Symposium on Cardiac Rhythm Disturbances I
Coronary Occlusion Effect on Cellular Electrical Activity of the Heart
Robert E. Ten Eick, Ph.D.,* Donald H. Singer, M.D.,** and Lloyd E. Solberg, M.D.*** M.D. ***
Severe disturbances of cardiac rate and rhythm are potentially dangerous sequellae of coronary occlusive events in man. 99 However, despite their common occurrence very little is known about the underlying mechanisms. Current theory holds that the mechanisms of cardiac arrhythmias, presumably including those underlying arrhythmias associated with myocardial infarction, are most easily understood in terms of the changes in cellular electrical activity that result from myocardial infarction. The problem with such an electrophysiologic approach to the study of human heart which has suffered an acute ischemic episode is that suitable specimens at the various stages of the infarction process are not available for study. It is even rare for an old resolved infarct to become available for study by the electrophysiologist. Recently, several groups of investigators have attempted to overcome the problems of having limited material and no reasonably controlled way to characterize the cellular electrophysiological changes associated with myocardial infarction by developing a canine model which appears to exhibit certain similarities to the infarcted human heart. The model is made by occluding either the anterior descending coronary artery, the so-called "Harris model,"12 or the circumflex coronary artery17 artery17 of the thoracotomized, anesthetized dog. The former procedure results in a large area of ischemic and infarcted tissue in the region of the anterior papillary From the Departments of Pharmacology and Medicine and The Reingold ECG Center, Northwestern University Medical School, Chicago, Illinois ':'Associate Professor of Pharmacology ':":'Associate Professor of Medicine and Pharmacology; Director, Reingold ECG Center, "':'Associate Northwestern University Medical School :::Formerly Formerly Northwestern University Medical School, Chicago, Illinois. Presently Resident in Internal Medicine, Mayo Clinic, Rochester, Minnesota Supported in part by U.S.P.H.S. Training Grant TO-I-GM 00162-14 and Grants-in-aid from the Chicago Heart Association (N eN 69-68, B 74-73) and the American Heart Association (74 1065). Dr. Ten Eick is a recipient of a U.S.P.H.S. Research Career Development Award. Portions of this work were done during Dr. Singer's tenure as an Established Investigator of the American Heart Association.
Medical Clinics of North America- Vol. Vo!. 60, No. 1, January 1976
49
50
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
muscle, largely sparing the posterior papillary muscle. The latter procedure similarly affects the posterior papillary muscle, sparing the anterior IS The resultant electrocardiographic changes, while papillary muscle. 18 not precisely mimicking those which occur in the human, seem largely 8 • 10 The cellular pathology observed in the dog model at both the similar. similar.s, light and electron microscopic levels also is remarkably like that seen in 48 specimens of infarcted human ventricular myocardium. 44,4s Therefore, • there is some evidence to support the notion that studies of the cellular electrical activity of the dog model can provide important insights into the electrophysiologic basis of the dysrhythmias which occur in the human heart in conjunction with a significant coronary occlusive event. With this premise in mind, we shall describe some of the changes in cellular electrical activity associated with coronary occlusion in dogs which are currently believed to be important factors in the development of infarct-induced ventricular arrhythmias. The evidence to be presented will support the notion that cellular mechanisms underlying infarct-induced dysrhythmia evolve after the occlusive event. The initial phase of arrhythmia, beginning within a few minutes of the onset of ischemia and lasting for 15 to 20 minutes, is supported by radical changes in the cellular milieu as well as by a significant neural component. Within 1 hour after coronary occlusion, changes in the membrane properties of the involved myocardium can be detected in the absence of changes in the overlying endocardium, epicardium, or Purkinje fiber fib er network. Several hours after occlusion evidence of electrical activity in the involved intramural myocardium is no longer obtainable except in small, isolated and widely scattered areas, thus possibly terminating its contribution to the production of rhythm disturbances. At the same time, however, the activity and properties of the endocardium and Purkinje network overlying the infarcted myocardium appear to change. These changes progress with varying time courses and, after a period of from days to weeks, seem to reverse and ultimately disappear simultaneously without evidence of any residual disturbances of cardiac rate and rhythm. 55 Thus, the heart is usually left with a scar at the site of the infarct but with a normal rhythm and no evidence of residual electrophysiologic changes in the surviving cells and tissues. tissues.'4 Before presenting specific data in support of our hypothesis regarding the nature of the changes in cellular electrophysiology which must be expected to be responsible for dysrhythmias associated with myocardial infarction, we shall briefly review current concepts as to the cellular mechanisms which underlie initiation and perpetuation of disturbances of cardiac rate and/or rhythm. Such disturbances can be viewed as resulting from alterations in normal and/or abnormal automaticity, abnormal conductivity, or both acting in concert. What do these terms mean? Automaticity refers to the ability of excitable cells, such as occur in the heart, to spontaneously generate impulses. Normally, impulses are generated because the cell in question does not maintain a stable level of membrane potential during electrical diastole but rather undergoes slow spontaneous depolarization toward a critical level of potential. If this critical level of potential, termed 'threshold potential' is
CORONARY OCCLUSION
51
reached, a spontaneous impulse is initiated. Cells exhibiting this capability are termed automatic and can serve as pacemakers for the heart. Ordinarily, the cardiac impulse is generated by specialized automatic (pacemaker) cells in the sinus node. However, cells in other portions of the specialized tissues of the atria and ventricles (His-Purkinje system) also are capable of forming impulses which can under certain conditions excite the heart. When impulses generated by automatic cells in portions of the heart other than the sinus node take control of the heart for one or more beats, disturbances of cardiac rate/rhythm will ensue. As will be subsequently discussed, this may also result in disturbances of impulse conduction. We will also present evidence to show that as a result of myocardial infarction even ordinary myocardial cells may become capable of spontaneous impulse formation, to be designated "abnormal" automaticity. The nature of the ionic mechanism(s) underlying such "abnormal" automaticityare tomaticity are not yet resolved and may differ from those postulated for spontaneous diastolic depolarization of normal pacemaker cells. Conductivity refers to the property of excitable cells which enables impulse propagation to occur. Normal impulse spread and the normal sequence of activation depend upon the occurrence of more or less normal conductivity in ordinary and specialized cells in all parts of the heart. If conductivity is depressed, the spread of electrical activity will proceed more slowly than normally. Decrement (i.e., progressive slowing of conduction