Heart as a Pump
Function of the Heart
as a Pump
J. Kachope
Heart as a Pump
The Heart as a Pump
Determinants of performance
•Cardiac myocyte contractility
•Frank-Sterling law
•Contractility
•Heart rate
•Cardiac loads and wall stress
Heart as a Pump
Pump Structure
•Made of 4 chambers – 2 atria and 2 ventricles
•Essentially two pumps in series
•Atrioventricular groove contains a fibrous skeleton
completely separating atria from ventricles
•Atrioventricular and semilunar valves control direction
of blood flow
•The rhythmic contraction of the heart is called a heart
beat
Heart as a Pump
Cardiomyocytes
•Cardiac cells are striated and consist of sarcomers like
skeletal muscles
•Unlike skeletal mm they branch and interdigitate
•Adjacent cells are attached end to end at Z lines to form
an intercalated disk
•25-30% of the myocytes is occupied by mitochondria
Heart as a Pump
Cardiomyocytes
Contractile elements of the myofibre
Heart as a Pump
Heart as a Pump
Cardiomyocytes
Sliding filament model
•A-band remained at constant length both in contracting muscle
despite the fact that the sarcomere had shortened, and in stretched
muscle, where the sarcomere was lengthened,
•I-band decreased in these experiments.
•The variable length I-band suggests that there is relative sliding
between the thick and thin filaments.
•both filaments were of constant length
•the myosin heads had a central role in force generation by
attaching to actin and producing a relative movement between the
thick and thin filaments- known as the swinging cross-bridge
model.
Heart as a Pump
Cardiomyocytes
The cross-bridge cycle
•In the absence of ATP myosin-S1 forms rigid and inextensible links
with actin, known as a rigor complex
•addition of ATP, binds to myosin-S1, releases the head from actin
•ATP is hydrolysed - ADP and Pi (on head)- `high energy' state
• head binds to actin - release of the hydrolysis products Pi and
ADP - conformational change in S1 which drives the actin filament
by a distance of between 4 and 10 nm.
•head stays locked in the rigor conformation with actin until a new
molecule of ATP binds and releases it.
•S1 is now ready to start a new cycle of attachment and force
generation at a new actin site which has become accessible
subsequent to thin filament movement.
Heart as a Pump
Cardiomyocytes
The cross-bridge cycle
Heart as a Pump
Frank-Starling law
•Within limits, the force developed in a muscle fibre
depends on the degree to which the fibre is stretched
•Initial fibre length is proportional to ventricular end
diastolic volume(EDV)
•As the EDV increases, the sarcomeres in the cardiac
muscle are stretched and the systolic intraventricular
pressure developed increases(contraction force)
•Stretching muscle fibres increases sensitivity of the
contractile mechanism to Ca++
•Beyond a certain amount of stretch(LV diastolic vol
180ml) there is less than optimum cross bridge formation
– the systolic intraventricular pressure drops
Heart as a Pump
Frank-Starling law:
•The Frank-Starling mechanism allows the heart to adapt rapidly to
changes in venous return
•It also maintains equal output from the right and left ventricles
F=EDP during ventricular filling
IC=Pressure increase during
isovolumic contraction
EJ=ejection phase change in vol
and pressure
IR=drop in pressure during
isovolumic relaxation
Heart as a Pump
Frank-Starling law:
Heart as a Pump
PRELOAD
•literally the load before LV contraction has started (ventricular enddiastolic volume)
•provided by the venous return that fills the left atrium, which in turn
empties into the LV during diastole.
•When the preload increases, the LV distends, the LV pressure
development becomes more rapid and rises to a higher peak pressure
and the stroke volume augments.
•physiologically determined by venous return - influenced by venous
compliance
Heart as a Pump
Determinants of Ventricular PRELOAD
• Total blood volume
•Blood volume distribution
•Gravitational effect
•Venous tone – smooth mm in walls of veins/venules
•Muscle pump effect – skeletal muscle squeeze
•Intrathoracic pressure – tension pneumothx, +ve pressure vent
•Pericardial pressure – tamponade
•Atrial contraction – “atrial kick”
Heart as a Pump
AFTERLOAD
•the load after the onset of contraction, against which the
LV contracts during LV ejection
•Tension or stress developed in the wall of the ventricle
during ejection
•Velocity and extent of ventricular muscle fibre
shortening inversely proportional to afterload (at a given
diastolic fibre length & ionotropic state)
Heart as a Pump
AFTERLOAD
•Laplace’s law
•Bigger LV radius- greater wall stress.
• at any LV size, the greater the pressure developed by the LV, the greater
the wall stress.
•increase myocardial oxygen uptake.
