CARDIOVASCULAR PHYSIOLOGY

Transcription

1 CARDIOVASCULAR PHYSIOLOGY LECTURE 5 Heart as a pump cardiac performance Coronary circulation. Particularities of the cardiac muscle metabolism. Ana-Maria Zagrean MD, PhD

2 Chemical energy required for cardiac contraction Efficiency of cardiac contraction - most of the expended chemical energy is converted into heat (75-80%) - a much smaller portion is converted into work output (WO) (20-25%). Efficiency of cardiac contraction = WO / total chemical energy expenditure Maximum efficiency of the normal heart ~ %. In heart failure, it decreases to as low as 5-10 %.

3 Cardiac Work Output (WO) Stroke work output of the heart = amount of energy converted to work / heartbeat (stroke). Minute work output = total amount of energy converted to work /1 minute (stroke work output x HR) Work output (WO) of the heart is used: 1) to move the blood from the low-pressure veins to the high-pressure arteries - volume-pressure work or External Work (EW) (WO LV ~ 6 x WO RV, given the different systolic press. in the 2 pumps). 2) a minor proportion of energy is used to accelerate the blood to its velocity of ejection through the aortic and pulmonary valves kinetic energy of blood flow = mass of blood ejected x v ejection 2. normally 1% of WO, up to 50% in Aortic Stenosis

4 Volume-pressure curves for the left ventricle Graphical Analysis of Ventricular Pumping. Relationship between LV volume and intraventricular pressure during diastole and systole. Red lines show the "volume-pressure diagram", demonstrating changes in intraventricular volume and pressure during the normal cardiac cycle. EW, external work (the area subtended by the volume-pressure diagram).

5 "Volume-Pressure Diagram" during the cardiac cycle: Volume-pressure curves for the LV - Diastolic pressure curve: *shows gradual filling of LV up to the end-diastolic pressure (EDP) *pressure greatly rises after 150 ml ventricular filling (no more stretch, pericardial limit) - Systolic pressure curve: *shows systolic pressure during LV contraction at each volume of filling; *increases even at low ventricular volumes *reaches a maximum ( mmhg for the LV, and mmhg for the RV) at ml. * for volumes > 170 ml, the systolic pressure actually decreases (actin and myosin filaments interrelation decreases)

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7 The 4 phases of the "volume-pressure diagram", during the normal cardiac cycle. Phase I: Period of filling. -initial ventricular volume ~50 ml (end-systolic volume), diastolic pressure ~0 mm Hg. -ventricular volume normally increases with 70 ml, up to ~120 ml (enddiastolic volume), and the diastolic pressure rise to about 5 mm Hg. Phase II: Period of isovolumic contraction. -volume of the ventricle constant (all valves closed) ~120 ml, the pressure inside the ventricle increases to equal the pressure in the aorta, at ~80 mm Hg. Phase III: Period of ejection. -systolic pressure rises higher during contraction of the ventricle (from 80 up to ~120 mmhg), while the volume of the ventricle decreases during ejection. Phase IV: Period of isovolumic relaxation. -aortic valve closes, no change in volume (~50 ml ESV), decrease of ventricular pressure back to diastolic pressure (~0 mm Hg).

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10 Preload and Afterload Preload - the degree of tension on the muscle when it begins to contract. - is usually considered to be the end-diastolic pressure (EDP) when the ventricle has become filled. - depends on the incoming blood in the right atrium (RA) = venous return Afterload - the load against which the muscle exerts its contractile force. - is the systolic pressure in the artery leading from the ventricle, (relation with the vascular resistance).

11 Pressure-Volume curve for the left ventricle during cardiac cycle. (EDV-ESV) Isovolumic relaxation ejection filling Aortic valves open (Afterload- arterial pressure) Isovolumic contraction (Preload EDP, degree of stretch in the resting state) Stroke volume is determined by: 1) preload (EDP), 2) afterload (arterial pressure) and 3) intrinsic inotropic state of the myocardium.

