Physiology_Levy

Physiology_Levy. prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell repolarizes (phase 3), the inactivated channels begin to transition to the closed state. During this period, called the relative refractory period, another action potential can be generated, but it requires a larger-than-normal depolarization of Vm. Only when Vm has returned to the resting level (phase 4) are all the sodium channels closed and thus able to be reactivated by the normal depolarization of Vm.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Genesis of Early Repolarization (Phase 1) In many cardiac cells that have a prominent plateau, phase 1 is an early, brief period of limited repolarization. This brief repolarization results in the notch between the end of the upstroke and the beginning of the plateau (see Figs. 16.1 16.3). Repolarization is brief because of activation of a transient outward current (ito) carried mainly by K+ . Activation of potassium channels during phase 1 causes a brief efflux of K+ from the cell because the cell interior is positively charged and intracellular [K+] greatly exceeds extracellular [K+] (see Fig. 16.3 ). The cell is briefly and partially repolarized as a result of this transient efflux of K+ . The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall (


Physiology_Levy

Physiology_Levy. The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall ( Fig. 16.5 ) and in ventricular Purkinje fibers. However, the notch is negligible in myocytes from the endocardial region of the left ventricle (see Fig. 16.5) because the density of i to channels is less in these cells. The notch is also less prominent in the presence 4 Chemical Electrostatic 3 2 1 0 Fast Na+ Channel Na+ Na+ – – – – – – – – – – – – – – – – – – – – K+ Channel (ito) K+ K+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Ca++ Ca++ Ca++ K+ K+ K+ Channels (iK, iK1) K+ K+ – – – – – – – – – – – – – – – – – – – – K+ Channels (iK, iK1) K+ K+ – – – – – – – – – – – – – – – – – – – – 0 1 3 4 2


Physiology_Levy

Physiology_Levy. K+ Channels (iK, iK1, ito) •Fig. 16.3 Principal Ionic Currents and Channels That Generate the Various Phases of the Action Potential in a Cardiac Cell. Phase 0, ThechemicalandelectrostaticforcesbothfavortheentryofNa+ intothecellthroughfastsodiumchannelstogeneratetheupstroke.Phase 1, BoththechemicalandelectrostaticforcesfavortheeffluxofK+ throughtransientoutwardcurrent(ito)channelstogenerateearly,partialrepolarization.Phase 2, Duringtheplateau,thenetinfluxofCa++ throughcalciumchannelsisbalancedbytheeffluxofK+ throughoutwardrectifyingcurrent(iK),inwardrectifyingcurrent(iK1),anditochannels.Phase 3, ThechemicalforcesthatfavortheeffluxofK+ throughiKandiK1channelspredominateovertheelectrostaticforcesthatfavortheinfluxofK+ throughthesesamechannels.Phase 4, ThechemicalforcesthatfavortheeffluxofK+ throughiKandiK1channelsveryslightlyexceedtheelectrostaticforcesthatfavortheinfluxofK+ throughthesesamechannels.


Physiology_Levy

Physiology_Levy. 0 1.5 3 4.5 10 msec pA Channel #1 current Channel #2 current •Fig. 16.4 Current (in Picoamperes [pA]) Through Two Individual Sodium Channels in a Cultured Heart Cell, Recorded With the Patch Clamp Technique. Membranevoltagewasheldat−85mV,thenabruptlychangedto−45mVatthetimeindicatedbythearrow, andheldatthispotentialfortheremainderoftherecord.(RedrawnfromCachelinAB,etal.J Physiol. 1983;340:389.) of 4-aminopyridine, which blocks the potassium channels that carry ito. Genesis of the Plateau (Phase 2) During the action potential plateau, Ca++ enters myocardial cells through calcium channels (described in next paragraph) that activate and inactivate much more slowly than the fast sodium channels do. During the flat portion of phase 2 (see


Physiology_Levy

Physiology_Levy. Figs. 16.1 16.3), this influx of Ca ++ is counterbalanced by the efflux of K+ . K+ exits through channels that conduct mainly the ito, iK, and iK1 currents. The ito current is responsible for phase 1, as described previously, but it is not completely inactivated until after phase 2 has expired. The iK and iK1 are described later in this section of the chapter. Ca++ enters the cell via voltage-regulated calcium channels, which are activated as Vm becomes progressively less negative during the action potential upstroke. Two types of calcium channels (L-type and T-type) have been identified in cardiac tissue. Some of their important characteristics are illustrated in Fig. 16.6 . L-type channels are so designated because once open, they inactivate slowly (see


Physiology_Levy

Physiology_Levy. Fig. 16.6 . L-type channels are so designated because once open, they inactivate slowly (see Fig. 16.6, lower panel) and enable a long-lasting Ca++ current. They are the predominant type of calcium channel in the heart, and they are activated during the action potential upstroke when Vm reaches approximately −20 mV. L-type channels are blocked by calcium channel antagonists such as verapamil, amlodipine, and diltiazem ( Fig. 16.7 T-type (or “transient”) calcium channels are much less abundant in the heart. They are activated at membrane potentials that are more negative (approximately −70 mV) than the potential that activates L-type channels (−20 mV). They also inactivate more quickly than do L-type channels (see Fig. 16.6 ; compare the upper and lower panels).


Physiology_Levy

Physiology_Levy. Fig. 16.6 ; compare the upper and lower panels). Opening of calcium channels results in an increase in Ca++ conductance (gCa) and calcium current (iCa) soon after •Fig. 16.5 Actionpotentialsrecordedfromtheepicardial(Epi)(A), midmyocardial(Mid)(B), andendocardial(Endo)(C) regionsofthefreewalloftheleftventricle.Thepreparationsweredrivenatabasiccyclelength(BCL):thatis,atinterstimulusintervalsof300and8000msec.Thevalueof0mVmembranepotentialisindicatedby“0.”(FromLiuD-W,etal.Circ Res. 1993;72:671.) the action potential upstroke (see Fig. 16.3 ). Because the intracellular concentration of Ca++ is much lower than the extracellular concentration of Ca++ (see Table 16.1 ), the increase in gCa promotes the influx of Ca++ into the cell throughout the plateau. This Ca++ influx during the plateau is involved in excitation-contraction coupling, as described in the section “


Physiology_Levy

Physiology_Levy. Various neurotransmitters and drugs may substantially influence gCa. The adrenergic neurotransmitter norepinephrine, the β-adrenergic receptor agonist isoproterenol, and various other catecholamines enhance gCa, whereas the parasympathetic neurotransmitter acetylcholine decreases gCa. Enhancement of gCa by catecholamines is the principal mechanism by which they enhance cardiac muscle contractility. During the plateau (phase 2) of the action potential, the concentration gradient for K+ across the cell membrane is virtually the same as it is during phase 4; at that time, however, Vm is positive. Therefore, there is a large gradient that favors efflux of K+ from the cell (see Fig. 16.3). If g K were the same during the plateau as it is during phase 4, efflux of K+ during phase 2 would greatly exceed the influx of Ca++ , and a sustained plateau could not be achieved.


Physiology_Levy

Physiology_Levy. Fig. 16.3). If g K were the same during the plateau as it is during phase 4, efflux of K+ during phase 2 would greatly exceed the influx of Ca++ , and a sustained plateau could not be achieved. •Fig. 16.6 Effects of Isoproterenol on the Ca++ Currents. ThecurrentswereconductedbyT-type(upper panel) andL-type(lower panel) calciumchannelsinatrialmyocytes.Upper panel, Themembranepotentialwaschangedfrom−80to−20mV.Lower panel, Themembranepotentialwaschangedfrom−30to+30mV.(RedrawnfromBeanBP.J Gen Physiol. 1985;86:1.) •Fig. 16.7 Effectsofdiltiazem,acalciumchannelantagonist,ontheactionpotentials(inmillivolts[mV])andisometriccontractileforces(inmillinewtons[mN])recordedfromapapillarymuscleinvitro.Thetrac-ingswererecordedundercontrolconditions(C)andinthepresenceofdiltiazeminconcentrationsof3,10,and30µmol/L.(RedrawnfromHirthC,etal.J Mol Cell Cardiol. 1983;15:799.)20 50 msec Action potential Force 0 mV 10 30 C and 3 C 3 10 30 mN 0.5 50 msec


Physiology_Levy

Physiology_Levy. However, as Vm approaches and then attains positive values near the peak of the action potential upstroke, gK suddenly decreases ( Fig. 16.8 ). The diminished K+ current associated with the reduction in gK prevents excessive loss of K+ from the cell during the plateau. ToenhancegCa,catecholaminesfirstbindtoβ-adrenergicreceptorsinthecardiaccellmembrane.Thisinteractionstimulatesthemembrane-boundenzymeadenylatecyclase,whichraisestheintracellularconcentrationofcyclicadenosinemonophosphate(cAMP;seealso ).TheriseincAMPactivatescAMP-dependentproteinkinase,whichinturnpromotesphosphorylationofL-typecalciumchannelsinthecellmembraneandthusaugmentstheinfluxofCa++ intothecells(see Fig.16.6 ).Conversely,acetylcholineinteractswithmuscarinicreceptorsinthecellmembranetoinhibitadenylatecyclase.Inthisway,acetylcholineantagonizestheactivationofcalciumchannelsandtherebydiminishesgCa.


Physiology_Levy

Physiology_Levy. The reduction in gK at both positive and low negative values of Vm is called inward rectification. Inward rectification is a characteristic of several K+ currents, including iK1 ( Fig. 16.9 ). For these channels, large K+ currents flow at negative values of Vm (i.e., gK is large). However, when Vm is near 0 mV or positive, as occurs during the plateau (phase 2), little or no K+ current flows (i.e., gK is small). Thus the substantial gK that prevails during phase 4 of the cardiac action potential (see Fig. 16.8 ) is large because of the iK1 channels, but current through these channels is greatly diminished during the plateau (see Fig. 16.9


Physiology_Levy

Physiology_Levy. Fig. 16.8 ) is large because of the iK1 channels, but current through these channels is greatly diminished during the plateau (see Fig. 16.9 Other potassium channels play a role in phase 2 of the action potential. These potassium channels are characterized as delayed iK channels. They are closed during phase 4 and are activated very slowly by the potentials that prevail toward the end of phase 0. Hence, activation of these channels tends to increase gK very gradually during phase 2. These channels play only a minor role during phase 2, but they contribute to the process of final repolarization (phase 3), as described in the section “ Genesis of Repolarization (Phase 3) .” There exist two types of iK channels, classified according to their rates of activation: The more slowly activating channel is designated the iKs channel, and the more rapidly activating channel is designated the iKr channel (see Fig. 16.8). The Nav1.5 SCN5A Cav1.2 CACNA1C ICa,L IK1 Ito,1 Ito,2 IKr IKs


Physiology_Levy

Physiology_Levy. Fig. 16.8). The Nav1.5 SCN5A Cav1.2 CACNA1C ICa,L IK1 Ito,1 Ito,2 IKr IKs Kir2.1/2.2 Kv4.2/4.3 Kv1.4/1.7 •Fig. 16.8 Changes in Ion Currents During the Various Phases of the Action Potential in a Fast-Response Cardiac Ventricular Cell. Upper panels, Depolarizingioncurrents.Lower panels, Repolarizingioncurrents.TheinwardcurrentsincludethefastNa+ (iNa)andL-typeCa++ (iCa,L)currents.OutwardcurrentsareiK1,ito,andtherapid(iKr)andslow(iKs)delayedrectifierK+ currents.Theclonesandgenesfortheprincipalioniccurrentsarealsoincluded.(RedrawnfromTomaselliG,MarbánE.Cardiovasc Res. 1999;42:270.) duration of the action potential in myocytes in various regions of the ventricular myocardium is determined in part by the relative distributions of these iKr and iKs channels.


