
Alexandra Burke-Smith
These all act to produce a slow pressor response.
 Cardiovascular structure:
- Haemodynamic effects:
o Increased preload and afterload.
o Increased vascular wall tension.
-
-
Non-haemodynamic effects:
o Increased expression of proto-oncogenes.
o Increased production of growth factors.
o Increased synthesis of extracellular matrix proteins.
These all act to induce vascular and cardiac hypertrophy and remodelling.
Pharmacology of ACE Inhibition


ACE is needed to convert Angiotensin I to II.
Angiotensin II, remember, increases blood
pressure (by vasoconstriction and
stimulation of the SNS).
o Therefore inhibition of ACE will
prevent angiotensin II production,
and so ACE inhibition reduces
blood pressure.
At the same time, a local hormone called
bradykinin is also broken down by ACE.
o Bradykinin is important local
vasodilating hormone.
o ACE inhibition therefore stops the bradykinin from being broken down, and so the bradykinin
therefore will have vasodilating effects, and so here ACE inhibition further acts to reduce the blood
pressure
AT2 ./ Ang II type 2 receptor antagonist actions:



No effects on the bradykinin system.
Selectively blocks the effects of Angiotensin II.
o Pressor effects.
o Stimulation of the noradrenaline system.
o Secretion of aldosterone.
o Effects on renal vasculature.
o Growth-promoting effects on the cardiac and vascular tissue.
Uricosuric (increased amount of uric acid in the urine) effect.
Aldosterone


Physiological effects – maintains body content of Na+, K+ (and water)
o Increases Na+ (and hence water) retention
o Increases K+ (and H+) excretion
Location of receptors
o Previously known
 Kidneys
57
LSS Cardiovascular System
o
Alexandra Burke-Smith
Recently discovered
 Brain
 Heart
 Vessels
Pathophysiologic effects in CVD









Myocardial fibrosis and necrosis
Inflammation, vascular fibrosis and injury
Prothrombotic effects – impaired fibrinolysis
Central hypertensive effects
Endothelial dysfunction
Autonomic dysfunction:
o Catecholamine potentiation
o Decreased heart rate variability
Ventricular arrhythmias
Sodium retension
Potassium and magnesium loss
Effects of stress
On both the sympathoadrenal system, and the renin-angriotensin system:
 Increased blood pressue
 Increased heart rate
 Increased Na+/water retention
 Increased coagulation
 Decreased fibrinolysis
 Increased platelet activation
58
LSS Cardiovascular System
Alexandra Burke-Smith
Regulation of the CVS
CVS 11 - Dr Ken MacLeod (k.macleod@imperial.ac.uk)
1.
2.
3.
4.
5.
6.
7.
Describe the local mechanisms that regulate blood flow
Describe how blood vessel diameter and heart rate are controlled by the autonomic nervous system
Describe how the autonomic nervous system changes the force of contraction of the heart
State the location of the baroreceptors
Define cardiac output, stroke volume and mean systemic arterial pressure and state their determinants
Indicate, using simple flow diagrams, how baroreceptors control blood pressure
Describe the changes in impulse activity in the carotid sinus nerve, parasympathetic and sympathetic nerves to
the heart and sympathetic vasoconstrictor nerves that take place following an increase or decrease in mean blood
pressure
8. Construct an integrated picture of the various systems that control blood pressure and be able to apply this to
specific clinical examples involving blood loss or fluid overload
Key Equations
Stroke Volume = End diastolic volume – End systolic volume
Cardiac Output = Heart Rate x Stroke Volume
(SV = EDV – ESV)
(CO = HR x SV)
Mean Systemic Arterial Pressure = Cardiac Output x Total Peripheral Resistance (MSBP = CO x TPR)
Design of the CVS






Systemic & pulmonary circulations
Right heart  lungs  left heart
Veins have capacitance (act as store of 61% of blood)
Venous volume distribution affected by
o peripheral venous “tone”
o gravity
o skeletal muscle pump
o breathing (decreased pressure in thoracic cavity)
Central venous pressure (mean pressure in the right atrium) determines the amount of blood flowing back to
the heart.
The amount of blood flowing back to the heart
determines stroke volume (using Starling’s Law of the
Heart)
Flow control



Veins – constriction determines compliance and venous
return
Arterioles – constriction determines:
o Blood flow to organs
o Mean arterial blood pressure
o The pattern of distribution of blood to organs
(especially important during exercise)
Flow is changed primarily by changing vessel radius
(F=P/R, and R is inversely proportional to r4)
59
LSS Cardiovascular System
Alexandra Burke-Smith
Ways of regulating blood flow
Local mechanisms
 Autoregulation – the intrinsic capacity to compensate for changes in perfusion pressure by changing
vascular resistance
- Without autoregulation, a decrease in pressure will result in a decrease in blood flow and a slight
increase in resistance
- With autoregulation, passive constriction as intravascular pressure falls results in an increase in the
blood flow close to the initial level, as well as a decrease in resistance
- Result of 2 theories/mechanisms:
o MYOGENIC THEORY - smooth muscle fibres respond to tension in the vessel wall; e.g. as
pressure rises muscle fibres contract; stretch-sensitive Ca2+ channels probably involved
o METABOLIC THEORY - as blood flow decreases “metabolites” accumulate and vessels dilate;
when flow increases “metabolites” are washed away. Involves e.g. CO2, H+, adenosine, K+
o SERATONIN RELEASE – injury results in a serotonin release from platelets which causes local
constriction
 Endothelial release – substances released from the lining of vessels
- NITRIC OXIDE – endothelium-derived relaxing factor synthesised from arginine
o Plays a key role in vasodilation
- PROSTACYCLIN & THROMBOXANE A2 – relative amounts for clotting
o Vasodilator and vasoconstrictor respectively
- ENDOTHELINS – potent vasoconstrictors
Systemic regulation
Circulating hormones affecting the vascular system:
 Kinins
o e.g. bradykinin, have complex interactions with renin-angiotensin system; relax vascular smooth
muscle
 ANP
o Atrial natriuretic peptide - secreted from the cardiac atria, vasodilator
o Circulating vasoconstrictors
 ADH – antidiuretic hormone (also known as vasopressin) secreted from posterior pituitary,
o noradrenaline released from adrenal medulla,
o angiotensin II formed by increased renin secretion from kidney
The Autonomic Nervous System (ANS)





The sympathetic nervous system is important in controlling the circulation
o Fibres originate in thoracic and lumbar nerves
o Short pre-ganglionic fibres with long post-ganglionic fibres that release noradrenaline
The parasympathetic nervous system is important in regulating heart rate, but has no effect on vessel radius
o Fibres originate in cranial and sacral nerves
o Long pre-ganglionic fibres with short post-ganglionic fibres that release acetylcholine
At all pre-ganglionic fibres, acetylcholine is released
SNS INNNERVATION TO BLOOD VESSELS:
Sympathetic nerve fibers innervate all vessels except capillaries and precapillary sphincters and some
metarterioles.
Large veins and the heart are also sympathetically innervated
60
LSS Cardiovascular System



Alexandra Burke-Smith
Distribution of sympathetic fibres is variable. There are more innervating the vessels supplying kidneys, gut,
spleen, and skin and fewer innervating skeletal muscle and the brain.
Noradrenaline preferentially binds α1-adrenoceptors to cause smooth muscle contraction and
vasoconstriction.
Circulating adrenaline binds with high affinity to smooth muscle β2-adrenoceptors to cause vasodilation in
some organs; however, the effect of adrenaline is very concentration-dependent.
o While it has a higher affinity for β2 than α1 or α2-adrenoceptors, at high concentrations it does bind
to αlpha adrenoceptors, which can override the vasodilatory effects of β2-adrenoceptor stimulation
and produce vasoconstriction.
The Vasomotor Centre (VMC)






Located in medulla and pons (brainstem)
Composed of:
o Vasoconstrictor area (PRESSOR)
o Vasodilator area (DEPRESSOR)
o Cardioregulatory inhibitory area
Transmits impulses distally through the spinal cord to almost all blood
vessels
Affected by many higher centres of the brain, e.g. the hypothalamus (may
exert excitatory or inhibitory effect)
Lateral portions – control heart activity by influencing heart rate and
contractility
Medial portion – transmits signals via vagus nerve to heart; tends to decrease heart rate
Nervous control of blood vessel diameter




Blood vessels receive sympathetic post-ganglionic
innervation
o Neurotransmitter involved = noradrenaline
There is always some level of tonic activity, known as the
BASELINE (basal level of constriction)
Control of nerve activity can accomplish dilation or constriction by changing levels of sympathetic nerve
discharge:
o Depressor – inhibits sympathetic activity
o Pressor – stimulates increased sympathetic activity
There is generally no parasympathetic innervation to the vascular system
Summary – control of vessel radius
61
LSS Cardiovascular System
Alexandra Burke-Smith
Cardiac Innervation


Heart rate is controlled by changing the
pulse rate of SAN activity, both via
sympathetic and parasympathetic nerves
Heart rate is increased by:
o increasing activity of sympathetic
nerves to heart
o decreasing activity of
parasympathetic nerves to heart
o increasing plasma adrenaline
Controlling force of contraction






SNS also influences contractility
Force of contraction is increased in two ways:
o Intrinsic mechanisms
o Extrinsic mechanisms
 Increased Ca2+ influx
 Increase Ca2+ uptake into
intracellular stores
EXTRINSIC MECHANISMS
Noradrenaline binds to the beta1adrenoreceptor present on the membrane of
myocytes
Binding causes the increase in cyclic AMP
which activates PKA (protein kinase A)
This activation leads to the phosphorylation of
Ca2+ handling proteins and channels, e.g. the L type Ca channel
The channel is then open for longer, which leads to a greater delivery of Ca2+ to myofilaments, increasing
force of contraction
Controlling stroke volume


Extrinsic control (to increase stroke volume)
o Increase activity of sympathetic nerves to heart
o Increase plasma adrenaline
Intrinsic control (to increase stroke volume)
o Increased end diastolic ventricular volume (due to Starling’s law – increased venous return 
increased stretch & preload  increased force). This in turn is increased by:
 Increased
respiratory
movements 
a decrease in
intrathoracic
pressure
 Increased
venous return
62
LSS Cardiovascular System

Alexandra Burke-Smith
Increased atrial pressure (also increased by increased venous return)
Integration of regulation
Fight or flight response
Leads to:
 Increased circulating catecholamines
 Increased respiratory movements
 Increased sympathetic activity
Providing Feedback


Feedback mechanisms can be summarised has consisting of 5 components:
o Set point
o Comparator
o Output
o Controlled variable
o Sensor
A disturbance to the controlled variable is the stimulator of the feedback mechanism
SET POINT
(determined within CNS)
COMPARATOR
(within CNS)
OUTPUT
(SNS, PNS, Ang II, ADH/Vasopressin)
CONTROLLED VARIABLE
(Arterial Blood Pressure)
SENSOR
(baroreceptors)
DISTURBANCE
Baroreceptors