12 Frank-Starling low of the heart: Within physiological limits, the heart pumps all the blood that returns to it. - Preload: the wall tension that corresponds to ED pressure venous return - skeletal mm pump & respiratory pump - sympathetic constriction of veins EDV length of sarcomere at beginning of contraction; length-tension relationship in cardiac muscle optimal sarcomere lengths max. no. of A-M cross-bridges, troponin affinity for Ca increase Ca uptake from extracellular fluid and release from SR - Afterload arterial blood pressure - Inotropic state of the heart - Stretch of the right atrial wall directly increases the heart rate by % increase the amount of blood pumped each minute

13 Frank-Starling law of the heart More blood in the ventricle at the beginning of contraction (EDV), the greater the stroke volume. Stroke volume is proportional to force.

14 The tension generated (force) is directly proportional to the initial length of the muscle fiber. Length-Tension Relationship Factors that influence this relationship: Intracellular Ca 2+ Changes in force due to fiber length Changes in force created by catecholamines discharges The ability of stretched muscle, up to an optimal length, to contract with increased work output is characteristic of all striated muscle.

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16 Left Ventricular Pressure Frank-Starling law of the heart End-systolic pressure-volume relation D D D C C C EDV Normal EDV EDV A A A B B B Left Ventricular Volume

17 Assessment of contractility by the use of a ventricular pressure-volume loop. The purple pressure-volume loop is the normal curve.

18 Myocardial contractility myocardial cell structure Cardiac myocytes are shorter then the skeletal ones, branched, interconnected from end to end by intercalated disks (desmosomes, gap junctions) in a mechanical and electrical syncytium: AP generated in the sinoatrial node travel in the entire heart in ~ 0.22 sec Contraction of a cardiac muscle cell ~ 0.3 sec Sarcolema -T tubules & terminal cisternae - sarcoplasmic reticulum (SR) Triad and its role in the excitation-contraction coupling

19 Myocardial contractility myocardial cell structure -Transverse T-tubule -particular to myocardium: radial, but also axial T tubules -invagination of the sarcolemma; extension of extracellular fluid -more developed in the ventricles; -scanty in atrial & Purkinje cells -oriented at the Z lines -enable fast impulse transmission / almost simultaneously stimulation of myofibrils -Sarcoplasmic reticulum -developed from ER, important as Ca store -closed set of anastomosing tubules wandering through the myofibrils: network SR (important for Ca re-uptake by Ca-ATPase pumps, inhibited by phospholamban) junctional SR (close to sarcolemma/t-tubules, Ca store) corbular SR (sac-like expansion) along the SR network, in I band (Ca storage enabled by calsequestrin)

20 Myocardial contractility myocardial cell structure Sarcoplasme: contains myoglobin (3.4 g/l) an O 2 store, which is 50% saturated at po 2 =5 mmhg, facilitates the diffusion of O 2 through the sarcoplasme Single central nucleus Mitochondria: up to 30% of the volume of the heart great oxidative capacity Rich capillary supply: ~ 1 capillary / myocardial cell; short diffusion distances Cardiac myocytes receive sympathetic and parasympathetic innervation that modulate cardiac muscle function.

21 Myocardial contractility myocardial cell structure Sarcomere - contractile unit, located between two Z lines, mm in resting myocytes, give the striated appearance, contains myofibrilary proteins: - contractil: myosin (thick), actin (thin); each myosin is surrounded by 6 actin filam. - regulatory: tropomyosin, troponin complex - accesory, non-contractile cytoskeletal filaments: titin/connectin, tropomodulin, nebulin

22 Cardiac sarcomere: major components Troponin C (TnC): binds to Ca2+ to produce a conformational change in TnI Troponin T (TnT): binds to tropomyosin, interlocking them to form a troponintropomyosin complex Troponin I (TnI): binds to actin and cover its myosin binding sites, to hold the troponintropomyosin complex in place and to inhibit A-M binding and contraction. TnI phosphorylation by beta1 agonists accelerates relaxation

23 Cardiac sarcomere and contraction Actin has ATP and Ca/Mg binding sites; interaction with tropomyosintroponin complex; present myosin binding sites Myosin - ATP-ase activity, interact with actin Contraction = shortening of the sarcomeres; sliding filament mechanism (repeated making and breaking of crossbridges between A & M filaments, in the presence of ATP). The crossbridges are the heads of the myosin molecules, which change their angles by binding to the actin sites, after tropomyosin Ca-dependent displacement.