Physiology_Levy

Physiology_Levy. The action potential plateau persists as long as the efflux of charge carried mainly by K+ is balanced by the influx of charge carried mainly by Ca++ . The effects of altering this balance are exemplified by the action of the calcium channel antagonist diltiazem in a papillary muscle preparation (see Fig. 16.7 ). With increasing concentrations of diltiazem, the plateau voltage becomes progressively less positive and the plateau duration diminishes. Conversely, administration of certain potassium channel antagonists prolongs the plateau substantially. Genesis of Final Repolarization (Phase 3) The process of final repolarization (phase 3) starts at the end •Fig. 16.9 Inward Rectified K+ of phase 2, when efflux of K+ from the cardiac cell begins to tricular Myocyte When the Potential Was Changed From a Holding exceed influx of Ca++ . As noted, at least three outward K+


Physiology_Levy

Physiology_Levy. Potential of −80 mV to Various Test Potentials. Positivevaluesalong currents (ito, iK, and iK1) contribute to the final repolariza tion (phase 3) of the cardiac cell (see Figs. 16.3 16.8 inwardcurrents.Thepointatwhichthecurrenttraceintersectsthe x-axisisthereversalpotential(open circle); itdenotestheNernstThe ito, iKr, and iKs currents help initiate repolarization. equilibriumpotential(EK),atwhichpointthechemicalandelectrostaticThese currents are therefore important determinants of forcesareequal.Vm,membranepotential.(RedrawnfromGilesWR, the duration of the plateau. For example, the duration of ImaizumiY.J Physiol [Lond]. 1988;405:123.) the plateau is substantially less in atrial myocites than in ventricular myocytes (


Physiology_Levy

Physiology_Levy. ImaizumiY.J Physiol [Lond]. 1988;405:123.) the plateau is substantially less in atrial myocites than in ventricular myocytes ( Fig. 16.10 ) because the magnitude •Fig. 16.10 Typical Action Potentials (in Millivolts, y-Axis). Thesepotentialswererecordedfromcellsintheventricle(A), sinoatrial(SA)node(B), andatrium(C). NotethatthetimecalibrationinB differsfromthatinA andC. Numbersonthecurvesdenotethephasesoftheactionpotential.(FromHoffmanBF,CranefieldPF.Electrophysiology of the Heart. NewYork:McGraw-Hill;1960.) of ito during the plateau is greater in atrial myocites than in ventricular myocytes. As already noted, the duration of the action potential in ventricular myocytes varies considerably with the location of these myocytes in the ventricular walls (see


Physiology_Levy

Physiology_Levy. Fig. 16.5). The i to and iK currents mainly account for these differences. In endocardial myocytes, in which the duration of the action potential is least, the magnitude of iK is greatest. The converse applies to the midmyocardial myocytes. The magnitude of iK and the duration of the action potential are intermediate for epicardial myocytes. The iK1 current does not participate in the initiation of repolarization because the conductance of these channels is very small over the range of Vm values that prevail during the plateau. However, the iK1 channels contribute substantially to the rate of repolarization once phase 3 has been initiated. As Vm becomes increasingly negative during phase 3, the conductance of the channels that carry the iK1 current progressively increases and thereby accelerates repolarization (see Fig. 16.3 Restoration of Ionic Concentrations (Phase 4)


Physiology_Levy

Physiology_Levy. Fig. 16.3 Restoration of Ionic Concentrations (Phase 4) The steady inward leak of Na+ that enters the cell rapidly during phase 0 and more slowly throughout the cardiac cycle would gradually depolarize the resting membrane voltage were it not for Na+,K+-ATPase, which is located in the cell membrane (see ). Similarly, most of the excess Ca++ ions that had entered the cell mainly during phase 2 are eliminated principally by a 3Na+-Ca++ antiporter, which exchanges three Na+ ions for one Ca++ ion. However, some of the Ca++ ions are eliminated by an ATP-driven Ca++ pump.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Fig. 16.1A ) consist of four principal components: an upstroke (phase 0), an early partial repolarization (phase 1), a plateau (phase 2), and a final repolarization (phase 3). However, in the slow-response action potential (see Fig. 16.1B ), the upstroke is much less steep, early repolarization (phase 1) is absent, the plateau is less prolonged and not as flat, and the transition from the plateau to the final repolarization is less distinct. Blocking fast sodium channels with tetrodotoxin in a fast-response fiber can generate slow responses under appropriate conditions. The Purkinje fiber action potentials shown in


Physiology_Levy

Physiology_Levy. Blocking fast sodium channels with tetrodotoxin in a fast-response fiber can generate slow responses under appropriate conditions. The Purkinje fiber action potentials shown in Fig. 16.11 clearly exhibit the two response types. In the control tracing (A), the typical fast-response action potential displays a prominent notch, as a result of ito, that separates the upstroke from the plateau. Progressively higher concentrations of tetrodotoxin produce a graded blockade of the fast sodium channels, as demonstrated in tracings B to E. The upstroke and notch are progressively less prominent in tracings B to D. In tracing E, the notch has disappeared, and the upstroke is very gradual; this action potential resembles a typical slow response.


Physiology_Levy

Physiology_Levy. •Fig. 16.11 Effect of Tetrodotoxin, Which Blocks Fast Sodium Channels, on the Action Potentials (Tracings A to E) Recorded in a Purkinje Fiber. Theconcentrationsoftetrodotoxinwere0mol/LintracingA,3×10−8mol/LintracingB,3×10−7mol/LintracingC,and3×10−6mol/LintracingsDandE;EwasrecordedlaterthanD.(RedrawnfromCarmelietE,VereeckeJ.Pflügers Arch. 1969;313:300.)100 mV 1 sec A B C D E Certain cells in the heart, notably those in the SA and AV nodes, exhibit slow-response action potentials. In these cells, depolarization is achieved mainly by influx of Ca++ through L-type calcium channels instead of influx of Na+ through fast sodium channels. Repolarization is accomplished in these fibers by inactivation of the calcium channels and by the increased K+ conductance through the iK1 and iK channels (see Fig. 16.3).


Physiology_Levy

Physiology_Levy. Fig. 16.3). An action potential traveling along a cardiac muscle fiber is propagated by local circuit currents, much as it is in nerve and skeletal muscle fibers (see ). When the wave of depolarization reaches the end of the cell, the impulse is conducted to adjacent cells through gap junctions (see Chapter 2). Impulses pass more readily along the length of the cell (isotropic) than laterally from cell to cell (anisotropic) because gap junctions are preferentially located at the ends of the cell. Gap junctions are rather nonselective in their permeability by ions and have a low electrical resistance that allows ionic current to pass from one cell to another. The electrical resistance of gap junctions is similar to that of cytoplasm. The flow of charge from cell to cell follows the principles of local circuit currents and therefore allows intercellular propagation of the impulse. Conduction of the Fast Response


Physiology_Levy

Physiology_Levy. Conduction of the Fast Response In fast-and slow-response fibers, the characteristics of conduction differ. In fast-response fibers, fast sodium channels are activated when the transmembrane potential •Fig. 16.12 Theroleoflocalcurrentsinthepropagationofawaveofexcitationdownacardiacfiber. of one region of the fiber suddenly changes from a resting value of approximately −90 mV to the threshold value of approximately −65 mV. The inward Na+ current then rapidly depolarizes the cell at that site. This portion of the fiber subsequently becomes part of the depolarized zone, and the border is displaced accordingly. The same process then begins at the new border. This process is repeated again and again, and the border moves continuously down the fiber as a wave of depolarization ( Fig. 16.12


Physiology_Levy

Physiology_Levy. Fig. 16.12 The conduction velocity along the fiber varies directly with the action potential amplitude and the rate of change of the potential (dVm/dt) during phase 0. The action potential amplitude is the potential difference between the fully depolarized and the fully polarized regions of the cell interior. The magnitude of the local current is proportional to this potential difference (see ). Because these local currents shift the potential of the resting zone toward the threshold value, they are local stimuli that depolarize the adjacent resting portion of the fiber to its threshold potential. The greater the potential difference between the depolarized and polarized regions (i.e., the greater the action potential amplitude), the more effectively local stimuli can depolarize adjacent parts of the membrane, and the more rapidly the wave of depolarization is propagated down the fiber.


Physiology_Levy

Physiology_Levy. The dVm/dt during phase 0 is also an important determinant of conduction velocity. If the active portion of the fiber depolarizes gradually, the local currents between the resting region and the neighboring depolarizing region are small. The resting region adjacent to the active zone is depolarized gradually, and more time is therefore required for each new section of the fiber to reach threshold. This allows some sodium channels to inactivate.


Physiology_Levy

Physiology_Levy. The resting membrane potential is another important determinant of conduction velocity. Changes in the resting membrane potential influence both the amplitude of the action potential and dVm/dt, which in turn alter the conduction velocity (Fig. 16.13 ). Depolarization of Vm inactivates the fast sodium channels, which in turn decreases the amplitude of the action potential and the dVm/dt, and as a consequence conduction velocity is slowed. In addition to changes in extracellular [K+], premature excitation of a cell that has not completely repolarized also results in a •Fig. 16.13 Effect of Changes in Extracellular Potassium Concentration (Extracellular [K+]) on the Action Potentials Recorded From a Purkinje Fiber. Thestimulusartifact(StintracingD)appearsasabiphasicspiketotheleftoftheupstrokeoftheactionpotential.Thehorizontal dashed lines


Physiology_Levy

Physiology_Levy. Electrocardiography. Philadelphia:FADavis;1973.) decrease in conduction velocity. This too reflects the fact that when Vm is depolarized, more fast sodium channels are inactivated, and thus only a fraction of the sodium channels are available to conduct the inward Na+ current during phase 0.


Physiology_Levy

Physiology_Levy. Conduction of the Slow Response Fig. 16.12 ) also propagate the slow response, whose conduction characteristics differ quantitatively from those of the fast response. The threshold potential is approximately −40 mV for the slow response, and conduction is much slower than for the fast response. The conduction velocities of the slow response in the SA and AV nodes are approximately 0.02 to 0.10 m/sec. The fast-response conduction velocities are approximately 0.30 to 1.00 m/sec for myocardial cells and 1.00 to 4.00 m/sec for the specialized conducting (Purkinje) fibers in the ventricles. Slow responses are more readily blocked than are fast responses; that is, conduction ceases before the impulse reaches the end of the myocardial fiber. Also, fast-response fibers can respond at repetition rates that are much faster than those of slow-response fibers.


