Physiology_Levy

Physiology_Levy. [Ca++] enhances contractile force, and very high extracellular [Ca++] induces cardiac arrest in systole (rigor). The free intracellular [Ca++] is the factor principally responsible for the contractile state of the myocardium.


Physiology_Levy

Physiology_Levy. The process by which the action potential of the cardiac myocyte leads to contraction is termed excitation-contraction coupling (see also Chapter 13). Cardiac muscle is excited when a wave of excitation spreads rapidly along the myocardial sarcolemma from cell to cell via gap junctions. Excitation also spreads into the interior of the cells via the T tubules, which invaginate the cardiac fibers at the Z lines. Electrical stimulation at the Z line or the application of Ca++ to the Z lines in a skinned cardiac fiber (whose sarcolemma is removed) elicits localized contraction of the adjacent myofibrils. During the plateau (phase 2) of the action potential, permeability of the sarcolemma by Ca++ increases. Ca++ flows down its electrochemical gradient and enters the cell through calcium channels in the sarcolemma and in the T tubules.


Physiology_Levy

Physiology_Levy. During the action potential, Ca++ enters the cell via calcium channels (L-type). However, the amount of Ca++ that enters the cell interior from the extracellular/ interstitial fluid is not sufficient to induce contraction of the myofibrils. Instead, it acts as a trigger (trigger Ca++) to release Ca++ from the sarcoplasmic reticulum, where the intracellular Ca++ is stored (see Fig. 13.2 ). Ca++ leaves the sarcoplasmic reticulum through Ca++ release channels, which are called ryanodine receptors because the channel protein binds ryanodine avidly. Cytoplasmic [Ca++] increases from a resting level of approximately 10−7 mol to levels of approximately 10−5 mol during excitation. This Ca++ then binds to the protein troponin C. The Ca++–troponin C complex interacts with tropomyosin to unblock active sites between the actin and myosin filaments. This unblocking initiates cross-bridge cycling and hence contraction of the myofibrils.


Physiology_Levy

Physiology_Levy. Mechanisms that raise cytosolic [Ca++] increase the force developed, and those that lower cytosolic [Ca++] decrease the force developed. For example, catecholamines increase the movement of Ca++ into the cell by phosphorylation of the sarcolemmal calcium channels via a cAMP-dependent protein kinase (see Fig. 13.4). This in turn causes the release of more Ca++ from the sarcoplasmic reticulum, and as a result, contractile force increases. Increasing extracellular [Ca++] increases the amount of Ca++ that enters the cell via the calcium channels and thereby increases contractile force as just described. Reducing the Na+ gradient across the sarcolemma also increases contractile force, an effect mediated by the 3Na+-Ca++ antiporter that normally extrudes Ca++ from the cell (see


Physiology_Levy

Physiology_Levy. Fig. 13.2 ). For example, reducing extracellular [Na+] causes less Na+ to enter the cell in exchange for Ca++ , which results in an increase in intracellular [Ca++] and thus contractile force. Raising intracellular [Na+] has a similar effect. In fact, this is the mechanism by which cardiac glycosides increase contractile force. Cardiac glycosides inhibit Na+,K+-ATPase and thereby raise intracellular [Na+] in the cells. The elevated cytosolic [Na+] reverses the direction of the 3Na+-Ca++ antiporter, and therefore less Ca++ is removed from the cell. The increase in intracellular [Ca++] results in an increase in contractile force. Finally, contractile force is diminished when intracellular [Ca++] is decreased by a reduction in extracellular [Ca++], by an increase in the Na+ gradient across the sarcolemma, or by the administration of a calcium channel antagonist that prevents Ca++ from entering the myocardial cell.


Physiology_Levy

Physiology_Levy. At the end of systole, the influx of Ca++ stops, and the sarcoplasmic reticulum is no longer stimulated to release Ca++ . In fact, the sarcoplasmic reticulum avidly takes up Ca++ by means of Ca++-ATPase. The Ca++-ATPase in the sarcoplasmic reticulum is similar to but distinct from the Ca++-ATPase found in the sarcolemma. Cytosolic [Ca++] is also reduced during diastole through the action of the 3Na+-Ca++ antiporter in the sarcolemma, as well as by a sarcolemmal Ca++-ATPase (see Fig. 13.2 Both cardiac contraction and relaxation are accelerated by catecholamines (see


Physiology_Levy

Physiology_Levy. Fig. 13.3 ). When catecholamines bind to their receptor (β1-adrenoceptor), adenylate cyclase is activated, thereby increasing intracellular cAMP levels, which then leads to activation of cAMP-dependent protein kinase A. Protein kinase A has multiple effects in the cell. As already described, it phosphorylates the calcium channel in the sarcolemma and causes increased entry of Ca++ into the cell, thus increasing the force of contraction. In addition, protein kinase A phosphorylates other proteins that facilitate relaxation. One such protein is phospholamban. Phospholamban normally inhibits the Ca++-ATPase of the sarcoplasmic reticulum. However, when phospholamban is phosphorylated, its inhibitory action is reduced, and uptake of Ca++ into the sarcoplasmic reticulum is enhanced. The increased activity of the Ca++-ATPase in the sarcoplasmic reticulum decreases intracellular [Ca++], thereby causing relaxation. Protein kinase A also phosphorylates troponin I, which in turn inhibits binding


Physiology_Levy

Physiology_Levy. activity of the Ca++-ATPase in the sarcoplasmic reticulum decreases intracellular [Ca++], thereby causing relaxation. Protein kinase A also phosphorylates troponin I, which in turn inhibits binding of Ca++ by troponin C. As a result, tropomyosin returns to its position of blocking the myosin-binding sites on the actin filaments, and relaxation results.


Physiology_Levy

Physiology_Levy. Contraction of cardiac muscle is influenced by both preload and afterload ( Fig. 16.37 ). Preload is the force that stretches the relaxed muscle fibers, thereby increasing their resting length (see Fig. 16.37B ). In the left ventricle, for example, the blood filling and thus the stretching of the wall during diastole represents the preload. Afterload is the force added to the muscle (see Fig. 16.37C ) against which the contracting muscle must act (see Fig. 16.37D ). Again from the perspective of the left ventricle, afterload is the pressure in the aorta that must be overcome by the contracting left ventricular muscle to open the aortic valve and eject the blood. Preload can be increased by greater filling of the left ventricle during diastole (i.e., increasing end-diastolic volume). From lower initial end-diastolic volumes, increments in filling pressure during diastole increase resting fiber length and elicit a greater systolic pressure during the subsequent contraction (see


Physiology_Levy

Physiology_Levy. Fig. 16.36 ). Systolic pressure increases until a maximal systolic pressure is reached at the optimal preload (see Fig. 16.36 ). If diastolic filling continues beyond this point, the pressure developed will no longer increase. At very high filling pressures, peak pressure development in systole is actually reduced.


Physiology_Levy

Physiology_Levy. At a constant preload, higher systolic pressure can be reached during ventricular contractions by an increase in the afterload (e.g., increasing aortic pressure by restricting the runoff of arterial blood to the periphery). Incremental increases in afterload produce progressively higher peak systolic pressures. However, if the afterload continues to increase, it becomes so great that the ventricle can no longer generate enough force to open the aortic valve. At this point, ventricular systole is totally isometric (i.e., there is no ejection of blood), and thus no change occurs in ventricular volume during systole. The maximal pressure developed by the left ventricle under these conditions is the maximal isometric force that the ventricle is capable of generating at a given preload. At preloads below the optimal filling volume, an increase in preload can yield greater maximal isometric force (see Fig. 16.36


Physiology_Levy

Physiology_Levy. Fig. 16.36 Preload and afterload depend on certain characteristics of the vascular system and the behavior of the heart. With regard to the vasculature, the degree of venomotor tone and peripheral resistance influences preload and afterload. With regard to the heart, a change in rate or stroke volume can also alter preload and afterload. Hence, cardiac and •Fig. 16.37 Preload and Afterload in a Papillary Muscle. A, Restingstage(noload)intheintactheartjustbeforeopeningoftheAVvalves.B, Preload(PL)intheintactheartattheendofventricularfilling.C, Supportedpreloadplusafterload(AL)intheintactheartjustbeforeopeningoftheaorticvalve.D, Liftingpreloadplusafterloadintheintactheartduringventricularejection,withadecreaseinventricularvolume.PL+ AL,totalload. vascular factors interact with each other to affect preload and afterload (see


Physiology_Levy

Physiology_Levy. vascular factors interact with each other to affect preload and afterload (see Contractility defines cardiac performance at a given preload and afterload. Contractility determines the change in peak isometric force (isovolumic pressure) at a given initial fiber length (end-diastolic volume). Contractility can be augmented by drugs, such as norepinephrine or digitalis, or by an increase in contraction frequency (tachycardia). The increase in contractility (positive inotropic effect) produced by these interventions is reflected by incremental increases in the force developed and in the velocity of contraction. Indices of Contractility A reasonable index of myocardial contractility can be derived from the contour of ventricular pressure curves ( Fig. 16.38 ). A hypodynamic heart is characterized by elevated end-diastolic pressure, slowly rising ventricular pressure, and a somewhat reduced ejection phase (curve C in Fig. 16.38 ). A hyperdynamic heart (curve B in Fig.


Physiology_Levy

Physiology_Levy. Fig. 16.38 ). A hyperdynamic heart (curve B in Fig. 16.38 ) is characterized by reduced end-diastolic pressure, fast-rising ventricular pressure, and a brief ejection phase. The slope of the ascending limb of the ventricular pressure curve indicates the maximal rate of force development by the ventricle. The maximal rate of change in pressure with time—that is, the maximum dP/dt—is illustrated by the tangents to the steepest portion of the ascending limbs of the ventricular pressure curves in Fig. 16.38 . The slope of the ascending limb is maximal during the isovolumic phase of systole (see Fig. 16.38 ). At any given degree of ventricular filling, the slope provides an index of the initial contraction velocity and hence an index of contractility. Similarly, the contractile state of the myocardium can be calculated from the velocity of blood flow that occurs initially in the ascending aorta during the cardiac cycle ( Fig.


Physiology_Levy

Physiology_Levy. Similarly, the contractile state of the myocardium can be calculated from the velocity of blood flow that occurs initially in the ascending aorta during the cardiac cycle ( Fig. 16.39 ). In addition, the ejection fraction, which is the ratio of the volume of blood ejected from the left ventricle per beat (stroke volume) to the volume of blood in the left ventricle at the end of diastole (end-diastolic volume), is widely used clinically as an index of contractility. •Fig. 16.38 Leftventricularpressurecurveswithtangentsdrawntothesteepestportionsoftheascendinglimbstoindicatemaximalratesofchangeinpressurewithtime(dP/dtvalues).A(blue curve), control;B(dashed red curve), hyperdynamicheart,aswithadministrationofnorepinephrine;C(green dashed curve), hypodynamicheart,asincardiacfailure.160 120 80 40 0 0 0.2 0.4 0.6 Time (sec) Left ventricular pressure (mm Hg) Max dP/dt B A C


Physiology_Levy

Physiology_Levy. The atria are thin-walled, low-pressure chambers that function more as large-reservoir conduits of blood for their respective ventricles than as important pumps for the forward propulsion of blood. The ventricles comprise a continuum of muscle fibers originating from the fibrous skeleton at the base of the heart (chiefly around the aortic orifice). These fibers sweep toward the cardiac apex at the epicardial surface. They pass toward the endocardium and gradually undergo a 180-degree change in direction to lie parallel to the epicardial fibers and to form the endocardium and papillary muscles.