Afferent neuron cell bodies from the internal carotid arteries to the brain via
the GLOSSOPHARYNGEAL NERVE
Afferent neuron cell bodies from aortic arch to brain via VAGUS NERVE
Both the glossopharyngeal and vagus nerve input lead to increased activity in
the VMC
Increased blood pressure  increased afferent activity to brain (although
increase is signoidal)
63
LSS Cardiovascular System
o
o
o
Alexandra Burke-Smith
Carotid sinus baroreceptors respond to pressures between 60 and 180 mmHg.
Baroreceptors respond to changes in arterial pressure.
Baroreceptors reflex is most sensitive at pressures around 90 – 100 mmHg.
Reciprocal innervation

Afferent input from baroreceptors to VMC 
o Stimulus of parasympathetic nerves to heart
o Inhibition of sympathetic innervation to heart arterioles and veins (causing a decrease in tonic
activity)
Effects of increased blood pressure

Increased afferent input via vagus nerve to VMC in medulla oblongata 
o Increased parasympathetic stimulation of the heart via vagus nerve  Decreased heart rate 
decreased blood pressure
o Decreased sympathetic stimulation of the heart  decreased heart rate & stroke volume 
decreased cardiac output  decreased blood pressure
 Also via sympathetic chain, there is decreased sympathetic stimulation to the blood vessels,
which produces vasodilation (this may cause a redistribution of blood supply to the different
organs)
Carotid sinus nerve activity




Decreased blood pressure  reduced stretch of baroreceptors 
o Decreased afferent activity to VMC via carotid sinus nerve
o Decreased efferent activity via vagus nerve to SAN (parasympathetic)  increased heart rate
o Increased sympathetic activity via cardiac nerve to ventricle  increased heart rate & increased
contractility
o Increased sympathetic activity via vasoconstrictor nerves to resistance vessels (arterioles) &
capacitance vessels (veins)  increased constriction
Increased blood pressure (reverse occurs)
Sympathetic vasoconstrictor nerves
allow the control of venous return
Haemorrhage  reduced blood
volume  reduced venous pressure
and return to heart  reduced atrial
pressure  reduced end diastolic
volume  reduced stroke volume
and cardiac output  DECREASED
blood pressure (therefore sequence
of events same as above)
64
LSS Cardiovascular System
Alexandra Burke-Smith
Summary - Maintaining arterial blood pressure
SUMMARY




Local mechanisms regulating blood flow
o Autoregulation, the endothelium and paracrine effects
Systemic regulation by hormones
o circulating vasoconstrictors, kinins, ANP
Neural regulatory mechanisms
o Nervous control of blood vessel diameter
o Cardiac innervation, changing cardiac contraction
o Baroreceptors
o Reciprocal innervation
Integration of control systems
65
LSS Cardiovascular System
Alexandra Burke-Smith
Responses to Cardiovascular Stress
CVS 12 - Dr Chris John (c.john@imperial.ac.uk)
1. Describe the cardiovascular problems associated with:
i. movement from a supine to standing position
ii. exercise
iii. haemorrhage
2. Explain how the components of the cardiovascular system respond to these various challenges
Change in Posture
Problem: movement from supine to standing position is a sever challenge to the human circulation
The Vertical Position

In a foot capillary, the usual blood pressure resulting from cardiac contraction ~25mmHg

On standing, there is the additional effect of gravity on a column of blood, which causes the pressure to
increase to 105mmHg (+80mmHg)
On standing, there is a decrease in blood pressure in areas above the heart, and an increase in the areas
below the heart
Lying Flat
Standing
Arterial
Pressures
Heart
–
100
Heart
– 100
Standing also increases the hydrostatic pressure in the blood
(mmHg)
Head – 95
Head – 55
vessels in the legs; blood pools in the veins and they are easily
Feet - 95
Feet - 195
distended due to their thin muscular wall
Venous Pressures Heart – 1
Heart – 1
(mmHg)
Head – 5
Head – -35
If hydrostatic pressure becomes greater than oncotic pressure,
Feet
5
Feet - 105
fluid is forced into the surrounding tissue beds – this reduces
EEFECTIVE circulating blood volume  decreased blood pressure
END RESULT
o Reduced venous return  decreased end-diastolic volume
o Decreased stroke volume
o TRANSIENT HYPOTENSION




Compensatory Mechanisms



Decrease in blood pressure is detected by arterial baroreceptors in the carotid sinus and aortic arch 
decreased firing to VMC
Max baroreceptor sensitivity occurs near normal mean arterial blood pressure
Effects of decrease blood pressure  reduced afferent input via vagus nerve to VMC in medulla oblongata

o reduced parasympathetic stimulation of the heart via vagus nerve  increased heart rate 
increased blood pressure
o reduced inhibition of sympathetic stimulation of the heart  increased heart rate & stroke volume
 increased cardiac output  increased blood pressure
 Also via sympathetic chain, there is reduced inhibition of sympathetic stimulation to the
blood vessels, which produces vasoconstriction (this may cause a redistribution of blood
supply to the different organs)
66
LSS Cardiovascular System
Alexandra Burke-Smith
Haemorrhage
Problem: reduction in ACTUAL circulating blood volume
Compensatory mechanisms similar to that as with change of posture:
 Reduced baroreceptor firing 
o Increased heart rate
o Increased heart contractility (helps to maintain CO)
o Increased TPR (via organ specific vasoconstriction)
Extra Compensatory mechanisms
 Autotransfusion
- Reduces the hydrostatic pressure, while the oncotic pressure remains the same:
o Reduces ultrafiltration from blood
o Increases reabsorption of fluid from interstitial fluid
- This bulks up blood volume using extracellular fluid and no erythrocytes

-
Decreased urinary output
ADH/Vasopressin release from pituitary  water retention in collecting duct
Angiotensin II synthesis  decreased renal blood flow
Aldosterone production  increased Na+ and therefore water retention
Haemorrhage Volumes




<10% blood loss (~500ml)  compensation via BP variation
20-30% blood loss (1-1.5l)  hypotension, but with maintained tissue perfusion
30-40% blood loss (1.5-2l)  shock; tissue perfusion not maintained which leads to tissue dysfunction and
possible infarction
Tissue resuscitation can be used initially as treatment, but then a blood transfusion should be performed
Exercise
Problem: significantly increased blood flow is required to certain tissues (heart, lungs and skeletal muscle), but total
peripheral resistance decreases, which may reduce mean arterial blood pressure (MABP = CO x TPR)
Exercise increases blood flow, metabolism and oxygen usage within tissues, leading to vasodilation  ACTIVE
HYPERAEMIA
Control Mechanisms



-
Afferent input to medullary cardiovascular center
o “preprogrammed” pattern
o Muscle chemoreceptors
Efferent output to heart, veins and arterioles
o Via autonomic nervous system
Control of TPR
Increases sympathetic activity in GI tract and kidney  profound vasoconstriction
Decreased sympathetic activity in heart, lungs, skeletal muscle and skin  vasodilation
Net result:
o Reduced TPR
o Increased CO
67
LSS Cardiovascular System
o
o
Alexandra Burke-Smith
Increased blood flow to muscles, heart, lungs
Reduced blood flow to GI tract and kidneys
 Control of CO
- Reduced parasympathetic activity and increase sympathetic activity  increased stroke volume and
increased heart rate
- If stroke volume increases, venous return must increase – this is due increased force of contraction by the
skeletal muscle pump, and increased breathing (which reduces the pressure in thoracic cavity)
- There are also NEGATIVE EFFECTS:
o Reduced plasma volume opposes increased venous return
o There is increased capillary pressure across muscle walls
o Loss of salt and water due to sweat
- Net result:
o increased heart rate
o increased contractility
o increased venous return  increased stroke volume
o increased cardiac output
 Overall result
- CO increases because of:
o Increased heart rate
o Increased contractility
o Increased venous return
- TPR decreases because of:
o Increased vasodilation
o (also increased vasodilation in GI tract and kidneys)
- However increase in CO > decrease in TPR, therefore there is an overall INCREASE IN BP
68
LSS Cardiovascular System
Alexandra Burke-Smith
Basic Haemostasis
CVS 13 - Dr Jim Crawley (j.crawley@imperial.ac.uk)
1. Describe in outline the normal haemostatic mechanisms including the interaction of vessel wall, platelets, clotting
factors and fibrinolytic system
2. Describe the causes of bleeding disorders
3. Describe the types of bleeding seen in different haemostatic disorders
4. Describe in outline how coagulation is regulated by the natural anticoagulant pathways
Haemostasis
“the biochemical process that enables both the specific and regulated cessation of bleeding in response to vascular
insult”



Response to a challenge to the vascular system
Role –
o to prevent blood loss from intact and injured vessels
o enable tissue repair
o modulate inflammation
Important clinical applications –
o Diagnosis of bleeding disorders
o Treatment of bleeding disorders
o Identification of risks for thrombotic disease
o Treatment of thrombotic disease
o Monitoring of anticoagulant drugs
Haemostatic plug formation
Is the response to injury to endothelial cell lining. Consists of 4 stages:
I.
II.
III.
IV.
I.



Vessel constriction
Primary haemostasis – formation of an unstable platelet plug
Secondary haemostasis – stabilisation of the plug with fibrin
Vessel repair and dissolution of clot
Vessel Constriction
Vascular smooth muscle cells contract locally, limiting blood flow to the injured vessels
This is a LOCAL CONTRACTILE RESPONSE to injury, and is mainly important in small blood vessels
A normal vessel wall consists of:
o A layers of endothelial cells – ANTICOAGULANT barrier, which again consists of anticoagulant
proteins:
 GAGs – glycosaminoglycan
 TFPI - tissue factor pathway inhibitor
 TM - thrombomodulin
 EPCR - endothelial protein C receptor
o Subendothelium which is PROCOAGULANT and consists of:
 Elastin
 Collagen
 VSMC (tissue factor) – vascular smooth muscle cells
 Fibroblasts (tissue factor)
69
LSS Cardiovascular System


II.





