1. Heart as a Pump Function of the Heart as a Pump J. Kachope

2. 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

3. 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

4. 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

5. Heart as a Pump Cardiomyocytes Contractile elements of the myofibre

6. Heart as a Pump

7. 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.

8. 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.

9. Heart as a Pump Cardiomyocytes The cross-bridge cycle

10. 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

11. 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

12. Heart as a Pump Frank-Starling law:

13. Heart as a Pump PRELOAD literally the load before LV contraction has started (ventricular end- diastolic 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

14. 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”

15. 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)

16. 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

17. 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.

18. 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

19. 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.

20. 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).

21. Heart as a Pump

22. 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

23. 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.

24. Heart as a Pump ATP generation carbohydrates G-6-phos Triose phos pyruvate Tricarboxylic Acid cycle Electron transport chain Lipid Protein glycerol NAD+NADH ADP ATP Amino acids glucose glycogen Acetyl CoA

25. 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 (2 nd Messenger pathways) Beta 1 receptors found in cells in the heart Increaswed ionotropy and chronotropy

26. 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.

27. 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.

28. 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.

29. Heart as a 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. Na+,K+, ATPase pump

30. 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.

31. 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

32. 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

33. 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

34. Heart as a Pump

35. 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.

36. 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