•Other determinants
•Arterial pressure
•CO
•SVR
•arterial compliance
•Dilatation
•elderly
•stenosis
Heart as a Pump
AFTERLOAD
•Laplace’s law
•cardiac hypertrophy: increased wall thickness balances the increased
pressure, and the wall stress remains unchanged during the phase of
compensatory hypertrophy.
•In congestive heart failure, heart dilates so that the increased radius
elevates wall stress. Furthermore, because ejection of blood is
inadequate, the radius stays too large throughout the contractile cycle,
and both end-diastolic and end-systolic tensions are higher.
Heart as a Pump
Heart rate
•Intrinsic rhythimicity
•Extrinsic factors eg autonomic nn system
•HR X Stroke vol = Cardiac output
•Heart rate increase decreases diastolic filling time
•increased heart rate during exercise
•adrenergic discharge
•activation of mechanoreceptors in the left atrium
•increase in contractile force (treppe phenomenon).
•peripheral vasodilation
Heart as a Pump
Heart Rate and Force-Frequency Relation
Treppe OR Bowditch effect.
•An increased heart rate progressively increases the force of
ventricular contraction,
•Conversely, a decreased heart rate has a negative staircase effect.
•When stimulation becomes too rapid, force decreases.(
more Na+ and
Ca++ ions enter the myocardial cell than can be handled by the Na+ pump and the
mechanisms for ca++ exit.)
•Opposing the force-frequency effect is the negative contractile
influence of the decreased duration of ventricular filling at high heart
rates.
•longer filling interval - better ventricular filling and the stronger the
subsequent contraction.
Heart as a Pump
Anrep Effect: abrupt increase in after load
•When the aortic pressure is elevated abruptly, a positive
inotropic effect follows within 1 or 2 minutes.
•Was called homeometric autoregulation (homeo = the
same; metric = length) because apparently independent
of muscle length and so a true inotropic effect.
•Mechanism : increased LV wall tension acts on
myocardial stretch receptors to increase cytosolic Na+
and then, by Na+/Ca++ exchange, cytosolic Ca++.
•differs from that of an increase in preload (which acts by
length-activation).
Heart as a Pump
Heart as a Pump
Contractility or the Inotropic State
Force which the heart muscle generates as it contracts.
Alternate name for contractility is the inotropic state
(ino = fiber; tropos = to move).
Factors that increase contractility include
•adrenergic stimulation (exercise, emotion),
•Drugs e.g digitalis, L-thyroxine/
•increase in extracellular Ca++.
•Decrease in extracellular Na+
•Decrease
•Drugs alchohol, high dose calcium blockers
•Loss of LV mass
Heart as a Pump
Acute changes in Contractility
•Bottom line is enhanced interaction between ca++
ions and the contractile proteins.
•increased systolic rate of rise and peak of the
cytosolic ca++ion concentration
•sensitization of the contractile proteins to a given
level of cytosolic ca++
•absence of any acceptable noninvasive index;
•Impossible to separate the cellular mechanisms of
contractility changes from those of load or heart rate.
Heart as a Pump
ATP generation
carbohydrates
glycogen
glucose
G-6-phos
Triose phos
pyruvate
glycerol
Lipid
Amino
acids
Acetyl CoA
Tricarboxylic
Acid
cycle
Protein
NADH
NAD+
Electron transport chain
ADP
ATP
Heart as a Pump
Beta 1 receptor activity
•Fall under adrenergic receptors-receptors for
noradrenaline and adrenaline,
•grouped into three families (numerous subtypes)
• b receptors (b1 and b2),
•a1 a2 receptors,
•They are all seven-span G Protein coupled
receptors.linked variously to the adenylate cyclase and
phosphoinositidase (2nd Messenger pathways)
•Beta 1 receptors found in cells in the heart
•Increaswed ionotropy and chronotropy
Heart as a Pump
A1 receptor activity
•Adenosine is a small ubiquitous molecule with a purine base and the
sugar ribose.
•several important cardioprotective properties, including regulation of
coronary blood flow and heart rate
•Endogenous adenosine is produced via the metabolism of ATP and
through S-adenosyl methionine (SAM) pathway. It then crosses the
cell membrane and interacts with specific receptors
•at A1 receptors on the extracellular surface of cardiac cells, activates
K+ channels in a way similar to acetylcholine.
•increase in K+ conductance shortens atrial action potential duration,
hyperpolarizes the membrane potential, and decreases atrial
contractility.
•Similar changes occur in the sinus and AV nodes
•adenosine A2A receptors causes coronary vasodilatation through the
production of cyclic AMP, stimulation of K+ channels, and decreased
intracellular calcium uptake.