Alexandra Burke-Smith
Other vital components of haemostasis circulate in the blood, in a quiescent state:
o Platelets
o Clotting factors
o Plasma proteins
Within a few seconds of injury, these components endeavour to minimise blood loss via local constriction
Primary haemostasis – formation of an unstable platelet plug
PLATELETS:
o Circulate in blood
o Derived from MEGAKARYOCYTES in the
bone marrow
o Each megakaryocyte produces a large
number of platelets
o Have a granulated cytoplasm, and are
highly specialised ANUCLEAR PLASMA
CELLS
o Many different ultrastructural features
(ass seen in diagram)
Formation of the plug consists of:
o Platelet ADHESION – recruitment of platelets from flowing blood to site of injury
o Platelet AGGREGATION – formation of the plug
o Between adhesion and aggregation, it can also be said that the platelets undergo
ADHESION:
o Within the blood, there are circulating platelets and VWF (von Willebrand factor – a glycoprotein)
o These do not interact, as the VWF are in a globular conformation therefore their binding sites are
hidden from the platelets – binding sites are called Gp1b (membrane glycoprotein Ib)
o Vascular injury damages the endothelium and exposes the sub-endothelial matrix which consists of
collagen
o The sub-endothelial collagen then binds to VWF, recruiting them to the endothelial surface
 The rheological (flowing force) shear forces of flowing blood through the vessel then
unravels the VWF on the endothelial surface
o Unravelled VWF has exposes binding site (Gp1b) therefore the platelets bind
o The platelets can also bind directly to the exposed collaged via Gp1a, but this is only under LOW
shear forces
 This binding recruits the platelets to the site of vessel damage
ACTIVATION – conversion from a passive to an interactive functional cell
o Change shape (spreads and flattens)
o Change membrane composition
o Present new proteins on their surface (GpIIb/GpIIIa)
o The platelets bound to the collagen or VWF release ADP and thromboxane –
these activate the platelets
 Collagen and thrombin also activate platelets
AGGREGATION
o Activated platelets bind more tightly to the collagen and VWF via GpIIb/IIIa
 GpIIb/IIIa also binds fibrinogen, which develops the platelet plug
o The platelet plug helps slow bleeding and provides a surface for coagulation
70
LSS Cardiovascular System
III.
Alexandra Burke-Smith
Secondary haemostasis – stabilisation of the plug with fibrin
 Also known as blood coagulation
 Stops blood loss
 Complex biochemical process
 Components involved from:
o Liver – most plasma haemostatic proteins
o Endothelial cells – VWF. TM, TFPI
o Megakaryocytes – VWF, FV
 These clotting factors circulate as inactive precursors (ZYMOGENS) – then activated by specific proteolysis
(to form either as SERINE PROTEASE ZYMOGENS or COFACTORS)
Zymogens (inactive)
Serine proteases
Cofactors
Inhibitors
Prothrombin (contains
GIa domain)
FVII (contains GIa
domain)
thrombin
TF
TFPI (Kunitz-type)
FVIIa (contains GIa
domain)
FVa
FIX (contains GIa domain)
FIXa (contains GIa
domain)
FVIIIa
FX (contains GIa domain)
FXa (contains GIa
domain)
FXIa
FXIIa
Protein C (serine
protease) (contains GIa
domain)
Protein S (cofactor for
APC) (contains GIa
domain)
Antithrombin (serpin)
FXI
FXII
FXIII
TISSUE FACTOR PATHWAY
Consists of two pathways; intrinsic and extrinsic:
o
o
Intrinsic pathway – initiated when FXII is activated (not biologically as important)
 FVIIIa is the only cofactor, all other activated clotting factors are serine proteases
Extrinsic pathway – primary driver of clotting cascade. Steps include:
1) Initiated when TF on surface of cells (which normally do not come into contact with blood) are exposed to
plasma clotting factors
o TF + FVII  TF-FVIIa complex
2) TF-FVIIa then activates FIX and FX
3) FXa activates prothrombin (ProT) inefficiently leading to the generation of trace amounts of thrombin.
71
LSS Cardiovascular System
Alexandra Burke-Smith
4) Thrombin can then activate FVIII and FV, which function as non-enzymatic cofactors for FIXa and FXa,
respectively.
5) FIXa-FVIIIa catalyses the conversion of increased quantities of FXa
6) FXa-FVa catalyse enhanced generation of thrombin (more efficient by bypassing initial step)
7) Thrombin at the site of vessel damage converts fibrinogen (Fbg) to fibrin (Fbn), which is the molecular
scaffold of a clot.
NOTE:
 cascade or amplification system
 zymogens which are converted to proteinases & cofactors which
need to be activated at surfaces
 The surface might be platelets (Pl) which localise and accelerate
the reactions
 The trigger to initiate coagulation in vivo is tissue factor
 Although FXII can be activated to FXIIa, this is mainly an in vitro
reaction, useful for some diagnostic tests
IV.
Vessel repair and dissolution of clot
Inhibitory coagulation mechanisms help keep clotting to the site of vessel
injury, therefore deficiencies these mechanisms are PRO-THROMBOTIC:

-
TFPI (Tissue Factor Pathway Inhibitor)
Targets initial tissue factor of extrinsic pathway, as well as FXa
This leads to the formation of a TF/FVIIa/Xa/TFPI complex
This shuts down the coagulation pathway
 The Protein C anticoagulant pathway (Activated Protein C/APC &
Protein S)
- APC  Protein S, which targets FVIIIa and FVa
- Generated thrombin then binds to THROMBOMODULIN of
endothelial cells, which shuts down any further thrombin
generation
 Antithrombin
- SERPIN (serine protease inhibitor)
- Inhibits FIXa, FXa and thrombin, completely shutting down the
cascade
NB: HEPARIN accelerates the action of antithrombin, therefore is used for
immediate anticoagulation in venous thrombosis and pulmonary
embolism
FIBRINOLYSIS




Restores vessel integrity
PLASMINOGEN binds to the fibrin clot, and via TPA (tissue plasminogen activator) is converted to PLASMIN
Plasmin then cleaves and degrades the fibrin clot into soluble fragments known as FDP (fibrin degradation
products), which are then cleared by the liver.
o FDP is elevated in DIC (disseminated intravascular coagulation)
tPA and a bacterial activator; STREPTOKINASE, are used in therapeutic thrombolysis for Myocardial
Infarction, ischaemic stroke etc. these are known as CLOT BUSTERS
72
LSS Cardiovascular System
Alexandra Burke-Smith
Clinical Haemostasis and Thrombosis
CVS 14 - Professor Mike Laffan (m.laffan@imperial.ac.uk)
1.
2.
3.
4.
5.
6.
Describe what is meant by abnormal bleeding
Describe patterns of abnormal bleeding with examples
Describe the manifestations of venous thrombosis
List the main risk factors for venous thrombosis
Give a rough estimate of its prevalence
Be acquainted with the principles of treatment of venous thrombosis
NB: normal haemostasis is a state of equilibrium between:
 Fibrinolytic factors & anticoagulant proteins
 Coagulation factors & platelets
Abnormal Bleeding – the result of an INCREASE in fibrinolytic factors and anticoagulant proteins, and a DECREASE
in coagulation factors and platelets
Characteristics
•
•
•
•
Spontaneous
Out of proportion to the trauma/injury
Unduly prolonged
Restarts after appearing to stop
Examples
•
•
•
•
•
Epistaxis not stopped by 10 mins compression or requiring medical attention/transfusion.
Cutaneous haemorrhage or bruising without apparent trauma (esp. multiple/large).
Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days
after wound. Spontaneous GI bleeding leading to anaemia.
Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.
Heavy, prolonged or recurrent bleeding after surgery or dental extractions.
Defects of Primary Haemostasis (the formation of an unstable platelet plug)
See previous lecture for details on primary haemostasis
Deficiency/defect
Collagen within subendothelial matrix of vessel wall
Von willebrand factor
platelets
Examples
Steroid therapy, age
Von willebrand disease (genetic)
Aspirin &other drugs, thrombocytopenia
Patterns of bleeding
•
•
•
•
•
•
Easy bruising
Nosebleeds (prolonged:>20 mins)
Gum bleeding (prolonged)
Menorrhagia
Bleeding after trauma/surgery
Petechiae (specific for thrombocytopenia)
o Typical of thrombocytopenia (decreased platelets) – small blood spots
73
LSS Cardiovascular System
Alexandra Burke-Smith
Defects of secondary haemostasis (fibrin mesh formation/coagulation)
See previous lecture for details on secondary haemostasis
Definition: Deficiency or defect of coagulation factors I-XIII
Common examples include:
• Haemophilia: FVIII or FIX (hereditary due to genetic defect)
• Liver disease (acquired – most coagulation factors are made in the liver)
• Drugs (warfarin – inhibits synthesis)
• Dilution
• Consumption (DIC – disseminated intravascular coagulation) (acquired)
Acquired coagulation disorders – DIC
•
•
•
•
•
•
Generalised activation of coagulation – Tissue factor
Haemostasis then takes place WITHIN blood vessels, and throughout the general circulation
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors & platelets
Activation of fibrinolysis depletes fibrinogen
Consequences:
o Widespread bleeding - from iv lines, bruising, internal
o Organ failure – due to deposition of fibrin in vessels
Patterns of bleeding
•
•
•
•
•
•
•
•
Often delayed (after primary haemostasis)
Deeper: joints and muscles
Not from small cuts etc.
Nosebleeds rare
Bleeding after trauma/surgery
After i/m injections
ECCHYMOSIS – easy bruising
o Virtually all bleeding disorders
HAEMARTHROSIS – spontaneous bleeding into joints
o Hallmark of haemophilia
o Increases pressure in joints
o Very painful and damaging
Defects of clot stability – excess fibrinolysis
•
•
Can be used in therapy to break down clots after MI (but this must be done carefully as can lead to
haemorrhage)
Due to either:
o Excess FIBRINOLYTIC components – plasma, tPA
 Can occur with some tumours
o Deficient ANTIFIBRINOLYTIC components – antiplasmin
 Can have a genetic antiplasmin deficiency
NB: ANTICOAGULANT excess is usually only due to therapeutic administration, e.g. heparin or hirudin
74
LSS Cardiovascular System
Alexandra Burke-Smith
Thrombosis – result of a DECREASE in fibrinolytic factors and anticoagulant proteins, with an INCREASE in
coagulation factors and platelets
What is thrombosis?
•
•
•
•
•
‘Intravascular coagulation’
‘Inappropriate coagulation’
Coagulation inside a blood vessel
‘Coagulation not preceded by bleeding’
Thrombi may be Venous or Arterial
Effects of thrombosis
•
•
Obstructed flow of blood
o Artery – myocardial infarction, stroke, limb ischaemia
o Vein – pain and swelling
Embolism
o Venous embolise to lungs (pulmonary embolus)
o Arterial emboli, usually from heart, may cause stroke or limb ischaemia
Venous Thrombo-embolism
•
•
•
•
Deep Vein Thrombosis (DVT) – venous return of blood is obstructed
o Causes painful, swollen legs
Pulmonary embolism – causes shortness of breath, chest pain, may lead to sudden death
Prevalence
o 1 in 1000-1,000 per annum (with incidence doubling each decade)
o However is cause of 10% of hospital deaths, and is a preventable cause of death
 25000 preventable deaths per annum
Consequences:
o Death- VT mortality 5%
o Recurrence - 20% in first 2 years
and 4%pa thereafter
o THROMBOPHLEBITIC syndrome Severe TPS in 23% at 2 years
(11% with stockings)
o Pulmonary hypertension - 4% at 2
years
Why do some people get thrombosis?
•
•
•
Genetic constitution
Effect of age and previous events,
illnesses, medication
Acute stimulus
VIRCHOW’S TRIAD: the 3 contibutory factors to thrombosis
•
Blood - dominant in venous thrombosis
o Deficiency of anticoagulant proteins – antithrombin, protein C, protein S
o Increased coagulant proteins & activity –
 Factor VIII
 Factor II &others
75
LSS Cardiovascular System
•
•
Alexandra Burke-Smith
 Factor V Leiden (increased activity due to activated protein C resistance)
 Thrombocytosis (increased platelets)
vessel wall - dominant in arterial thrombosis
o Many proteins active in coagulation are expressed on the surface of endothelial cells and their
expression altered in inflammation
 Thrombomodulin
 Tissue factor
 Tissue factor pathway inhibitor
flow - complex, contributes to both
o reduced flow (STASIS) increases the risk of venous thrombosis. This can occur due to:
 surgery
 fracture
 long haul flight
 bed rest
Thrombophilia – increased risk of thrombosis
•
•
Clinical:
o Thrombosis at young age
o ‘idiopathic thrombosis’
o Multiple thromboses
o Thrombosis whilst anticoagulated
Laboratory
o Identifiable cause of increased risk
 AT deficiency
 Factor V Leiden
 global measures of coagulation activity.
Absolute and Relative Risks
76
LSS Cardiovascular System
Alexandra Burke-Smith
Acquired risks for thrombosis
•
Numerous conditions will alter blood coagulation, vessel wall and/or flow to precipitate thrombosis or make
it more likely, e.g.
o Oral contraceptive pill
o Pregnancy
o Malignancy
o Surgery
o Inflammatory response
Therapy and venous thrombosis
•
•
Treatment
o LYSE CLOTS – e.g. using TPA (this presents with a high risk of bleeding)
o LIMIT RECCURENCE/EXTENSTION
 Increase anticoagulant activity - e.g: heparin (immediate acting, parenteral)
 Lower Procoagulant factors – e.g. warfarin (oral, slow acting for long term therapy)
Prevention (NICE Guidelines 2010)
o Assess individual risk and circumstantial risk
o All patients admitted should have VTE risk assessment
o Give prophylactic antithrombotic therapy
o E.g. heparin for in-patients
o TED stockings
77
LSS Cardiovascular System
Alexandra Burke-Smith
Introduction to Atherosclerosis
CVS 15 - Dorian O. Haskard (d.haskard@imperial.ac.uk)
Recognize:
1. The changes in the walls of arteries that lead to atherosclerosis.
2. How atherosclerosis leads to clinical manifestations
3. The time-course of atherosclerosis
Areas of Medicine involved/affected by atherosclerosis:
 Neurology – Cerebrovascular disease
 Acute medicine – heart attack, stroke
 Metabolic medicine – lipids
 Endocrinology – diabetes
 Vascular surgery – revascularization
 Cardiac surgery – revascularization
 Cardiology – coronary disease
Atherosclerosis