velocity) and varying degrees of block may ensue. re entry may develop. Dysrhythmia resulting from slow conduction and reentry Conductivity is governed by a number of factors, the more important of which include membrane excitability, responsiveness, and refractoriness. The level of the diastolic membrane potential (and therefore the occurrence of spontaneous diastolic depolarization); action potential configuration; the passive electrical properties of the cell membrane and the electrophysiologic response of the membrane to extrinsic factors such as catecholamines, potassium, metabolic products, physical distention, and so forth, may all affect impulse conduction to a varying degree. Considerations of the manner in which these various extrinsic and intrinsic factors influence conductivity is beyond the scope of this article. However, the reader should be aware that changes in any of these properties, particularly when they occur to a varying extent in neighboring locales, may alter conduction in such a way as to cause fragmentation of the excitation wave and reentry. For a more thorough treatment of the general mechanisms underlying disturbances of cardiac rate and rhythm and predisposing the heart to arrhythmia, the 15, 33, 36, 43 reader is referred to several recent reviews on the subject. 33 , 15,33,36,43 Myocardial infarction is the result of cellular death as a result of prolonged, profound myocardial ischemia. The rate at which cell death occurs will largely depend on the magnitude of the difference between the supply of oxygen and nutrients (and elimination of metabolic products by cellular perfusion) and the demand of the myocardium. Cells with the greatest imbalance will die most rapidly while those with only modest imbalances will survive for longer periods. Any event or inter-
52
ROBERT E. TEN EICK, DONALD
H. SINGER, AND LLOYD E. SOLBERG
vention which either increases perfusion or decreases the demand for perfusion when occurring following an occlusive event, may modify the extent of injury and the time course of its development during the period of ischemia. Thus, increases in heart rate or contractile force might be expected to increase the size and rate of development of the infarct. Conversely, decreases in heart rate or contractile force or the opening of collateral vessels to provide limited perfusion in the ischemic zone might be expected to decrease the size and rate of development of the infarction. This concept of the relationship between supply and demand for cardiac perfusion and the extent of cellular damage has received substantial support from some recent experimental results. Reduction in heart rate (by creation of atrioventricular block) has been shown to greatly diminish evidence evidence· of ischemic injury resulting from a 40 minute acute circumflex coronary artery ligation.':' ligation.~:' Pretreatment with propranoloPl, denervation~:' would appear to exert similarly propranoloPl. 41 and cardiac denervation':' protective effects. These findings are pertinent to considerations of rate and rhythm control in myocardial infarction. With respect to bradyarrhythmia management, the relationship between rate and cellular electrical changes would suggest that pacing should be carried out at the lowest rate which is clinically effective in order to minimize ischemic damage. In addition, the findings emphasize the importance of control of extrasystoles since enhancement of contractile force of the postextrasystolic beat also might be expected to accentuate injury. The reader should refer to proceedings of a recent symposium on myocardial infarction for a more comprehensive discussion of the question. t The remainder of this article will deal with changes in cellular activity which may provide the underlying bases of the cardiac arrhythmias associated with myocardial infarction. The electrophysiologic sequellae of myocardial infarction will be discussed in terms of alterations in automaticity and conductivity. Intrinsic and extrinsic factors which may influence these variables will be distinguished. The discussion will be concerned with possible mechanisms operating during each of the various periods following an acute coronary occlusive event. Very little evidence can be found in transmembrane potential recordings that significant change in intrinsic cellular electrical activity occurs anywhere in the heart until approximately 20 minutes have elapsed. Even cells located in the zone of the posterior papillary muscle which would have ultimately experienced extensive cell death and 17 ,42 disruption 17, 42 are only minimally, if at all, changed when removed following circumflex coronary artery ligations of less than 20 minutes duration (Fig. 1). This finding of lack of change seems somewhat paradoxical because during this same period the in situ canine heart ex10 rhythm.lO, , 41, 43 Representative periences severe disturbances of rate and rhythm. disturbances are illustrated by the 3, 5, 7, and 20 minute panels of Figure 2. One can see in the local surface electrogram of the posterior papillary muscle (PPM:CEG) that there was abnormal local electrical activity occurring within the ischemic muscle which was not reflected ':'Elson, Singer, and Ten Eick: Unpublished observations. tCirculation Research, 34-35 (Suppl. 11), September 1974.
53
CORONARY OCCLUSION
Endo.
PPM-Sham
OMZ OMZ
1500mStC, 1500msI'
~
J \-~ ':-...A...:=: .~
100
mV
PPM-20'Ugation PPM-20'Ligation L Transmembrane potentials from subendocardial (Endo) and deep myocardial Figure 1. zone (DMZ) cells in posterior papillary muscle slice preparations from sham-operated control dog (PPM:sham) and from dog subjected to a 20 minute ligation (PPM:20 minute ligation) to show absence of significant electrophysiologic changes during this period. Note that the DMZ is the site where maximum ischemic damage is observed following more prolonged occlusions. Time and voltage calibrations are in the upper right hand corner. See text for discussion.
in the surface electrocardiographic leads. In addition, numerous ventricular extrasystoles are seen simultaneously in all recordings. Thus it is clear that the heart, made ischemic in situ for periods less than 20 minutes, experiences considerable arrhythmia despite the fact that persistent intrinsic changes in the cell membrane characteristics have not yet occurred. The question then arises, if there is "normal" electrophysiology, why does arrhythmia occur? The severity of the dysrhythmias observed during this early time period can be reduced although not abolished by spinal transsection or cardiac sympathectomy and by administration of 25 These findings suggest that beta-adrenergic receptor blocking agents. 25 there may be an underlying neural component, most likely a sympathetic one, to the origin of the dysrhythmias occurring immediately after infarct. How such a neural component might support infarct-induced arrhythmia remains speculative. However, one possible mecha48 review.4B It is nism has been put forth by Wit and Friedman in a recent review. now well known that catecholamines can cause the occurrence of 46 ,47 slowly propagated impulses in severely depolarized Purkinje fibers 46
Figure 2. Changes in the electrical activity of the in situ canine heart during the hour following abrupt ligation of the circumflex coronary artery. From top to bottom, recordings of AVF; and surface electrograms from the non-ischemic surface electrocardiogram lead I and AVF; anterior papillary muscle (APM CEG) and the ischemic posterior papillary muscle (PPM CEG). Time, in minutes, following coronary ligation at which the records were obtained is indicated above each panel. Time calibration is at the lower right. See text for discussion.