Physiology_Levy

Physiology_Levy. At the apex of the heart, the fibers twist and turn inward to form papillary muscles. At the base of the heart and around the valve orifices, these myocardial fibers form a thick, powerful muscle mass that not only decreases the ventricular circumference to implement the ejection of blood but also narrows the AV valve orifices, which aids in closure of the valve. Ventricular ejection is also accomplished by a decrease in the longitudinal axis as the heart begins to narrow toward the base. The early contraction of the apical part of the ventricles, coupled with the approximation of the ventricular walls, propels the blood toward the ventricular outflow tracts. The right ventricle, which develops a mean pressure that is approximately one seventh that developed by the left ventricle, is considerably thinner than the left ventricle.


Physiology_Levy

Physiology_Levy. The cardiac valve leaflets consist of thin flaps of flexible, tough, endothelium-covered fibrous tissue that are firmly attached at the base to the fibrous valve rings. Movement of the valve leaflets is essentially passive, and the orientation of the cardiac valves is responsible for the unidirectional flow of blood through the heart. There are two types of valves in the heart: atrioventricular and semilunar ( Figs. 16.40 16.41


Physiology_Levy

Physiology_Levy. Figs. 16.40 16.41 The tricuspid valve, located between the right atrium and the right ventricle, is made up of three cusps, whereas the mitral valve, which lies between the left atrium and the left ventricle, has two cusps. The total area of the cusps of each AV valve is approximately twice that of the respective AV orifice, and so considerable overlap of the leaflets occurs when the valves are in the closed position. Attached to the free edges of these valves are fine, strong ligaments (chordae tendineae cordis) that arise from the powerful papillary muscles of the respective ventricles. These ligaments prevent the valves from becoming everted during ventricular


Physiology_Levy

Physiology_Levy. Atrial systoleIsovol. contractionRapid ejectionReduced ejectionIsovol. relaxationRapid ventricular filling 0 0.1 0.2 0.3 0.4 0.60.5 0.7 0.8 Time (sec) Ventricular systole S P P R c a 4 1 2 3 v T Q Left atrial pressure Mitral valve opens Mitral valve closes Left ventricular pressure Aortic valve opens Aortic valve closes Aortic pressure Heartsounds VenouspulseElectrocardiogram •Fig. 16.39 Leftatrial,aortic,andleftventricularpressurepulsescorrelatedintimewithaorticflow,ventricularvolume,heartsounds,venouspulse,andtheelectrocardiogramforacompletecardiaccycleinahumansubject.Isovol,isovolumic. systole. In a normal heart, the valve leaflets remain relatively close together during ventricular filling. The partial approximation of the valve surfaces during diastole is caused by eddy currents that prevail behind the leaflets and by tension that is exerted by the chordae tendineae cordis and papillary muscles.


Physiology_Levy

Physiology_Levy. CHAPTER 16 Elements of Cardiac Function •Fig. 16.40 Illustrationofaheartsplitperpendiculartotheinterventricularseptumtodepicttheanatomicalrelationshipsoftheleafletsoftheatrioventricularandaorticvalves.Pulmonary artery Left atrium Left auricular appendage Mitral valve—anterior cusp Pulmonary veins Superior vena cava Aorta Aorta Mitral valve— posterior cusp Right ventricle Left ventricle Left ventricle Papillary muscle Papillary muscles appendage Orifices of coronary arteries Posterior cusp Anterior cusp •Fig. 16.41 Illustrationoffourcardiacvalvesasviewedfromthebaseoftheheart.Notehowtheleafletsoverlapintheclosedvalves.Anterior cusp Right cusp Left cusp Posterior cusp Anulus fibrosus Medial cusp valve The pulmonic and aortic valves are located between the right ventricle and the pulmonary artery and between the left ventricle and the aorta, respectively. These valves consist of three cup-like cusps that are attached to the valve rings (see


Physiology_Levy

Physiology_Levy. Figs. 16.40 16.41 ). At the end of the reduced ejection phase of ventricular systole, blood flow briefly reverses toward the ventricles. This reversal of blood flow snaps the cusps together and prevents regurgitation of blood into the ventricles. During ventricular systole, the cusps do not lie back against the walls of the pulmonary artery and aorta; instead, they float in the bloodstream at a point approximately midway between the vessel walls and their closed position. Behind the semilunar valves are small outpocketings (sinuses of Valsalva) of the pulmonary artery and aorta. In these sinuses, eddy currents develop, which tend to keep the valve cusps away from the vessel walls. Furthermore, the orifices of the right and left coronary arteries are behind the right and the left cusps, respectively, of the aortic valve. Were it not for the presence of the sinuses of Valsalva and the eddy currents developed therein, the coronary ostia could be blocked by the valve cusps, and coronary


Physiology_Levy

Physiology_Levy. of the aortic valve. Were it not for the presence of the sinuses of Valsalva and the eddy currents developed therein, the coronary ostia could be blocked by the valve cusps, and coronary blood flow would cease.


Physiology_Levy

Physiology_Levy. The Pericardium The pericardium invests the entire heart and the cardiac portion of the great vessels, and it is reflected onto the cardiac surface as the epicardium. The sac normally contains a small amount of fluid, which provides lubrication for the continuous movement of the enclosed heart. The pericardium is not very distensible; it strongly resists a large, rapid increase in cardiac size and hence prevents sudden overdistention of the chambers of the heart. However, in congenital absence of the pericardium or after its surgical removal, cardiac function is not seriously affected. Nevertheless, with the pericardium intact, an increase in diastolic pressure in one ventricle increases the pressure and decreases the compliance of the other ventricle.


Physiology_Levy

Physiology_Levy. Four sounds are usually generated by the heart, but only two are ordinarily audible through a stethoscope. With electronic amplification, the less intense sounds can be detected and recorded graphically as a phonocardiogram. This means of registering faint heart sounds helps delineate the precise timing of the heart sounds in relation to other events in the cardiac cycle. The first heart sound is initiated at the onset of ventricular systole ( Fig. 16.42 ) and reflects closure of the AV valves. It is the loudest and longest of the heart sounds, has a crescendo-decrescendo quality, and is heard best over the apical region of the heart. The tricuspid valve sounds are heard best in the fifth intercostal space just to the left of the sternum; the mitral sounds are heard best in the fifth intercostal space at the cardiac apex.


Physiology_Levy

Physiology_Levy. •Fig. 16.42 Thefirstandsecondheartsoundsofthephonocardio-gram(bottom tracing) areshowninregardtotheirrelationshiptotheP,R,andTwavesoftheelectrocardiogram(top tracing). 0 0.2 1.2 1.40.8 1.00.4 0.6 1.6 Time (sec) Phonocardiogram ElectrocardiogramP R T 2 1 The second heart sound, which occurs with abrupt closure of the semilunar valves (see


Physiology_Levy

Physiology_Levy. The second heart sound, which occurs with abrupt closure of the semilunar valves (see Fig. 16.42 ), is composed of higher frequency vibrations (higher pitch) and is of shorter duration and lower intensity than is the first heart sound. The portion of the second sound caused by closure of the pulmonic valve is heard best in the second thoracic interspace just to the left of the sternum, whereas that caused by closure of the aortic valve is heard best in the same intercostal space but to the right of the sternum. The aortic valve sound is generally louder than the pulmonic valve, but in cases of pulmonary hypertension, the reverse is true. The nature of the second heart sound changes with respiration. During expiration, a single heart sound is heard that reflects simultaneous closing of the pulmonic and aortic valves. However, during inspiration, closure of the pulmonic valve is delayed, mainly as a result of increased blood flow from an inspiration-induced increase in venous return.


Physiology_Levy

Physiology_Levy. With this delayed closure of the pulmonic valve, the second heart sound can be heard as two components; this is termed physiological splitting of the second heart sound. A third heart sound is sometimes heard in children with thin chest walls or in patients with left ventricular failure. It consists of a few low-intensity, low-frequency vibrations heard best in the region of the cardiac apex. The vibrations occur in early diastole and are caused by the abrupt cessation of ventricular distention and by the deceleration of blood entering the ventricles. A fourth, or atrial, sound consists of a few low-frequency oscillations. This sound is occasionally heard in individuals with normal hearts. It is caused by the oscillation of blood and cardiac chambers as a result of atrial contraction. The Cardiac Cycle


Physiology_Levy

Physiology_Levy. The Cardiac Cycle The phase between the start of ventricular systole and opening of the semilunar valves (when ventricular pressure rises abruptly) is called the isovolumic (literally, “same volume”) contraction period. This term is appropriate because ventricular volume remains constant during this brief period (see Fig. 16.39 ). The onset of isovolumic contraction also coincides with the peak of the R wave on an ECG, initiation of the first heart sound, and the earliest rise in ventricular pressure on the ventricular pressure curve after atrial contraction. Opening of the semilunar valves marks the onset of the ventricular ejection phase, which may be subdivided dWith inspiration, intrathoracic pressure is reduced (see Chapter 21), which then increases venous blood flow to the right atrium.


Physiology_Levy

Physiology_Levy. Chapter 21), which then increases venous blood flow to the right atrium. Inoverloadedhearts,asincongestiveheartfailure,whenventricularvolumeisverylargeandtheventricularwallsarestretchedmaximally,athirdheartsoundisoftenheard.Athirdheartsoundinpatientswithheartdiseaseisusuallyagravesign.Whenthethirdandfourth(atrial)soundsareaccentuated,asoccursincertainabnormalconditions,tripletsofsoundsresemblingthesoundofagallopinghorse(calledgallop rhythms)mayoccur.Mitralinsufficiencyandmitralstenosisproduce,respectively,systolicanddiastolicmurmursthatareheardbestatthecardiacapex.Aorticinsufficiencyandaorticstenosis,incontrast,produce,respectively,diastolicandsystolicmurmursthatareheardbestinthesecondintercostalspacejusttotherightofthesternum.Thecharacteristicsofthemurmursserveasanimportantguideinthediagnosisofvalvulardisease.


Physiology_Levy

Physiology_Levy. into an earlier, shorter phase (rapid ejection) and a later, longer phase (reduced ejection). The rapid ejection phase is distinguished from the reduced ejection phase by three characteristics: (1) a sharp rise in ventricular and aortic pressure that terminates at peak ventricular and aortic pressure, (2) an abrupt decrease in ventricular volume, and (3) a pronounced increase in aortic blood flow (see Fig. 16.39 ). The sharp decrease in left atrial pressure at the onset of ventricular ejection results from descent of the base of the heart and consequent stretching of the atria. During the reduced ejection period, runoff of blood from the aorta to the peripheral blood vessels exceeds the rate of ventricular output, and aortic pressure therefore declines. Throughout ventricular systole, the blood returning from the peripheral veins to the atria produces a progressive increase in atrial pressure.


Physiology_Levy

Physiology_Levy. During the rapid ejection period, left ventricular pressure slightly exceeds aortic pressure and aortic blood flow accelerates (continues to increase), whereas during the reduced ventricular ejection phase, aortic pressure is higher and aortic blood flow decelerates. This reversal of the ventricular-aortic pressure gradient in the presence of continuous flow of blood from the left ventricle to the aorta is the result of storage of potential energy in the stretched arterial walls. This stored potential energy causes blood flow from the left ventricle into the aorta to decelerate. The peak of the flow curve coincides with the point at which the left ventricular pressure curve intersects the aortic pressure curve during ejection. Thereafter, flow decelerates (continues to decrease) because the pressure gradient has been reversed.