Noted by Rudolph Virchow in 1952
Term coined by Felix Marchand in 1904
There are 6 stages involved:
I.
Lesion prone location within a coronary artery
- Smooth muscle within the vessel wall undergoes
ADAPTIVE THICKENING
II.
Type II lesion
- Macrophage foam cells appear
III.
Type III lesion (pre-atheroma)
- Small pools of extracellular lipids form within the vessel
wall
IV.
Type IV lesion (atheroma)
- Macrophage foam cells form NECROTIC CORE (consisting
of dead cells and extracellular lipids)
V.
Type V lesion (fibroatheroma)
- The necrotic core becomes encased by a FIBROUS CAP),
which separates coagulation factors from tissue factors
VI.
Type VI l lesion (complicated lesion)
- The fibrous thickening may reduce blood flow
- Atheroma may break down, causing a thrombus, fissure
and/or haematoma
Risk factors

-
Potentially modifiable:
Smoking
Lipids
Blood pressure
Diabetes
Obesity
78
LSS Cardiovascular System

-
Alexandra Burke-Smith
Lack of exercise
Not modifiable
Age
Sex
Genetic background
NB: smoking, hypertension and high cholesterol can be considered the BIG 3,
and combined lead to a 16x increased risk
Paradigms (ideas) of pathogenesis
 Inevitable consequence of ageing
 The cholesterol hypothesis
 Inflammation and immunity
The cholesterol hypothesis



1904 N.N. Anitschkow – studied advanced plaque in a rabbit fed cholesterol for 124
o This lead to the formation of a fibrous plaque surrounding foam cells, and a necrotic core consisting
of cholesterol crystals and calcium
The cholesterol controversy: “the view that raised plasma cholesterol is per se a cause of coronary heart
disease is untenable” BMJ 1976
Evidence: in favour of cholesterol as a major aetiological factor
o EXPERIMENTAL – e.g. rabbits, mice
o CLINICAL GENETIC – e.g. familial hypercholesterolaemia
o EPIDEMIOLOGICAL – e.g. Framlingham; a long standing epidemiological survey
o INTERVENTIONAL – e.g. randomised controlled trials of statins
Foam Cells






LDLs deposit in the SUBINTIMAL SPACE (intima is the component of the subendothelial layer of vessel wall,
between the endothelium and the internal elastic lamina)
o The vessel wall consists of many layers (from lumen outwards)
 Endothelium
 Subendothelium – Intima
 Internal elastic lamina
 Media
 Adventitia
The LDLs then bind to MATRIX PROTEOGLYCANS
o NATIVE LDLs are encased with a phospholipid case by apoB
o The native LDL is then oxidised and modified to form a MODIFIED apoB
The modified apoB is recognised as NON-SELF by macrophages, and is taken up by SCAVENGER RECEPTORS
to form a MACROPHAGIC FOAM CELL
The foam cells then release inflammatory mediators (e.g. cytokines, chemokines & oxidised phospholipids)
and/or lead to cell death
o This damage causes increased recruit and adhesion of MONOCYTES by the endothelium
With normal levels of oxidised LDLS, HOMEOSTATIC DEBRIS DISPOSAL occurs
With INCREASED levels of oxidised LDLs, this leads to an INFLAMMATORY RESPONSE
79
LSS Cardiovascular System
Alexandra Burke-Smith
Inflammatory basis of atherosclerosis
Increased levels of activated macrophagic foam cells lead to release of:
 Free radicals
 Proteases
 VSMC growth factors
 Angiogenic factors
 Apoptosis
Why is atherosclerosis focal?




The branches and curvatures of blood vessels are more likely to be “HOT SPOTS” for atheroma formation
Blood flow is FAST, LAMINAR, SHEAR
At these hot-spots, blood flow is more disorganised
The endothelium is very sensitive to these changes in blood flow
Terminology of Atherosclerosis





Stenosis – the gradual loss of lumenal diameter leading to critical reduction in blood flow
o This can be observed by ANGIOGRAPHY
Ischaemia – insufficient blood supply to meet metabolic demands of tissues leads to hypoxic cellular
dysfunction
o Typically experienced as pain on exertion, e.g. angina pectoris (heart pain), intermittent claudication
(in legs)
Atheroslcerotic plaque – the localised area of fat deposition and tissue breakdown (necrosis) within the
arterial wall
Plaque erosion – the breakdown of endothelial lining of the lesion WITHOUT full rupture of the fibrous cap
Plaque rupture – the breakdown of the fibrous cap of tissue separating plaque from blood
Effects of plaque erosion/rupture



-
Plaque growth
Platelet recruitment (involving adhesion and degranulation) and blood coagulation at site
This may lead to silent non-occlusive thrombus and plaque growth
Occlusive thrombosis
Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow
Embolism
Definition – the dislodgment of solid material (e.g. platelet plug, thrombus, cholesterol-rich plaque contents)
into the arterial circulation leading to occlusion at distant sites
Consequences depend on the size of the embolus and the target organ of the arterial circulation (e.g. brain,
eye, bowel, limbs)
Effects of arterial occlusion


Transient occlusion – short ischaemia from an occlusion that spontaneously resolves
o E.g. in brain: TIA, in eye: amaurosis fugax
Infarction – the death of tissue due to unresolved ischaemia
o E.g. in heart: MI (heart attack)., in brain: CVA-cerebrovascular attack (stroke)
80
LSS Cardiovascular System
Alexandra Burke-Smith
Natural history of atherosclerosis
Development from:
 Normal vessel  intermediate lesions  advances lesions  complications (stenosis, rupture etc)
 This may occur over a period of >60 years:
o Normal vessel – neonatal
o Intermediate lesions – 40 yrs
o Advanced lesions – 50 yrs
o Complications - >60 yrs
 Glasgow Phenomenon – describes the early expansion of arteries before constriction of the lumen occurs
(also known as POSITIVE ARTERIAL REMODELLING)
o This is not seen by an angiogram
 Window of opportunity for CLINICAL INTERVENTION
o Used at the complications stage (>60 yrs)
o Secondary prevention
o Catheter based interventions
o Revascularisation surgery
o Treatment of heart failure
 Window of opportunity for PRIMARY PREVENTION
o Used during the development of advanced lesions from intermediate lesions
o Life-style changes
o Risk factor management
 Aim is to shift away from clinical intervention to primary prevention
Pathogenesis
Atherosclerosis – a chronic inflammatory response in the walls of arteries, in large part in reaction to the deposition
of lipoproteins (plasma proteins that carry cholesterol and triglycerides)
The main cell types involved:
 Vascular endothelial cells
 White blood cells (leukocytes)
o Particularly monocytes/macrophages
 Platelets
 Vascular smooth muscle cells
81
LSS Cardiovascular System
Alexandra Burke-Smith
Vascular endothelium in atherosclerosis
CVS 16 - Anna M. Randi (a.randi@imperial.ac.uk)
Recognize:
1. The importance of the vascular endothelium for the health of blood vessels
2. The role of endothelium in regulating permeability and leukocyte recruitment
3. The role of the vascular endothelium in atherosclerosis
a. Regulation of permeability and leukocyte recruitment
b. The role of flow in regulating endothelial function
c. Endothelial aging: cell senescence in atherosclerosis
d. Pro and cons of angiogenesis in atherosclerosis
Structure of Arteries & Veins
3 layers (except capillaries and venules):
 TUNICA INTIMA
- Endothelium
- Basement membrane
- Lamina propria (smooth muscle and connective tissue)
- Internal elastic membrane
 TUNICA MEDIA
- Smooth muscle cells
- External elastic membrane
 TUNICA ADVENTITIA
- Vasa vasorum
- Nerves
Vascular endothelium







Surface separating blood from other tissues
Very extensive - Surface area >1000m2, Weight >100g
Acts as a vital barrier separating blood from tissues
Formed by a monolayer of cells, one cell deep
o CONTACT INHIBITION – mechanism at cell junctions which stops further cell growth
Very flat cells, about 1-2 micrometres thick and 10-20 micrometers in diameter
Not all cells are the same
In vivo, cells live a long life and have a low proliferation rate (unless new vessels are required)
Endothelial cells
Regulates:
 Thrombosis & haemostasis
- Antithrombotic factors
- Procoagulant factors
 Angiogenesis
- Growth factors
- Matrix proteins
 Vascular tone & permeability
- Vasodilator factors
- Vasoconstricting factors
82
LSS Cardiovascular System
Alexandra Burke-Smith
 Inflammation
- Adhesion molecules
- Inflammatory mediators
Regulation of endothelial homeostasis





At rest, there is a homeostatic balance between different factors:
o Anti-inflammatory & pro-inflammatory
o Anti-thrombotic & pro-thrombotic
o Anti-proliferative & pro-angiogenic
Infection, injury etc, may temporarily tip the balance leading to an activated endothelium, but then will
return to its resting state
The endothelium may be activated by:
o Smoking
o Viruses
o Mechanical stress
o Inflammation
o High blood pressure
o Oxidised LDLs
o High glucose
This activation leads to:
o Thrombosis
o Senescence
o Increased permeability
o Leukocyte recruitment
Chronic activation of the endothelium may also lead to ATHEROSCLEROSIS
Role of the endothelium in atherosclerosis
Vascular permeability