54
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
and human and canine ventricular muscle (Ten Eick, unpublished observation). However, because under standard tissue bath conditions no changes from normal are seen in the resting potential for nearly 20 minutes following circumflex ligation, one might ask how sufficient depolarization is achieved to permit the occurrence of the catecholamine dependent, slowly propagated impulses. It has been shown that immediately following coronary ligation the coronary sinus K+ concen13, 30 Such an increase in coronary sinus K+ can only tration increases. 1It,t. 13.30 be the reflection of a significant increase in the extracellular K+ concentration. It has been suggested that, in situ, the myocardial extracellular 20 level,2°' K+ concentration may approach the intracellular level. • 23 This increase in the extracellular K+ concentration could cause the degree of depolarization necessary to permit the slowly propagated, Ca++-dependent, catecholamine-induced impulses to occur and contribute to the conduction disturbances in situ at a time when the ischemic myocardium is otherwise normal. There is currently little information available with which to assess possible roles for other substances found to increase in concentration in the coronary sinus following coronary ligation. However, a mechanism involving a loss of the cell's normal ability to regulate its transmembrane ion gradients for K+ and Na+ is sufficient to explain the slowly propagated impulses detectable in the ischemic myocardium. The accumulation of potassium in the extracellular spaces would serve to partially depolarize the otherwise normal cells. This, in turn, would inactivate the Na+ system responsible for the rapid upstroke of the action potential (thus contributing to the slowing of conduction velocity), provide the conditions for activating the Ca++ system responsible for supporting very slowly propagating impulses, and probably cause the socalled "currents of injury" registered in the S-T segment of the electrocardiogram during ischemic episodes. Neuronal release of catecholamines (possibly some of it caused by K+ induced depolarization of sympathetic nerve terminals) under these conditions would be expected to permit development of or strengthen an already existing depolarizing 44 32 •,44 current carried32 by Ca++ which, in turn, should support or enhance conduction of slowly propagated impulses in the partially depolarized fibers. The occurrence of slowly propagated impulses in the partially depolarized fibers would then predispose the heart to reentry and possi47 46 •,47 bly sustained dysrhythmia. 46 Because a disruption of the normal Na+ and K+ transmembrane gradients alone could be sufficient to cause a reduction in resting potential and in turn produce slower than normal impulse propagation, it should not be surprising that neither beta-receptor blockade nor cardiac sympathectomy reliably abolishes the arrhythmias which develop immediately after coronary occlusion. Thus, in the very early period after ligation it appears as though the dysrhythmias are largely caused by extrinsic factors, principally K+ loss from intracellular sites, rather than by effects causing persistent changes in the intrinsic electrical properties of the myocardial cell membrane. An approach to the therapy of rhythm disturbances caused by such mechanisms should incorporate measures to prevent the occurrence of catecholamine-dependent slowly propagated impulses by means of beta-
55
CORONARY OCCLUSION
blockade and to return the membrane potential of the involved cells toward normal, preferably by increasing the rate of the membrane Na+ pump. Unfortunately, clinically applicable means to achieve the latter goal are currently not available. In contrast to what is seen during the first 15 to 20 minutes after coronary occlusion, during the next hour or two, intrinsic changes in the cellular membrane characteristics of the involved myocardium become evident. Concomitantly, beginning after 20 minutes of occlusion histologic, biochemical, and electrophysiologic evidence of irreversible cellular damage and cell death can be detected. The histological and biochemical consequences of coronary occlusion during this period have been 14 , 16,20-23,26,42 co-workers.14, well characterized by J ennings and his co-workers. 16,20-23,26.42 Their findings conclusively indicate that irreversible structural disruption of myocardial cells involving damage to the mitochondria, nucleus, and myofilaments occurs and that progressively more and more cells are involved as the time after occlusion increases. They also find the cellular energy supplies of ATP and other substances containing high energy 22 21 •,22 phosphate bonds are extremely depleted. 21 Cellular metabolism is al18 •, 21, 21, 22. 22, 50 and even the tered as a result of changes in enzyme activities 18 membrane Na+ N a+ - K+ activated ATPase activity is drastically reduced (Okita, G. T., Ten Eick, R. E., and Singer, D. H.: Unpublished observations). The changes in cellular biochemistry reflect alterations occurring within the cell but provide little evidence of changes in the electrical function of the cell membrane. Evidence that specific membrane 37 4o -- 4o changes occur has been obtained from electrophysiological studies. 37 During the 20 minute to 1 to 2 hour period, these membrane changes appear restricted to the deep or intramural myocardial cells. There is no evidence that, under standard tissue bath conditions, there is any Purkinje fiber, endocardial, or epicardial involvement resulting in an intrinre· Figure 3. Representative recordings from surface Purkinje fibers (PF), endocardial (Endo) cells, and epicardial (Epi) cells in non· isolated perfused specimens of nonischemic posterior papillary muscle (PPM: sham); ischemic posterior (PPM:sham); (PPM:ligated) papillary muscle (PPM :ligated) and non-ischemic non·ischemic anterior papillary muscles (APM:ligated) showing that circumflex ligation for 60 min· minutes did not appreciably alter the electrophysiologic behavior of cells in these locations. The trace with the 50 msec time marks indicates the approximate position of zero potential. Maximal dV/dt of phase 0 of the action potential is indicated by the amplitude of the upward deflection of the bottom trace in each panel. Time and voltage calibrations are shown in the lower right hand corner. The calibration of the maximal dV/dt is: 500 V/sec equals the 100 m mV V calibration.
.!I: 1JS: .jr= .Jr= .m:: .m: .n=: db1r: .U= lbtt:
PPM-sham
PF PF Endo Enda
Epl
PPM-ligated APM-lIgatld APM-lIgated PPM-Iigated
.n:: Jb .IS:: J;C J~ 1k 500lTlMC 500msec
100 ] mV
56
E. TEN EICK, DONALD ROBERT E.
H.
E. SOLBERG SINGER, AND LLOYD E.
-hfL J L- f;= 20
la APMAPMIIgoted IIgated
I
ts::: ts: ~
Is
-P\--
25
pp pp MMsham sham ~ 1
~ J "-+-_
PPMPPMligated ligoted
(1-12)
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2
~ ----
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4
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6
7
8
~ K &K
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12
11
1001500 100I500 mV VIs VIs
-r---r---,
--'
J'\JC J\JC
!