24 Cardiac muscle is generally similar to skeletal muscle in the interaction of the actin and myosin during cross-bridge cycling, the resynthesis of ATP, and the termination of contraction/relaxation.

25 Excitation-Contraction Coupling in Cardiac Muscle STEPS: 1. AP from SAN travels through gap junctions in adjacent myocytes/conductive tissue. AP spreads over cell membranes and deep into the T tubules 2. AP-triggered voltage change opens L-type Ca channel on cardiac myocytes membrane inward Ca current (during the AP s plateau) 3. Tetrad: [Ca] i (10%) triggers the Ca-induced Ca release from SR Ca channels / ryanodine receptors critical dependence of cardiac contraction on extracellular Ca 4. [Ca] i (90%) from SR stores Ca binds to troponin C tropomyosin is moved out and release the myosin binding sites on the actin filaments promotes actin-myosin interaction and contraction

26 Excitation-Contraction Coupling in Cardiac Muscle 5. Myosin cross-bridges bind to the underlying actin one direction movement of the myosin head, which pulls the actin filament toward the center of the sarcomere 6. Actin & myosin binding myocardial cells contract, developing a tension proportional to [Ca]i 7. Late stage of AP phase 2 (plateau): influx of Ca2+ through L-type Ca2+ channels decreases less Ca2+ released by the SR - prevent a further increase in [Ca2+]i 8. Relaxation occurs when [Ca]i is restored/decreased to resting values by -Ca-ATPase pump (SERCA)- disinhibited by phospholamban phosphorylation -sarcolemmal Ca pump -electrogenic 3Na-1Ca antiporter 9. ATP is needed for relaxation, to release myosin from the actin (if not rigor status). Partial hydrolysis of ATP and release of ADP energizes the myosin head for another cross-bridge cycle.

27 AP plateau: opening of the voltagedependent L-type Ca 2+ channels. Ca 2+ influx is small but critical for the opening of SR Ca ++ channels. Ca 2+ release from the SR increases [Ca 2+ ]i to allow contraction. Relaxation occurs as the [Ca 2+ ]i is lowered from the combined actions of the sarcolemmal 3Na + -1Ca 2+ antiporter, Ca 2+ uptake by the SR and Ca 2+ extrusion by the sarcolemmal Ca 2+ pump. AP in cardiac muscle ( 0.3 sec) overlaps the contraction, resulting in a long refractory period; modulation of L-type Ca 2+ channel can be used as an alternative strategy to increase the force of contraction.

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30 Myocardial relaxation and intracellular Ca2+ (1) Extrusion of Ca2+ into the Extracellular Fluid! Even during the plateau of AP the myocyte extrudes some Ca2+. After the membrane potential returns to more negative values, the extrusion processes trigger a [Ca2+]i fall. The cells extrude all the Ca2+ that enters the cytosol from the extracellular fluid through L-type Ca2+ channels. Ca2+ extrusion into the extracellular fluid occurs by (1) sarcolemmal Na-Ca exchanger (NCX1), which operates at relatively high levels of [Ca2+]i; Effect of cardiac glycosides (digitalis) to [Ca2+]i (2) a sarcolemmal Ca2+ pump, which may function at even low levels of [Ca2+]i, but contributes only modestly to relaxation.

31 Myocardial relaxation and intracellular Ca2+ (2) Re-uptake of Ca2+ into the SR Even during the plateau of AP, some of the Ca2+ accumulating in the cytoplasm is sequestered into the SR by the Ca2+ pump SERCA. Regulated by phospholamban. (3) Dissociation of Ca2+ from Troponin C As [Ca2+]i falls, Ca2+ dissociates from troponin C, blocking actin-myosin interactions and causing relaxation. β1-adrenergic agonists accelerate relaxation by promoting phosphorylation of troponin I, which in turn enhances the dissociation of Ca2+ from troponin C.