Physiology_Levy

Physiology_Levy. Fig. 16.39 shows a tracing of a venous pulse curve recorded from a jugular vein. Three waves are apparent. The a wave occurs with the rise in pressure caused by atrial contraction. The c wave is caused by impact of the common carotid artery with the adjacent jugular vein and, to some extent, by the abrupt closure of the tricuspid valve in early ventricular systole. The v wave reflects the rise in pressure associated with atrial filling. Except for the c wave, the CHAPTER 16 Elements of Cardiac Function venous pulse curve closely resembles the left atrial pressure curve. At the end of ventricular ejection, a volume of blood approximately equal to that ejected during systole remains in the ventricular cavities. This residual volume is fairly constant in normal hearts. However, residual volume decreases somewhat when the heart rate increases or when peripheral vascular resistance has diminished.


Physiology_Levy

Physiology_Levy. Closure of the aortic valve produces the characteristic incisura (notch) on the descending limb of the aortic pressure curve, and it also produces the second heart sound (with some vibrations evident on the atrial pressure curve). The incisura marks the end of ventricular systole. The period between closure of the semilunar valves and opening of the AV valves is termed isovolumic relaxation. It is characterized by a precipitous fall in ventricular pressure without a change in ventricular volume. The major portion of ventricular filling occurs immediately after the AV valves open. At this point, the blood that returned to the atria during the previous ventricular systole is abruptly released into the relaxing ventricles. This period of ventricular filling is called the rapid filling phase. In Fig.


Physiology_Levy

Physiology_Levy. Fig. 16.39 , the onset of the rapid filling phase is indicated by the decrease in left ventricular pressure below left atrial pressure. This pressure reversal opens the mitral valve. The rapid flow of blood from atria to relaxing ventricles produces transient decreases in atrial and ventricular pressures and a sharp increase in ventricular volume. The rapid ventricular filling phase is followed by a phase of slow ventricular filling called diastasis. During diastasis, blood returning from the peripheral veins flows into the right ventricle and blood from the lungs flows into the left ventricle. This small, slow addition to ventricular filling is indicated by gradual rises in atrial, ventricular, and venous pressures and in ventricular volume (see Fig. 16.39


Physiology_Levy

Physiology_Levy. Fig. 16.39 Anincreaseinmyocardialcontractility,asproducedbycatecholaminesorbydigitalisinapatientwithafailingheart,maydecreaseresidualventricularvolumeandincreasethestrokevolumeandejectionfraction.Inseverelyhypodynamicanddilatedhearts,residualvolumecanbecomemuchgreaterthanstrokevolume. The onset of atrial systole occurs soon after the beginning of the P wave (atrial depolarization) of the ECG. The transfer of blood from atrium to ventricle achieved by atrial contraction completes the period of ventricular filling. Atrial systole is responsible for the small increases in atrial, ventricular, and venous pressure, as well as in ventricular volume (see Fig. 16.39 ). Throughout ventricular diastole, atrial pressure barely exceeds ventricular pressure. This small pressure difference indicates that the pathway through the open AV valves during ventricular filling has low resistance.


Physiology_Levy

Physiology_Levy. Because there are no valves at the junction of the venae cavae and right atrium or at the junction of the pulmonary veins and left atrium, atrial contraction may force blood in both directions. However, little blood is actually pumped back into the venous tributaries during the brief atrial contraction, mainly because of the inertia of the inflowing blood.


Physiology_Levy

Physiology_Levy. The contribution of atrial contraction to ventricular filling is governed to a great extent by the heart rate and the position of the AV valves. At slow heart rates, filling practically ceases toward the end of diastasis, and atrial contraction contributes little additional filling. During tachycardia, however, diastasis is abbreviated and the atrial contribution can become substantial. Should tachycardia become so severe that the rapid filling phase is attenuated, atrial contraction assumes great importance in rapidly propelling blood into the ventricle during this brief period of the cardiac cycle. If the period of ventricular relaxation is so brief that filling is seriously impaired, even atrial contraction cannot provide adequate ventricular filling. The consequent reduction in cardiac output may result in syncope (fainting).


Physiology_Levy

Physiology_Levy. Atrialcontractionisnotessentialforventricularfilling,ascanbeobservedinpatientswithatrialfibrillationorcompleteheartblock.Inatrialfibrillation,theatrialmyofiberscontractinacontinuous,uncoordinatedmannerandthereforecannotpumpbloodintotheventricles.Incompleteheartblock,theatriaandventriclesbeatindependentlyofeachother.However,ventricularfillingmaybenormalinpatientswiththesetwoarrhythmias.Incertaindiseasestates,theAVvalvesmaybemarkedlynarrowed(stenotic).Insuchconditions,atrialcontractionplaysamuchmoreimportantroleinventricularfillingthanitdoesinanormalheart. The changes in left ventricular pressure and volume throughout the cardiac cycle are summarized in Fig. 16.43 . Diastolic filling starts when the mitral valve opens (point A in


Physiology_Levy

Physiology_Levy. The changes in left ventricular pressure and volume throughout the cardiac cycle are summarized in Fig. 16.43 . Diastolic filling starts when the mitral valve opens (point A in Fig. 16.43 ), and it terminates when the mitral valve closes (point C). The initial decrease in left ventricular pressure (from points A to B), despite the rapid inflow of blood from the left atrium, is attributed to progressive ventricular relaxation and distensibility. During the remainder of diastole (from points B to C), the increase in ventricular pressure reflects ventricular filling and changes in the passive elastic characteristics of the ventricle. Note that only a small increase in pressure accompanies the substantial increase in ventricular volume during diastole (from points B to C). •Fig. 16.43 Schematizedpressure-volumeloopoftheleftventricleforasinglecardiaccycle.


Physiology_Levy

Physiology_Levy. The small pressure increase reflects the compliance of the left ventricle during diastole. The small increase in pressure just before the mitral valve closes (to the left of point C) is caused by the contribution of atrial contraction to ventricular filling. With isovolumic contraction (from points C to D), pressure rises steeply, but ventricular volume does not change because the mitral and aortic valves are both closed. When the aortic valve opens (point D), and during the first (rapid) phase of ejection (from points D to E), the large reduction in volume is associated with a steady increase in ventricular pressure. This reduction in volume is followed by reduced ejection (from points E to F) and a small decrease in ventricular pressure. Closure of the aortic valve (point F) is followed by isovolumic relaxation (from points F to A), which is characterized by a sharp drop in pressure. Ventricular volume does not change during the interval between closing of the aortic valve and


Physiology_Levy

Physiology_Levy. by isovolumic relaxation (from points F to A), which is characterized by a sharp drop in pressure. Ventricular volume does not change during the interval between closing of the aortic valve and opening of the mitral valve (from points F to A) because both the mitral and aortic valves are closed. The mitral valve opens (point A) to complete one cardiac cycle.


Physiology_Levy

Physiology_Levy. Several key cardiovascular system parameters are evident on a left ventricular pressure-volume loop (P-V loop), or may be calculated from it. End-diastolic volume is obtained at mitral valve closure (point C in Fig. 16.43 ) and the end-systolic volume at mitral valve opening (point A). The stroke volume is then apparent as the “width” of the P-V loop and is calculated as follows: The preload of the left ventricle, considered here as left ventricular end-diastolic pressure, is the pressure coordinate when the mitral valve closes (point C in


Physiology_Levy

Physiology_Levy. Fig. 16.43 ). The •Fig. 16.44 A, Leftventricularpressure-volumeloopsrecordedinahuman.Theleftventriclewassubjectedtodifferentpreloadsbytransientocclusionofbloodflowintheinferiorvenacava.Aspreload(leftventricularend-diastolicpressure[LVEDP])wasdecreased,bothend-diastolicvolumeandend-systolicvolumedecreased,butend-diastolicvolumedecreasedmore,whichresultedindecreasedstrokevolume.B, CardiacfunctioncurveswhenstrokevolumeisplottedasafunctionofLVEDPforanormalheartinthebasalstate(blue line), aheartwithincreasedcontractility(red line), andaheartwithreducedcontractility(green line). Atanygivenpreload,strokevolumeishigherinheartswithincreasedcontractilityandlowerinheartswithdecreasedcontractilitythanstrokevolumeinthenormalbasalstate.(A, FromSenzakiH,etal.Single-beatestimationofend-systolicpressure-volumerelationinhumans.Anewmethodwiththepotentialfornoninvasiveapplication.Circulation. 1996;94[10]:2497-2506.) approximate “diastolic” arterial blood pressure may be read when the aortic valve opens


Physiology_Levy

Physiology_Levy. 1996;94[10]:2497-2506.) approximate “diastolic” arterial blood pressure may be read when the aortic valve opens (point D), and the approximate “systolic” arterial blood pressure is read during systole (point E). Left ventricular P-V loops recorded from a human (


Physiology_Levy

Physiology_Levy. Fig. 16.44A ) are similar to the schematized version (see Fig. 16.43 ). The slope of the end-systolic P-V relation (line extending from the dot in Fig. 16.44A ) defines contractility; a steeper slope indicates increased contractility. In this subject, partial occlusion of the inferior vena cava reduced the preload of the left ventricle on successive beats (as the inflow of blood to the left ventricle was reduced, as a consequence of the reduced return of blood to the right ventricle) and the effect was successively smaller stroke volume of the left ventricle. This illustrates, in humans, the operation of the Frank-Starling law of the heart ( Chapter 13), whereby changes in preload (left ventricular volume) change myocardial fiber length, and thus the strength of the subsequent contraction, as well as stroke volume produced. This important phenomenon is characterized by the cardiac function curve (see Fig. 16.44B).


Physiology_Levy

Physiology_Levy. As preload increases, stroke volume increases (solid blue line). If contractility of the heart is increased, as in the action of norepinephrine, the slope of the end-systolic P-V relation becomes steeper, and the entire cardiac function curve shifts upward (solid red line), which reflects the fact that the ventricle is now able to produce a larger stroke volume at a given preload. The increased stroke volume at any given preload is largely produced by a decreased end-systolic volume: Hearts with increased contractility are able to “squeeze down” to a greater extent. Conversely, if the ventricle is damaged, as after cardiac ischemia, or if its contractility is otherwise reduced from normal (as after calcium channel blockade), the cardiac function curve is shifted downward (green line), which reflects a reduced stroke volume at any given preload. The cardiac function curve is also known as ventricular function curves or Starling curves. To assess the integrated functioning of the


Physiology_Levy

Physiology_Levy. which reflects a reduced stroke volume at any given preload. The cardiac function curve is also known as ventricular function curves or Starling curves. To assess the integrated functioning of the cardiovascular system ( ), cardiac output, rather than stroke volume, is usually measured; preload of the heart is considered to be the filling pressure of the right ventricle, typically measured as mean right atrial pressure (Pra), or central venous pressure.