500msec
Figure 4. Representative recordings from comparable sites in non-ischemic anterior papillary muscle (APM:ligated), non-ischemic posterior papillary muscle (PPM:sham) and ischemic posterior papillary muscle (PPM:ligated) specimens to illustrate electrophysiologic changes associated with circulnflex circumflex ligation. Note variability of electrophysiologic activity within the PPM:ligated specimen but not in either the APM:ligated or the PPM:sham isolated specimens under standard tissue bath conditions. The number at the upper left of each panel indicates the approximate location of the cell from which the given recording was obtained and can be anatomically located from the position of the corresponding numbers in the papillary muscle schematically depicted above. The recordings labeled lA, 18, and 1 and 2A, 28 and 2 were obtained from cells in comparable locations in sections of APM:ligated, PPM:sham and PPM:ligated preparations, respectively. Note that records 1 and 3 from the PPM:ligated PPM:sham PPM :ligated preparation are similar to those in the PPM: sham preparation (panel 18). However, note differences between action potentials shown in panels 28 and 2. Also, note variation in electrical activity between nearby locations within the PPM:ligated specimen (panels 1 to 12). Calibrations for time, transmembrane potential and Vmax are given at the lower left.
57
CORONARY OCCLUSION 10
>E
. ..J ~
80
60
~ >= Z
UJ ILl
.... ~
0
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Q.
40
'"z = 20 Cl) U)
UJ ILl
er: er
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,
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4
, i
7
,
,
,
i
20
12 (K+)
of
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,
i
40
....
, I
200
(mM)
Figure 5. Depicts the change in the relationship between the resting potential (ordinate) of deep myocardial zone cells and the extracellular K+ concentration caused by in situ ischemia. The upper curve (PPM:sham, open squares) was generated from resting potential determinations from isolated preparations of non-ischemic posterior papillary muscle exposed to a modified Tyrode's solution containing progressively higher concentrations of K+. K+. The de terminations for ischemic postelower curve (PPM:ligated; filled squares) shows similar determinations rior papillary muscle. The slopes of the curve were 42 and 59 mV per 10 fold change in [K+]o for the PPM:ligated and PPM:sham curves, respectively. Standard errors are indicated by the [K+]"s under the two conI brackets. The differences between the resting potentials at similar [K+]os of2,4,7,12 ditions are statistically significant (P < 0.05) at [K+]o [K+] 0 of 2,4,7,12 and 20 mM. See text for discussion of the possible significance of the change.
sic change in membrane function that could explain the occurrence of cardiac arrhythmia (Figure 3). However, the changes in the electrophysiologic behavior of the deep myocardial cell membrane in the ischemic papillary muscle are several and include: partial depolarization of the diastolic or resting potential (Fig. 4); altered response of the resting potential to K+ (Fig. 5), changes in the action potential configuration such that in some cells lengthening and in others shortening of duration is observed (Fig. 4 and 6); altered response of the action potential duration to change in the rate of stimulation (Fig. 7); marked reduction in upstroke velocity of the action potential (Fig. 4) which is characterized by a unique shift in the relationship between action potential upstroke up stroke velocity and the membrane potential at the moment when cellular excitation occurs (Fig. 8). This shift, depicted in Figure 8, is such that premature impulses which under normal conditions would be too early to propagate, may propagate slowly in the ischemic tissue, perhaps to some extent as a result of the Ca++ dependent mechanism described previously. Finally, there is evidence that spontaneous impulse formation, probably as a result of oscillations in membrane potential to threshold potential, can occur in the deep myocardium of papillary muscle made ischemic by coronary occlusion (Fig. 6 and 9). All of these changes in membrane function occur to varying extents in different, closely adjacent locales within the ischemic portion of the myocardium. Thus,
58
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
these changes create a rather large degree of electrophysiologic nonuniformity in and around the ischemic portions. The nature of these changes and their spatial distribution could provide the conditions believed necessary for altered conduction and automaticity and predispose the heart to disturbances of rate and rhythm. Findings that disturbances of impulse formation and conduction occur in isolated (in tissue bath) specimens of papillary muscle made ischemic in situ support this contention (see Fig. 6). However, despite the existence of these several putative mechanisms, rather little ectopic activity can be detected during the 20 minute to 2 hour period. Beginning approximately 20 minutes after occlusion, the frequency and severity of the rhythm disturbances subside in the canine modeP2.24 modeP2,24 (Fig. 2) and, although periodic episodes of ectopic activity may be observed, they occur relatively infrequently over the next several hours. This finding seems to indicate that either the involved
\'00 I ~ ~ ~oo mste msec SOO
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160
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162 162
400
m
188
164
~ 168
290
Jt::s •
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2.93
~ •
• •
•
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I 1I Itcond .. cond II
Figure 6. An association between prolongation of action potential duration, accentuation of prolongation following a period of slow stimulation, failure to shorten immediately upon resumption of rapid stimulation, and the occurrence of oscillations during phase 2 of repolarization. Row A shows five pairs of records from subendocardial (cells 1 to 3) and deep myocardial (cells 4 to 8) zone cells in a PPM:ligated preparation stimulated at cycle length 800 msec. Approximate locations of these cells are indicated in the accompanying diagram. Note the prolongation of action potential duration of the deep cells (action potential durations measured as time to repolarize to -60mv are listed beneath each pair of records with the subendocardial cell value appearing first in each case). Rows B through D show continuous records from the same cells as in Row A, panel 5. The first two action potentials in row B were observed while stimulating at a slow rate (cycle length 6000 msec). The third and subsequent action potentials were obtained after resumption of stimulation at cycle length 800 msec. Note that the subendocardial cell appears little different despite variations in cycle length while the deep cell demonstrates further prolongation of action potential duration at the slow rate (cycle length 6000 msec) and a failure to shorten rapidly upon resumption of the rapid rate (cycle length 800 msec). The latter resulted in a failure to repolarize prior to the next regular stimulation and a further prolongation of action potential duration ensued. After 10 beats, the deep cell shortened sufficiently to completely repolarize prior to the inscription of the next action potential. However, shortening to the original action potential duration was not attained.
59
CORONARY OCCLUSION
240 240 220 220 U 200 0200 Cl) C1I
1BO ~ 180
o 160 0160 a..