32 Phospholamban effect on heart activity Phospholamban, an integral SR membrane protein with a single transmembrane segment, is an important regulator of SR Ca-pump (SERCA). Its phosphorylation by any of several kinases (like protein kinase A PKA, secondary to β1-adrenergic stimulation) relieves phospholamban's inhibition of SERCA, allowing Ca 2+ resequestration in the SR to accelerate. The net effect of its phosphorylation is an increase in the rate of cardiac muscle relaxation. Also, a positive inotropic effect (more Ca available in the SR).

33 What is specific to cardiac muscle APs that propagate between adjacent cardiac myocytes through gap junctions initiate contraction of cardiac muscle. Cardiac contraction requires Ca 2+ entry through L-type Ca 2+ channels, that will locally determine important Ca-induced Ca release The regulatory protein troponin C (TNNC1 subtype) has just a single, active low-affinity Ca2+ binding site, rather than the two high-affinity and two low-affinity sites of troponin C TNNC2 in skeletal muscle. The termination of cardiac contraction has an additional feature: SR Ca2+ pump activity is inhibited by the regulatory protein phospholamban. When phospholamban is phosphorylated by camp-dependent protein kinase (PKA), its ability to inhibit the SR Ca2+ pump is lost. Thus, activators of PKA, such as epinephrine, may enhance the rate of cardiac myocyte relaxation.

34 What is specific to cardiac muscle In cardiac muscle, the strength of contraction is not regulated by frequency summation or multiple-fiber summation possible, but through modulating the contractile force generated during each individual muscle twitch. The contractile force is enhanced (positive inotropic effect) by: - modulating the magnitude of the rise in [Ca2+]i : Norepinephrine (NE) acts on β-type adrenergic receptor to increase camp, activate PKA and phosphorylate the L-type Ca2+ channels, thereby increasing Ca2+ influx and contractile force. - camp pathway also increase the Ca2+ sensitivity of the contractile apparatus by phosphorylating one or more of the regulatory proteins. - NE increase the Ca2+ permeability of voltage-gated Na+ channels - prolongation of AP through inhibition of K channels increase Ca inflow The contractile force is decreased (negative inotropic effect) by: Ach acts on muscarinic receptors, increase cgmp phosphorylation of L-type Ca2+ channels at distinct sites decrease in Ca2+ influx during the cardiac AP decrease in the force of contraction.

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36 Myocardial Contractility = INOTROPISM - Inotropism = the intrinsic ability of the cardiac muscle to develop force at a given muscle length - estimated by the ejection fraction = stroke volume/end-diastolic volume = (55-60%) - End-diastolic volume: EDV= ml ml - End-systolic volume: ESV=40-50 ml ml - Stroke volume: volume of blood pumped with each contraction = EDV - ESV ~ 70 ml - Heart rate = number of beats per minute - Cardiac output = volume of blood per minute = Stroke volume x Heart rate - Pulse: rhythmic stretching of arteries by heart contraction

37 Myocardial Contractility Duration of contraction: function of AP duration ~ 0.2 sec in A ~ 0.3 sec in V When cardiac muscle is stretched, it contracts more forcefully: length-tension relationship in cardiac muscle (Frank-Starling Low of the Heart: optimal sarcomere lenths, no. of A-M cross-bridges, troponin affinity for Ca, increase Ca uptake and release from SR)