Physiology_Levy

Physiology_Levy. Measurement of Cardiac Output The Fick Principle In 1870 the German physiologist Adolph Fick contrived the first method for measuring cardiac output in intact animals and people. The basis for this method, called the Fick principle, is simply an application of the law of conservation of mass. The principle is derived from the fact that the quantity of O2 delivered to the pulmonary capillaries via Terminal bronchiole To pulmonary veins From pulmonary artery Pulmonary artery q1 q2 O2 consumption 250 mL O2 /min [O2 ] pv 0.20 mL O2 /mL blood [O2 ] pa 0.15 mL O2 /mL blood q1 + q2 = q3 Alveolus q3 Pulmonary vein Alveoli •Fig. 16.45 Schema Illustrating the Fick Principle for Measuring Cardiac Output. Thechangeincolorfrompulmonaryarterytopulmonaryveinrepresentsthechangeincolorofthebloodasvenousbloodbecomesfullyoxygenated.


Physiology_Levy

Physiology_Levy. the pulmonary artery, plus the quantity of O2 that enters the pulmonary capillaries from the alveoli, must equal the quantity of O2 that is carried away by the pulmonary veins. The Fick principle is depicted schematically in Fig. 16.45. The rate of O2 delivery to the lungs (q1) equals the O2 concentration in pulmonary arterial blood ([O2]pa), multiplied by pulmonary arterial blood flow (Q), which equals cardiac output; that is, Equation 16.1 If q2 is the net rate of O2 uptake by the pulmonary capillaries from the alveoli, then at steady state, q2 equals the O2 consumption of the body. The rate at which O2 is carried away by the pulmonary veins (q3) equals the O2 concentration in pulmonary venous blood ([O2]pv), multiplied by total pulmonary venous flow, which is virtually equal to pulmonary arterial blood flow (Q); that is, Equation 16.2 From the law of conservation of mass, Equation 16.3 Therefore, Equation 16.4 When this is solved for cardiac output, Equation 16.5


Physiology_Levy

Physiology_Levy. Equation 16.2 From the law of conservation of mass, Equation 16.3 Therefore, Equation 16.4 When this is solved for cardiac output, Equation 16.5 Eq. 16.5 is the statement of the Fick principle.


Physiology_Levy

Physiology_Levy. To determine cardiac output by this method, three values must be known: (1) O2 consumption of the body, (2) the O2 concentration in pulmonary venous blood ([O2]pv), and (3) the O2 concentration in pulmonary arterial blood ([O2]pa). O2 consumption is computed from measurements of the volume and O2 content of expired air over a given interval. Because the O2 concentration of peripheral arterial blood is essentially identical to that in the pulmonary veins, [O2]pv is determined with a sample of peripheral arterial blood withdrawn by needle puncture. The compositions of pulmonary arterial blood and mixed systemic venous blood are virtually identical to one another. Samples for O2 analysis are obtained from the pulmonary artery or right ventricle through a catheter. A very flexible catheter with a small balloon near the tip can be inserted into a peripheral vein. As the flexible tube is advanced, the flowing blood carries it toward the heart. By monitoring the pressure changes, the


Physiology_Levy

Physiology_Levy. with a small balloon near the tip can be inserted into a peripheral vein. As the flexible tube is advanced, the flowing blood carries it toward the heart. By monitoring the pressure changes, the physician can advance the catheter tip into the pulmonary artery.


Physiology_Levy

Physiology_Levy. With the values depicted in Fig. 16.45 , cardiac output can be calculated as follows: If the O2 consumption is 250 mL/minute, the arterial (pulmonary venous) O2 content is 0.20 mL of O2 per milliliter of blood, and the mixed venous (pulmonary arterial) O2 content is 0.15 mL of O2 per milliliter of blood, cardiac output equals 250/ (0.20 − 0.15) = 5000 mL/minute. The Fick principle is also used to estimate the O2 consumption of organs when blood flow and the O2 content of arterial and venous blood can be determined. Algebraic rearrangement reveals that O2 consumption equals blood flow multiplied by the difference in the arteriovenous O2 concentration. For example, if blood flow through one kidney is 700 mL/minute, the arterial O2 content is 0.20 mL of O2 per milliliter of blood, and the renal venous O2 content is 0.18 mL of O2 per milliliter of blood, the rate of O2 consumption by that kidney must be 700 (0.20 − 0.18) = 14 mL of O2 per minute.


Physiology_Levy

Physiology_Levy. In the clinic, cardiac output is most commonly measured noninvasively with Doppler echocardiography. By this method, the velocity of blood in the ascending aorta is measured. Obtaining the cross-sectional area of the aorta (also measured by echocardiography) allows the volume of blood ejected in a single beat (i.e., stroke volume) to be determined (see Eq. 17.1 ). Multiplying stroke volume by the heart rate then yields a value for cardiac output in liters per minute.


Physiology_Levy

Physiology_Levy. Eq. 17.1 ). Multiplying stroke volume by the heart rate then yields a value for cardiac output in liters per minute. Consumption of O2 by the heart depends on the amount and type of activity that the heart performs. Under basal conditions, myocardial O2 consumption (V˜O2) is approximately 8 to 10 mL/minute/100 g of heart. It can increase severalfold during exercise and decrease moderately in such conditions as hypotension and hypothermia. The O2 content of cardiac venous blood is normally low (≈5 mL/ dL), and the myocardium can receive little additional O2 by further extraction of O2 from coronary blood. Therefore, increased O2 demands of the heart must be met mainly by an increase in coronary blood flow (see ). In experiments in which the heartbeat is arrested but coronary perfusion is maintained, O2 consumption falls to 2 mL/ minute/100 g or less, which is still six to seven times greater than the O2 consumption of resting skeletal muscle.


Physiology_Levy

Physiology_Levy. Cardiac work has external and internal components. Left ventricular work per beat (stroke work) is approximately equal to the product of stroke volume and the mean aortic pressure against which the blood is ejected by the left ventricle. External cardiac work (We) may be defined as follows: Equation 16.6 That is, each small increment in volume that is pumped, (dV) is multiplied by the associated pressure (P), and the products (PdV) are integrated over the time interval of interest (t2 − t1) to calculate total work. Added to this is kinetic work due to the velocity (v) of blood flow and the density (ρ) of blood. The mean pressure during expulsion is used to simplify this to Equation 16.7 At resting levels of cardiac output, the kinetic energy component is negligible. However, with high cardiac output, as in strenuous exercise, the kinetic energy component can account for up to 50% of total cardiac work. The internal work (Wi) of the heart can be written as


Physiology_Levy

Physiology_Levy. The internal work (Wi) of the heart can be written as Equation 16.8 where α is a proportionality constant that converts T dt into units of work, T is wall tension, and dt is time. Clinically, V˜O2 and left ventricular power are difficult to measure; however, both are closely related to the systolic pressure–time index, the integral of left ventricular pressure, and time during systole. Such measurements are important because internal work is a large determinant of myocardial O2 need. An alternative approach to evaluate cardiac work and its relation to O2 consumption has been developed in which P-V loops (see Fig. 16.44 ) are examined in conditions with varied preload and afterload; contractility is maintained constant.


Physiology_Levy

Physiology_Levy. Fig. 16.44 ) are examined in conditions with varied preload and afterload; contractility is maintained constant. Simultaneously halving aortic pressure and doubling cardiac output, or vice versa, result in the same value for cardiac work. However, the O2 requirements are greater for any given amount of cardiac work when a major proportion of the work is pressure work, as opposed to volume work. An increase in cardiac output at a constant aortic pressure (volume work) is accomplished with only a small increase in left ventricular O2 consumption, whereas increased


Physiology_Levy

Physiology_Levy. CHAPTER 16 Elements of Cardiac Function arterial pressure at constant cardiac output (pressure work) is accompanied by a large increase in myocardial O2 consumption. Thus myocardial O2 consumption may not be well correlated with overall cardiac work. The magnitude and duration of left ventricular pressure are correlated with left ventricular O2 consumption. The work of the right ventricle is one-seventh that of the left ventricle because pulmonary vascular resistance is much less than systemic vascular resistance.


Physiology_Levy

Physiology_Levy. The efficiency of the heart may be calculated as the ratio of the work accomplished to the total energy used. If the average O2 consumption is assumed to be 9 mL/minute/100 g for the two ventricles, a 300-g heart will consume 27 mL of O2 per minute. This value is equivalent to 130 small calories when the respiratory quotient is 0.82. Together, the two ventricles do approximately 8 kg-m of work per minute, which is equivalent to 18.7 small calories. Therefore, the gross efficiency of the heart is approximately 14%: Equation 16.9 Thegreaterenergydemandofpressureworkthanofvolumeworkisclinicallyimportant,especiallyinaorticstenosis.Inthiscondition,leftventricularO2consumptionisincreased,mainlybecauseofthehighintraventricularpressuredevelopedduringsystole.However,coronaryperfusionpressure(andhenceO2supply)iseithernormalorreducedbecauseofthepressuredropacrossthenarroworificeofthediseasedaorticvalve.


Physiology_Levy

Physiology_Levy. The actual gross mechanical efficiency of the heart is slightly higher (18%) than the value calculated and is determined through subtracting the O2 consumption of the nonbeating (asystolic) heart (≈2 mL/minute/100 g) from the total cardiac O2 consumption in the calculation of efficiency. The efficiency of the heart as a pump is relatively low. During physical exercise, efficiency improves because mean blood pressure does not change appreciably, whereas cardiac output and work increase considerably, without a proportional increase in myocardial O2 consumption. Of interest is that the chemical efficiency of the heart is rather high, as indicated by the estimate of 60% for the efficiency of generating ATP from oxidative phosphorylation. The energy expended in cardiac metabolism that does not contribute to the propulsion of blood through the body appears in the form of heat. The energy of flowing blood is also dissipated as heat.


Physiology_Levy

Physiology_Levy. Myocardial Adenosine Triphosphate and Its Relation to Mechanical Function The chemical energy that fuels cardiac contractile work and relaxation is derived from ATP hydrolysis (


Physiology_Levy

Physiology_Levy. The chemical energy that fuels cardiac contractile work and relaxation is derived from ATP hydrolysis ( Fig. 16.46 •Fig. 16.46 Overall Scheme for Production and Utilization of Adenosine Triphosphate (ATP) Within a Cardiac Myocyte. Pathwaysforutilizationofglucose,fattyacids(FA),andlactateareindicated,asaretherequirementsforO2andH+bytheelectrontransportchaininmitochondria.ADP,adenosinediphosphate;CoA,coenzymeA;CPT-I,carnitinepalmitoyltransferase;G-6-P,glucose-6-phosphate;GLUT,glucosetransporter;NADH,nicotinamideadenosinedehydrogenase;PDH,pyruvatedehydrogenase;Pi,inorganicphosphate;SR,sarcoplasmicreticulum;TG,triglyceride.ATPase FACPT-I Cardiomyocyte Citric Acid CycleCO2 Acetyl-CoA Acetyl-CoA NADH NADH Lactate GLUT Glycogen Cytosol Contractile work, SR Ca++ uptake, lon homeostasis G-6-P PDH Pyruvate Electron Transport Chain TGATP ATP ATP ADP + Pi ADP + Pi ADP + Pi H+ O2 Mitochondrion — GLYCOLYSIS Fatty Acid ˛-Oxidation


Physiology_Levy

Physiology_Levy. The healthy heart has a relatively constant level of ATP (≈5µmol/g wet weight) despite an extremely high rate of ATP hydrolysis (≈0.3µmol/g−1/second−1). The tissue content of ATP is low in relation to the rate of breakdown and production; complete turnover of the myocardial ATP content occurs approximately every 12 seconds in the heart at rest. ATP hydrolysis (see


Physiology_Levy

Physiology_Levy. Fig. 16.46) provides energy for contractile work (actin-myosin interaction and cell shortening), pumping Ca++ back into the sarcoplasmic reticulum at the end of systole and maintaining normal ion gradients (low Na+ and high K+ in the cell). Approximately two thirds of the ATP hydrolyzed by the heart is used to fuel contractile work, and the remaining third is used for ion pumps and “housekeeping” functions such as synthesis of proteins and nucleic acids. The Ca++-ATPase of the sarcoplasmic reticulum is the primary ion pump consuming ATP. This process occurs during the end of systole, when cytosolic Ca++ is rapidly sequestered into the sarcoplasmic reticulum to initiate diastolic relaxation. In the healthy heart, the rate of ATP hydrolysis is exquisitely matched to the rate of ATP resynthesis. There is no significant change in the concentration of ATP or ADP even with the onset of heavy exercise.