Physiology_Levy

Physiology_Levy. Fig.16.13 Because of the rapid development of artificial pacemakers and other electrical devices for correcting cardiac rhythm disturbances, detailed knowledge of cardiac excitability is essential. The excitability characteristics of various types of cardiac cells differ considerably, depending on whether the action potentials are fast or slow responses. Once the fast response has been initiated, the depolarized cell is no longer excitable until it has partially repolarized (see


Physiology_Levy

Physiology_Levy. Once the fast response has been initiated, the depolarized cell is no longer excitable until it has partially repolarized (see Fig. 16.1A ). In the fast response, the interval from the beginning of the action potential until the fiber is able to conduct another action potential is called the effective refractory period which extends from the beginning of phase 0 to a point in phase 3 at which repolarization has reached approximately −50 mV. At approximately this value of Vm, many of the fast sodium channels have transitioned from the inactivated state to the closed state. However, the cardiac fiber is not fully excitable until it has been completely repolarized. Before complete repolarization (i.e., during the relative refractory period), an action potential may be evoked only when the stimulus is stronger than a stimulus that could elicit a response during phase 4.


Physiology_Levy

Physiology_Levy. When a fast response is evoked during the relative refractory period of a previous excitation, its characteristics vary with the membrane potential that exists at the time of stimulation ( Fig. 16.14). The later in the relative refractory period that the fiber is stimulated, the greater are the increases in the amplitude of the response and the slope of the upstroke because the number of fast sodium channels that have recovered from inactivation increases as repolarization proceeds. As a consequence, propagation velocity also increases the later in the relative refractory period that the fiber is stimulated. Once the fiber is fully repolarized, the response is constant no matter what time in phase 4 the stimulus is applied.


Physiology_Levy

Physiology_Levy. •Fig. 16.15 Effects of Excitation at Various Times After the Initiation of an Action Potential in a Slow-Response Fiber. Inthis fiber,excitationverylateinphase3(orearlyinphase4)inducesa small,nonpropagated(local)response(wavea).Laterinphase4,a •Fig. 16.14 Changesinactionpotentialamplitudeandupstrokeslopeasactionpotentialsareinitiatedatdifferentstagesoftherelativerefractoryperiodoftheprecedingexcitation.(RedrawnfromRosenMR,etal.Am Heart J. 1974;88:380.) In slow-response fibers, the relative refractory period frequently extends well beyond phase 3 (see Fig. 16.1B ). Even after the cell has completely repolarized, it may be difficult to evoke a propagated response for some time. This characteristic of slow-response fibers is called postrepolarization refractoriness.


Physiology_Levy

Physiology_Levy. Action potentials evoked early in the relative refractory period are small, and the upstrokes are not very steep (Fig. 16.15 ). The amplitudes and upstroke slopes progressively improve as action potentials are elicited later in the relative refractory period. Recovery of full excitability is much slower than recovery of the fast response. Impulses that arrive early in the relative refractory period are conducted much more slowly than those that arrive late in that period. The long refractory periods also lead to conduction blocks. Even when slow responses recur at low frequency, the fiber may be able to conduct only a fraction of these impulses; for example, in certain conditions, only alternate impulses may be propagated. •Fig. 16.16 Effectofchangesincyclelength(CL)ontheactionpotentialduration(APD)ofPurkinjefibers.(ModifiedfromSingerD,TenEickRE.Am J Cardiol. 1971;28:381.) Effects of Cycle Length


Physiology_Levy

Physiology_Levy. •Fig. 16.16 Effectofchangesincyclelength(CL)ontheactionpotentialduration(APD)ofPurkinjefibers.(ModifiedfromSingerD,TenEickRE.Am J Cardiol. 1971;28:381.) Effects of Cycle Length Cycle length is the time between successive action potentials. Changes in cycle length alter the duration of the action potential in cardiac cells ( Fig. 16.16 Fig. 16.5 ) and thus change their refractory periods. As a consequence, changes in cycle length are often important factors in the initiation or termination of certain arrhythmias (irregular heart rhythms). The changes in action potential duration produced by stepwise reductions in cycle length from 2000 to 200 msec in a Purkinje fiber are shown in


Physiology_Levy

Physiology_Levy. The changes in action potential duration produced by stepwise reductions in cycle length from 2000 to 200 msec in a Purkinje fiber are shown in Fig. 16.16 . Note that as cycle length diminishes, the duration of the action potential decreases. This direct correlation between action potential duration and cycle length is mediated by changes in gK that involve at least two types of potassium channels: namely, those that conduct the delayed rectifier K+ currents (iKr and iKs) and those that conduct the transient outward K+ current (ito).


Physiology_Levy

Physiology_Levy. The iK current is activated at values of Vm near zero, but the current activates slowly, remains activated for hundreds of milliseconds, and also inactivates very slowly. As a consequence, as the basic cycle length diminishes, each action potential tends to occur earlier in the inactivation period of the iK current initiated by the preceding action potential. Therefore, the shorter the basic cycle length, the greater the outward K+ current during phase 2 and hence the shorter the action potential duration. The ito current also influences the relationship between cycle length and action potential duration. The ito current is also activated at near zero potential, and its magnitude varies inversely with cardiac frequency. Therefore, as cycle length decreases, the consequent increase in the outward K+ current shortens the plateau. Natural Excitation of the Heart and the Electrocardiogram


Physiology_Levy

Physiology_Levy. Natural Excitation of the Heart and the Electrocardiogram Excitation of the heart normally occurs in an ordered manner, which allows effective pumping of blood. This ordered excitation occurs via the heart’s conduction system ( Fig. 16.17 ). The SA node is the pacemaker of the heart and initiates the spread of action potentials throughout the atria. This spread of excitation reaches the AV node, where conduction is slowed so that atrial contraction can occur and the ventricles can be adequately filled. Excitation then spreads rapidly throughout the ventricles via the Purkinje fibers so that the ventricular myocytes contract in a coordinated manner. The properties of each component of the heart’s conduction system are described in the next sections. •Fig. 16.17 Thecardiacconductionsystem. CHAPTER 16 Elements of Cardiac Function


Physiology_Levy

Physiology_Levy. •Fig. 16.17 Thecardiacconductionsystem. CHAPTER 16 Elements of Cardiac Function The autonomic nervous system controls various aspects of cardiac function, such as the heart rate and contraction strength. However, cardiac function does not require intact innervation. Indeed, a patient with a cardiac transplant, whose heart is completely denervated, may still adapt well to stressful situations. The ability of a denervated, transplanted heart to adapt to changing conditions lies in certain intrinsic properties of cardiac tissue, especially its automaticity.


Physiology_Levy

Physiology_Levy. The properties of automaticity (the ability to initiate its own beat) and rhythmicity (the regularity of pacemaking activity) allow a perfused heart to beat even when it is completely removed from the body. The vertebrate heartbeat is myogenic in origin. If the coronary vasculature of an excised heart is artificially perfused with blood or an oxygenated electrolyte solution, rhythmic cardiac contractions may persist for many hours. Some cells in the atria and ventricles can initiate beats; such cells reside mainly in nodal tissues or specialized conducting fibers of the heart.


Physiology_Levy

Physiology_Levy. As noted, the region of the mammalian heart that ordinarily generates impulses at the greatest frequency is the SA node; it is the main cardiac pacemaker. Detailed mapping of the electrical potentials on the surface of the right atrium has revealed that two or three sites of automaticity, located 1 or 2 cm from the SA node itself, serve along with the SA node as an atrial pacemaker complex. At times, all these loci initiate impulses simultaneously. At other times, the site of earliest excitation shifts from locus to locus, depending on certain conditions, such as the level of autonomic neural activity.


Physiology_Levy

Physiology_Levy. In humans, the SA node is approximately 8 mm long and 2 mm thick, and it lies posteriorly in the groove at the junction between the superior vena cava and the right atrium. The sinus node artery runs lengthwise through the center of the node. The SA node contains two principal cell types: (1) small, round cells that have few organelles and myofibrils and (2) slender, elongated cells that are intermediate in appearance between the round and “ordinary” atrial myocardial cells. The round cells are probably the pacemaker cells; the slender, elongated cells probably conduct the impulses within the node and to the nodal margins. A typical transmembrane action potential recorded from an SA node cell is depicted in Fig. 16.10B. In comparison with the transmembrane potential recorded from a ventricular myocardial cell (see


Physiology_Levy

Physiology_Levy. A typical transmembrane action potential recorded from an SA node cell is depicted in Fig. 16.10B. In comparison with the transmembrane potential recorded from a ventricular myocardial cell (see Fig. 16.10A ), the resting potential of the SA node cell is usually less negative, the upstroke of the action potential (phase 0) is less steep, the plateau is not sustained, and repolarization (phase 3) is more gradual. These are characteristic attributes of the slow response. Tetrodotoxin (which blocks the fast Na+ current) has no influence on the SA nodal action potential because the action potential upstroke is not produced by an inward Na+ current through fast channels. Thus tetrodotoxin has no effect on cells that exhibit the slow response.


Physiology_Levy


Physiology_Levy

Physiology_Levy. •Fig. 16.18 Mechanisms Involved in the Changes in Frequency of Pacemaker Firing. A, Areductionintheslope(fromwaveatowave b)ofslowdiastolicdepolarizationdiminishesthefiringfrequency.TP,thresholdpotential.B, Anincreaseinthethresholdpotential(fromTP-1toTP-2)oranincreaseinthemagnitudeofthemaximumdiastolicpotential(fromwavesegmentsatod)alsodiminishesthefiringfrequency.(FromHoffmanBF,CranefieldPF.Electrophysiology of the Heart. NewYork:McGraw-Hill;1960.) The transmembrane potential during phase 4 is much less negative in SA (and AV) nodal automatic cells than in atrial or ventricular myocytes because nodal cells lack the iK1 (inward rectifying) type of potassium channel. Thus the ratio of gK to gNa during phase 4 is much less in nodal cells than in myocytes. Hence, during phase 4, Vm deviates much more from the K+ Nernst equilibrium potential (EK) in nodal cells than it does in myocytes.


Physiology_Levy

Physiology_Levy. The principal feature of a pacemaker cell that distinguishes it from the other cells manifests in phase 4. In nonautomatic cells, the potential remains constant during this phase, whereas a pacemaker fiber is characterized by slow diastolic depolarization throughout phase 4. Depolarization proceeds at a steady rate until a threshold is attained, and an action potential is then triggered. Pacemaker cell frequency may be varied by a change in (1) the rate of depolarization during phase 4, (2) the maximal negativity during phase 4, or (3) the threshold potential (


Physiology_Levy

Physiology_Levy. Pacemaker cell frequency may be varied by a change in (1) the rate of depolarization during phase 4, (2) the maximal negativity during phase 4, or (3) the threshold potential ( Fig. 16.18). When the rate of slow diastolic depolarization is increased, the threshold potential is attained earlier, and the heart rate increases. A rise in the threshold potential delays the onset of phase 0, and the heart rate is reduced. Similarly, when the maximal negative potential is increased, more time is required to reach the threshold potential, when the slope of phase 4 remains unchanged, and the heart rate therefore diminishes. Ionic Basis of Automaticity Several ionic currents contribute to the slow diastolic depolarization that characteristically occurs in the automatic


Physiology_Levy

Physiology_Levy. Ionic Basis of Automaticity Several ionic currents contribute to the slow diastolic depolarization that characteristically occurs in the automatic ChangesinautonomicneuralactivitydonotusuallychangetheheartratebyalteringthethresholdlevelofVminthenodalpacemakercells.However,certainantiarrhythmicdrugs,suchasquinidineandprocainamide,doshiftthethresholdpotentialoftheautomaticcellstolessnegativevalues. cells in the heart. In the pacemaker cells of the SA node, at least three ionic currents mediate the slow diastolic depolarization: (1) an outward K+ current, iK; (2) a hyperpolarization-induced inward current, if; and (3) an inward Ca++ current, ICa ( Fig. 16.19 The repetitive firing of the pacemaker cell begins with the iK current. Efflux of K+ tends to repolarize the cell after the upstroke of the action potential. K+ continues to move out well beyond the time of maximal repolarization, but its efflux diminishes throughout phase 4 (see


Physiology_Levy

Physiology_Levy. Fig. 16.19 ). As the current diminishes, its opposition to the depolarizing effects of the two inward currents (if and iCa) also gradually decreases. The progressive diastolic depolarization is mediated by the if and iCa currents, which oppose the repolarizing effect of the iK current. The inward current if is activated near the end of repolarization and is carried mainly by Na+ through specific channels that differ from the fast sodium channels. The current was dubbed “funny” because its discoverers had not expected to detect an inward Na+ current in pacemaker cells at the end of repolarization. This current is activated as the membrane potential becomes hyperpolarized beyond −50 mV. The more negative the membrane potential at this time, the greater the activation of if.