38 Inotrop POSITIVE factors -Adrenergic agonits - β rec (+) AC camp PKA phosphorilation 1. increase activation of L-type Ca channels & Ca inflow; 2. inhibit of phospholamban and calmodulin, thus increasing SERCA and sarcolemmal Ca pump activity (e.g., isoproterenol) 3. increase the Ca sensitivity of the contractile aparatus - Cardiac gangliosides -Na/K pump Na-Ca exchanger (NCX1) - Extracellular Ca 2+ : decrease Na + -Ca 2+ exchange & increase Ca 2+ influx through L-type Ca 2+ channels - Extracellular Na + : reduce Na + gradient, decr. Ca 2+ extrusion - Heart frequency : increases SR stores of Ca 2+ & increases Ca 2+ influx during AP (staircase phenomenon) intracellular Ca 2+

39 Inotropic negativ factors - L-type Ca channels blockers - verapamil - diltiazem - nifedipine - PS stim. Ach M rec. (-) AC camp PKA decrease activation of L-type Ca channels & Ca inflow - Ca 2+ extracel. : by increasing Ca 2+ extrusion through Na-Ca exchanger & by reducing Ca 2+ entry through L-type Ca2+ channels during the AP plateau - Na + extracel. : increases Ca 2+ extrusion through Na-Ca exchanger decreasing [Ca 2+ ]i - K + extracel. - H + intracel. - reduce Ca 2+ entry during the plateau of the cardiac AP - used in supraventricular arrhythmias and hypertension

40 Other Ca 2+ regulation factors specific to cardiac muscle - garden-hose effect - the coronary artery pressure itself influences ventricular function by distending the heart from within its walls, and so invokes Starling s low of the heart. Changing perfusion pressure also modify calcium release during excitation-contraction coupling. - heart rate positive (Bowditch) staircase: cumulative increase in [Ca 2+ ] i Ca stores contractility - ph effect: intracell H + competes with Ca 2+ for binding on troponine complex

41 Nervous reflex regulation: Autonomic Nervous Regulation S and PS branches of the autonomic nervous system influence HR and AV node conduction through antagonistic control PS: 70 beats/min-[ SAN: intrinsic rate of /min ]- S: >100/min (Ach, muscarinic rec) (NE, b1 rec) PS tone - decrease HR and AV conduction; vagal escape - strong vagal stimulation can decrease the strength of myocardial contraction by % - nitric oxide (NO) vasodilatation S tone -increase HR, AV conduction and contractility (b1 Rec) -normally S discharge continuously at a slow rate 30% CO -determine vasoconstriction by a1 Rec -vasodilatation by b2 Rec (heart, skeletal mm fight or flight response

42 Distribution of the autonomic nervous system in myocardium Cardiac output can be increased more than 100% by sympathetic stimulation, and can be decreased to almost zero by vagal (parasympathetic) stimulation.

43 Effect on the cardiac output of different degrees of sympathetic or parasympathetic stimulation. The picture shows relation between RA pressure at the input of the right heart and CO from the LV into the aorta. CO changes caused by nerve stimulation result both from changes in heart rate and from changes in contractile strength of the heart.

44 Coronary Circulation Main L & R coronary arteries: left for the anterior & left lateral portions of LV, and right for most of the RV and the posterior part of the LV. - epicardial arteries on the surface of the heart; - intramuscular arteries penetrate from the surface into the cardiac muscle mass; compressed during systole - subendocardial arterial plexus -! inner 0.1 mm of the endocardial surface is also nourished directly from the intracardiac blood

45 Coronary Circulation Coronary venous blood flow: - from the LV returns to the RA by way of the coronary sinus (~75% of the total coronary blood flow); - from the RV returns through small anterior cardiac veins that flow directly into the RA. -! a very small amount of coronary venous blood also flows back into the heart through very minute thebesian veins, which empty directly into all chambers of the heart.