The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial
space:
o This causes lipoprotein trapping and oxidative modification
o The modified LDLs may then be taken up by macrophages forming foam cells, which causes chronic
inflammation
Leukocyte recruitment



Contact inhibition at endothelial junctions regulates the movement of leukocytes from blood into tissues
The activation of the endothelium  LEUKOCYTE ADHESION CASCADE
o Capture
o Rolling
o Arrest
o Adhesion
o Intravascular crawling
o Paracellular and transcellular transmigration
This involves:
o selectins (E, P & L-selectins)
o chemoattractants (MCP-1, IL-8)
83
LSS Cardiovascular System



Alexandra Burke-Smith
o ICAM-1, VCAM-1
o Integrins (LFA-1, VLA-4)
VESSEL DIFFERENCES:
o Capillary – endothelial cells surrounded by basement membrane and pre-capillary cells (perycites)
o Post-capillary venule – structure similar to capillaries but more pericytes
o Artery – 3 thick layers rich in cells and extracellular matrix
Recruitment of blood leukocytes into tissues takes place normally during INFLAMMATION
o Leukocytes adhere in POST-CAPILLARY VENULES
In ATHEROSCLEROSIS, leukocytes adhere to the activated endothelium of LARGE ARTERIES and get stuck in
the subendothelial space (in the smooth muscle layer)
o Newly formed post-capillary venules at the base of developing lesions provide a further portal for
leukocyte entry
Blood flow








Laminar Flow
Occurs normally
Streamlined
Outermost layer moving slowest and centre
moving fastest
Leads to high shear stress
Antithrombotic
Antimigration
Antigrowth
Promotes:
o NO production
o Factors that inhibit coagulation, leukocyte
adhesion, smooth muscle cell proliferation
o Endothelial survival








Disturbed flow
Occurs at branch-points
Blood flow interrupted
Fluid passes a constriction, sharp turn, rough surface
etc
Leads to low shear stress
Prothrombotic
Promigration
Progrowth
Promotes:
o Coagulation, leukocyte adhesion, smooth muscle
cell proliferation
o Endothelial apoptosis
Senescence







REPLICATIVE SENESCENCE: the limited proliferative capacity of human cells in culture
In response to stress and damage, CELLULAR SENESCENCE locks cells in a permanent form of growth arrest
This is linked to progressive shortening and dysfunction of TELOMERES (ends of chromosomes)
Senescent cells have a distinct morphology and acquire specific markers, e.g. beta-gal
OXIDATIVE SENESCENCE is telomere independent
In atherosclerotic lesions, vascular cells have morphological features of senescence
o associated with beta-gal activity within arteries
CONSEQUENCES of endothelial senescence:
84
LSS Cardiovascular System
Alexandra Burke-Smith
o
o
Can be
induced
by CV risk
factors,
such as
oxidative
stress,
that
induced
increased
cell
replicatio
n to replace dead or damaged cells
These changes result in a pro-inflammatory,
Angiogenesis







Formation of new blood vessels by sprouting from pre-existing vessels
Initiated by pro-angiogenic stimulation of a pre-existing mature blood vessel
Involves a large number of cells
Important in many diseases e.g. cancer
Cascade of events lead by specialised endothelial tip cells
Cascade involves:
o Angiogenic factor production
o Release of factor
o Extracellular receptor binding
 Intracellular signalling occurs
o Extracellular activation
 Endothelial matrix degradation
o Extracellular proliferation
o Directional migration
o Extracellular matrix remodelling
o Tube formation
o Loop formation
o Vascular stabilization
THE JANUS PARADOX:
o Angiogenesis promotes plaque growth, but can be used therapeutically to induce new formation in
ischaemic tissues
 Delivers growth factors and stem cells to the ischaemic region to induce new vessel growth
Pathogenesis of Atherosclerosis: Inflammation Model



Endothelial dysfunction leads to:
o Increased endothelial permeability
o Leukocyte migration and adhesion
This leads to fatty-streak formation and foam-cell formation
There is then a formation of an advances, complicated lesion of atherosclerosis
o Macrophage accumulation & formation of a necrotic core
85
LSS Cardiovascular System
o
Alexandra Burke-Smith
Angiogenesis also occurs
86
LSS Cardiovascular System
Alexandra Burke-Smith
Atherosclerosis Pathology: the role of lipids,
macrophages and vascular smooth muscle
CVS 17 - Dr Joseph J Boyle (j.boyle@imperial.ac.uk)
1.
2.
3.
4.
Recognize:
How lipoproteins that are deposited in the arterial wall stimulate macrophage functions
The protective and deleterious functions of macrophages that result in a chronic inflammatory response in the
vessel wall
The way in which vascular smooth muscle cells (VSMC) remodel the structure of the artery and protect plaque
integrity
The different roles of macrophages and VSMC in plaque instability
Macrophages
•
•
•
•
•
•
•
•
•
White blood cells can injure host tissue if they are activated excessively or inappropriately
In atherosclerosis, the main inflammatory cells are macrophages
Macrophages are derived from blood monocytes
There are many different types of macrophages
Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory
sequences on DNA
We do not yet understand the regulation
Two main classes - resident or inflammatory macrophages
Inflammatory macrophages adapted to kill microorganisms (germs)
Resident macrophages – normally homeostatic
o suppressed inflammatory activity
o Alveolar resident macrophages (surfactant lipid homeostasis)
o Osteoclasts (calcium and phosphate homeostasis)
o Spleen (iron homeostasis)
Lipoproteins
•
Low density lipoprotein (LDL)
o ‘bad’cholesterol
o synthesised in liver
o carries cholesterol from liver to rest of body including
arteries
•
High density lipoprotein (HDL)
o ‘good cholesterol’
o carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol
transport”)
Oxidised LDL(s), modified LDL(s)
o Due to action of free radicals on LDL (see later)
o Not one single substance
o families of highly inflammatory and toxic forms of LDL found in vessel walls.
•
Sub-endothelial trapping of LDL
•
Low density lipoproteins (LDL) leak through the endothelial barrier by uncertain mechanisms
87
I.
LSS Cardiovascular System
•
•
Alexandra Burke-Smith
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer
Trapped LDL is susceptible to modification
Modification of trapped LDL
•
•
•
•
Best studied modification is oxidation
Chemically represents partial burning
LDL becomes oxidatively modified by free radicals
Oxidised LDL is phagocytosed by macrophages to form a foam cell - this stimulates chronic inflammation
Familial Hypelipidemia (FH)
•
•
•
•
Autosomal recessive genetic disease
Massively elevated cholesterol (20mmol/L)
failure to clear LDL from blood
xanthomas (fatty cholesterol lumps visible on skin) and early atherosclerosis
o if untreated fatal myocardial infarction before age 20
Cholesterol Homeostasis
•
•
•
•
•
HMGCoA reductase is the rate limiting enzyme of cholesterol synthesis
SREBP (sterol response element binding protein)
o Activated by low cholesterol
o Activates gene for HMGCoA reductase
o If LDL receptor (LDLR) is working properly, increased LDL levels inactivate liver SREBP and reduce
cholesterol synthesis
This is Negative feedback
In LDLR-negative patients, macrophages accumulate cholesterol
In atherosclerotic lesions, there is a second LDL receptor - not under feedback control
o Called the ‘scavenger receptor’ since it hoovers up chemically modified LDL
o Now known that scavenger receptors are a family of pathogen receptors that ‘accidentally’ bind
oxidised LDL
Macrophage Scavenger receptors

-
Receptor A
Expresses CD204
Binds to oxidised LDL
Binds to Gram-positive bacteria like Staphylococci and Streptococci
Binds to dead cells