Physiology_Levy

Physiology_Levy. The second current responsible for diastolic depolarization is the inward rectifying Ca++ current, iCa. This current is activated toward the end of phase 4 as the membrane potential reaches a value of approximately −35 mV (see


Physiology_Levy

Physiology_Levy. Fig. 16.19 ). Once the calcium channels are activated, influx of Ca++ into the cell increases. This influx accelerates the rate of diastolic depolarization, which then leads to the action potential upstroke. A decrease in extracellular •Fig. 16.19 Themembranepotentialchanges(blue trace, top half) thatoccurinsinoatrialnodecellsareproducedbythreeprincipalcurrents(green trace, bottom half): theinwardCa++ current(iCa);ahyperpolarization-inducedinwardcurrent(if),andanoutwardK+ current(iK).Thethinnoisygreen trace showsnetmembranecurrentandtheapproximatetimecourseoftherepolarizingoutwardK+ current(iK),thehyperpolarization-inducedinwardcurrent(if),andtheL-typeCa++ current(iCa).Thethick bold red line inthecurrenttraceindicatesthemagnitudeanddirectionofestimatedIf.(RedrawnfromvanGinnekenACG,GilesW.J Physiol. 1991;434:57.)


Physiology_Levy

Physiology_Levy. •Fig. 16.20 Membrane Action Potentials Recorded From an Sino-atrial Node Pacemaker Cell. TheconcentrationofCa++inthebathwasreducedfrom2to0.2mmol/L(“mM”).(ModifiedfromKohlhardtM,etal.Basic Res Cardiol. 1976;71:17.)–60 0 Ca++ 2 mM 500 msec Ca++ 0.2 mM mV Fig. 16.20 ) or the addition of calcium channel antagonists diminishes the amplitude of the action potential and the slope of the slow diastolic depolarization in SA node cells. Research evidence indicates that additional ion currents—including a sustained (background) inward Na+ current (iNa), the T-type Ca++ current, and the Na+/Ca++ exchange current triggered by spontaneous release of Ca++ from the sarcoplasmic reticulum—may also be involved in pacemaking. These observations illustrate the many ways to sustain this vital function.


Physiology_Levy

Physiology_Levy. The autonomic neurotransmitters affect automaticity by altering membrane ionic currents. The adrenergic transmitters increase all three currents involved in SA nodal automaticity. To increase the slope of diastolic depolarization, the augmentation of if and iCa by adrenergic transmitters must exceed the enhancement of iK by these same transmitters. The hyperpolarization induced by acetylcholine released from vagus nerve endings in the heart is achieved by the activation of specific potassium channels: the aThe ionic basis for automaticity in AV node pacemaker cells resembles that in SA node cells. Similar mechanisms also account for automaticity in ventricular Purkinje fibers, except that the fast Na+ current rather than iCa is involved. Also, a voltageand time-dependent K+ current rather than the hyperpolarization-induced inward current if has been suggested to mediate the slow diastolic depolarization; however, this remains to be clarified.


Physiology_Levy

Physiology_Levy. acetylcholine-regulated potassium channels (KACh). Acetylcholine also depresses the if and iCa currents. The autonomic neural effects on cardiac cells are described in greater detail in When the SA node or other components of the atrial pacemaker complex are excised or destroyed, pacemaker cells in the AV junction generally take over the pacemaker function for the entire heart. After some time, which may vary from minutes to days, automatic cells in the atria usually become dominant again and resume their pacemaker function. Purkinje fibers in the specialized conduction system of the ventricles also display automaticity. These fibers characteristically fire at a very slow rate. When the AV junction cannot conduct cardiac impulses from the atria to the ventricles, these idioventricular pacemakers in the Purkinje fiber network initiate the ventricular contractions, but at a frequency of only 30 to 40 beats per minute.


Physiology_Levy

Physiology_Levy. Ifanectopicfocusinoneoftheatriasuddenlybegantofireatahighrate(e.g.,150impulsesperminute)inanindividualwithanormalheartrateof70beatsperminute,theectopicsitewouldbecomethepacemakerfortheentireheart.Ifthatrapidectopicfocussuddenlystoppedfiring,theSAnodewouldremainbrieflyquiescentbecauseofoverdrivesuppression.TheintervalfromtheendoftheperiodofoverdriveuntiltheSAnoderesumesfiringiscalledthesinus node recovery time. Inpatientswithsicksinussyndrome,thesinusnoderecoverytimeisprolonged.Theconsequentperiodofasystole(absenceofaheartbeat)maycauselossofconsciousness. The automaticity of pacemaker cells diminishes after these cells have been excited at a high frequency. This phenomenon is known as overdrive suppression. Because the intrinsic rhythmicity of the SA node is greater than that of the other latent pacemaking sites in the heart, firing of the SA node tends to suppress the automaticity in other loci.


Physiology_Levy

Physiology_Levy. Overdrive suppression results from the activity of membrane Na+,K+-ATPase. A certain amount of Na+ enters the cardiac cell during each depolarization. The more frequently the cell is depolarized, the more Na+ enters the cell per minute. At high excitation frequencies, the activity of Na+,K+-ATPase increases to extrude this larger amount of Na+ from the cell. The activity of Na+,K+-ATPase hyperpolarizes the cell because three Na+ ions are extruded by the pump in exchange for two K+ ions that enter the cell (see ). Therefore, slow diastolic depolarization requires more time to reach the firing threshold. In addition, when the overdrive suddenly ceases, the activity of Na+,K+-ATPase does not slow instantaneously but temporarily remains overactive. This continued extrusion of Na+ opposes the gradual depolarization of the pacemaker cell during phase 4, and it temporarily suppresses the cell’s intrinsic automaticity.


Physiology_Levy

Physiology_Levy. From the SA node, the cardiac impulse spreads radially throughout the right atrium (see Fig. 16.17 ) along ordinary atrial myocardial fibers at a conduction velocity of approximately 1 m/second. A special pathway, the anterior interatrial myocardial band (or Bachmann’s bundle), conducts the SA node impulse directly to the left atrium. The wave of excitation proceeds inferiorly through the right atrium and ultimately reaches the AV node (see Fig. 16.17 ), which is normally the sole entry route of the cardiac impulse to the ventricles.


Physiology_Levy

Physiology_Levy. SomepeoplehaveaccessoryAVpathways.Becausethesepathwaysoftenserveasapartofareentryloop(seethesection“


Physiology_Levy

Physiology_Levy. The atrial plateau (phase 2) is briefer and less developed, and repolarization (phase 3) is slower (see Fig. 16.10 ) than in a typical ventricular fiber. The action potential duration in atrial myocytes is briefer than that in ventricular myocytes because efflux of K+ is greater during the plateau in atrial myocytes than in ventricular myocytes. The presence of an ultrarapid K+ current (IKur) in atrial myocytes, but not in ventricular myocytes, contributes to greater K+ efflux and shorter action potentials in atrial myocytes.


Physiology_Levy

Physiology_Levy. The atrial excitation wave reaches the ventricles via the AV node. In adult humans, this node is approximately 15 mm long, 10 mm wide, and 3 mm thick. The node is situated posteriorly on the right side of the interatrial septum near the ostium of the coronary sinus. The AV node contains the same two cell types as the SA node, but the round cells •Fig. 16.21 Membranepotentialsrecordedfromanatrioventricularnodecellundercontrolconditions(C)andinthepresenceofthecalciumchannelantagonistdiltiazematconcentrationsof0.1,0.3,and1µmol/L.(RedrawnfromHirthC,etal.J Mol Cell Cardiol. 1983;15:799.)–25 0 25 msec C 0.1 0.3 1 mV in the AV node are less abundant and the elongated cells predominate. The AV node is made up of three functional regions: the atrionodal (AN) region, or the transitional zone between the atrium and the remainder of the node; (2) the nodal (N) region, or the midportion of the AV node; and the nodal-His (NH) region, or the zone in which nodal fibers gradually merge with the bundle


Physiology_Levy

Physiology_Levy. the atrium and the remainder of the node; (2) the nodal (N) region, or the midportion of the AV node; and the nodal-His (NH) region, or the zone in which nodal fibers gradually merge with the bundle of His, which is the upper portion of the specialized conducting system for the ventricles (see


Physiology_Levy

Physiology_Levy. Fig. 16.17). Normally, the AV node and the bundle of His are the only pathways along which the cardiac impulse travels from atria to ventricles. Several features of AV conduction are of physiological and clinical significance. The principal delay in conduction of impulses from the atria to the ventricles occurs in the AN and N regions of the AV node. Conduction velocity is actually less in the N region than in the AN region. However, the path length is substantially greater in the AN region than in the N region. Conduction times through the AN and N regions account for the delay between the start of the P wave (the electrical manifestation of atrial excitation) and the QRS complex (the electrical manifestation of ventricular excitation) on an ECG (see the section “ Electrocardiography”). In terms of function, the delay between atrial and ventricular excitation enables optimal ventricular filling during atrial contraction.


Physiology_Levy

Physiology_Levy. Electrocardiography”). In terms of function, the delay between atrial and ventricular excitation enables optimal ventricular filling during atrial contraction. In the N region, slow-response action potentials prevail. The resting potential is approximately −60 mV, the upstroke velocity is low (≈5 V/sec), and the conduction velocity is approximately 0.05m/sec. Tetrodotoxin, which blocks the fast sodium channels, has virtually no effect on action potentials in this region (or on any other slow-response fibers). Conversely, calcium channel antagonists decrease the amplitude and duration of the action potentials ( Fig. 16.21 ) and depress AV conduction. bThe shapes of the action potentials in the AN region are intermediate between those in the N region and those in the atria. Similarly, action potentials in the NH region are transitional between those in the N region and those in the bundle of His. CHAPTER 16 Elements of Cardiac Function


Physiology_Levy

Physiology_Levy. CHAPTER 16 Elements of Cardiac Function Like other slow-response action potentials, the relative refractory period of cells in the N region extends well beyond the period of complete repolarization; that is, these cells display postrepolarization refractoriness (see Fig. 16.15 ). As the heart rate increases, the time between successive atrial depolarizations is decreased, and conduction through the AV junction slows. Abnormal prolongation of the AV conduction time is called a first-degree AV block (see the section ”). Most of the prolongation of AV conduction induced by an increase of atrial frequency takes place in the N region of the AV node.