46 Collateral Circulation in the Heart. In a normal heart, almost no large communications exist among the larger coronary arteries, but many anastomoses do exist among the smaller arteries sized µm in diameter. The degree of damage to the heart muscle (secondary to atherosclerotic coronary constriction or by sudden coronary occlusion) is determined to a great extent by the degree of collateral circulation that has already developed or that can open within minutes after the occlusion. Minute anastomoses in the normal coronary arterial system

47 Phasic flow of blood through the coronary capillaries of the LV during cardiac systole and diastole: strong compression of the LV muscle around the intramuscular vessels during systolic contraction. For the RV the phasic changes are partial, because the force of contraction of the RV muscle is far less than that of the LV. Coronary Blood Flow In resting conditions coronary blood flow in adults averages about 225 ml/min (4 5 % of the total CO). During strenuous exercise: 4-7 fold increase CO together with increased arterial pressure 6-9 fold increased work output of the heart, with only 3-4 times increase in coronary blood flow! increase of the ratio (heart energy expenditure / coronary blood flow) shows a relative deficiency of coronary blood supply the need for increasing the "efficiency" of cardiac utilization of energy.

48 Control of Coronary Blood Flow 1. Regulation through Local Muscle Metabolism Metabolic factors, especially myocardial oxygen consumption/oxygen demand, are the major controllers of myocardial blood flow. Normally ~70% of the oxygen in the coronary arterial blood is removed as the blood flows through the heart muscle little additional oxygen can be supplied to the heart musculature the need to increase the coronary blood flow, through local arteriolar vasodilation, proportional to cardiac muscle metabolism/ degree of activity. Vasodilator substances released from the muscle cells in response to increased metabolism: -Adenosine: low oxygen conc. in the muscle cells ATP degrades to adenosine monophosphate further degraded to adenosine adenosine release into the tissue fluids of the heart muscle vasodilation (action maintained for only 1-3 hrs) Most of adenosine is reabsorbed into the cardiac cells to be reused. Obs: Blockers of adenosine do not prevent coronary vasodilation caused by increased heart muscle activity. - Other vasodilators: adenosine phosphate compounds, potassium ions, hydrogen ions, carbon dioxide, bradykinin, prostaglandins, nitric oxide.

49 Control of Coronary Blood Flow 2. Autonomic Nervous Control of Coronary Blood Flow: Direct & Indirect effects Direct effects: action of Ach (vagus nerves) and NE/E (sympathetic nerves) on the coronary vessels Ach has a direct effect to dilate the coronary arteries, even the distribution of vagal nerve fibers to the ventricular coronary system is reduced. NE has either vascular constrictor or vascular dilator effects, depending on the presence or absence of constrictor receptors (alpha receptors, > on epicardial coronary vessels) and dilator receptors (beta receptors, > on intramuscular arteries). Both alpha and beta receptors exist in the coronary vessels sympathetic stimulation cause slight overall coronary constriction or dilation, but usually constriction. Excess sympathetic drive severe alpha vasoconstrictor effects vasospastic myocardial ischemia. Indirect effects: secondary changes in coronary blood flow caused by increased/decreased activity of the heart, mostly opposite to the direct effects, that play a major role in normal control of coronary blood flow. Sympathetic stimulation increases both HR and contractility increases the rate of metabolism vasodilation of coronary vessels through local blood flow regulatory mechanisms blood flow increases. Vagal stimulation slows the heart and has a slight depressive effect on heart contractility decrease cardiac oxygen consumption

50 Particularities of Cardiac Muscle Metabolism - derives mainly from oxidative metabolism of fatty acids (70%) and, to a lesser extent, of lactate and glucose (anaerobic conditions, ischemic cardiac pain due to production of lactate and ph decrease) - is measured by the rate of oxygen consumption in the heart - is used to provide the work of contraction. - >95% of the metabolic energy is used to form ATP in the mitochondria. ATP is then used for cardiac muscular contraction and other cellular functions. -in severe coronary ischemia, ATP degrades to adenosine diphosphate adenosine monophosphate adenosine dilation of the coronary arterioles during coronary hypoxia. Adenosine diffusion from the muscle cells into the circulating blood with serious cellular consequence. Within 30 min. of severe coronary ischemia, about one half of the adenine base can be lost from the affected cardiac muscle cells. New synthesis of adenine is only possible at a rate of 2%/hour. For a coronary ischemia that persisted for 30 minutes, relief of the ischemia may be too late for the cardiac cells to survive.