-
Receptor B
Expresses CD36
Binds to oxidised LDL
Binds to malaria parasites
Binds to dead cells
Macrophages within atherosclerotic plaques
Generate of free radicals that further oxidise lipoproteins
• Macrophage Oxidative enzymes
• Can modify native LDL  modified LDL
• NADPH Oxidase
88
LSS Cardiovascular System
•
Alexandra Burke-Smith
o superoxide O2MYELOPEROXIDASE
o HOCl hypochlorous acid (bleach) from ROS + Clo HONOO Peroxynitrite
II.
Phagocytose/scavenge modified lipoproteins, and become foam cells
III.
Become activated by modified lipoproteins/free intracellular cholesterol to express/secrete
a. Inflammatory mediators (eg TNFa, IL-1, MCP-1) that recruit more monocytes
• Cytokines – protein immune hormones that activate endothelial cell adhesion molecules
o Interleukin-1 upregulates vascular cell adhesion molecule 1 VCAM-1
o VCAM-1 mediates tight monocyte binding
o Atherosclerosis is reduced in mice without IL-1 or VCAM-1
• Chemokines - small proteins chemoattractant to monocytes
o Monocyte chemotactic protein-1 (MCP-1)
o MCP-1 binds to a monocyte G-protein coupled receptor CCR2
o Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice
• Positive feedback loop / vicious cycle leading to self-perpetuating inflammation
b. Chemoattractants and growth factors for Vascular Smooth Muscle Cells (VSMC)
• Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to
proliferate and deposit extracellular matrix, reducing their contractile filaments
• Platelet derived growth factor
o Vascular smooth muscle cell chemotaxis
o Vascular smooth muscle cell survival
o Vascular smooth muscle cell division (mitosis)
• Transforming growth factor beta
o Increased collagen synthesis
o Matrix deposition
c. Proteinases that degrade tissue (e.g. the fibrous cap)
• Metalloproteinases (=MMPs)
o Family of ~28 homologous enzymes
o Activate each other by proteolysis
o Degrades collagen
o Catalytic mechanism based on Zinc
• Vulnerable yet stable plaques have certain characteristics:
o Large soft eccentric lipid-rich necrotic core
o Thin fibrous cap
o Reduced VSMC and collagen content
o Increased VSMC apoptosis
o Infiltrate of activated macrophages expressing MMPs
d. Tissue factor that stimulates coagulation upon contact with blood
• Crosstalk between inflammation and coagulation: healing wound need to clot blood and fight infection
• Tissue factor (TF) is a 263 amino acid membrane protein expressed on activated macrophages
• TF initiates the coagulation cascade
• Macrophage TF is increased in atherosclerosis
89
IV.
LSS Cardiovascular System
•
Alexandra Burke-Smith
Erosion/rupture of the fibrous cap leads to access of the plasma coagulation cascade to macrophage tissue
factor with consequent thrombosis
Die by apoptosis – contributing to the lipid-rich core of the plaque
• Oxidised LDL derived metabolites are toxic e.g. 7-keto-cholesterol
• Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
• Once overwhelmed, macrophages die via apoptosis
• Releases macrophage tissue factor and toxic lipids into the ‘central death zone’ called lipid necrotic core
o Thrombogenic and toxic material accumulates, walled off by the fibrous plaque, until plaque
ruptures which causes it to meet blood
SUMMARY
•
•
•
Macrophages are the major inflammatory cell type in atherosclerosis
protective functions in the plaque
o Clearing debris (modified lipoproteins, dead cells)
o Stimulating “wound healing” response involving VSMCs
deleterious functions
o Release of free radicals that modify LDL
o Recruitment of further monocytes via cytokines and chemokines
o Expression of MMPs that may destabilise the fibrous cap
o Expression of tissue factor that can stimulate thrombosis
90
LSS Cardiovascular System
Alexandra Burke-Smith
CHD, Angina and MI – investigation and treatment
CVS 18 - Professor Peter Collins (p.collins@imperial.ac.uk)
1.
2.
3.
4.
State the main cardiac factors which give rise to chest pain
State the main clinical investigations that help diagnose angina
State some of the drug treatments for angina
Define myocardial ischemia and its pathophysiology
Causes of Coronary Heart Disease
•
•
•
•
•
•
•
•
Risk factors may be classified as non-modifiable or modifiable
Non-modifiable:
o Gender
o Age
o Menopause
o Family history
o Ethnicity
Modifiable:
o Hypertension
o Diabetes
o Smoking
o Lipids
o Lifestyle
o Obesity
o Oestrogen status
The major modifiable CHD risk factors are:
o Smoking
o Hypertension
o Dyslipidaemia
o A cluster of these 3 risk factors is associated with a 16x increased risk for CHD
The cause of CHD has nothing to do with the heart muscle itself, but is a disease of the coronary arteries
which supply blood to cardiac muscle known as ATHEROSCLEROSIS
Atherosclerosis consist of 3 phases:
o Initiation
o Progression
o Complication
There is now a substantial body of research that suggests the origins of atherosclerosis begin at an early age.
o the extent of atherosclerosis increases progressively with advancing age
o CHD is highly prevalent and that even relatively young individuals may have a substantial plaque
burden that will require aggressive intervention.
aim of treatment of CHD is to shift away from aggressive intervention, + replace it wil primary prevention.
The AHA statement is an example of diet/ lifestyle modification recommendations for prevention:
o Aim for a healthy body weight**
o Consume an overall healthy diet**
o Be physically active**
o Aim for the recommended lipid profile
o Aim for a normal blood pressure
o Aim for a normal glucose level
o Avoid use of and exposure to tobacco products
91
LSS Cardiovascular System
Alexandra Burke-Smith
Body Weight
•
•
•
In order to maintain a healthy body weight, we need a energy balance between energy consumed and used
on a day to day basis
Our modern lifestyle can be considered a “toxic environment” which promotes a POSITIVE energy balance of
too much consumed and too little used
o The increased consumption of energy is due to large portion sizes, high fat/energy/glycaemic index
foods, soft drinks with high sugar levels, the high accessibility/variety of foods, relatively low cost of
food and advertising of food
o The decreased use of energy can be said to be caused by TV, online shopping, car travel, elevators,
“energy saving” devices, i.e. less physical activity is required to carry out daily activities
Moderate weight-loss is associated will reduced blood pressure and lipid counts
o Moderate weight loss may also allow a reduction or discontinuation of anti-hypertensive and antidiabetic medications
Myocardial ischaemia
•
•
•
•
It is defined as a lack of oxygen to the heart muscle.
o Myocardial pertaining to the heart muscle, and ischaemia pertaining to lack of oxygen.
causes a fixed narrowing in the coronary arteries, due to fatty build up (i.e. atherosclerosis). It also causes
spasm of the blood vessels.
Myocardial ischaemia is caused by an imbalance between myocardial blood flow and metabolic demand,
where blood supply does not equal demand.
o The coronary artery lumen must be reduced by more than 75% to significantly affect myocardial
blood supply.
Factors affecting coronary blood flow:
o Aortic blood pressure – a decreased blood pressure reduces coronary flow.
o Myocardial work – exercise increases coronary flow.
o Coronary artery narrowing – fixed narrowing (such as a “fatty plaque”), or an acute plaque change
(due to rupture or haemorrhage), or a blood clot in the vessel (thrombus), or vasoconstriction.
o Aortic valve dysfunction.
o Increased right atrial pressure.
Angina Pectoris
•
•
•
Chest discomfort due to myocardial ischaemia typically associated with coronary artery disease
Types of angina include:
o STABLE - angina occurring over several weeks without major deterioration, although symptoms may
vary considerable over time (e.g.. with exertion, stress)
o UNSTABLE - Abruptly worsening angina or new angina at low work load. This leads to a decreased
exercise capacity.
o VARIANT (prinzmetal) - spontaneous (i.e. no precipitating cause) angina with ST elevation on ECG
o SYNDROME X –Rare. Angina with objective evidence of myocardial ischaemia in the absence of
evident coronary atherosclerosis or epicardial (large vessel) disease
Other terminology used when describing angina:
o DECUBITUS – chest pain when lying flat (in bed)
o NOCTURNAL – at night
o ACUTE CORONARY INSUFFICIENCY – unstable
o CRESCENDO – increasing in frequency and severity
92
LSS Cardiovascular System
Alexandra Burke-Smith
Cardiac Chest pain
•
•
•
Diagnosis often made from history, but examination confirms
Information obtained O/E:
o Site
o Character
o Mode of onset - sudden or gradual
o Progression
o Radiation – e.g. left arm, neck etc
o Positional bodily function
o Precipitating or relieving factors - does anything make it better or worse?
o Any current treatment
o Depth of pain
There are different causes of cardiac chest pain, with distinct features:
o MYOCARDIAL INFARCTION
 Sudden
 Severe
 Sweating
o AORTIC DISSECTION
 Tearing pain
 In abdomen or back
o PERICARDITIS
 Pain sharp & sudden
 Pain while breathing
 Postural
NB: only 20% of MI are preceded by angina, but 50% are followed by angina
Investigations of Angina
•
•
•
•
•
•
Good history:
o Past medical history
o Previous illness
o Rheumatic fever
o Diabetes
o Hypertension
o Previous treatment, hospitalisation
o Medication
o Allergies
Blood pressure
Lipids
ECG
o Exercise ECG – valuable
 Disease severity correlates with degree of ST depression
 There is also a crude correlation between exercise capacility and prognosis after MI
Stress test
angiography
Role of imaging in CAD (computer aided diagnosis)
•
Diagnosis
93
LSS Cardiovascular System
•
•
•
•
•
•
•
•
•
Alexandra Burke-Smith
Coronary anatomy & function
Myocardial anatomy & function
Valve anatomy & function
Objective assessment of symptoms
Disease severity & burden
Acute & chronic risk assessment
Myocardial viability, stunning & hibernation
Guiding revascularisation
Monitoring therapy
Subspecialty Cardiac Imaging
•
•
•
•
Echocardiography
o Rest
o Stress
o Specialist (e.g. trans-oesophageal)
Radionuclide imaging
o Myocardial perfusion scintigraphy
o Radionuclide ventriculography
Magnetic resonance imaging
X-ray computed tomography
o Coronary calcium imaging
o Percutaneous transluminal coronary angioplasty (PTCA)
 Tube inserted into an artery at the groin and directed towards the coronary arteries
 A dye is injected and X-rays of the heart and coronary arteries are taken
 No benefit on longevity
Treatment
•
•
Aims of therapy:
o Reduce morbidity and mortality
o Eliminate angina with minimal adverse effect allowing the patient to return to normal activities
Overview of management:
o Education and risk factor management –
 The patient needs to have the diagnosis explained to them, given a basic understanding of
the underlying cause(s), what steps they can take to improve the condition, and how to
recognise the symptoms of ACS/MI
 Risk factor assessment should be carried out and steps taken to modify those identified.
These include poor diet, physical inactivity, cig smoking, hypercholesterolaemia, DM or
insulin resistance syndrome, and hypertension
o
o
o
o
Anti-platelet therapy –
 should be initiated from the outset
 Where ASA is contraindicated, clopidogrel, which is a platelet ADP-ase inhibitor, should be
used.
Anti-anginal drug treatment –
 should be started on follow-up arranged to monitor symptom relief and adverse effects
follow-up
revascularisation therapy (PCI or CABG)  Where there is failure of drug treatment or prognostic indication (from angiography),
revascularisation should be considered
94
LSS Cardiovascular System
Alexandra Burke-Smith
Anti-anginal drugs




Beta-blockers
Atenolol, metoprolol, bisoprolol
Calcium antagonists
Dihydropyridines (nifedipine, amlodipine)
Others (diltiazem, verapamil)
Nitrates
GTN, long-acting nitrates (ISMN, ISDN)
Nicorandil
Your choice of a drug or combination will be based on:
• evidence from clinical trials
• the drug’s efficacy on an individual patient’s angina
• presence of adverse side effects and the patient’s ability to tolerate them
• the existence of co-morbidities that would make one drug more preferable than the other, for example:
o using a combination of beta-blocker and Ca antagonists to treat angina and hypertension
o avoidance of nitrates when there is outflow tract obstruction
o choosing diltaizem or verapamil in preference to beta-blockers when you suspect vasospastic angina
Coronary Angioplasty
•
•
•
•
The coronary blood vessels that supply the heart are vital as even under resting conditions the oxygen
supply from the resting blood flow is almost completely exhausted. Thus, the only way to increase oxygen
supply in times of higher demand is to increase flow. The supply of blood to the cardiac muscle is vital for
survival thus any disruption in the coronary circulation is likely to cause problems.
If coronary artery disease is present the coronary vessels can be narrowed restricting the supply of blood
during periods of higher demand. If coronary flow is reduced to the point that the myocardium it supplies
becomes hypoxic, angina pectoris develops. In severe angina, sufferers experience pain at rest and not just
on exertion. In most cases flow is reduced because of an atherosclerotic plaque. If the myocardial ischaemia
is severe and/or prolonged irreversible changes occur resulting in myocardial infarction.
If coronary disease is symptomatic treatment is by revascularisation either by angiography or coronary
artery bypass grafting.
Despite recent advances angina and myocardial infarction remain common in the developed world and are a
significant cause of morbidity and mortality.
Summary of treatment
•
•
•
•
Anti-anginal treatment is only a part of the overall management of angina
Beta-blockers 1st-line, then choose a combination that suits the patient and his co-morbidities (if exist)
Use at least three agents where possible before accepting failure of medical therapy
Consider revascularisation at any time if prognostically indicated or if drug treatment fails
Myocardial Infarction
•
•
•
Caused by coronary thrombosis with full occlusion of a coronary artery
o Coronary thrombosis in turn is caused by atherosclerosis
When an atheroma plaque ruptures (known as a plaque fissure), two things may occur:
o The fissure may heal, forming an INTRA-INTIMAL thrombus
o The fissure may form an INTRA-INTIMAL and INTRA-LUMINAL thrombus
An intra-luminal thrombus may in turn form a complete OCCLUSIVE thrombus, which leads to myocardial
infarction
95
LSS Cardiovascular System
Alexandra Burke-Smith
Hypertension
CVS 19 - Professor Alun Hughes (a.hughes@imperial.ac.uk)
Recognize that:
1. Blood pressure levels are continuously distributed in a population
2. Blood pressure in individuals is associated with increased risk of cardiovascular disease - particularly strokes, heart
attacks and heart failure
3. The definition of hypertension is arbitrary and is based on the balance of the risks of elevated blood pressure
versus the risks of investigation and treatment
4. Established (essential/primary) hypertension is due to elevated peripheral vascular resistance
5. The increase in peripheral resistance in hypertension is due to active and structural narrowing of small arteries
and loss of capillaries (rarefaction)
6. 90-95% of cases of hypertension have no identifiable cause – this is termed primary or essential hypertension
7. Secondary hypertension is rare, but important causes include renal disease, oral contraceptive use, tumours
secreting aldosterone (Conn's syndrome), and tumours secreting catecholamines (pheochromocytoma)
8. The cause of essential/primary hypertension is unknown but the strongest evidence implicates renal
abnormalities and/or excessive activity of the sympathetic nervous system
Epidemiology of Hypertension