Heart as a Pump
A1 receptor activity
• The cardiovascular effects of adenosine include
• Potent vasodilatation
• Increase in heart rate, due to vagal inhibition at low doses
• Bradycardia and AV block at high doses
• Reduced adrenergic activity
After activation of the adenosine receptors, adenosine reenters the
cell and is converted to ATP and SAM or deaminated to inosine
Exogenously administered adenosine is rapidly taken up by the
cells, especially red blood cells and endothelial cells, explaining the
remarkably short half-life of five seconds.
Heart as a Pump
Na+,K+, ATPase pump
•Also known as the sodium pump,
• critical role in generating and maintaining the MEMBRANE
POTENTIAL.
•an electrogenic ION PUMP, transporting 3 Na+ ions out of the
cytosol in exchange for 2 K+ ions from the extracellular medium
and producing an electrochemical gradient of Na+ across the
plasma membrane.
• Ion-dependent ATP hydrolysis and
transient phosphorylation of the
protein at this site changes the
conformation of the protein, allowing
ion transport across the membrane.
Heart as a Pump
Na+,K+, ATPase pump
The activity of this pump is regulated by several factors, including thyroid
hormone and, with regard to K+ homeostasis, catecholamines, insulin, and the
state of K+ balance .
An example of its importance in humans can be seen when Na+-K+-ATPase is
partially inhibited by a massive overdose of digitalis, marked hyperkalemia
(plasma K+ concentration up to 13.5 meq/L) can occur, because of the relative
inability of K+ to enter the cells.
In chronic diseases such as renal failure and heart failure, Na+-K+-ATPase
activity is often reduced, due to an acquired defect in cell function
K+ leaves and Na+ enters the cells down passive gradients. The net effect is as
much as a 10 to 15 percent reduction in total body K+ stores in association with
a high cell Na+ concentration, a low cell K+ concentration, but no change in the
plasma K+ concentration because the excess extracellular K+ has time to be
excreted in the urine if renal function is adequate.
Heart as a Pump
PDE activity
•Ubiquitous enzyme that splits a phosphodiester bond in 3`, 5`
cyclic nucleotides (cAMP, cCMP, cGMP) to generate a nucleoside
monophosphate. cAMP and cGMP
•phosphodiesterases are important in SECOND MESSENGER
PATHWAYS involving these cyclic nucleotide second messengers as
they rapidly degrade the second messenger, thus providing a sharp
time-limited signal.
Heart as a Pump
PDE activity
•Phosphodiesterase (PD) inhibitors, such as amrinone,
milrinone, and enoximone, decrease the rate of cyclic AMP
degradation.
•The ensuing increase in cyclic AMP concentration leads to
enhanced calcium influx into the cell, a rise in cell calcium
concentration, and increased contractility.
•These drugs also induce
systemic vasodilation via
inhibition of peripheral PD
Heart as a Pump
Long acting membrane Ca++ channels
•Calcium can enter the general cytoplasm of a cell either
from the extracellular fluid, or by release from
intracellular stores.
•Following agonist stimulation of many tissues there is
frequently a biphasic rise in intracellular calcium;
•an initial transient liberation from intracellular stores and
then prolonged entry of extracellular calcium.
•Extracellular calcium entry
•Voltage-dependent calcium entry involves the opening of
voltage-sensitive calcium channels
Heart as a Pump
Long acting membrane Ca++ channels
•Typically they can be divided into four classes: L, T, N,
and P types
•L-type channels are activated by high voltage and are
modulated by 1,4-dihydropyridines.
•They are the major pathway for calcium entry in cardiac
and smooth muscle cells.
•They can be blocked by calcium antagonists such as
verapamil, diltiazem, and some dihydropyridines.
•opening in the heart can be promoted by catecholamines
Heart as a Pump
Heart as a Pump
Apoptosis and myocyte necrosis
apoptosis
•cell death under direct genetic control- Programmed cell
death
•Cardiac cells do not regenarate.
•cells lose their cell junctions and microvilli, the
cytoplasm condenses and nuclear chromatin marginates
into a number of discrete masses.
•nucleus fragments, cytoplasm contracts and
mitochondria and ribosomes become densely compacted.
•dilation of the endoplasmic reticulum and its fusion with
the plasma membrane, the cell breaks up into several
membrane- bound vesicles - apoptotic bodies phagocytosed by adjacent cells.
Heart as a Pump
Apoptosis and myocyte necrosis
•Activation of particular genes is thought to be necessary
for apoptosis to occur.
•Apoptosis induced by numerous cytotoxic agents
Alpha & beta adrenoceptor activation
Renin Angiotensin Aldosterone system activation
cytokines
• can be suppressed by expression of the gene bcl-2
which produces a cytoplasmic protein Bcl-2.
•Necrosis: cell death due to pathological insult eg infxn,
infarction, cytotoxic drugs