Ventricular Activation Patterns of Spontaneous and Induced Ventricular Rhythms in Canine One-Day-Old Myocardial Infarction

Transcription

1 152 Ventricular Activation Patterns of Spontaneous and Induced Ventricular Rhythms in Canine One-Day-Old Myocardial Infarction Evidence for Focal and Reentrant Mechanisms Nabil El-Sherif, Rahul Mehra, William B. Gough, and Robert H. Zeiler From the Veterans Administration and SUNY, Downstate Medical Centers, Brooklyn, New York SUMMARY. We studied isochronal maps of ventricular activation during spontaneous multiform ventricular rhythms (rates /min) and pacing-induced ventricular tachyarrhythmias (rate /min) in dogs 1 day after myocardial infarction. Recordings were obtained from the entire epicardial surface and from selected endocardia! and intramural sites utilizing a computerized multiplexing technique. Spontaneous ventricular rhythms had a focal origin from the surviving subendocardial Purkinje network underlying the infarction and showed frequent shift of the pacemaker site. On the other hand, fast ventricular tachyarrhythmias were consistently induced in the same dogs by bursts of rapid ventricular pacing or programmed premature stimulation and had a tendency to degenerate into ventricular fibrillation. Pacing-induced rhythms were due to reentrant activation that developed mainly in the surviving, electrophysiologically abnormal, epicardial layer overlying the infarction. The last stimulated beat that initiated reentry resulted in a continuous arc of functional conduction block and two slowly circulating activation fronts around both ends of the arc of block. The activation fronts rejoined on the distal side of the arc of block before breaking through the arc to reactivate an area proximal to the block. This resulted in splitting of the initial single arc of block into two separate arcs. Reentrant activation subsequently continued as two synchronous circuits which conducted in clockwise and counterclockwise directions, respectively. Reentry spontaneously terminated when the leading edge of both reentrant circuits encountered refractory tissue and failed to advance. The presence of two synchronous circuits was the hallmark of a stable reentrant activation. The development of three or more asynchronous circuits resulted in an activation pattern that was "prefibrillatory." This pattern was seen to develop during pleomorphic ventricular rhythms and ventricular tachycardias of the torsades de pointes type that degenerated into ventricular fibrillation. Ventricular fibrillation was maintained by continuously changing multiple asynchronous circuits. The transition from a stable reentrant activation pattern to that of ventricular fibrillation was probably related to nonhomogeneous shortening of refractoriness in different parts of the myocardium. (C/rc Res 51: , 1982 ) SPONTANEOUS multiform ventricular rhythms are consistently seen in dogs one day after ligation of the left anterior descending coronary artery. These rhythms were shown to arise from surviving, albeit abnormal, subendocardial Purkinje network underlying the infarction (Friedman et al., 1973a 1973b; Lazzara et al., 1973a; Scherlag et al., 1974; Horowitz et al., 1975). In the same dogs, ventricular stimulation, either in the form of short bursts of rapid ventricular pacing or programmed premature stimulation, consistently induced very fast ventricular tachyarrhythmias that had the tendency to degenerate into ventricular fibrillation. The present study provides evidence that the spontaneous ventricular rhythms are due to focal activity in surviving ischemic Purkinje network while pacing-induced fast ventricular rhythms are secondary to reentrant circuits in surviving ischemic myocardial tissue. For this purpose, we studied isochronal maps of ventricular activation utilizing multiple simultaneous electrograms and a multiplexing recording system. Methods We studied 11 adult mongrel dogs hours after ligation of the left anterior descending artery distal to the anterior septal branch. Details of the surgical procedure have been described elsewhere (Scherlag et al., 1974). Dogs were anesthetized with sodium pentobarbital (30 mg/kg, iv) and maintained throughout the experiment with supplemental doses as required. The animal was ventilated with room air through an endotracheal tube using a Harvard positive pressure pump. A jugular vein was cannulated for the administration of fluids, and femoral arterial pressure was monitored through a polyethylene catheter connected to a Statham transducer. In order to slow the sinus rhythm, stimulation of the right or left vagosympathic trunk was accomplished by delivery of 0.5-msec square wave pulses of 1-10 V intensity at a frequency of Hz through two silver wires (0.012 inch in diameter) (Lazzara et al., 1973b).