Affects ~1 billion worldwide
BP distribution is unimodal and any distinction between normal
and abnormal is arbitrary
Hypertension definition: the level of blood pressure above
which investigation and treatment do more good than harm
Prevalence of hypertension increases with advancing age
o At young ages, the prevalence was higher in males than
in females; from age 60, however, the trend was
reversed, with prevalence higher in women than in
men.
o Pulse pressure also rises with age, therefore the majority
of people >60 yrs are expected to be hypertensive; by
current definitions
o The reasons for gender differences in BP are not known,
although it has been suggested (but not proven) that
estrogen may be responsible for lower BP in younger
women
There is an association between hypertension and increased risk
of stroke
o However there is no threshold for BP risk
BP causes disease in the whole population, not jst
hypertensive individuals
o 50% of the attributanle burden of hypertension
falls to the left of the solid line on the graph
opposite (yellow half of graph)
Pathophysiology of Primary Hypertension
96
LSS Cardiovascular System
Alexandra Burke-Smith
Classification


Primary hypertension – 90-95% of cases
o Also known as essential hypertension
Secondary hypertension – 5% of cases
o Identifiable causes
 Renal disease, including renal artery stenosis
 Tumours secreting aldosterone (Conn’s syndrome)
 Tumours secreting catecholamines (pheochromocytoma)
 Oral contraceptive pill
 Pre-eclampsia (pregnancy associated hypertension)
 Rare genetic causes, e.g. Liddle’s syndrome
Aetiology
 Genetics – twin and other studies suggest 30-50% of variation in blood pressure is attributable to genetic
variation
- Monogenic (Rare) – causes <1% of hypertension
o Liddle’s syndrome – mutation in amiloride-sensitive tubular epithelial Na channel
o Apparent mineralocorticoid excess – mutation in 11beta-hydroxysteroid dehydrogenase
- Complex polygenic (common)
o Multiple genes with small effects
o May have appositive or negative effect
o Interaction with sex, other genes, environment
 Environment
- Dietary salt (sodium)
o A low salt environment is associated with a decrease in blood pressure in both men and women
- Obesity
- Alcohol
- Pre-natal environment (birth weight)
- Pregnancy (pre-eclampsia)
Haemodynamics



BP = CO x PVR
Typically, established hypertension is associated with:
o Uniformly increased peripheral resistance
o Reduced arterial compliance
o Normal cardiac output
o Normal blood and extracellular volume
Elevated PVR is accounted for by:
o Active narrowing of arteries – vasoconstriction
o Structural narrowing of arteries – growth and remodelling
o Loss of capillaries - rarefaction
97
LSS Cardiovascular System
Alexandra Burke-Smith
Candidate causes



-
Kidney
Key role in BP regulation
Relation to salt intake and reabsorption
Sympathetic nervous system
Evidence linking high sympathetic sympathetic activity to the development of hypertension
Endocrine/paracrine factors
There is inconsistent evidence, but some suggests a link to hypertension
The Kidney






The kidney exerts a major influence on BP – Guton’s concept of ‘infinite gain’ of renal sodium/water/BP
regulation
Impaired renal function or blood flow is the commonest secondary cause of hypertension (e.g. renal
parenchymal disease, renal artery stenosis),
Most monogenic causes of hypertension affect renal Na+ excretion
Salt intake is strongly linked with blood pressures of human populations. Populations with low salt have low
population blood pressures and no rise in BP with age.
Animals with reduced renal Na+ handling (genetic or experimental) develop hypertension. Excess salt intake
in many animals results in elevated blood pressure
In rats hypertension can be ‘transplanted’ with the kidney, there is similar, though incomplete data, in man
The major risks attributable to elevated blood pressure













coronary heart disease
stroke
peripheral vascular disease/atheromatous disease
heart failure
atrial fibrillation
dementia /cognitive impairment
retinopathy
increase in left ventricular wall mass (LVMI) and changes in chamber size
thickened walls (hypertrophy) of large arteries and acceleration of atherosclerosis
arterial rupture or dilations (aneurysms). This can lead to thrombosis or haemorrhage (e.g. strokes)
retina illustrates microvascular damage in hypertension. There is thickening of the wall of small arteries,
arteriolar narrowing, vasospasm, impaired perfusion and increased leakage into the surrounding tissue
microvasculature damage –
o reduction in capillary density  impaired perfusion and increased PVR
o elevated capillary pressure  damage and leakage
Renal dysfunction is common in hypertension (e.g. increased (micro)albumin excretion in urine).
o Extreme (accelerated/malignant hypertension) is now rare but leads to progressive renal failure
98
LSS Cardiovascular System
Alexandra Burke-Smith
Pathophysiology of Heart Failure
CVS 20 - Professor Peter Collins (p.collins@imperial.ac.uk)
1.
2.
3.
4.
5.
Provide an up-to-date definition of heart failure
Appreciate the epidemiology and prognosis for heart failure
Explain in general terms the underlying pathophysiology producing heart failure
List the symptoms and signs of heart failure and appreciate suitable investigations to assist in its diagnosis
Appreciate the principles of current treatments
Overview
Origins of Heart failure



the heart is unable to maintain an appropriate blood pressure without support
Evolutionary origin – the body response similar to that of exercise and haemorrhage
Definition: a clinical syndrome caused by an abnormalilty of the heart and recognised by a characteristic
pattern of haemodynamic, renal, neural and hormonal responses
Epidemiology








Prevalence 1 - 3 %; 10% in those over 75 years
Incidence 0.5 - 1.5 % per annum
Prognosis worse than cancer. 50% dead in 3 y
In community mean age 76 y. Men: women is 50:50
5% of acute hospital admissions and 10% bed occupancy
40% readmission rate in one year
40% of hospital admissions mortality in one year
Approximately 2% of total health budget
Signs and symptoms


-
-
Symptoms – subjective, expressed by patient
Ankle swelling
Exertional breathlessness
Fatigue
Orthopnoea
PND
Nocturia
Anorexia + Weight loss
Signs – objectives, observed by doctor
CLINICAL (O/E)
o Tachycardia
o Decreased pulse volume
o Pulsus alternans
o Increased Jugular venous pressure
o Pitting Oedema
o Rales
o Hepatomegaly
o Ascites
INVESTIGATIONS
o X-ray
99
LSS Cardiovascular System
o
o
o
o
o
Alexandra Burke-Smith
Echocardiogram
Radionuclide ventriculography
Ambulatory ECG monitoring
Exercise test (VO2)
Cardiac catheter
Nature of heart failure






Patient is breathless, tired and retains fluid
Heart is damaged
Heart less effective as a pump
Marked neurohormonal activation
Quality of life is poor
Life expectancy reduced
Cardiac X-ray comparison
Normal X-ray ↓
Abnormal X-ray ↓
The NYHA Classification of Functional Capacity
100
LSS Cardiovascular System
Alexandra Burke-Smith
Progression


Following onset, there is a
relatively stable progression,
where acute coronary events
or sudden death may occur.
Following this progression,
deterioration from mild to
severe heart failure occurs –
eventually leading to death
Syndromes of heart failure
Entity – synonym/variant

Acute heart failure – pulmonary oedema

Circulatory collapse – cardiogenic shock (poor peripheral perfusion, oliguria, hypotension)

Chronic heart failure – untreated, congestive, undulating, treated, compensated
Causes of heart failure
General causes





Arrythmias
Valve disease
Pericardial disease
Congenital heart disease
Myocardial disease
Myocardial diseases





Coronary artery disease
Cardiomyopathy
o Dilated (DCM)
o specific or idiopathic (IDCM)
o hypertrophic (HCM, HOCM, ASH)
o restrictive
o arrhythmic right ventricular caropmyopathy (ARVC)
Hypertension
Drugs
o Beta-blockers
o Calcium antagonists
o Anti-arrhythmics
Other/unknown
Heart Disease







Coronary heart disease is the leading cause of death in Europe
Modern treatment increases survival
Survivors are left with a damaged heart
50% of all survivors develop heart failure
Deaths due to heart attacks are declining but due to heart failure are increasing
The population is ageing and heart failure is commoner in old age
Only a minority of patients with heart failure are receiving the latest drugs
101
LSS Cardiovascular System
Alexandra Burke-Smith
Myocardial infarction





Of the left ventricle
Initially – baseline area at risk before infarction
Within hours – infarct expansion
Within days – left ventricular expansion due to thinning of wall
Thinning due to cell slippage, hypertrophy, loss of cells and fibrosis
Cardiomyopathy



Definition: heart disease in the absence of a known cause and particularly coronary artery disease, valve
disease, and hypertension
Cause of approx 5% of heart failure in a population
Types:
o Hypertrophic cardiomyopathy (HCM)
o Dilated cardiomyopathy (DCM)
o Restrictive cardiomyopathy
o Arrhythmic right ventricular cardiomyopathy (ARVC)
Causes of dilated CM








Idiopathic dilated cardiomyopathy
Genetic and/or Familial cardiomyopathies
Infectious causes
o Viruses & HIV
o Mycobacteria
o Rickettsia
o Fungus
o Bacteria
o Parasites
Toxins and poisons
o Ethanol
o Metals
o Cocaine
o Carbon dioxide or hypoxia
Drugs
o Chemotherapeutic agents
o antiviral agents
Metabolic disorders
o Nutritional deficiencies and endocrine diseases
Collagen disorders, autoimmune cardiomyopathies
Peri-partum cardiomyopathy, neuromuscular disorders
Causes of restrictive CM


Associated with fibrosis
o Diastolic dysfunction –
 Elderly
 Hypertrophy
 Ischaemia
 Scleroderma
Infiltrative disorders
102
LSS Cardiovascular System


Alexandra Burke-Smith
o Amyloidosis
o sarcoid disease
o inborn errors of metabolism
o neoplasia
Storage disorders
o Haemochromatosis and haemosiderosis
o Fabry disease
o glycogen storage disease
Endomyocardial disorders
o Endomyocardial fibrosis
o hypereosinophilic syndrome
o carcinoid, metastases, radiation damage
Causes of death





Progression of heart failure
o Increased myocardial wall stress
o Increased retention of sodium and water
Sudden death
o Opportunistic arrhythmia
o Acute coronary event (often undiagnosed)
Cardiac event e.g. myocardial infarction
Other cardiovascular event e.g. stroke, PVD
Non cardiovascular cause
Hormonal mediators in heart failure