Physiology_Levy

Physiology_Levy. Impulses tend to be blocked in the AV node at stimulation frequencies that are easily conducted in other regions of the heart. If the atria are depolarized at a high repetition rate, only a fraction (e.g., half) of the atrial impulses might be conducted through the AV junction to the ventricles. The conduction pattern in which only a fraction of the atrial impulses are conducted to the ventricles is called a second-degree AV block (see the section ”). This type of block may protect the ventricles from excessive contraction frequencies, wherein the filling time between contractions might be inadequate. Retrograde conduction can occur through the AV node. However, the conduction time is significantly longer, and the impulse is blocked at lower repetition rates when the impulse is conducted in the retrograde instead of the ante-grade direction. In addition, the AV node is a common site for reentry (see the section “


Physiology_Levy

Physiology_Levy. As in the SA node, the autonomic nervous system regulates AV conduction. Weak vagal activity may simply prolong the AV conduction time. Thus for any given atrial cycle length, the atrium-to-His or atrium-to-ventricle conduction time is prolonged by vagal stimulation. Stronger vagal activity may cause some or all of the impulses arriving from the atria to be blocked in the node. The conduction pattern in which none of the atrial impulses reaches the ventricles is called a third degree, or complete, AV block (see the section ”). The vagally induced delay or absence of conduction through the AV node occurs mainly in the N region. This effect of vagal stimulation reflects the action of acetylcholine to hyperpolarize the membrane of the conducting fibers in the N region (Fig. 16.22 ). The greater the hyperpolarization at the time of arrival of the atrial impulse, the more impaired the AV conduction.


Physiology_Levy

Physiology_Levy. Cardiac sympathetic nerves, in contrast, facilitate AV conduction. They decrease the AV conduction time and enhance the rhythmicity of latent pacemakers in the AV junction. The norepinephrine released at the postganglionic sympathetic nerve terminals increases the amplitude and slope of the upstroke of the AV nodal action potentials, principally in the AN and N regions of the node.


Physiology_Levy

Physiology_Levy. The bundle of His passes subendocardially down the right side of the interventricular septum for approximately 1 cm •Fig. 16.22 Effects of a Brief Vagal Stimulus (St) on the Transmembrane Potential. Thisresponsewasrecordedfromanatrioventricular(AV)nodalfiber(red trace). Compoundactionpotentialswererecordedfromtheatrium(A1,A2,A3;upper blue trace)andfromtheHis-Purkinjesystem(H;lower blue trace).Notethatshortlyaftervagalstimulation,themembraneofthefiberwashyperpolarized.Theatrialexcitation(A2)thatarrivedattheAVnodewhenthecellwashyperpolarizedfailedtobeconducted,asdenotedbytheabsenceofadepolarizationintheHiselectrogram(H).Theatrialexcitationsthatpreceded(A1)andfollowed(A3)excitationA2wereconductedtotheHisbundleregion.(RedrawnfromMazgalevT.etal.Am J Physiol. 1986;251:H631.) and then divides into the right and left bundle branches (see


Physiology_Levy

Physiology_Levy. Fig. 16.17 ). The right bundle branch, a direct continuation of the bundle of His, proceeds down the right side of the interventricular septum. The left bundle branch, which is considerably thicker than the right, arises almost perpendicular from the bundle of His and perforates the interventricular septum. On the subendocardial surface of the left side of the interventricular septum, the left bundle branch splits into a thin anterior division and a thick posterior division. Conductionofimpulsesintherightorleftbundlebranchorineitherdivisionoftheleftbundlebranchmaybeimpaired.Conductionblocksmaydevelopinoneormoreoftheseconductionpathwaysasaconsequenceofcoronaryarterydiseaseordegenerativeprocessesassociatedwithaging,andtheygiverisetocharacteristicECGpatterns.Blockofeitherofthemainbundlebranchesisknownasright orleft bundle branch block. Blockofeitherdivisionoftheleftbundlebranchiscalledleft anterior orleft posterior hemiblock.


Physiology_Levy

Physiology_Levy. The right bundle branch and the two divisions of the left bundle branch ultimately subdivide into a complex network of conducting fibers, called Purkinje fibers, that spread out over the subendocardial surfaces of both ventricles. Purkinje fibers have abundant, linearly arranged sarcomeres, as do myocytes. However, the transverse (T) tubular system, which is well developed in myocytes, is absent in the Purkinje fibers of many species. Purkinje fibers are the broadest cells in the heart: 70 to 80 µm in diameter, in comparison with diameters of 10 to 15 µm for ventricular myocytes. Partly because of the large diameter of the Purkinje fibers, conduction velocity (1 to 4 m/second) in these fibers exceeds that in any other fiber type within the heart. The increased conduction velocity enables rapid activation of the entire endocardial surface of the ventricles.


Physiology_Levy

Physiology_Levy. The action potentials recorded from Purkinje fibers resemble those of ordinary ventricular myocardial fibers. However, because of the long refractory period of Purkinje fiber action potentials, many premature excitations of the atria are conducted through the AV junction but are then blocked by the Purkinje fibers. Blockade of these atrial excitations prevents premature contraction of the ventricles. This function of protecting the ventricles against the effects of premature atrial depolarization is especially pronounced at slow heart rates because the action potential duration, and hence the effective refractory period, of the Purkinje fibers vary inversely with the heart rate (see Fig. 16.16 ). At slow heart rates, the effective refractory period of the Purkinje fibers is especially prolonged.


Physiology_Levy

Physiology_Levy. Fig. 16.16 ). At slow heart rates, the effective refractory period of the Purkinje fibers is especially prolonged. In contrast to Purkinje fibers, the effective refractory period of AV node cells does not change appreciably over the normal range of heart rates and actually increases at very rapid heart rates. Therefore, when the atrium is excited at high repetition rates, it is the AV node that normally protects the ventricles from these excessively high frequencies.


Physiology_Levy

Physiology_Levy. The first portions of the ventricles to be excited by impulses arriving from the AV node are the interventricular septum (except the basal portion) and the papillary muscles. The activation wave spreads into the substance of the septum from both its left and right endocardial surfaces. Early contraction of the septum makes it more rigid and allows it to serve as an anchor point for contraction of the remaining ventricular myocardium. Furthermore, early contraction of the papillary muscles prevents eversion of the AV valves into the atria during ventricular systole.


Physiology_Levy

Physiology_Levy. The endocardial surfaces of both ventricles are activated rapidly, but the wave of excitation spreads from endocardium to epicardium at a slower velocity (≈0.3 to 0.4 m/sec). The epicardial surface of the right ventricle is activated earlier than that of the left ventricle because the right ventricular wall is appreciably thinner than the left. In addition, the apical and central epicardial regions of both ventricles are activated somewhat earlier than their respective basal regions. The last portions of the ventricles to be excited are the posterior basal epicardial regions and a small zone in the basal portion of the interventricular septum. The conditions necessary for reentry (defined in the following box) are illustrated in


Physiology_Levy

Physiology_Levy. The conditions necessary for reentry (defined in the following box) are illustrated in Fig. 16.23 . In each of the four panels, a single bundle of cardiac fibers splits into a left branch and a right branch. A connecting bundle runs cSimilar directional changes in the refractory period also occur in ventricular myocytes in response to changes in heart rate. •Fig. 16.23 The Role of Unidirectional Block in Reentry. A, Anexcitationwavetravelingdownasinglebundle(S)offiberscontinuesdowntheleft(L)andright(R)branches.Thedepolarizationwaveenterstheconnectingbranch(C)frombothendsandisextinguishedatthezoneofcollision.B, ThewaveisblockedintheLandRbranches.C, AbidirectionalblockexistsintheRbranch.D, AunidirectionalblockexistsintheRbranch.Theantegradeimpulseisblocked,buttheretrogradeimpulseisconductedthroughandreenterstheSbundle. between the two branches. Normally, the impulse moving down the single bundle is conducted along the left and right branches (see


Physiology_Levy

Physiology_Levy. between the two branches. Normally, the impulse moving down the single bundle is conducted along the left and right branches (see Fig. 16.23A ). As the impulse reaches the link to the connecting bundle ( Fig. 16.23C), it enters from both sides and becomes extinguished at the point of collision. The impulse from the left side cannot proceed because the tissue beyond is absolutely refractory; it has just been depolarized from the other direction. The impulse also cannot pass through the connecting bundle from the right for the same reason. Fig. 16.23B shows that the impulse cannot complete the circuit if an antegrade block exists in the left and right branches of the fiber bundle. Also, if a bidirectional block exists at any point in the loop (e.g., branch R in Fig. 16.23C ), the impulse also cannot reenter.


Physiology_Levy

Physiology_Levy. Fig. 16.23C ), the impulse also cannot reenter. Incertainconditions,acardiacimpulsemayreexcitesomemyocardialregionthroughwhichithadpassedpreviously.Thisphenomenon,knownasreentry, isresponsibleformanyclinicalarrhythmias(disturbancesincardiacrhythm).Thereentrymaybeorderedorrandom.Inorderedreentry,theimpulsetraversesafixedanatomicalpath,whereasinrandomreentry,thepathcontinuestochange. A necessary condition for reentry is that at some point in the loop the impulse can pass in one direction but not in the other. This phenomenon is called unidirectional block. As shown in Fig. 16.23D , the impulse may travel down


Physiology_Levy

Physiology_Levy. CHAPTER 16 Elements of Cardiac Function the left branch normally but is blocked in the antegrade direction in the right branch because of some pathological change in the myocardial cells in that branch. The impulse that was conducted down the left branch and through the connecting branch of the connecting bundle may then be able to penetrate the depressed region in the right branch from the retrograde direction, even though the antegrade impulse had been blocked previously at this same site. Why is the antegrade impulse blocked but not the retrograde impulse? The reason is that the antegrade impulse arrives at the depressed region in the right branch earlier than the retrograde impulse because the path length of the ante-grade impulse is very short, whereas the retrograde impulse traverses a much longer path. Therefore, the antegrade impulse may be blocked simply because it arrives at the depressed region during its effective refractory period. If the retrograde impulse is delayed


Physiology_Levy

Physiology_Levy. a much longer path. Therefore, the antegrade impulse may be blocked simply because it arrives at the depressed region during its effective refractory period. If the retrograde impulse is delayed sufficiently, the refractory period may have ended in the affected region, and the impulse can then be conducted back through this region and return to the single bundle.


Physiology_Levy

Physiology_Levy. Although unidirectional block is a necessary condition for reentry, it alone cannot cause reentry. For reentry to occur, the effective refractory period of the reentered region must be shorter than the conduction time around the loop. In Fig. 16.23D , if the tissue just beyond the depressed zone in the right branch is still refractory from the ante-grade depolarization, the retrograde impulse will not be conducted into the single bundle branch. Therefore, the conditions that promote reentry are those that prolong the conduction time or shorten the effective refractory period.