Coronary Occlusion Effect on Cellular Electrical Activity of the Heart
Robert E. Ten Eick, Ph.D.,* Donald H. Singer, M.D.,** and Lloyd E. Solberg, M.D.*** M.D. ***
Severe disturbances of cardiac rate and rhythm are potentially dangerous sequellae of coronary occlusive events in man. 99 However, despite their common occurrence very little is known about the underlying mechanisms. Current theory holds that the mechanisms of cardiac arrhythmias, presumably including those underlying arrhythmias associated with myocardial infarction, are most easily understood in terms of the changes in cellular electrical activity that result from myocardial infarction. The problem with such an electrophysiologic approach to the study of human heart which has suffered an acute ischemic episode is that suitable specimens at the various stages of the infarction process are not available for study. It is even rare for an old resolved infarct to become available for study by the electrophysiologist. Recently, several groups of investigators have attempted to overcome the problems of having limited material and no reasonably controlled way to characterize the cellular electrophysiological changes associated with myocardial infarction by developing a canine model which appears to exhibit certain similarities to the infarcted human heart. The model is made by occluding either the anterior descending coronary artery, the so-called "Harris model,"12 or the circumflex coronary artery17 artery17 of the thoracotomized, anesthetized dog. The former procedure results in a large area of ischemic and infarcted tissue in the region of the anterior papillary From the Departments of Pharmacology and Medicine and The Reingold ECG Center, Northwestern University Medical School, Chicago, Illinois ':'Associate Professor of Pharmacology ':":'Associate Professor of Medicine and Pharmacology; Director, Reingold ECG Center, "':'Associate Northwestern University Medical School :::Formerly Formerly Northwestern University Medical School, Chicago, Illinois. Presently Resident in Internal Medicine, Mayo Clinic, Rochester, Minnesota Supported in part by U.S.P.H.S. Training Grant TO-I-GM 00162-14 and Grants-in-aid from the Chicago Heart Association (N eN 69-68, B 74-73) and the American Heart Association (74 1065). Dr. Ten Eick is a recipient of a U.S.P.H.S. Research Career Development Award. Portions of this work were done during Dr. Singer's tenure as an Established Investigator of the American Heart Association.
Medical Clinics of North America- Vol. Vo!. 60, No. 1, January 1976
49
50
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
muscle, largely sparing the posterior papillary muscle. The latter procedure similarly affects the posterior papillary muscle, sparing the anterior IS The resultant electrocardiographic changes, while papillary muscle. 18 not precisely mimicking those which occur in the human, seem largely 8 • 10 The cellular pathology observed in the dog model at both the similar. similar.s, light and electron microscopic levels also is remarkably like that seen in 48 specimens of infarcted human ventricular myocardium. 44,4s Therefore, • there is some evidence to support the notion that studies of the cellular electrical activity of the dog model can provide important insights into the electrophysiologic basis of the dysrhythmias which occur in the human heart in conjunction with a significant coronary occlusive event. With this premise in mind, we shall describe some of the changes in cellular electrical activity associated with coronary occlusion in dogs which are currently believed to be important factors in the development of infarct-induced ventricular arrhythmias. The evidence to be presented will support the notion that cellular mechanisms underlying infarct-induced dysrhythmia evolve after the occlusive event. The initial phase of arrhythmia, beginning within a few minutes of the onset of ischemia and lasting for 15 to 20 minutes, is supported by radical changes in the cellular milieu as well as by a significant neural component. Within 1 hour after coronary occlusion, changes in the membrane properties of the involved myocardium can be detected in the absence of changes in the overlying endocardium, epicardium, or Purkinje fiber fib er network. Several hours after occlusion evidence of electrical activity in the involved intramural myocardium is no longer obtainable except in small, isolated and widely scattered areas, thus possibly terminating its contribution to the production of rhythm disturbances. At the same time, however, the activity and properties of the endocardium and Purkinje network overlying the infarcted myocardium appear to change. These changes progress with varying time courses and, after a period of from days to weeks, seem to reverse and ultimately disappear simultaneously without evidence of any residual disturbances of cardiac rate and rhythm. 55 Thus, the heart is usually left with a scar at the site of the infarct but with a normal rhythm and no evidence of residual electrophysiologic changes in the surviving cells and tissues. tissues.'4 Before presenting specific data in support of our hypothesis regarding the nature of the changes in cellular electrophysiology which must be expected to be responsible for dysrhythmias associated with myocardial infarction, we shall briefly review current concepts as to the cellular mechanisms which underlie initiation and perpetuation of disturbances of cardiac rate and/or rhythm. Such disturbances can be viewed as resulting from alterations in normal and/or abnormal automaticity, abnormal conductivity, or both acting in concert. What do these terms mean? Automaticity refers to the ability of excitable cells, such as occur in the heart, to spontaneously generate impulses. Normally, impulses are generated because the cell in question does not maintain a stable level of membrane potential during electrical diastole but rather undergoes slow spontaneous depolarization toward a critical level of potential. If this critical level of potential, termed 'threshold potential' is
CORONARY OCCLUSION
51
reached, a spontaneous impulse is initiated. Cells exhibiting this capability are termed automatic and can serve as pacemakers for the heart. Ordinarily, the cardiac impulse is generated by specialized automatic (pacemaker) cells in the sinus node. However, cells in other portions of the specialized tissues of the atria and ventricles (His-Purkinje system) also are capable of forming impulses which can under certain conditions excite the heart. When impulses generated by automatic cells in portions of the heart other than the sinus node take control of the heart for one or more beats, disturbances of cardiac rate/rhythm will ensue. As will be subsequently discussed, this may also result in disturbances of impulse conduction. We will also present evidence to show that as a result of myocardial infarction even ordinary myocardial cells may become capable of spontaneous impulse formation, to be designated "abnormal" automaticity. The nature of the ionic mechanism(s) underlying such "abnormal" automaticityare tomaticity are not yet resolved and may differ from those postulated for spontaneous diastolic depolarization of normal pacemaker cells. Conductivity refers to the property of excitable cells which enables impulse propagation to occur. Normal impulse spread and the normal sequence of activation depend upon the occurrence of more or less normal conductivity in ordinary and specialized cells in all parts of the heart. If conductivity is depressed, the spread of electrical activity will proceed more slowly than normally. Decrement (i.e., progressive slowing of conduction velocity) and