-
Constrictors
Noradrenaline
Renin/angiotensin II
Endothelin
Vasopressin
NPY
Dilators
ANP
Prostaglandin E2 & metabolites
EDRF
Dopamine
CGRP
Growth factors
Insulin
TNF alpha
Growth hormone
Angiotensin II
Catecholamine
Nitric oxide
Cytokines
Oxygen radicals
103
LSS Cardiovascular System
Alexandra Burke-Smith
Inflammatory markers and cytokines involved






All cell types
Interleukin-1b
Interleukin-6
Tissue necrosis factor alpha
Heart
Troponin T
Troponin I
Vessel wall
ICAM-1
VCAM-1
E-selectin
P-selectin
Macrophages
Lipoprotein-associated phospholipase A2
Secretory phospholipase A2
Liver
C-reactive protein
Fibrinogen
Serum Amyloid A
Adipose
Management and treatment of heart failure
Management algorithm for heart failure








Establish that patient has heart failure
Determine aetiology of heart failure
Identify concomitant disease relevant to heart failure
Assess severity of symptoms
Predict prognosis
Anticipate complications
Choose appropriate treatment
Monitor progress and tailor treatment
Objectives of treatment



Prevention
o Of myocardial damage – occurrence, progression and further episodes
o Reoccurrence – symptoms, fluid accumulation, hospitalisation
Relief of symptoms and signs
o Eliminate oedema and fluid retention
o Increase exercise capacity
o Reduce fatigue and breathlessness
Prognosis
o Reduce mortality
104
LSS Cardiovascular System
Alexandra Burke-Smith
Management






Eliminate causes and precipitating factors - Limit/avoid alcohol
Prevent myocardial ischaemia -Treat hypertension
Prevent paroxysmal arrhythmias - Reduce salt intake
Check drugs prescribed and taken - Assess lipids
Encourage exercise - Flu immunisation
Advice on lifestyle - Discourage smoking
Treatment options





Drugs
o Diuretics
o Beta-blockers
o ACE inhibitors
o Aspirins, statins, anticoagulants
o Ang II receptor inhibitors, nitrates, hydralazin
o Antiarrhythmics, IV inotropes
Surgery, CABG or valve surgery
Implantable cardioverter-defibrillator
Maemofiltration, peritoneal dialysis or haemodialysis
Aortic balloon pump, ventricular assist devices, cardiomyoplasty, volume reduction, transplantation
Treatment of severe heart failure




-
IV drugs
Diuretics
Nitrates
Positive inotropes
Fluid control
Haemofiltration
Peritoneal dialysis
haemodialysis
Devices
ICD or pacing
Intraaortic balloon pump
Ventricular assist device
Total artificial heart
Surgery
CABG for “hibernation”
Valve surgery
Cardiomyoplasty
Volume reduction/restriction
transplantation
105
LSS Cardiovascular System
Alexandra Burke-Smith
Practical 1 – Measurement of Systemic Arterial Blood
Pressure
Background information



BP is a measurement routinely made for diagnostic purposes
The pressure that is measured is pulsatile, having its maximum value during ventricular systole and its
minimum immediately prior to the next cardiac systole
Determined by physical factors (e.g. elasticity of arterial walls) and the physiological factors; stroke volume,
heart rate + vascular peripheral resistance
Learning objectives
1. Obtain an accurate measurement of systolic and diastolic blood pressures using a sphygmomanometer and
stethoscope and state the values.
2. Explain how methodological factors can affect the accuracy of measurement of arterial blood pressure and
take appropriate precautions to obtain “correct” values
3. Explain the principles of the methods used
Method








Can be measured directly by inserting needle/catheter attached to a pressure transducer into a peripheral –
however this is invasive, and must be under aseptic conditions
Sphygmomanometer – consists of an inextensible material cuff containing an inflatable bag
o The cuff is wrapped around an extremity so that the inflatable bag lies between the cuff and the skin
(directly over the artery to be compressed)
The pressure in the cuff is raised until the artery is occluded, and then released at a rate of 2-3mmHg per
second – as this occurs a series of Korotokoff sounds can be detected using a stethoscope placed over the
artery
Two assumptions are made:
1. The pressure in the limb tissue under the centres of the cuff is the same as that in the bag
2. The artery offers no resistance to collapse by external pressure
This means that:
o When pressure in bag > systolic BP – flow of blood prevented
o When pressure in bad is between systolic and diastolic BP – blood flow periodically
o When pressure < diastolic BP – flow of blood continuous
Systolic pressure = transition from no flow to periodic flow (heard by stethoscope)
Auscultation as the pressure drops:
o Nothing
o Series of taps (phase 1)
o Murmur sound (phase 2)
o Loud banging (phase 3)
o Sudden softening/muffling (phase 4)
o Cessation of all sound (phase 5)
Systolic pressure corresponds to the start of
phase 1, diastolic pressure to the start of phase
5
106
LSS Cardiovascular System
Alexandra Burke-Smith
Practical 2 – The Electrocardiogram
Learning Objectives
1. Be familiar with the normal ECG waveform
2. Describe the precautions and conventions employed in recording the standard 12-lead human ECG
3. Know how the recordings of the six standard limb leads are obtained from the four electrodes
attached to the limbs
4. Know how the recordings of the sex pre-cordial (chest) leads are obtained
Why can we record ECGs?







First, consider the heart as a triangular wedge of excitable cells in a
large dish of saline with two electrodes placed at a distance from each
end. An oscilloscope can then be used to trace the potential across this
wedge.
Initially, the muscles are in their resting state and although each cell has
a resting membrane potential, there is no potential between the
extracellular electrodes
When the cells closest to electrode 1 depolarise, their membrane
potential is reversed creating a wave of depolarisation, which acts as a
dipole between the depolarised cells and those in their resting state. As
a result electrode 2 becomes negative relative to electrode 1, resulting
in an upward deflection
Provided the electrodes are fixed, the magnitude of this deflection is
determined by the voltage of the dipole itself. This is determined by the
demand for depolarising current, which depends on the conduction
velocity towards electrode 2 and the fact that the width of the wedge is
increasing
When all the cells are depolarised, the dipole ceases to exist  no
potential difference between the electrodes
A wave of repolarisation then starts at those closest to electrode 1,
which creates another dipole but with the poles reverse resulting in a
downward deflection
At the end of repolarisation, there is no potential difference. The
deflection caused by repolarisation is longer but smaller than that
caused by depolarisation. This is because the time course of
repolarisation of myocardial cells is much longer than that of
depolarisation.
NB: the size + direction of the deflection recorded depends on the angle between the axis of the recording
electrodes + the direction of the depolarising wave, therefore the 6 limb leads show different tracings. Remember
that in this model, the wave of depolarisation is assumed to be going from electrode 1 towards electrode 2.
Limb Leads



Right foot – zero reference point
Electrodes placed at right arm, left arm + left foot – assumed to form an equilateral triangle known as
Einthoven’s triangle, with the heart lying in the centre
Remember these leads are all in the same plane, therefore only record the electrical activity in this (frontal)
plane
107
LSS Cardiovascular System
Alexandra Burke-Smith
Standard limb leads






The three electrodes are connected to form bipolar electrodes.
By convention the apparatus is connected to that when a wave of
depolarisation moves towards the positive electrode, an upward deflection is
recorded.
Lead I RA  LA (LA designated as positive)
Lead II RA  LF (LF designated as positive)
Lead III LA  LF (LF designated as positive)
Remember any given wave of depolarisation and its derived vector will be seen from a different angle
Augmented limb leads






3 additional leads designate one electrode as positive, and record the signal
between this and the remaining two leads connected to form a negative electrode;
situated halfway between the two connected points
aVR RA  (LA + LF) (RA designated as positive)
aVL LA  (RA + LF) (LA designated as positive)
aVF LF  (RA + LA) (LF designated as positive)
This provides more angles from which the electrical signal can be recorded
However again these are all on the same plane – to record the heart’s electrical
activity from a plane at right to this using chest electrodes
Chest leads (precordial)



Firstly, the three standard limb leads are electronically connected together to form one indifferent negative
electrode
Then a unipolar positive exploring electrode is placed on the
chest wall in 6 positions (labelled V1-V6 in Arabic numbers)
Anatomical locations (NB: ICS = intercostal space)
o V1 – right 4th ICS parasteneral
o V2 – left 4th ICS parasteneral
o V3 – left, midway between V2 + V4
o V4 – left 5th ICS, mid-clavicular line
o V5 – left anterior axillary line on the same horizontal
plane as V4
o V6 – left mid-axillary line
The ECG waveform
1. P wave: the intitial depolarisation of the SAN and its spread
across the atria
2. PR Interval: After the P wave, the recording returns to the
baseline. There is then an interval caused by the delay in
conjuction thorugh the junctional fibres and AVN
3. QRS complex: depolarisation of the septum and ventricles. R
wave is the first upward wave of the complex. Any
downward deflection after the Q wave which goes below the
baseline is called the S wave
4. There is then another interval
108
LSS Cardiovascular System







Alexandra Burke-Smith
5. T wave: repolarisation of the ventricles
The limb leads look at the mean ventricular depolarisation on the mean frontal plane axis of the ventricles
(towards the apex of the left ventricle; depends on the oritentation of the heart in the thorax and the
relative muscle masses of the ventricles) from different angles
This means that they will all show a different form of the ECG wave
It is by examining these different waveforms that it is possible to estimate the MFPA of the ventricles
The same considerations apply to the chest leads, which are all positive electrodes:
o The first part of the ventricles is to depolarise the septum, which occurs from left to right
o The second part is ventricular depolarisation, where again the left ventricle makes the greater
contribution
Lead V1 will therefor show a “right ventricular complex” – small septal depolarisation moving towards the
electrode gives a small upward r wave, followed by a deep S wave caused by ventricular depolarisation
Lead V6 will show a “left ventricular complex” – small q wave (septal depolarisation) followed by large
upright R wave (ventricular depolarisation)
Lead V3 will show a “transition zone” characterised by biphasic equipotential (waves are equal in magnitude
but opposite in direction)
The electrocardiograph



Consists of two essential parts:
o Amplifier – needed to magnify the very small potential differences produced at the surface of the
body by the electrical activity of the heart
o Recording system – gives a visual, permanent display of these recordings. Consists of a high-density
thermal print head that records the ECG on special heat sensitive paper
The international standards for the gain (amplification) and paper speed of an ECG:
o Gain – a signal of 1mV = deflection of 10mm
o Speed – 25mm per second, therefore large square=0.2s, little square=0.04s
Normal ECG recording shown on next page
Analysis
ECG is normally analysed for:

Rate – mean heart rate

Conduction of excitation – considered in two phases:
o PR Interval – measures time required for activity to propagate through atria, AVN and bundle of His
o QRS duration – gives the time required for excitation to spread throughout the ventricles

Duration of electrical systole – estimated by measuring the QT interval

Comparison with Normal values - for PR, QS + QT interval

Estimated mean frontal plan axis
109
LSS Cardiovascular System
Alexandra Burke-Smith
110