Physiology_Levy

Physiology_Levy. ATP resynthesis occurs primarily through oxidative phosphorylation in mitochondria (>98%) and, to a small degree, through glycolysis (<2%). Oxidative phosphorylation requires O2 and H2. The O2 is delivered to the myocardium and consumed in the mitochondria to make H2O, and the H2 is from the metabolism of carbon fuels (mainly fatty acids, glucose, and lactate) and the generation of the reduced form of nicotinamide adenine dinucleotide (NADH). Pyruvate dehydrogenase (PDH) regulates the oxidation of glucose and lactate. The activity of PDH is inhibited by product inhibition from acetyl–coenzyme A and NADH. Also, PDH activity is inhibited when phosphorylated by PDH kinase and activated when dephosphorylated by PDH phosphatase. ATP is formed from ADP and inorganic phosphate with the use of H+ . Of importance is that the rates of ATP formation and breakdown depend on an adequate delivery of O2 to the myocardium, which is a function of myocardial blood flow and oxygenation of arterial


Physiology_Levy

Physiology_Levy. of H+ . Of importance is that the rates of ATP formation and breakdown depend on an adequate delivery of O2 to the myocardium, which is a function of myocardial blood flow and oxygenation of arterial blood. An increase in ATP breakdown in the myocardium, such as occurs when heart rate, systolic blood pressure, and contractility are increased (as during exercise), necessitates an increase in O2 delivery to the myocardium so that the mitochondria can generate sufficient ATP by oxidative phosphorylation to meet the demand for ATP. Thus the rate of myocardial O2 consumption is tightly linked to the work rate (or power) of the myocardium.


Physiology_Levy

Physiology_Levy. The heart is versatile in its use of substrates, and within certain limits, uptake of a particular substrate is directly proportional to its arterial concentration. The use of one substrate by the heart is also influenced by the presence or absence of other substrates. For example, the addition of lactate to the blood that perfuses a heart metabolizing glucose leads to a reduction in glucose uptake and vice versa. At normal blood concentrations, glucose and lactate are consumed at approximately equal rates.


Physiology_Levy

Physiology_Levy. In contrast, uptake of pyruvate is very low, as is its arterial concentration. For glucose, the threshold concentration is approximately 4 mmol/L. Below this blood level, no glucose is taken up by the myocardium. Insulin reduces the glucose threshold and increases the rate of glucose uptake by the heart. Cardiac utilization of lactate occurs in most circumstances; insulin does not affect its uptake by the myocardium. Under hypoxic conditions, glucose utilization is facilitated by an increase in the rate of transport across the myocardial cell wall. However, lactate cannot be metabolized by the hypoxic heart and is produced by the heart under anaerobic conditions. Associated with lactate production by the hypoxic heart is the breakdown of cardiac glycogen.


Physiology_Levy

Physiology_Levy. Of the total cardiac O2 consumption, only 35% to 40% can be accounted for by the oxidation of carbohydrate. Thus the heart derives the major part of its energy from the oxidation of noncarbohydrate sources: namely, esterified and nonesterified fatty acids, which account for approximately 60% of the myocardial O2 consumption in people in the postabsorptive state. Various fatty acids have different thresholds for myocardial uptake, but these


Physiology_Levy

Physiology_Levy. CHAPTER 16 Elements of Cardiac Function acids are generally used in direct proportion to their arterial concentration. Ketone bodies, especially acetoacetate, are readily oxidized by the heart, and they are a major source of energy in diabetic acidosis. As is true of carbohydrate substrates, use of a specific noncarbohydrate is influenced by the presence of other substrates, whether noncarbohydrate or carbohydrate. Therefore, within certain limits, the heart preferentially uses the substrate that is available in the largest concentration. The oxidation of amino acids makes a small contribution to myocardial energy expenditure. Normally, the heart derives its energy by oxidative phosphorylation, in which each mole of glucose yields 36 mol of ATP. However, during hypoxia, glycolysis takes over, and 2 mol of ATP is provided by each mole of glucose; β-oxidation of fatty acids is also curtailed. If hypoxia is prolonged, cellular creatine phosphate and eventually ATP are depleted.


Physiology_Levy

Physiology_Levy. In ischemia, lactic acid accumulates and decreases intracellular pH. This condition inhibits glycolysis, fatty acid use, and protein synthesis, and therefore it results in cellular damage and eventually necrosis of myocardial cells.


Physiology_Levy

Physiology_Levy. 1. The transmembrane action potentials recorded from cardiac myocytes may contain the following five phases: Phase 0: The action potential upstroke is initiated when a suprathreshold stimulus rapidly depolarizes the membrane by activating the fast sodium channels. Phase 1: The notch is an early partial repolarization that is achieved by the efflux of K+ through channels that conduct the transient outward current (ito). Phase 2: The plateau represents a balance between the influx of Ca++ through calcium channels and the efflux of K+ through several types of potassium channels. Phase 3: Final repolarization is initiated when the efflux of K+ exceeds the influx of Ca++ . The resultant partial repolarization rapidly increases K+ conductance and restores full repolarization. Phase 4: The resting potential of the fully repolarized cell is determined by conductance of the cell membrane to K+ , mainly through iK1 channels.


Physiology_Levy

Physiology_Levy. Phase 4: The resting potential of the fully repolarized cell is determined by conductance of the cell membrane to K+ , mainly through iK1 channels. 2. Fast-response action potentials are recorded from atrial and ventricular myocardial fibers and from ventricular specialized conducting (Purkinje) fibers. Such an action potential is characterized by a large amplitude, a steep upstroke, and a relatively long plateau. The effective refractory period of fast-response fibers begins at the upstroke of the action potential and persists until midway through phase 3. The fiber is relatively refractory during the remainder of phase 3, and it regains full excitability soon after it is fully repolarized (phase 4). 3.


Physiology_Levy

Physiology_Levy. 3. Slow-response action potentials are recorded from normal SA and AV nodal cells and from abnormal myocardial cells that have been partially depolarized. The action potential is characterized by a less negative resting potential, a smaller amplitude, a less steep upstroke, and a shorter plateau than is typical of the fast-response action potential. The upstroke in slow-response fibers is produced by the activation of calcium channels. Slow-response fibers become absolutely refractory at the beginning of the upstroke, and partial excitability may not be regained until very late in phase 3 or until after the fiber is fully repolarized. 4.


Physiology_Levy

Physiology_Levy. 4. Normally, the SA node serves as the cardiac pacemaker to initiate the cardiac impulse. This impulse is propagated from the SA node to the atria and ultimately reaches the AV node. After a delay in the AV node, the cardiac impulse is propagated throughout the ventricles. Ectopic foci in the atrium, the AV node, or the His-Purkinje system may initiate propagated cardiac impulses if the normal pacemaker cells in the SA node are suppressed or if the rhythmicity of the ectopic automatic cells is abnormally enhanced. 5.


Physiology_Levy

Physiology_Levy. 5. Under certain abnormal conditions, afterdepolarizations may be triggered by an otherwise normal action potential. EADs arise early in phase 3 of a normal action potential. They are more likely to occur when the basic cycle length of the initiating beats is very long and when the cardiac action potentials are abnormally prolonged. DADs appear late in phase 3 or in phase 4. They are more likely to occur when the basic cycle length of the initiating beats is short and when the cardiac cells are overloaded with Ca++ . 6. Reentrant arrhythmias occur when a cardiac impulse traverses a loop of cardiac fibers and reenters previously excited tissue, when the impulse is conducted slowly around the loop, and when the impulse is blocked unidirectionally in some section of the loop. 7.


Physiology_Levy

Physiology_Levy. 7. The ECG, which is recorded from the surface of the body, traces the conduction of the cardiac impulse throughout the heart. The ECG may be used to detect and analyze certain cardiac arrhythmias, such as altered SA rhythms, AV conduction blocks, premature depolarizations, ectopic tachycardias, and atrial and ventricular fibrillation. 8. On excitation, voltage-gated calcium channels open to admit extracellular Ca++ into the cardiac myocytes. The influx of Ca++ triggers the release of Ca++ from the sarcoplasmic reticulum. The elevated intracellular [Ca++] elicits contraction of the myofilaments. Relaxation is accomplished through the restoration of resting cytosolic [Ca++] by the pumping of Ca++ back into the sarcoplasmic reticulum and the exchange of Ca++ for extracellular Na+ across the sarcolemma. Velocity and force of contraction are functions of intracellular [Ca++]. Force and velocity are inversely related, and so with no load, velocity is maximal. In


Physiology_Levy

Physiology_Levy. Abriel H, Rougier J-S, Jalife J. Ion channel macromolecular complexes in cardiomyocites: Roles in sudden cardiac death. Circ Res. 2015;116:1971. Bers DM, Guo T. Calcium signaling in cardiac ventricular myocytes. Ann N Y Acad Sci. 2005;1047:86. Cannell MB, Kong CH. Local control in cardiac E-C coupling. J Mol Cell Cardiol. 2012;52:298. an isovolumic contraction, no external shortening occurs. 9. In ventricular contraction, preload is stretch of the fibers by blood during ventricular filling. Afterload is the arterial pressure against which the ventricle ejects the blood. An increase in myocardial fiber length, as occurs with augmented ventricular filling (preload) during diastole, produces a more forceful ventricular contraction. This relationship between fiber length and strength of contraction is known as the Frank-Starling law of the heart. 10.


Physiology_Levy

Physiology_Levy. 10. Contractility is an expression of cardiac performance at a given preload and afterload. Contractility can be modulated by the autonomic nervous system. 11. To determine cardiac output, according to the Fick principle, the O2 consumption of the body (q2) and the oxygen content of arterial blood ([O2]a) and mixed venous blood ([O2]v) are measured. Cardiac output = q2/([O2]a − [O2]v). It can also be measured noninvasively by Doppler echocardiography. 12. In the normal heart, the rate of ATP hydrolysis is matched by the rate of ATP synthesis. ATP is generated by oxidative phosphorylation of fatty acids and glucose, a process that requires O2. When the rate of ATP hydrolysis increases, as during exercise, the consumption of O2 for oxidative phosphorylation also increases. The rate of O2 utilization is thereby coupled to the rate of cardiac work. The myocardium functions only aerobically, and in general it uses substrates in proportion to their arterial concentration.