Physiology_Levy

Physiology_Levy. The functional characteristics of the various components of the reentry loops responsible for specific cardiac arrhythmias are diverse. Some loops are large and involve entire specialized conduction bundles, whereas others are microscopic. The loop may include myocardial fibers, specialized conducting fibers, nodal cells, and junctional tissues in almost any conceivable arrangement. In addition, the various cardiac cells in the loop may be normal or abnormal.


Physiology_Levy

Physiology_Levy. The propagation velocity along a multicellular cardiac conduction fiber is normally facilitated by gap junctions that lie between consecutive conducting fibers. Variations in the protein structure of the connexins in the gap junctions can affect the propagation velocity along these fibers. The chemical structure of the specific connexins can vary locally in cardiac tissues and, as a result, can establish local variations in propagation velocity. Such topical variations in velocity might include regions of unidirectional block that induce reentrant rhythm disturbances.


Physiology_Levy

Physiology_Levy. Triggered activity is so named because it is always coupled to a preceding action potential. Because reentrant activity is also coupled to a preceding action potential, the arrhythmias induced by triggered activity are usually difficult to distinguish from those induced by reentry. Triggered activity is caused by afterdepolarizations, of which two types •Fig. 16.24 Effect of Pacing at Different Cycle Lengths (CL) on Cesium-Induced Early Afterdepolarizations (EADs) in a Purkinje Fiber. A, EADsarenotevident.B, EADsfirstappear(arrows). ThethirdEADreachesthresholdandtriggersanactionpotential(third arrow). C, EADsthatappearaftereachdrivendepolarizationtriggeranactionpotential.D, Triggeredactionpotentialsoccurinsalvos.(ModifiedfromDamianoBP,RosenM.Circulation. 1984;69:1013.) are recognized: early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). EADs may appear either at the end of the action potential plateau (phase 2) or approximately midway through repolarization


Physiology_Levy

Physiology_Levy. early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). EADs may appear either at the end of the action potential plateau (phase 2) or approximately midway through repolarization (phase 3), whereas DADs occur near the very end of repolarization or just after full repolarization (phase 4).


Physiology_Levy

Physiology_Levy. EADs are more likely to occur when the prevailing heart rate is slow; a rapid heart rate suppresses EADs ( Fig. 16.24 ). EADs are also more likely to occur in cardiac cells with prolonged action potentials than in cells with shorter action potentials. For example, EADs can be induced more readily in myocytes from the midmyocardial region of the ventricular walls than in myocytes from the endocardial or epicardial regions because of the longer action potential of midmyocardial myocytes (see Fig. 16.5 ). Certain antiarrhythmic drugs, such as quinidine, prolong the action potential. As a consequence, such drugs increase the likelihood that EADs may occur. Hence, some antiarrhythmic drugs are also proarrhythmic. Insomecases,mutationsintheconnexin40gene(GJA5) underliethedevelopmentofatrialfibrillation.Thismutationimpairstheassemblyofgapjunctionsinmyocytesandthereforereduceselectricalcouplingofthecells,asdescribedbyGollobMHandcolleagues(2006).


Physiology_Levy

Physiology_Levy. The direct correlation between a cell’s action potential duration and its susceptibility to EADs is related to the time required for calcium channels in the cell membranes to recover from inactivation. When action potentials are sufficiently prolonged, the calcium channels that were activated at the beginning of the plateau have sufficient time to recover from inactivation and thus may be reactivated before the cell fully repolarizes. This secondary activation could then trigger an EAD. ThepathologicalsignificanceofEADswasrecognizedinconnectionwiththecongenitalanddrug-inducedlongQTsyndrome.Astheactionpotentiallengthens,EADsoccurandcausetriggeredautomaticity.Intheelectrocardiogram,thisproblemismanifestedaspolymorphicventriculartachycardia,alsocalledtorsades de pointes. Episodesoftorsadesdepointescanbeself-limitedbutmayprogresstoventricularfibrillationandsuddendeath.Hypokalemiaandbradycardia(see


Physiology_Levy

Fig.16.24) areclinicalhallmarksofthiscondition.RestoringextracellularK+ tonormallevelsandincreasingheartratearetwoapproachesusedtoovercomethepropensityfordevelopmentoftorsadesdepointes.


Physiology_Levy

Physiology_Levy. In contrast to EADs, DADs are more likely to occur when the heart rate is high (Fig. 16.25 ). DADs are associated with elevated intracellular [Ca++]. The amplitudes of DADs are increased by interventions that raise intracellular [Ca++], such as increasing extracellular [Ca++] and administering toxic amounts of digitalis glycosides. The elevated levels of intracellular Ca++ provoke the oscillatory release of Ca++ from the sarcoplasmic reticulum. Hence, in myocardial cells, DADs are accompanied by small rhythmic changes in the force developed. The high intracellular [Ca++] also activates certain membrane channels that allow the passage of Na+ and K+ . The net flux of these cations constitutes a transient inward current (iti), that contributes to the appearance of DADs. The elevated intracellular [Ca++] may also activate the 3Na+-Ca++ antiporter. This electrogenic antiporter, which moves three Na+ ions into the cell for each Ca++ ion that it releases, also creates a net inward cation


Physiology_Levy

Physiology_Levy. [Ca++] may also activate the 3Na+-Ca++ antiporter. This electrogenic antiporter, which moves three Na+ ions into the cell for each Ca++ ion that it releases, also creates a net inward cation current that contributes to the appearance of DADs.


Physiology_Levy

Physiology_Levy. The ECG enables physicians to infer the course of cardiac electrical impulses by recording the variations in electrical potential at various loci on the surface of the body. By analyzing the details of these fluctuations in electrical potential, the physician gains valuable insight into (1) the anatomical orientation of the heart; (2) the relative sizes of its chambers; (3) various disturbances in rhythm and conduction; (4) the extent, location, and progress of ischemic damage to the myocardium; (5) the effects of •Fig. 16.25 Transmembrane Action Potentials Recorded From Purkinje Fibers. Acetylstrophanthidin,adigitalisglycoside,wasaddedtothebath,andsequencesofsixdrivenbeats(denotedbythedots)wereeachproducedatabasiccyclelength(BCL)of800(A), 700(B), 600(C), and500(D) msec.NotethatdelayedafterpotentialsoccurredafterthedrivenbeatsandthattheseafterpotentialsreachedthresholdafterthelastdrivenbeatinB toD. (FromFerrierGR,etal.Circ Res. 1973;32:600.) altered electrolyte concentrations; and (6)


Physiology_Levy

Physiology_Levy. toD. (FromFerrierGR,etal.Circ Res. 1973;32:600.) altered electrolyte concentrations; and (6) the influence of certain drugs (notably digitalis, antiarrhythmic agents, and calcium channel antagonists). Because electrocardiography is an extensive and complex discipline, only the elementary principles are considered in this section.


Physiology_Levy

Physiology_Levy. P-R QRS Q P R S T QT ST 0.1 sec •Fig. 16.26 Importantdeflectionsandintervalsofatypicalscalarelectrocardiogram.


Physiology_Levy

Physiology_Levy. In electrocardiography, a lead is the electrical connection from the patient’s skin to a recording device (electrocardiograph) that measures the electrical activity of the heart. The system of leads used to record routine ECGs is oriented in certain planes of the body. The diverse electrical events that exist in the heart at any moment can be represented by a three-dimensional vector (a quantity with magnitude and direction). A system of recording leads oriented in a given plane detects only the projection of the three-dimensional vector on that plane. The potential difference between two recording electrodes represents the projection of the vector on the line between the two leads. Components of vectors projected on such lines are not vectors but scalar quantities (having magnitude but not direction). Hence, a recording of changes in the difference in potential between two points on the skin surface over time is called a scalar ECG.


Physiology_Levy

Physiology_Levy. A scalar ECG detects temporal changes in the electrical potential between some point on the surface of the skin and an indifferent electrode or between pairs of points on the skin surface. The cardiac impulse progresses through the heart in a complex three-dimensional pattern. Hence, the precise configuration of the ECG varies from individual to individual, and in any given individual, the pattern varies with the anatomical location of the leads. The graphic display of the electrical impulse recorded in an ECG is called a tracing. In general, a tracing consists of P, QRS, and T waves (


Physiology_Levy

Physiology_Levy. In general, a tracing consists of P, QRS, and T waves ( Fig. 16.26). The P wave reflects the spread of depolarization through the atria, the QRS wave (or complex) reflects depolarization of the ventricles, and the T wave represents repolarization of the ventricles (repolarization of the atria occurs, and is therefore masked, during ventricular depolarization). The PR interval (or more precisely, the PQ interval) is a measure of the time from the onset of atrial activation to the onset of ventricular activation; it normally ranges from 0.12 to 0.20 second. A large fraction of this time involves passage of the impulse through the AV conduction system. Pathological prolongations of the PR interval are associated with disturbances in AV conduction. Such disturbances may be produced by inflammatory, circulatory, pharmacological, or neuronal mechanisms.


Physiology_Levy

Physiology_Levy. The configuration and amplitude of the QRS complex vary considerably among individuals. The duration is usually between 0.06 and 0.10 second. An abnormally prolonged QRS complex may indicate a block in the normal conduction pathways through the ventricles (such as a block of the left or right bundle branch). During the ST interval, the entire ventricular myocardium is depolarized. Therefore, the ST segment normally lies on the isoelectric line. Any appreciable deviation of the ST segment from the isoelectric line may indicate ischemic damage to the myocardium. The QT interval, sometimes referred to as the period of “electrical systole” of the ventricles, is closely correlated with the mean action potential duration of the ventricular myocytes. The duration of the QT interval is approximately 0.4 second, but it varies inversely with the heart rate, mainly because the duration of the myocardial cell’s action potential varies inversely with the heart rate (see Fig. 16.16


Physiology_Levy

Physiology_Levy. Fig. 16.16 In most leads, the T wave is deflected in the same direction from the isoelectric line as the major component of the QRS complex, although biphasic (i.e., oppositely directed) T waves are perfectly normal in certain leads. Deviation of the T wave and QRS complex in the same direction from the isoelectric line indicates that the repolarization process is proceeding in a direction counter to that of the depolarization process. T waves that are abnormal either in direction or in amplitude may indicate myocardial damage, electrolyte disturbances, or cardiac hypertrophy. The original ECG lead system was devised by Willem Einthoven at the beginning of the 20th century. In this system, the vector sum of all cardiac electrical activity at any moment is called the resultant cardiac vector. This directional electrical force is considered to lie in the center of an equilateral triangle whose apices are located in the left and right shoulders and the pubic region (


Physiology_Levy

Physiology_Levy. Fig. 16.27 ). This triangle, called Einthoven’s triangle, is oriented in the frontal plane of the body. Hence, only the projection of the resultant cardiac vector on the frontal plane is detected by this system of leads. For convenience, the electrodes are connected to the right and left forearms rather than to the corresponding shoulders because the arms represent simple electrical extensions of leads from the shoulders. Similarly, the leg represents an extension of the lead system from the pubis, and thus the third electrode is generally connected to an ankle (usually the left one). Certain conventions dictate the manner in which these standard limb leads are connected to the electrocardiograph. Lead I records the potential difference between the left arm and the right arm. The connections are such that when the •Fig. 16.27 Einthoven’striangle,illustratingtheelectrocardiographicconnectionsforstandardlimbleadsI,II,andIII.