varying degrees of block may ensue. re entry may develop. Dysrhythmia resulting from slow conduction and reentry Conductivity is governed by a number of factors, the more important of which include membrane excitability, responsiveness, and refractoriness. The level of the diastolic membrane potential (and therefore the occurrence of spontaneous diastolic depolarization); action potential configuration; the passive electrical properties of the cell membrane and the electrophysiologic response of the membrane to extrinsic factors such as catecholamines, potassium, metabolic products, physical distention, and so forth, may all affect impulse conduction to a varying degree. Considerations of the manner in which these various extrinsic and intrinsic factors influence conductivity is beyond the scope of this article. However, the reader should be aware that changes in any of these properties, particularly when they occur to a varying extent in neighboring locales, may alter conduction in such a way as to cause fragmentation of the excitation wave and reentry. For a more thorough treatment of the general mechanisms underlying disturbances of cardiac rate and rhythm and predisposing the heart to arrhythmia, the 15, 33, 36, 43 reader is referred to several recent reviews on the subject. 33 , 15,33,36,43 Myocardial infarction is the result of cellular death as a result of prolonged, profound myocardial ischemia. The rate at which cell death occurs will largely depend on the magnitude of the difference between the supply of oxygen and nutrients (and elimination of metabolic products by cellular perfusion) and the demand of the myocardium. Cells with the greatest imbalance will die most rapidly while those with only modest imbalances will survive for longer periods. Any event or inter-
52
ROBERT E. TEN EICK, DONALD
H. SINGER, AND LLOYD E. SOLBERG
vention which either increases perfusion or decreases the demand for perfusion when occurring following an occlusive event, may modify the extent of injury and the time course of its development during the period of ischemia. Thus, increases in heart rate or contractile force might be expected to increase the size and rate of development of the infarct. Conversely, decreases in heart rate or contractile force or the opening of collateral vessels to provide limited perfusion in the ischemic zone might be expected to decrease the size and rate of development of the infarction. This concept of the relationship between supply and demand for cardiac perfusion and the extent of cellular damage has received substantial support from some recent experimental results. Reduction in heart rate (by creation of atrioventricular block) has been shown to greatly diminish evidence evidence· of ischemic injury resulting from a 40 minute acute circumflex coronary artery ligation.':' ligation.~:' Pretreatment with propranoloPl, denervation~:' would appear to exert similarly propranoloPl. 41 and cardiac denervation':' protective effects. These findings are pertinent to considerations of rate and rhythm control in myocardial infarction. With respect to bradyarrhythmia management, the relationship between rate and cellular electrical changes would suggest that pacing should be carried out at the lowest rate which is clinically effective in order to minimize ischemic damage. In addition, the findings emphasize the importance of control of extrasystoles since enhancement of contractile force of the postextrasystolic beat also might be expected to accentuate injury. The reader should refer to proceedings of a recent symposium on myocardial infarction for a more comprehensive discussion of the question. t The remainder of this article will deal with changes in cellular activity which may provide the underlying bases of the cardiac arrhythmias associated with myocardial infarction. The electrophysiologic sequellae of myocardial infarction will be discussed in terms of alterations in automaticity and conductivity. Intrinsic and extrinsic factors which may influence these variables will be distinguished. The discussion will be concerned with possible mechanisms operating during each of the various periods following an acute coronary occlusive event. Very little evidence can be found in transmembrane potential recordings that significant change in intrinsic cellular electrical activity occurs anywhere in the heart until approximately 20 minutes have elapsed. Even cells located in the zone of the posterior papillary muscle which would have ultimately experienced extensive cell death and 17 ,42 disruption 17, 42 are only minimally, if at all, changed when removed following circumflex coronary artery ligations of less than 20 minutes duration (Fig. 1). This finding of lack of change seems somewhat paradoxical because during this same period the in situ canine heart ex10 rhythm.lO, , 41, 43 Representative periences severe disturbances of rate and rhythm. disturbances are illustrated by the 3, 5, 7, and 20 minute panels of Figure 2. One can see in the local surface electrogram of the posterior papillary muscle (PPM:CEG) that there was abnormal local electrical activity occurring within the ischemic muscle which was not reflected ':'Elson, Singer, and Ten Eick: Unpublished observations. tCirculation Research, 34-35 (Suppl. 11), September 1974.
53
CORONARY OCCLUSION
Endo.
PPM-Sham
OMZ OMZ
1500mStC, 1500msI'
~
J \-~ ':-...A...:=: .~
100
mV
PPM-20'Ugation PPM-20'Ligation L Transmembrane potentials from subendocardial (Endo) and deep myocardial Figure 1. zone (DMZ) cells in posterior papillary muscle slice preparations from sham-operated control dog (PPM:sham) and from dog subjected to a 20 minute ligation (PPM:20 minute ligation) to show absence of significant electrophysiologic changes during this period. Note that the DMZ is the site where maximum ischemic damage is observed following more prolonged occlusions. Time and voltage calibrations are in the upper right hand corner. See text for discussion.
in the surface electrocardiographic leads. In addition, numerous ventricular extrasystoles are seen simultaneously in all recordings. Thus it is clear that the heart, made ischemic in situ for periods less than 20 minutes, experiences considerable arrhythmia despite the fact that persistent intrinsic changes in the cell membrane characteristics have not yet occurred. The question then arises, if there is "normal" electrophysiology, why does arrhythmia occur? The severity of the dysrhythmias observed during this early time period can be reduced although not abolished by spinal transsection or cardiac sympathectomy and by administration of 25 These findings suggest that beta-adrenergic receptor blocking agents. 25 there may be an underlying neural component, most likely a sympathetic one, to the origin of the dysrhythmias occurring immediately after infarct. How such a neural component might support infarct-induced arrhythmia remains speculative. However, one possible mecha48 review.4B It is nism has been put forth by Wit and Friedman in a recent review. now well known that catecholamines can cause the occurrence of 46 ,47 slowly propagated impulses in severely depolarized Purkinje fibers 46
Figure 2. Changes in the electrical activity of the in situ canine heart during the hour following abrupt ligation of the circumflex coronary artery. From top to bottom, recordings of AVF; and surface electrograms from the non-ischemic surface electrocardiogram lead I and AVF; anterior papillary muscle (APM CEG) and the ischemic posterior papillary muscle (PPM CEG). Time, in minutes, following coronary ligation at which the records were obtained is indicated above each panel. Time calibration is at the lower right. See text for discussion.