Physiology_Levy

Physiology_Levy. Gima K, Rudy Y. Ionic current basis of electrocardiographic waveforms. Circ Res. 2003;90:889. Priori SG. The fifteen years of discoveries that shaped molecular electrophysiology: time for appraisal. Circ Res. 2010;107: 451. Upon completion of this chapter, the student should be able to answer the following questions: 1. What physical properties of blood vessels and blood determine hemodynamics, and how are they defined by Poiseuille’s law? 2. How is arterial compliance related to stroke volume and pulse pressure? How does arterial compliance affect the arterial pulse wave and cardiac work? 3. What are mean, systolic, diastolic, and pulse pressures, and how are they measured? 4. What vessels constitute the microcirculation? How is pulsatile blood flow in large arteries converted into steady flow in the microcirculation? 5. What are the hydrostatic and osmotic factors that underlie Starling’s hypothesis for capillary function? 6.


Physiology_Levy

Physiology_Levy. 5. What are the hydrostatic and osmotic factors that underlie Starling’s hypothesis for capillary function? 6. How do intrinsic and extrinsic factors modulate peripheral circulation, and how do these factors affect blood flow in particular organs? 7. How does the myogenic hypothesis account for autoregulation of blood flow? What is the effect of tissue metabolism on autoregulation?


Physiology_Levy

Physiology_Levy. 7. How does the myogenic hypothesis account for autoregulation of blood flow? What is the effect of tissue metabolism on autoregulation? he vasculature consists of a closed system of tubes or vessels that distributes blood from the heart to the tissues and returns blood from the tissues to the heart. It can be divided into three components: the arterial system, which takes blood from the heart and distributes it to the tissues; the venous system, which returns blood from the tissues to the heart; and the microcirculation, which separates the arterial and venous systems and is the site where nutrients and cellular waste products are exchanged between blood and tissues. These components of the vasculature are described in this chapter. In addition, the properties of blood flow to specific vascular beds and tissues are considered. As an introduction to this material, the physics of blood/fluid flow through the vasculature (i.e., hemodynamics) is reviewed.


Physiology_Levy

Physiology_Levy. The physics of fluid flow through rigid tubes provides a basis for understanding the flow of blood through blood vessels, even though the blood vessels are not rigid tubules (i.e., they are distensible) and blood is not a simple homogeneous fluid. Knowledge of these physical principles underlies understanding of the interrelationships among velocity of blood flow, blood pressure, and the dimensions of the various components of the systemic circulation. Velocity of the Bloodstream Velocity, as relates to fluid movement, is the distance that a particle of fluid travels with regard to time, and it is expressed in units of distance per unit time (e.g., centimeters per second). Flow, in contrast, is the rate of displacement of a volume of fluid, and it is expressed in units of volume per unit time (e.g., cubic centimeters per second). In a rigid tube, velocity (v) and flow (Q) are related to one another by the cross-sectional area (A) of the tube: Equation 17.1


Physiology_Levy

Physiology_Levy. Equation 17.1 The interrelationships among velocity, flow, and area are shown in Fig. 17.1 . Because conservation of mass requires that the fluid flowing through a rigid tube be constant, the velocity of the fluid varies inversely with the cross-sectional area. Thus fluid flow velocity is greatest in the section of the tube with the smallest cross-sectional area and slowest in the section of the tube with the greatest cross-sectional area. Fig. 15.3 , velocity decreases progressively as blood traverses the arterial system. In the capillaries, velocity decreases to a minimal value. As the blood then passes centrally through the venous system toward the heart, velocity progressively increases again. The relative velocities in the various components of the circulatory system are related only to the respective cross-sectional areas.


Physiology_Levy

Physiology_Levy. The total energy in a hydraulic system consists of three components: pressure, gravity, and velocity. The velocity of blood flow can have an important effect on the pressure within the tube. Consider the effect of velocity on pressure in a tube with different cross-sectional areas ( Fig. 17.2 ). In this system, the total energy remains constant. The total pressure within the tube equals the lateral (static) pressure plus the dynamic pressure. The gravitational component can be neglected because the tube is horizontal. The total pressures in segments A, B, and C are equal, provided that •Fig. 17.1 Asfluidflowsthroughatubeofvariablecross-sectionalarea(A),thelinearvelocity(v)variesinverselywiththecross-sectionalarea.Q,flow.


Physiology_Levy

Physiology_Levy. ˜v2/2 = 3.8 mm Hg 15 mm Hg 3.8 mm Hg •Fig. 17.2 Inanarrowsection(B)ofatube,thelinearvelocity(v)andhencethedynamiccomponentofpressure(ρv2/2)aregreaterthaninthewidesections(AandC),ofthesametube.Ifthetotalenergyisvirtuallyconstantthroughoutthetube(i.e.,iftheenergylossbecauseofviscosityisnegligible),thelateralpressureinthenarrowsectionislowerthanthelateralpressureinthewidesectionsofthetube(seetheheightsofthecolumnoffluidabovecompartmentsA,B,andCeach,whichreflectpressure). the energy loss from viscosity is negligible (i.e., this fluid is an “ideal fluid”). The effect of velocity on the dynamic component (Pdyn) can be estimated as follows: Equation 17.2 where ρ is the density of the fluid (grams per cubic centimeters) and v is velocity (centimeters per second). Assume that the fluid has a density of 1 g/cm3. In section A in Fig. 17.2 , the lateral pressure is 100 mm Hg; note that 1 mm Hg equals 1330 dynes/cm2. According to


Physiology_Levy

Physiology_Levy. Eq. 17.2, P dyn = 5000 dynes/cm2, or 3.8 mm Hg. In the narrow section B of the tube, where the velocity is twice as high, Pdyn = 20,000 dynes/ cm2, or 15 mm Hg. Thus the lateral pressure in section B is 15 mm Hg lower than the total pressure, whereas the lateral pressures in sections A and C are only 3.8 mm Hg lower. In most arterial locations, the dynamic component is a negligible fraction of the total pressure. However, at sites of an arterial constriction or obstruction, the high flow velocity is associated with large kinetic energy, and the dynamic pressure component may therefore increase significantly. Hence, the pressure would be reduced, and perfusion of distal segments would be correspondingly decreased. This example helps explain how pressure changes in a vessel that is narrowed by atherosclerosis or spasm of the blood vessel •Fig. 17.3 Laminar and Turbulent Flow. A,


Physiology_Levy

Physiology_Levy. be correspondingly decreased. This example helps explain how pressure changes in a vessel that is narrowed by atherosclerosis or spasm of the blood vessel •Fig. 17.3 Laminar and Turbulent Flow. A, Whenflowislaminar,allelementsofthefluidmoveinstreamlinesthatareparalleltotheaxisofthetube;thefluiddoesnotmoveinaradialorcircumferentialdirection.Thelayeroffluidincontactwiththewallismotionless;thefluidthatmovesalongthecentralaxisofthetubehasthemaximalvelocity.B, Inturbulentflow,theelementsofthefluidmoveirregularlyinaxial,radial,andcircumferentialdirections.Vorticesfrequentlydevelop.


Physiology_Levy

Physiology_Levy. wall: that is, in narrowed sections of a tube, the dynamic component increases significantly because the flow velocity is associated with large kinetic energy. The most fundamental law that governs the flow of fluids through cylindrical tubes was derived empirically by the French physiologist Jean Léonard Marie Poiseuille in the 1840s. He was interested primarily in the physical determinants of blood flow, but he replaced blood with simpler liquids in his measurements of flow through glass capillary tubes. His work was so precise and important that his observations have been designated Poiseuille’s law. Poiseuille’s law applies to the steady (i.e., nonpulsatile) laminar flow of newtonian fluids through rigid cylindrical tubes. A newtonian fluid is one whose viscosity remains constant, and laminar flow is the type of motion in which the fluid moves as a series of individual layers, with each layer moving at a velocity different from that of its neighboring layers (


Physiology_Levy

Physiology_Levy. Fig. 17.3A ). In the case of laminar flow through a tube, the fluid consists of a series of infinitesimally thin concentric tubes sliding past one another, of which the central tube has the highest velocity. The velocities of the concentric laminae decrease parabolically towards the vessel wall. Despite the differences between the vascular system (i.e., flow is pulsatile, the vessels are not rigid cylinders, and blood is not a newtonian fluid), Poiseuille’s law does provide valuable insight into the determinants of blood flow through the vascular system. In certain unusual situations, however, flow can become turbulent (see Fig. 17.3B ), rather than laminar. Under these conditions, vortices (swirls) are present, and the distribution of flow velocities is chaotic. This condition is described in more detail later in this chapter.


Physiology_Levy

Physiology_Levy. Poiseuille’s law describes the laminar flow of fluids through cylindrical tubes in terms of pressure, the dimensions of the tube, and the viscosity of liquid: Equation 17.3 Pi − Po = pressure gradient from the inlet (i) of the tube to the outlet (o) r = radius of the tube η= viscosity of the fluid l = length of the tube As is clear from the equation, flow through the tube increases as the pressure gradient is increased, and it decreases as either the viscosity of the fluid or the length of the tube increases. The radius of the tube is a critical factor in determining flow because it is raised to the fourth power. Resistance to Flow In electrical theory, Ohm’s law is that the resistance (R) equals the ratio of voltage drop (E) to current flow (I). Equation 17.4 Similarly, in fluid mechanics, hydraulic resistance (R) may be defined as the ratio of the pressure drop (Pi − Po,) to flow (Q): Equation 17.5


Physiology_Levy

Physiology_Levy. Equation 17.4 Similarly, in fluid mechanics, hydraulic resistance (R) may be defined as the ratio of the pressure drop (Pi − Po,) to flow (Q): Equation 17.5 For the steady, laminar flow of a newtonian fluid through a cylindrical tube, the physical components of hydraulic resistance may be appreciated by the rearranging of Poiseuille’s law to yield the hydraulic resistance equation: Equation 17.6 Thus when Poiseuille’s law applies, the resistance to flow depends on only the dimensions of the tube and the characteristics of the fluid. The principal determinant of resistance to blood flow through any vessel is the caliber of the vessel because resistance varies inversely as the fourth power of the radius of the tube. In


Physiology_Levy

Physiology_Levy. Fig. 17.4 , the resistance to flow through small blood vessels is measured, and the resistance per unit length of vessel (R/l) is plotted against the vessel diameter. As shown, resistance is highest in the capillaries (diameter of 7 µm), and it diminishes as the vessels increase in diameter 1000 100 10 1 0.1 0.01 58 5850 5042 4234 3426 2618 187 Vessel diameter (µm) R/l(mm Hg/[mm3/sec])/µm Capillaries Arterial side Venous side •Fig. 17.4 Resistance Per Unit Length (R/l) of Individual Small Blood Vessels. Thecapillaries,withadiameterof7µm,aredenotedbythevertical dashed line. Resistancesofarteriolesareplottedtotheleftoftheverticaldashedline,andresistancesofvenules,totherightoftheverticaldashedline.Forbothtypesofvessels,theresistanceperunitlengthisinverselyproportionaltothefourthpowerofthevesseldiameter.(RedrawnfromLipowskyHH,etal.Circ Res. 1978;43:738.) on the arterial and venous sides of the capillaries. Values of R/l are virtually inversely proportional to the fourth power of the


Physiology_Levy

Physiology_Levy. Res. 1978;43:738.) on the arterial and venous sides of the capillaries. Values of R/l are virtually inversely proportional to the fourth power of the diameter (or radius) of the larger vessels on both sides of the capillaries.