Physiology_Levy

Physiology_Levy. potential at the left arm (VLA) exceeds the potential at the right arm (VRA), the tracing is deflected upward from the isoelectric line. In Fig. 16.27 Fig. 16.28 , this arrangement of connections for lead I is designated by a plus sign at the left arm and by a minus sign at the right arm. Lead II records the potential difference between the right arm and the left leg, and the tracing is deflected upward when the potential at the left leg (VLL) exceeds VRA. Finally, lead III registers the potential difference between the left arm and the left leg, and the tracing is deflected upward when VLL exceeds VLA. These connections were chosen arbitrarily so that the QRS complexes are upright in all three standard limb leads in most normal individuals. If the frontal projection of a resultant cardiac vector at some moment is represented by an arrow (tail negative, head positive), as in


Physiology_Levy

Physiology_Levy. If the frontal projection of a resultant cardiac vector at some moment is represented by an arrow (tail negative, head positive), as in Fig. 16.27 , the potential difference, VLA − VRA, recorded in lead I is represented by the component of the vector projected along the horizontal line between the left arm and the right arm, also shown in Fig. 16.27 . If the vector makes an angle (θ) of 60 degrees with the horizontal line (as in Fig. 16.28A), the deflection recorded in lead I is upward because the positive arrowhead lies closer to the left arm than to the right arm. The deflection in lead II is also upright because the arrowhead lies closer to the left leg than •Fig. 16.28 MagnitudeanddirectionoftheQRScomplexesinlimbleadsI,II,andIIIwhenthemeanelectricalaxis(θ)is60degrees(A), 120degrees(B), and0degrees(C).


Physiology_Levy

Physiology_Levy. to the right arm. The magnitude of the lead II deflection is greater than that in lead I because in this example, the direction of the vector parallels that of lead II; therefore, the magnitude of the projection on lead II exceeds that on lead I. Similarly, in lead III, the deflection is upright and its magnitude equals that in lead I. If the vector in Fig. 16.27A is the result of electrical events that occur during the peak of the QRS complex, the orientation of this vector is said to represent the mean electrical axis of the heart in the frontal plane. The positive rotatory direction of this axis is assumed to be in the clockwise direction from the horizontal plane (contrary to the usual mathematical convention). In normal individuals, the average mean electrical axis is approximately +60 degrees (as in Fig. 16.28A ). Therefore, QRS complexes are usually upright in all three leads and largest in lead II. If the mean electrical axis shifts substantially to the right (as in


Physiology_Levy

Physiology_Levy. Fig. 16.28A ). Therefore, QRS complexes are usually upright in all three leads and largest in lead II. If the mean electrical axis shifts substantially to the right (as in Fig. 16.28B , in which θ= 120 degrees), projections of the QRS complexes on the standard leads change considerably. In this case, the largest upright deflection is in lead III, and the deflection in lead I is inverted because the arrowhead is closer to the right arm than to the left arm. Such a shift is termed right axis deviation and occurs with hypertrophy (i.e., increased thickness) of the right ventricle. When the axis shifts to the left, as occurs with hypertrophy of the left ventricle (see Fig. 16.28C , where θ= 0 degrees), the largest upright deflection is in lead I, and the QRS complex in lead III is inverted.


Physiology_Levy

Physiology_Levy. Fig. 16.28C , where θ= 0 degrees), the largest upright deflection is in lead I, and the QRS complex in lead III is inverted. In addition to limb leads I, II, and III, other limb leads that are also oriented in the frontal plane are routinely recorded in patients. These leads are (1) aVR, for which the right arm is defined as the positive lead and the middle of the heart is defined as the negative lead (i.e., the left arm and ankle leads are connected together); (2) aVL, for which the left arm is the positive lead and the middle of the heart is defined as the negative lead (i.e., the right arm and ankle leads are connected together); and (3) aVF, for which the ankle (foot) lead is defined as positive and the middle of the heart is defined as the negative lead (i.e., the two arm leads are connected together). The axes of these leads form angles of +90 degrees for aVF, −30 degrees for aVL, and −150 degrees for aVR (all with respect to the horizontal axis).


Physiology_Levy

Physiology_Levy. Leads can also be applied to the surface of the chest, so-called precordial leads, to determine the projections of the cardiac vector on the sagittal and transverse planes of the body. These precordial leads are recorded from six selected points on the anterior and lateral surfaces of the chest in the vicinity of the heart. The leads extend from the right border of the sternum in the fourth intercostal space (lead V1) to under the left arm (midaxillary line) in the fifth intercostal space (lead V6). Each precordial lead (V1 to V6) is defined as a positive lead, whereas the middle of the heart is defined as the negative lead. Detailed analysis of the ECG, as detected by the various lead systems just described, is beyond the scope of this book. Interested students are referred to textbooks on electrocardiography for more information.


Physiology_Levy

Physiology_Levy. Changesinthemeanelectricalaxismayoccuriftheanatomicalpositionoftheheartisalteredoriftherelativemassoftherightandleftventriclesisabnormal,asitisincertaincardiovasculardisturbances.Forexample,theaxistendstoshifttowardtheleft(morehorizontal)inshort,stockyindividualsandtowardtheright(morevertical)intall,thinpersons.Inaddition,inleftorrightventricularhypertrophy(increasedmyocardialmassofeitherventricle),theaxisshiftstowardthehypertrophiedside. Cardiac arrhythmias are disturbances in either impulse initiation or impulse propagation. Disturbances in impulse initiation include those that arise from the SA node and •Fig. 16.29 Electrocardiographic Tracings of Heart Rhythms. A, Normalsinusrhythm.B, Sinus tachycardia.C, Sinusbradycardia. those that originate from various ectopic foci. The principal disturbances in impulse propagation are reentrant rhythms and conduction blocks.


Physiology_Levy

Physiology_Levy. those that originate from various ectopic foci. The principal disturbances in impulse propagation are reentrant rhythms and conduction blocks. Mechanisms that vary the firing frequency of cardiac pacemaker cells were described previously. Changes in the firing rate of the SA node are usually produced by cardiac autonomic nerves. When the firing rate of the SA node is decreased, the heart rate also decreases (bradycardia). Conversely, increased SA node firing results in elevation of the heart rate (tachycardia). Examples of ECGs of sinus tachycardia and sinus bradycardia are shown in Fig. 16.29 . The P, QRS, and T deflections are all normal, but duration of the cardiac cycle (the PP interval) is altered. The changes in cardiac frequency are characteristically gradual. A rhythmic variation of the PP interval at the respiratory frequency (i.e., a respiratory sinus arrhythmia) is a normal, common occurrence (see Fig. 18.7


Physiology_Levy

Physiology_Levy. Fig. 18.7 Various physiological, pharmacological, and pathological processes can impede transmission of an impulse through the AV node. The site of block can be localized more precisely by an electrocardiogram of the His bundle (Fig. 16.30 ). To obtain such tracings, an electrode catheter is inserted into a peripheral vein and advanced centrally into the right side of the heart until the electrode lies in the AV junctional region. When the electrode is properly positioned, a distinct deflection (H in Fig. 16.30 ) is registered as the cardiac impulse passes through the bundle of His. The time intervals required for propagation from the atrium to the bundle of His and from the bundle of His to the ventricles (His-to-ventricle interval) may be measured accurately. Abnormal prolongation of the atrium-to-His or His-to-ventricle interval indicates block above or below the bundle of His, respectively.


Physiology_Levy

Physiology_Levy. Premature depolarizations occur occasionally in most normal individuals, but they arise more commonly in certain abnormal conditions. Such depolarizations may originate in the atria, AV junction, or ventricles. One type of premature depolarization follows a normally conducted depolarization at a constant time interval (the coupling interval). If the normal depolarization is suppressed in some way (e.g., by vagal stimulation), the premature depolarization is also abolished. Such premature depolarizations are called coupled extrasystoles, or simply extrasystoles, and they


Physiology_Levy

Physiology_Levy. P A H V T QRS 0.2 sec •Fig. 16.30 ElectrocardiogramoftheHisbundle(lower tracing, retouched)andleadIIrecordingofthescalarelectrocardiogram(upper tracing). ThedeflectionH,whichrepresentsconductionoftheimpulseoverthebundleofHis,isclearlyvisiblebetweentheatrial andtheventricular(V)deflections.TheconductiontimefromtheatriatothebundleofHisisdenotedbytheA-Hinterval;thatfromthebundleofHistotheventricles,bytheH-Vinterval.(CourtesyofDr. J. Edelstein.) ThreedegreesofAVblockcanbedistinguished,asshownin


Physiology_Levy


Physiology_Levy

Physiology_Levy. •Fig. 16.31 Atrioventricular (AV) Blocks. A, First-degreeblock;thePRintervalis0.28second(normal, <0.20sec).B, Second-degreeblock(ratioofPwavestoQRScomplexes,2:1).C, Third-degreeblock;notethedissociationbetweenthePwavesandtheQRScomplexes. •Fig. 16.32 Premature Atrial Depolarization and Premature Ventricular Depolarization. Theprematureatrialdepolarization(A; secondbeat)ischaracterizedbyaninvertedPwave(justbelowthesecond“P”)andnormalQRScomplexesandTwaves.Theintervalaftertheprematureatrialdepolarizationisnotmuchlongerthantheusualintervalbetweenbeats.Thebriefrectangulardeflectionjustbeforethelastatrialdepolarizationisastandardizationsignal.Theprematureventriculardepolarization(B) ischaracterizedbybizarre,invertedQRScomplexesandelevatedTwavesandisfollowedbyacompensatorypause.


Physiology_Levy

Physiology_Levy. generally reflect a reentry phenomenon. A second type of premature depolarization occurs as the result of enhanced automaticity in some ectopic focus. This ectopic center may fire regularly, and a zone of tissue that conducts unidirectionally may protect this center from being depolarized by the normal cardiac impulse. If this premature depolarization occurs at a regular interval or at an integral multiple of that interval, the disturbance is called parasystole. A tracing of a premature atrial depolarization is shown in


Physiology_Levy

Physiology_Levy. A tracing of a premature atrial depolarization is shown in Fig. 16.32A . With a premature atrial depolarization, the normal interval between beats is shortened. In addition, the configuration of the premature P wave differs from that of the other normal P waves because the course of atrial excitation, which originates at some ectopic focus in the atrium, differs from the normal spread of excitation, which originates at the SA node. The QRS complex of the premature depolarization is generally normal because the ventricular excitation spreads over the usual pathways. A tracing of a premature ventricular depolarization is shown in


Physiology_Levy

Physiology_Levy. A tracing of a premature ventricular depolarization is shown in Fig. 16.32B . Propagation of the impulse is abnormal, and the configuration of the QRS complex and T wave is entirely different from the normal ventricular deflections because the premature excitation originates at some ectopic focus in the ventricles. The time interval between the premature QRS complex and the preceding normal QRS complex is shortened, whereas the interval after the premature QRS complex and the next normal QRS complex is prolonged by a compensatory pause. The interval from the QRS complex just before the premature excitation to the QRS complex just after it is virtually equal to the duration of two normal cardiac cycles. •Fig. 16.33 Paroxysmaltachycardias.A, supraventriculartachycardia;PwavesprecedeeachQRScomplex.B, ventriculartachycardia;Pwavesnotreadilyobserved.