54
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
and human and canine ventricular muscle (Ten Eick, unpublished observation). However, because under standard tissue bath conditions no changes from normal are seen in the resting potential for nearly 20 minutes following circumflex ligation, one might ask how sufficient depolarization is achieved to permit the occurrence of the catecholamine dependent, slowly propagated impulses. It has been shown that immediately following coronary ligation the coronary sinus K+ concen13, 30 Such an increase in coronary sinus K+ can only tration increases. 1It,t. 13.30 be the reflection of a significant increase in the extracellular K+ concentration. It has been suggested that, in situ, the myocardial extracellular 20 level,2°' K+ concentration may approach the intracellular level. • 23 This increase in the extracellular K+ concentration could cause the degree of depolarization necessary to permit the slowly propagated, Ca++-dependent, catecholamine-induced impulses to occur and contribute to the conduction disturbances in situ at a time when the ischemic myocardium is otherwise normal. There is currently little information available with which to assess possible roles for other substances found to increase in concentration in the coronary sinus following coronary ligation. However, a mechanism involving a loss of the cell's normal ability to regulate its transmembrane ion gradients for K+ and Na+ is sufficient to explain the slowly propagated impulses detectable in the ischemic myocardium. The accumulation of potassium in the extracellular spaces would serve to partially depolarize the otherwise normal cells. This, in turn, would inactivate the Na+ system responsible for the rapid upstroke of the action potential (thus contributing to the slowing of conduction velocity), provide the conditions for activating the Ca++ system responsible for supporting very slowly propagating impulses, and probably cause the socalled "currents of injury" registered in the S-T segment of the electrocardiogram during ischemic episodes. Neuronal release of catecholamines (possibly some of it caused by K+ induced depolarization of sympathetic nerve terminals) under these conditions would be expected to permit development of or strengthen an already existing depolarizing 44 32 •,44 current carried32 by Ca++ which, in turn, should support or enhance conduction of slowly propagated impulses in the partially depolarized fibers. The occurrence of slowly propagated impulses in the partially depolarized fibers would then predispose the heart to reentry and possi47 46 •,47 bly sustained dysrhythmia. 46 Because a disruption of the normal Na+ and K+ transmembrane gradients alone could be sufficient to cause a reduction in resting potential and in turn produce slower than normal impulse propagation, it should not be surprising that neither beta-receptor blockade nor cardiac sympathectomy reliably abolishes the arrhythmias which develop immediately after coronary occlusion. Thus, in the very early period after ligation it appears as though the dysrhythmias are largely caused by extrinsic factors, principally K+ loss from intracellular sites, rather than by effects causing persistent changes in the intrinsic electrical properties of the myocardial cell membrane. An approach to the therapy of rhythm disturbances caused by such mechanisms should incorporate measures to prevent the occurrence of catecholamine-dependent slowly propagated impulses by means of beta-
55
CORONARY OCCLUSION
blockade and to return the membrane potential of the involved cells toward normal, preferably by increasing the rate of the membrane Na+ pump. Unfortunately, clinically applicable means to achieve the latter goal are currently not available. In contrast to what is seen during the first 15 to 20 minutes after coronary occlusion, during the next hour or two, intrinsic changes in the cellular membrane characteristics of the involved myocardium become evident. Concomitantly, beginning after 20 minutes of occlusion histologic, biochemical, and electrophysiologic evidence of irreversible cellular damage and cell death can be detected. The histological and biochemical consequences of coronary occlusion during this period have been 14 , 16,20-23,26,42 co-workers.14, well characterized by J ennings and his co-workers. 16,20-23,26.42 Their findings conclusively indicate that irreversible structural disruption of myocardial cells involving damage to the mitochondria, nucleus, and myofilaments occurs and that progressively more and more cells are involved as the time after occlusion increases. They also find the cellular energy supplies of ATP and other substances containing high energy 22 21 •,22 phosphate bonds are extremely depleted. 21 Cellular metabolism is al18 •, 21, 21, 22. 22, 50 and even the tered as a result of changes in enzyme activities 18 membrane Na+ N a+ - K+ activated ATPase activity is drastically reduced (Okita, G. T., Ten Eick, R. E., and Singer, D. H.: Unpublished observations). The changes in cellular biochemistry reflect alterations occurring within the cell but provide little evidence of changes in the electrical function of the cell membrane. Evidence that specific membrane 37 4o -- 4o changes occur has been obtained from electrophysiological studies. 37 During the 20 minute to 1 to 2 hour period, these membrane changes appear restricted to the deep or intramural myocardial cells. There is no evidence that, under standard tissue bath conditions, there is any Purkinje fiber, endocardial, or epicardial involvement resulting in an intrinre· Figure 3. Representative recordings from surface Purkinje fibers (PF), endocardial (Endo) cells, and epicardial (Epi) cells in non· isolated perfused specimens of nonischemic posterior papillary muscle (PPM: sham); ischemic posterior (PPM:sham); (PPM:ligated) papillary muscle (PPM :ligated) and non-ischemic non·ischemic anterior papillary muscles (APM:ligated) showing that circumflex ligation for 60 min· minutes did not appreciably alter the electrophysiologic behavior of cells in these locations. The trace with the 50 msec time marks indicates the approximate position of zero potential. Maximal dV/dt of phase 0 of the action potential is indicated by the amplitude of the upward deflection of the bottom trace in each panel. Time and voltage calibrations are shown in the lower right hand corner. The calibration of the maximal dV/dt is: 500 V/sec equals the 100 m mV V calibration.
.!I: 1JS: .jr= .Jr= .m:: .m: .n=: db1r: .U= lbtt:
PPM-sham
PF PF Endo Enda
Epl
PPM-ligated APM-lIgatld APM-lIgated PPM-Iigated
.n:: Jb .IS:: J;C J~ 1k 500lTlMC 500msec
100 ] mV
56
E. TEN EICK, DONALD ROBERT E.
H.
E. SOLBERG SINGER, AND LLOYD E.
-hfL J L- f;= 20
la APMAPMIIgoted IIgated
I
ts::: ts: ~
Is
-P\--
25
pp pp MMsham sham ~ 1
~ J "-+-_
PPMPPMligated ligoted
(1-12)
t\:::
2
~ ----
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3
4
5
6
7
8
~ K &K
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9
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~ ---'"""-
-¥-~
,.,\" ~
12
11
1001500 100I500 mV VIs VIs
-r---r---,
--'
J'\JC J\JC
!