Physiology_Levy

Physiology_Levy. Changes in vascular resistance occur when the caliber of vessels changes. The most important factor that leads to a change in vessel caliber is contraction of the circular smooth muscle cells in the vessel wall. Changes in internal pressure also alter the caliber of blood vessels and therefore alter the resistance to blood flow through these vessels. Blood vessels are elastic tubes. Hence, the greater the transmural pressure (i.e., the difference between internal and external pressure) across the wall of a vessel, the greater the caliber of the vessel and the less its hydraulic resistance. It is apparent from Fig. 15.3 that the greatest drop in pressure occurs in the very small arteries and arterioles. However, capillaries, which have a mean diameter of approximately 7 µm, have the greatest resistance to blood flow. Nevertheless, of all the different varieties of blood vessels that lie in series with one another (as in


Physiology_Levy

Physiology_Levy. Fig. 15.3 ), the arterioles, not the capillaries, have the greatest resistance. This seeming paradox is related to the relative numbers of parallel capillaries and parallel arterioles: There are far more capillaries than arterioles in the systemic circulation, and total resistance across the many capillaries arranged in parallel is much less than total resistance across the fewer arterioles arranged in parallel. In addition, arterioles have a thick coat of circularly arranged smooth muscle fibers that can vary the lumen radius. Even small changes in radius alter resistance greatly, as can be seen from the hydraulic •Fig. 17.5 Forresistances(R1,R2,andR3)arrangedinseries,totalresistance(Rt)equalsthesumoftheindividualresistances.P,pressure;Q,flow. Eq. 17.6 ), wherein R varies inversely with r4. In the cardiovascular system, the various types of vessels listed along the horizontal axis in


Physiology_Levy

Physiology_Levy. Eq. 17.6 ), wherein R varies inversely with r4. In the cardiovascular system, the various types of vessels listed along the horizontal axis in Fig. 15.3 lie in series with one another. The individual members of each category of vessels are ordinarily arranged in parallel with one another (see Fig. 15.1 ). Thus capillaries are in most instances parallel elements throughout the body, except in the renal vasculature (in which the peritubular capillaries are in series with the glomerular capillaries) and the splanchnic vasculature (in which the intestinal and hepatic capillaries are aligned in series with each other). The total hydraulic resistance of components arranged in series or in parallel can be derived in the same manner as those for analogous combinations of electrical resistance. Resistance of Vessels in Series In the system depicted in


Physiology_Levy

Physiology_Levy. Resistance of Vessels in Series In the system depicted in Fig. 17.5 , three hydraulic resistances, R1, R2, and R3, are arranged in series. The pressure drop across the entire system (i.e., the difference between inflow pressure [Pi] and outflow pressure [Po]) consists of the sum of the pressure drops across each of the individual resistances (equation a in Fig. 17.5 ). In the steady state, the flow (Q) through any given cross-section must equal the flow through any other cross-section. When each component in equation (a) is divided by Q (equation [b] in Fig. 17.5 ), it is evident from the definition of resistance ( Eq. 17.5 ) that for resistances in series, the total resistance (Rt) of the entire system equals the sum of the individual resistances; that is, Equation 17.7 Resistance of Vessels in Parallel For resistances in parallel, as illustrated in


Physiology_Levy

Physiology_Levy. Equation 17.7 Resistance of Vessels in Parallel For resistances in parallel, as illustrated in Fig. 17.6 , inflow and outflow pressure is the same for all tubes. In steady state, the total flow (Qt) through the system equals the sum of the flows through the individual parallel elements (equation [a] in Fig. 17.5). Because the pressure gradient (Pi − Po) is identical for all parallel elements, each term •Fig. 17.6 Forresistances(R1,R2,andR3)arrangedinparallel,thereciprocalofthetotalresistance(Rt)equalsthesumofthereciprocalsoftheindividualresistances.P,pressure;Q,flow. in equation (a) may be divided by that pressure gradient to yield equation (b). From the definition of resistance, equation (c) in Fig. 17.5 may be derived. According to this equation, for resistances in parallel, the reciprocal of the total resistance (Rt) equals the sum of the reciprocals of the individual resistances; that is, Equation 17.8


Physiology_Levy

Physiology_Levy. Equation 17.8 In a few simple illustrations, some of the fundamental properties of parallel hydraulic systems become apparent. For example, if the resistances of the three parallel elements in Fig. 17.6 were all equal, then Equation 17.9 Therefore, from Eq. 17.8, Equation 17.10 When the reciprocals of these terms, are equated, Equation 17.11 Thus the total resistance is less than the individual resistances. For any parallel arrangement, the total resistance must be less than that of any individual component. For example, consider a system in which a tube with very high resistance is added in parallel to a low-resistance tube. The total resistance of the system must be less than that of the low-resistance component by itself because the high-resistance component affords an additional pathway, or conductance, for flow of fluid.


Physiology_Levy

Physiology_Levy. Consider the physiological relationship between the total peripheral resistance (TPR) of the entire systemic vascular bed and the resistance of one of its components, such as the renal vasculature. TPR is the ratio of the arteriovenous (AV) pressure difference (arterial pressure [Pa] − venous pressure [Pv]) to the flow through the entire systemic vascular bed (i.e., the cardiac output [Qt]). For example, the renal vascular resistance (Rr) would be the ratio of the same AV pressure difference (Pa − Pv) to renal blood flow (Qr).


Physiology_Levy

Physiology_Levy. In an individual with an Pa of 100 mm Hg, a peripheral Pv of 0 mm Hg, and a cardiac output of 5000 mL/min, TPR is 0.02 mm Hg/mL/minute, or 0.02 peripheral resistance units (PRUs). Normally, the rate of blood flow through one kidney would be approximately 600 mL/ minute. Renal resistance would therefore be 100 mm Hg ÷ 600 mL/minute, or 0.17 PRUs, which is 8.5 times greater than the TPR. In an organ such as the kidney, which weighs only approximately 1% as much as the whole body, the vascular resistance is much greater than that of the entire systemic circulation. Hence, it is not surprising that the resistance to flow would be greater for a component organ, such as the kidney, than for the entire systemic circulation because the systemic circulation has not only one kidney but also many more alternative pathways for blood to flow.


Physiology_Levy

Physiology_Levy. Fig. 17.3A ), a thin layer of fluid in contact with the tube wall adheres to the wall and hence is motionless. The layer of fluid just central to the external lamina must shear against this motionless layer, and therefore that layer moves slowly but with a finite velocity. Similarly, the next more central layer moves still more rapidly; the longitudinal velocity profile is that of a paraboloid (see Fig. 17.3A ). The fluid elements in any given lamina remain in that lamina as the fluid moves longitudinally along the tube. The velocity at the center of the stream is maximal and equal to twice the mean velocity of flow across the entire cross-section of the tube. Irregular motions of the fluid elements may develop in the flow of fluid through a tube; such flow is called turbulent. In this condition, fluid elements do not remain confined to a specific laminae; instead, rapid, radial mixing occurs (see


Physiology_Levy

Physiology_Levy. Fig. 17.3B ). Greater pressure is necessary to force a given flow of fluid through the same tube when the flow is turbulent than when it is laminar. In turbulent flow, the pressure drop is approximately proportional to the square of the flow rate, whereas in laminar flow, the pressure drop is proportional to the first power of the flow rate. Hence, to produce a given flow, a pump such as the heart must do considerably more work if turbulent flow develops. Whether turbulent or laminar flow exists in a tube under given conditions may be predicted on the basis of a dimensionless number called Reynold’s number (NR). This number represents the ratio of inertial to viscous forces. For a fluid flowing through a cylindrical tube,


Physiology_Levy

Physiology_Levy. Equation 17.12 where ρ= fluid density, D = tube diameter, v = mean velocity, and η= viscosity. When NR is 2000 or less, the flow is usually laminar; when NR is 3000 or greater, the flow is turbulent; and when NR is between 2000 and 3000, the flow is transitional between laminar and turbulent. Eq. 17.12 indicates that high fluid densities, small tube diameters, high flow velocities, and low fluid viscosities predispose to turbulence. In addition to these factors, abrupt variations in tube dimensions or irregularities in the tube walls may produce turbulence. Shear Stress on the Vessel Wall As blood flows through a vessel, it exerts a force on the vessel wall parallel to the wall. This force is called a shear stress (τ). Shear stress is directly proportional to the flow rate and viscosity of the fluid: Equation 17.13


Physiology_Levy


Physiology_Levy

Physiology_Levy. aneurysm. Itoccursmostoftenintheproximalportionsoftheaortaandisextremelyserious.Onereasonforitspredilectionforthissiteisthehighvelocityofbloodflow,withassociatedlargeshearratevaluesattheendothelialwall.Shearstressatthevesselwallalsoinfluencesmanyothervascularfunctions,suchasthepermeabilityofthevesselwallsbylargemolecules,thebiochemicalactivityofendothelialcells,theintegrityoftheformedelementsinblood,andbloodcoagulation.Anincreaseinshearstressontheendothelialwallisalsoaneffectivestimulusforthereleaseofnitricoxide(NO)fromvascularendothelialcells;NOisapotentvasodilator(seethesection“ •Fig. 17.7 Therelativeviscosityofwholebloodincreasesataprogressivelygreaterrateasthehematocritratioincreases.Foranygivenhematocritratio,theapparentviscosityofbloodislowerwhenmeasuredinabiologicalviscometer(suchasahindlegbloodvessel)thaninaconventionalcapillarytubeviscometer.(RedrawnfromLevyMN,ShareL.Circ Res. 1953;1:247.)9010 1 2 3 4 5 6 7 8 7030 50 Hematocrit ratio Relative viscosity Hind leg Capillary tube


Physiology_Levy

Physiology_Levy. Res. 1953;1:247.)9010 1 2 3 4 5 6 7 8 7030 50 Hematocrit ratio Relative viscosity Hind leg Capillary tube viscometer


Physiology_Levy

Physiology_Levy. Rheologic Properties of Blood The viscosity of a given newtonian fluid at a specified temperature stays constant over a wide range of tube dimensions and flows. However, for a nonnewtonian fluid such as blood, viscosity may vary considerably as a function of tube dimensions and flows. Therefore, the term viscosity does not have a unique meaning for blood. The term apparent viscosity is frequently used for the derived value of blood viscosity obtained under the particular conditions of measurement. Rheologically, blood is a suspension of formed elements, principally erythrocytes, in a relatively homogeneous liquid, the blood plasma. Because blood is a suspension, the apparent viscosity of blood varies as a function of the hematocrit (ratio of the volume of red blood cells to the volume of whole blood). The viscosity of plasma is 1.2 to 1.3 times that of water. The upper curve in


Physiology_Levy

Physiology_Levy. Fig. 17.7 shows that the apparent viscosity of blood with a normal hematocrit ratio of 45% is 2.4 times that of plasma. In severe anemia, blood viscosity is low. As the hematocrit increases, the slope of the curve increases progressively; it is especially steep at the upper range of erythrocyte concentrations (see Fig. 17.7 For any given hematocrit, the apparent viscosity of blood depends on the dimensions of the tube used in estimating the viscosity. Fig. 17.8 demonstrates that the apparent viscosity of blood diminishes progressively as tube diameter decreases to less than approximately 0.3 mm. The diameters of the blood vessels with the highest resistance, the arterioles, are considerably less than this critical value. This phenomenon Fig. 17.7 also illustrates that the apparent viscosity of blood, when measured in living tissues, is considerably less than the apparent viscosity of the same blood measured in a conventional capillary tube viscometer.