Physiology_Levy

Physiology_Levy. •Fig. 16.33 Paroxysmaltachycardias.A, supraventriculartachycardia;PwavesprecedeeachQRScomplex.B, ventriculartachycardia;Pwavesnotreadilyobserved. As noted, a compensatory pause usually follows a premature ventricular depolarization. This pause occurs because the ectopic ventricular impulse does not disturb the natural rhythm of the SA node. There are two possible reasons for this: The ectopic ventricular impulse is not conducted in a retrograde direction through the AV conduction system, or the SA node had already fired at its natural interval before the ectopic impulse could have reached and depolarized it prematurely. Likewise, the SA nodal impulse generated just before or after the ventricular extrasystole generally does not affect the ventricle because the AV junction and perhaps also the ventricles are still refractory from the premature ventricular excitation.


Physiology_Levy

Physiology_Levy. In contrast to the gradual rate changes that characterize sinus tachycardia, tachycardias that originate from an ectopic focus typically begin and end abruptly. Such ectopic tachycardias are generally called paroxysmal tachycardias. Episodes of paroxysmal tachycardia may persist for only a few beats or for many hours or days, and episodes often recur. Paroxysmal tachycardias may result from (1) rapid firing of an ectopic pacemaker, (2) triggered activity secondary to afterpotentials that reach threshold, or (3) an impulse that circles a reentry loop repetitively. Under certain conditions, cardiac muscle undergoes an irregular type of contraction that is ineffectual in propelling blood. Such an arrhythmia is termed fibrillation, and the disturbance may involve either the atria or the ventricles. Fibrillation probably represents a reentry phenomenon in which the reentry loop fragments into multiple, irregular circuits.


Physiology_Levy

Physiology_Levy. The electrocardiographic changes in atrial fibrillation are shown in


Physiology_Levy

Physiology_Levy. Fig. 16.34A . This arrhythmia occurs in various types of chronic heart disease. The atria do not contract and relax sequentially during each cardiac cycle, and thus they do not contribute to ventricular filling. Instead, the atria undergo a continuous, uncoordinated rippling motion. P waves do not appear on the ECG; instead, the tracing shows continuous irregular fluctuations in potential called f waves. The AV node is activated at intervals that may vary considerably from cycle to cycle. Hence, no constant interval occurs between successive QRS complexes or between successive ventricular contractions. Because the strength of ventricular contraction depends on the interval between beats (see ), the volume and rhythm of the pulse are irregular. In many affected patients, the atrial reentry loop and the pattern of AV conduction are more regular than they are in atrial fibrillation. The rhythm is then referred to as atrial flutter. •Fig. 16.34 Atrial(A)andventricular(B)fibrillation.


Physiology_Levy

Physiology_Levy. Fig.16.34B ),thefluctuationsinpotentialarehighlyirregular. Ventricular fibrillation is often initiated when a premature impulse arrives during the vulnerable period of the cardiac cycle. This period coincides with the downslope of the T wave on the ECG. During this period, the excitability of cardiac cells varies spatially. Some fibers are still in their effective refractory periods, others have almost fully recovered their excitability, and still others are able to conduct impulses, but only at very slow conduction velocities. As a consequence, the action potentials are propagated over the chambers in many irregular wavelets that travel along circuitous paths and at various conduction velocities. As a region of cardiac cells becomes excitable again, it is ultimately activated by one of the wave fronts traveling around the chamber. Hence, the process is self-sustaining.


Physiology_Levy

Physiology_Levy. •Fig. 16.35 Electrocardiogramsrecordedfromanormalsubject(A) andfromapatientwithlongQTsyndrome(B). Q SQ S P PT T R R 1 sec. Normal Q SQ S P P T R R Long QT A B Insomeindividuals,theintervalbetweentheQRScomplexandtheTwaveisabnormallyprolonged,aconditiontermedlong QT syndrome (Fig.16.35 ).SeveralcongenitalformsoflongQTsyndromehavebeenidentifiedinhumansubjects.TwoofthemanygenesthathavebeenidentifiedasabasisforthissyndromearetheHERG gene(aK+ channelgene),locatedonchromosome7,andtheSCN5A gene(aNa+ gene),locatedonchromosome3.PatientswithcongenitalformsoflongQTsyndromemayhaveperiodicepisodesofsyncope(fainting),andapproximately10%ofpediatricsubjectswiththisdisordermaydiesuddenly,withoutanyprecedingsymptoms.Insomeindividualswithsilentionchannelmutations,longQTsyndromemaynotbeevidentuntiladrugistakenthataffectstheionchannelinvolved.Manydrugs,includingseveralantiarrhythmicagents,havebeenidentifiedascausingacquiredlongQTsyndrome.


Physiology_Levy

Physiology_Levy. Atrial fibrillation may be changed to a normal sinus rhythm by drugs that prolong the refractory period. As the cardiac impulse completes the reentry loop, it may then encounter refractory myocardial fibers. When atrial fibrillation does not respond adequately to drugs, electrical defibrillation may be used to correct this condition. Dramatic therapy is required for ventricular fibrillation. Conversion to a normal sinus rhythm is accomplished by means of a strong electrical current that places the entire myocardium briefly in a refractory state. Techniques have been developed to administer the current safely through the intact chest wall. In successful cases, the SA node again takes over the normal pacemaker function for the entire heart. The Cardiac Pump The great amount of work performed by the heart over an individual’s lifetime is impressive. A useful way to


Physiology_Levy

Physiology_Levy. The Cardiac Pump The great amount of work performed by the heart over an individual’s lifetime is impressive. A useful way to Implantablecardioverter-defibrillator(ICD)deviceshavebeendevelopedtopreventdeathinpatientsinwhomeitherventricularfibrillationorparoxysmalventriculartachycardiahassuddenlydeveloped.Theformerislethalunlessitistreatedimmediately,andthelatteroftenleadstoventricularfibrillationandsuddendeath.TheICDdeviceisimplantedsubcutaneouslyintheleftsubclavicularregionofthechestwall.Atrialandventricularleadsenablerecordingoftherightatrialandrightventricularelectrocardiogramsandprovidetheabilityforrightatrialorrightventricularpacing,orboth.Thedefibrillationcoilintherightventricleenablestheapplicationofastrongelectricalcurrenttotheventricleandtherebyusuallyterminatesthelethalarrhythmia. understand how the heart accomplishes its important task is to consider the relationships between the structure and function of its components. Relationship of Heart Structure to Function


Physiology_Levy

Physiology_Levy. understand how the heart accomplishes its important task is to consider the relationships between the structure and function of its components. Relationship of Heart Structure to Function The Myocardial Cell ). Of importance is that both are striated as a result of regular arrangement of the contractile proteins actin and myosin, and generation of force and contraction of muscle fiber occur as a result of their interactions (i.e., sliding filament mechanism). Skeletal muscle and cardiac muscle show similar length-force relationships. As shown in , this relationship for the heart may be expressed graphically, as in Fig. 16.36, by substituting ventricular systolic pressure for force and end-diastolic ventricular volume for resting myocardial fiber (and hence sarcomere) length. The lower curve in Fig.


Physiology_Levy

Physiology_Levy. Fig. 16.36, by substituting ventricular systolic pressure for force and end-diastolic ventricular volume for resting myocardial fiber (and hence sarcomere) length. The lower curve in Fig. 16.36 represents the increment in pressure produced by each increment in volume when the heart is in diastole. The upper curve represents the peak force or pressure developed by the ventricle during systole as a function of initial fiber length (or diastolic filling pressure). This curve illustrates the Frank-Starling law of the heart. The pressure-volume curve during diastole is initially quite flat (compliant), which indicates that large increases in volume can be accommodated with only small increases in pressure. In contrast, the development of systolic pressure is considerable at the lower filling pressures. However, the ventricle becomes much less distensible with greater filling, as evidenced by the sharp rise in the diastolic pressure curve at large intraventricular volumes.


Physiology_Levy

Physiology_Levy. In a normal intact heart, peak force may be attained at a filling pressure of approximately 12 mm Hg. At this intraventricular diastolic pressure, which is near the upper limit observed in a normal heart, sarcomere length is near its resting length of 2.2 µm. However, the force causes filling pressures to peak as high as 30 mm Hg. At even higher diastolic pressures (>50 mm Hg), sarcomere length is no greater than 2.6 µm. This ability of the myocardium to resist stretch at high filling pressures probably resides in the noncontractile constituents of the heart tissue (connective tissue), and it may serve as a safety factor against overloading of the heart in diastole. Usually, ventricular diastolic pressure is approximately 0 to 7 mm Hg, and the average diastolic sarcomere length is approximately 2.2 µm. Thus a normal heart operates on the ascending portion of the Frank-Starling curve, as depicted in


Physiology_Levy

Physiology_Levy. Fig. 16.36 •Fig. 16.36 Relationshipofmyocardialrestingfiberlength(sarco-merelength)orend-diastolicvolumetotheforcedevelopedorpeaksystolicventricularpressureduringventricularcontractioninanintactheart.(RedrawnfromPattersonSW,etal.J Physiol. 1914;48:465.) Cardiac muscle functions as a syncytium; that is, a stimulus applied to any part of the cardiac muscle results in contraction of the entire muscle. Gap junctions with high conductance are present in the intercalated disks between adjacent cells and facilitate conduction of the cardiac impulse from one cell to the next. Cardiac muscle must contract repetitively for a lifetime, and hence it requires a continuous supply of O2. Cardiac muscle is therefore very rich in mitochondria. The large number of mitochondria (see Fig. 13.1 B), which have the enzymes necessary for oxidative phosphorylation, allows rapid oxidation of substrates and synthesis of ATP and thus sustains the myocardial energy requirements.


Physiology_Levy

Physiology_Levy. Fig. 13.1 B), which have the enzymes necessary for oxidative phosphorylation, allows rapid oxidation of substrates and synthesis of ATP and thus sustains the myocardial energy requirements. CHAPTER 16 Elements of Cardiac Function To provide adequate O2 and substrate for its metabolic machinery, the myocardium is also endowed with a rich capillary supply, approximately one capillary per fiber. Thus diffusion distances are short, and O2, CO2, substrates, and waste material can move rapidly between the myocardial cell and capillary. The transverse (T) tubular system within myocardial cells participates in this exchange of substances between capillary blood and myocardial cells (as described later, the T tubule system also plays a key role in excitation-contraction coupling). The T tubular system is absent or poorly developed in the atrial cells of many mammals.


Physiology_Levy

Physiology_Levy. Results of the earliest studies on isolated hearts indicated that optimal concentrations of Na+ , K+ , and Ca++ in extracellular fluid are necessary for contraction of cardiac muscle. Without Na+ , the heart is not excitable and does not beat. As already described, the resting membrane potential is independent of the extracellular [Na+] gradient across the membrane but very much dependent on extracellular [K+]. Decreases or increases in extracellular [K+], especially if they are large or occur quickly, can lead to arrhythmias, loss of excitability of the myocardial cells, and even cardiac arrest. Ca++ is also essential for cardiac contraction. Removal of Ca++ from the extracellular fluid results in decreased contractile force and eventual arrest in diastole. Conversely, an increase in extracellular [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