500msec
Figure 4. Representative recordings from comparable sites in non-ischemic anterior papillary muscle (APM:ligated), non-ischemic posterior papillary muscle (PPM:sham) and ischemic posterior papillary muscle (PPM:ligated) specimens to illustrate electrophysiologic changes associated with circulnflex circumflex ligation. Note variability of electrophysiologic activity within the PPM:ligated specimen but not in either the APM:ligated or the PPM:sham isolated specimens under standard tissue bath conditions. The number at the upper left of each panel indicates the approximate location of the cell from which the given recording was obtained and can be anatomically located from the position of the corresponding numbers in the papillary muscle schematically depicted above. The recordings labeled lA, 18, and 1 and 2A, 28 and 2 were obtained from cells in comparable locations in sections of APM:ligated, PPM:sham and PPM:ligated preparations, respectively. Note that records 1 and 3 from the PPM:ligated PPM:sham PPM :ligated preparation are similar to those in the PPM: sham preparation (panel 18). However, note differences between action potentials shown in panels 28 and 2. Also, note variation in electrical activity between nearby locations within the PPM:ligated specimen (panels 1 to 12). Calibrations for time, transmembrane potential and Vmax are given at the lower left.
57
CORONARY OCCLUSION 10
>E
. ..J ~
80
60
~ >= Z
UJ ILl
.... ~
0
"-
Q.
40
'"z = 20 Cl) U)
UJ ILl
er: er
"',
0
,
2
, i
4
, i
7
,
,
,
i
20
12 (K+)
of
milieu
,
i
40
....
, I
200
(mM)
Figure 5. Depicts the change in the relationship between the resting potential (ordinate) of deep myocardial zone cells and the extracellular K+ concentration caused by in situ ischemia. The upper curve (PPM:sham, open squares) was generated from resting potential determinations from isolated preparations of non-ischemic posterior papillary muscle exposed to a modified Tyrode's solution containing progressively higher concentrations of K+. K+. The de terminations for ischemic postelower curve (PPM:ligated; filled squares) shows similar determinations rior papillary muscle. The slopes of the curve were 42 and 59 mV per 10 fold change in [K+]o for the PPM:ligated and PPM:sham curves, respectively. Standard errors are indicated by the [K+]"s under the two conI brackets. The differences between the resting potentials at similar [K+]os of2,4,7,12 ditions are statistically significant (P < 0.05) at [K+]o [K+] 0 of 2,4,7,12 and 20 mM. See text for discussion of the possible significance of the change.
sic change in membrane function that could explain the occurrence of cardiac arrhythmia (Figure 3). However, the changes in the electrophysiologic behavior of the deep myocardial cell membrane in the ischemic papillary muscle are several and include: partial depolarization of the diastolic or resting potential (Fig. 4); altered response of the resting potential to K+ (Fig. 5), changes in the action potential configuration such that in some cells lengthening and in others shortening of duration is observed (Fig. 4 and 6); altered response of the action potential duration to change in the rate of stimulation (Fig. 7); marked reduction in upstroke velocity of the action potential (Fig. 4) which is characterized by a unique shift in the relationship between action potential upstroke up stroke velocity and the membrane potential at the moment when cellular excitation occurs (Fig. 8). This shift, depicted in Figure 8, is such that premature impulses which under normal conditions would be too early to propagate, may propagate slowly in the ischemic tissue, perhaps to some extent as a result of the Ca++ dependent mechanism described previously. Finally, there is evidence that spontaneous impulse formation, probably as a result of oscillations in membrane potential to threshold potential, can occur in the deep myocardium of papillary muscle made ischemic by coronary occlusion (Fig. 6 and 9). All of these changes in membrane function occur to varying extents in different, closely adjacent locales within the ischemic portion of the myocardium. Thus,
58
ROBERT E. TEN EICK, DONALD
H.
SINGER, AND LLOYD E. SOLBERG
these changes create a rather large degree of electrophysiologic nonuniformity in and around the ischemic portions. The nature of these changes and their spatial distribution could provide the conditions believed necessary for altered conduction and automaticity and predispose the heart to disturbances of rate and rhythm. Findings that disturbances of impulse formation and conduction occur in isolated (in tissue bath) specimens of papillary muscle made ischemic in situ support this contention (see Fig. 6). However, despite the existence of these several putative mechanisms, rather little ectopic activity can be detected during the 20 minute to 2 hour period. Beginning approximately 20 minutes after occlusion, the frequency and severity of the rhythm disturbances subside in the canine modeP2.24 modeP2,24 (Fig. 2) and, although periodic episodes of ectopic activity may be observed, they occur relatively infrequently over the next several hours. This finding seems to indicate that either the involved
\'00 I ~ ~ ~oo mste msec SOO
~IOO
AN N
A
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~
160
(lOGO....,) (to 6OrrN)
B B
c
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172
mV
~ ~
162 162
400
m
188
164
~ 168
290
Jt::s •
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2.93
~ •
• •
•
•
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•
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I 1I Itcond .. cond II
Figure 6. An association between prolongation of action potential duration, accentuation of prolongation following a period of slow stimulation, failure to shorten immediately upon resumption of rapid stimulation, and the occurrence of oscillations during phase 2 of repolarization. Row A shows five pairs of records from subendocardial (cells 1 to 3) and deep myocardial (cells 4 to 8) zone cells in a PPM:ligated preparation stimulated at cycle length 800 msec. Approximate locations of these cells are indicated in the accompanying diagram. Note the prolongation of action potential duration of the deep cells (action potential durations measured as time to repolarize to -60mv are listed beneath each pair of records with the subendocardial cell value appearing first in each case). Rows B through D show continuous records from the same cells as in Row A, panel 5. The first two action potentials in row B were observed while stimulating at a slow rate (cycle length 6000 msec). The third and subsequent action potentials were obtained after resumption of stimulation at cycle length 800 msec. Note that the subendocardial cell appears little different despite variations in cycle length while the deep cell demonstrates further prolongation of action potential duration at the slow rate (cycle length 6000 msec) and a failure to shorten rapidly upon resumption of the rapid rate (cycle length 800 msec). The latter resulted in a failure to repolarize prior to the next regular stimulation and a further prolongation of action potential duration ensued. After 10 beats, the deep cell shortened sufficiently to completely repolarize prior to the inscription of the next action potential. However, shortening to the original action potential duration was not attained.
59
CORONARY OCCLUSION
240 240 220 220 U 200 0200 Cl) C1I
1BO ~ 180
o 160 0160 a..