Physiology_Levy

Physiology_Levy. 0.60 6 5 4 3 2 1 0.50.20.1 0.40.3 Tube diameter (mm) Relative viscosity •Fig. 17.8 Therelativeviscosityofbloodrelativetothatofwaterincreasesasafunctionoftubediameteruptoadiameterofapproximately0.3mm.(RedrawnfromFåhraeusR,LindqvistT.Am J Physiol. 1931;96:562.) therefore reduces the resistance to flow in blood vessels that possess the greatest resistance. The influence of tube diameter on apparent viscosity is explained in part by the actual change in blood composition as it flows through small tubes. The composition of blood changes because the red blood cells tend to accumulate in the faster axial stream, whereas plasma tends to flow in the slower marginal layers. Because the axial portions of the bloodstream contain a greater proportion of red cells and this axial portion moves at greater velocity, the red blood cells tend to traverse the tube in less time than plasma does. Furthermore, the hematocrit of the blood contained in small blood vessels is lower than that in blood in large


Physiology_Levy

Physiology_Levy. velocity, the red blood cells tend to traverse the tube in less time than plasma does. Furthermore, the hematocrit of the blood contained in small blood vessels is lower than that in blood in large arteries or veins.


Physiology_Levy

Physiology_Levy. The physical forces responsible for the drift of erythrocytes toward the axial stream and away from the vessel walls when blood is flowing at normal rates are not fully understood. One factor is the great flexibility of red blood cells. At low flow rates, like those in the microcirculation, rigid particles do not migrate toward the central axis of a tube, whereas flexible particles do. The concentration of flexible particles near the tube’s central axis is enhanced by an increase in the shear rate. The apparent viscosity of blood diminishes as the shear rate is increased (


Physiology_Levy

Physiology_Levy. The apparent viscosity of blood diminishes as the shear rate is increased ( Fig. 17.9 ), a phenomenon called shear thinning. The greater the amount of flow, the greater the rate that one lamina of fluid shears against an adjacent lamina. The greater tendency for erythrocytes to accumulate in the axial laminae at higher flow rates is partly responsible for this nonnewtonian behavior. However, a more important factor is that at very slow flow rates, the suspended cells tend to form aggregates; such aggregation increases blood viscosity. As flow is increased, this aggregation decreases, and so does the apparent viscosity of blood (see Fig. 17.9


Physiology_Levy

Physiology_Levy. Fig. 17.9 The tendency for erythrocytes to aggregate at low flow rates depends on the concentration of the larger protein molecules in plasma, especially fibrinogen. For this reason, changes in blood viscosity with flow rate are much more pronounced when the concentration of fibrinogen is high. In addition, at low flow rates, leukocytes tend to adhere to the endothelial cells of the microvessels and thereby increase the apparent viscosity of the blood.


Physiology_Levy

Physiology_Levy. •Fig. 17.9 Decreaseintheviscosityofblood(cp,centipoise)atincreasingratesofshear(sec−1).Theshearrateisthevelocityofonelayeroffluidinrelationtothatoftheadjacentlayersandisdirectionallyrelatedtotherateofflow.(RedrawnfromAminTM,SirsJA.Q J Exp Physiol. 1985;70:37.)2400 7 6 5 4 3 18060 120 Shear rate/sec–1 Viscosity (cp) •Fig. 17.10 Effectoftheplasmafibrinogenconcentrationontheflexibilityofhumanerythrocytes.(RedrawnfromAminTM,SirsJA.Q J Exp Physiol. 1985;70:37.)40 8 6 4 2 0 31 2 Fibrinogen concentration (mg/mL) Erythrocyte flexibility (% min–1)


Physiology_Levy

Physiology_Levy. The deformability of erythrocytes is also a factor in shear thinning, especially when the hematocrit is high. The mean diameter of human red blood cells is approximately 7 µm, but they are able to pass through openings with a diameter of only 3 µm. As blood with densely packed erythrocytes flows at progressively greater rates, the erythrocytes become more and more deformed. Such deformation diminishes the apparent viscosity of blood. The flexibility of human erythrocytes is enhanced as the concentration of fibrinogen in plasma increases ( Fig. 17.10 ). If the red blood cells become hardened, as they are in certain spherocytic anemias, shear thinning may diminish. The Arterial System


Physiology_Levy

Physiology_Levy. Fig. 17.10 ). If the red blood cells become hardened, as they are in certain spherocytic anemias, shear thinning may diminish. The Arterial System The systemic and pulmonary arterial systems distribute blood to the capillary beds throughout the body. The arterioles are high-resistance vessels of this system that regulate the distribution of flow to the various capillary beds. The aorta, the pulmonary artery, and their major branches have a large amount of elastin in their walls, which makes these vessels highly distensible (i.e., compliant). This distensibility serves to dampen the pulsatile nature of blood flow that results as the heart pumps blood intermittently. When blood is ejected from the ventricles during systole, these vessels distend, and during diastole, they recoil and propel the blood forward (Fig. 17.11 ). Thus the intermittent output of the heart is converted to a steady flow through the capillaries.


Physiology_Levy

Physiology_Levy. The elastic nature of the large arteries also reduces the work of the heart. If these arteries were rigid rather than compliant, the pressure would rise dramatically during systole. This increased pressure would require the ventricles to pump against a large load (i.e., afterload) and thus increase the work of the heart. Instead, as blood is ejected into these vessels, they distend, and the resultant increase in systolic pressure, and thus the work of the heart, are reduced. Aspeopleage,theelastincontentofthelargearteriesisreducedandreplacedbycollagen.Thisreducesarterialcompliance( Fig.17.12 ).Thuswithage,systolicpressureincreases,asdoesthedifferencebetweensystolicanddiastolicbloodpressure,calledthepulse pressure (describedinthenextsection). Determinants of Arterial Blood Pressure


Physiology_Levy

Physiology_Levy. Determinants of Arterial Blood Pressure Arterial blood pressure is routinely measured in patients, and it provides a useful estimate of their cardiovascular status. Arterial pressure can be defined as mean arterial pressure (Pa), which is the pressure averaged over time, and as systolic (maximal) and diastolic (minimal) arterial pressure within the cardiac cycle ( Fig. 17.13 ). The difference between systolic and diastolic pressure is termed pulse pressure. The determinants of arterial blood pressure are arbitrarily divided into “physical” and “physiological” factors. The two Systole Arterial blood flows through the Diastole Arterial blood continues to flow through capillaries throughout systole. the capillaries throughout diastole.


Physiology_Levy

Physiology_Levy. Systole Arterial blood flows through the Diastole Arterial blood continues to flow through capillaries throughout systole. the capillaries throughout diastole. A When the arteries are normally compliant, a B During ventricular diastole the previously substantial fraction of the stroke volume is stretched arteries recoil. The volume of blood stored in the arteries during ventricular systole. that is displaced by the recoil furnishes The arterial walls are stretched. continuous capillary flow throughout diastole. Left atrium Left atrium Left ventricle Left ventricle Aorta Aorta Capillaries Capillaries Systole A volume of blood equal to the entire stroke volume must flow through the capillaries during systole. Diastole Flow through the capillaries ceases during diastole. C When the arteries are rigid, virtually none D Rigid arteries cannot recoil appreciably during of the stroke volume can be stored in the diastole. arteries.


Physiology_Levy

Physiology_Levy. C When the arteries are rigid, virtually none D Rigid arteries cannot recoil appreciably during of the stroke volume can be stored in the diastole. arteries. •Fig. 17.11 Whenarteriesarenormallycompliant(A andB),bloodflowsthroughthecapillariesthroughoutthecardiaccycle.Whenthearteriesarerigid,bloodflowsthroughthecapillariesduringsystole (C),butflowceasesduringdiastole(D). physical factors, or fluid mechanical characteristics, are fluid volume (i.e., blood volume) within the arterial system and the static elastic characteristics (compliance) of the system. The physiological factors are cardiac output (which equals heart rate × stroke volume) and peripheral resistance. To estimate Pa from an arterial blood pressure tracing, the area under the pressure curve is divided by the time interval involved (see Fig. 17.13 ). Alternatively, Pa can be approximated from the measured values of systolic pressure (Ps) and diastolic pressure (Pd) by means of the following formula: Equation 17.14


Physiology_Levy

Physiology_Levy. Fig. 17.13 ). Alternatively, Pa can be approximated from the measured values of systolic pressure (Ps) and diastolic pressure (Pd) by means of the following formula: Equation 17.14 Consider that Pa depends on only two physical factors: mean blood volume in the arterial system and arterial compliance ( Fig. 17.14 ). Arterial volume (Va), in turn, depends on the rate of inflow, (Qh) into the arteries from the heart (cardiac output) and on the rate of outflow (Qr) from the arteries through the resistance vessels (peripheral runoff). These relationships are expressed mathematically as


Physiology_Levy

Physiology_Levy. Equation 17.15 where dVa/dt is the change in arterial blood volume per unit of time. If Qh exceeds Qr, arterial volume increases, the arterial walls are stretched further, and pressure rises. The converse happens when Qr exceeds Qh. When Qh equals Qr, Pa remains constant. Thus increases in cardiac output raise Pa, as do increases in peripheral resistance. Conversely, decreases in cardiac output or peripheral resistance decrease Pa. Arterial pulse pressure is systolic pressure minus diastolic pressure. It is principally a function of just one physiological factor, stroke volume, which determines the change in arterial blood volume (a physical factor) during ventricular systole. This physical factor, in addition to a second physical factor (arterial compliance), determines the arterial pulse pressure (see Fig. 17.14


Physiology_Levy

Physiology_Levy. Fig. 17.14 As described previously, Pa depends on cardiac output and peripheral resistance. During the rapid ejection phase of systole, the volume of blood introduced into the arterial system exceeds the volume that exits the system through the arterioles. Arterial pressure and volume therefore peak; the peak arterial pressure is systolic pressure. During the remainder of the cardiac cycle (i.e., ventricular diastole), exceeds cardiac ejection. The resultant decrement in arterial blood volume thus causes pressure to fall to a minimum, which is diastolic pressure. Fig. 17.15 illustrates the effect cardiac ejection is zero, and peripheral runoff now greatly of stroke volume on pulse pressure when arterial compliance is constant.


Physiology_Levy

Physiology_Levy. Fig. 17.15 illustrates the effect cardiac ejection is zero, and peripheral runoff now greatly of stroke volume on pulse pressure when arterial compliance is constant. •Fig. 17.12 Pressure-volumerelationshipsofaortasobtainedat autopsyfromhumansindifferentagegroups(denotedbythenumbers•Fig. 17.13 Arterial Systolic, Diastolic, Pulse, and Mean Pres-attherightendofeachofthecurves).Notethatcompliance(ΔV/ΔP)sure. Meanarterialpressure(P)representstheareaunderthearterialdecreaseswithage.(RedrawnfromHallockP,BensonIC.J Clin Invest. pressurecurve(dark red) dividedbythedurationofthecardiaccycle1937;16:595.)(t2− t1). •Fig. 17.14 Thetwophysicaldeterminantsofpulsepressurearearterialcompliance(Ca)andthechangeinarterialvolume.Thetwophysiologicaldeterminantsofmeanarterialpressure(P)arecardiacoutputandtotalperipheralresistance. Arterial compliance (Ca), the ratio of blood volume to mean blood pressure (see Eq. 19.1 ), also affects pulse pressure. This relationship is illustrated in