2 El-Sherif et al. /Ventricular Activation Patterns 153 The heart was exposed through a left thoracotomy or midsternotomy and cradled in the opened pericardium. Ventricular pacing was achieved via two fine Teflon-insulated stainless steel wires (0.005 inch in diameter) inserted by a 21-gauge hypodermic needle into the right ventricular wall. Both regular pacing and programmed premature stimulation were performed using a programmable digital stimulator (model DTU-101 VIVA, Bloom Associates, Ltd.). The stimulator delivered rectangular pulses of variable duration (usually 2-5 msec) and twice diastolic threshold with an accuracy up to 1 msec interval. The recording system was capable of acquiring 64 channels of multiplexed data and digitally storing it on magtape through the DRUB DMA interface of a PDP-11/34 computer (Digital Equipment Corporation). Sixty-four close bipolar electrograms were amplified by high impedance amplifiers and fed through a programmable gain amplifier (PGA) and an A/D converter. Each channel was sampled at 1.0 khz, and 12 bit A/D conversion was performed. The data could be acquired as a single run or in the automatic sequence mode where the run interval, time between runs, and the total sequence duration could be individually varied. Data from a reference lead of a selected run was plotted on a model 4010 graphics terminal (Tektronics) and a time window was chosen for processing. Data then were read from the magtape and the scalars were stored on a computer disk. Each electrogram was amplified and displayed along with its first derivative for the operator to choose the points for computer measurement of activation time using a vertical cursor. Activation times of bipolar electrograms were determined by computing the time of the peak or fastest deflection as previously reported (El-Sherif et al., 1981a). The data then were plotted on a Versatec printer/plotter. The program also permitted autoscaling of the electrograms. Isochronal maps could be plotted by the computer based on the activation times determined. Both geometry of the heart and the position of each electrode were stored in the computer before the map was drawn. The program plotted a histogram of activations on the screen by scanning the activation times and counting activations in each 10 msec "bin." The window for which the isochronal map was to be drawn was chosen with the help of vertical cursors. A triangulation routine then was activated to plot the isochronal map on the printer plotter. Computer-drawn isochronal maps were utilized mainly for studies of activation during spontaneous ventricular rhythms. Pacing-induced reentrant rhythms had more complex activation patterns. Electrograms showing conduction block were determined as previously reported (El-Sherif et al., 1981a), and the isochronal maps were constructed manually at 20-msec intervals. Some isochronal lines were interpolated in the absence of actual recordings of activation at 20-msec intervals. These will be referred to in the text. The recording electrodes were made of quadruple Teflon-insulated silver wire (0.005 inch in diameter). The bipolar electrodes had an interpolar distance of 1 to 1.5 mm. Electrograms were recorded from four different arrays of bipolar electrodes: (1) Electrodes were sutured into a flexible mylon mesh sock that was contoured to fit the heart. Fortyfive to sixty-one electrodes could be distributed over the ventricular epicardium to obtain the overall epicardial activation pattern. Different socks were used with varying distribution of electrodes, e.g., closer interelectrode distance over the infarction or border zones. Specific electrode arrangements will be shown in the Results. Separate channels were used to record an electrocardiographic limb lead, a time code, and a pacing signal. (2) To obtain epicardial recordings at closer interelectrode distance (4-6 mm apart), individual bipolar electrodes were sutured into a square or a rectangular paper grid similar in shape to the composite electrode (El-Sherif et al., 1977). The grid was positioned to record more detailed information about the activation pattern within a localized region of the epicardium. (3) Close bipolar recordings (0.5-1 mm interpolar distance) from the endocardial surface were obtained with plunge wires inserted via a 21-gauge needle into the left ventricular cavity and hooked gently into the endocardium. (4) Intramural recordings were obtained with specially designed 21-gauge needles (Kasell and Gallagher, 1977) of different lengths. Each needle contained 10 electrodes 1 mm apart and thus allowed the recordings of five bipolar electrograms with 1- mm interpolar distance. Shorter needles were inserted through the free ventricular wall and longer needles were used to record from the ventricular septum. Intramural needles were usually inserted after the overall epicardial map was obtained to analyze intramural activation at particular sites. The distance between separate needles ranged from 5 to 15 mm. These recordings were especially useful when programmed stimulation resulted in a stable reproducible reentrant pattern. After termination of the electrophysiological study, the anatomical locations of endocardial and intramural recording sites were determined and correlated with the epicardial recording sites. The anatomical location of the infarction was first determined by gross examination. The heart then was cut transversely at 0.5-cm intervals and the sections were stained by the NBT macroscopic enzyme-mapping procedure (Nachlas and Shnitka, 1963). NBT results in an intense blue staining reeaction in undamaged regions of the heart, while areas of ischemic injury appear as clearly delineated pale zones. A tridimensional outline of the infarction was then constructed and correlated with the recorded electrograms. For histological examination, tissue blocks were fixed in acetate-buffered neutral 10% foramalin, embedded in paraffin, and cut at a thickness of 5 to 7 jum. The sections were stained with hematoxylin and eosin. Results Figure 1 shows electrocardiographic (ECG) recordings from an open chest anesthetized dog 24 hours following ligation of the left anterior descending coronary artery. Panel A shows sinus tachycardia with a rate of 160/min and two ectopic beats with a uniform QRS configuration and late fixed coupling. In panel B, vagal-induced sinus slowing unravelled the presence of a multiform vetntricular rhythm with an average rate of 155/min. The rhythm started with a ventricular beat having the same QRS configuration and coupling interval as the two beats in panel A. In all other experiments, multiform ventricular rhythms with average rates of /min were consistently seen 1 day post-myocardial infarction. The sinus rate in these dogs was usually within 10 beats of the average rate of the ventricular rhythm. Slight waxing and waning of the rate of both rhythms occurred frequently. This resulted in the cardiac rhythm being dominated occasionally by either the sinus or ventricular rhythm. However, vagal-induced slowing of the sinus rhythm invariably unravelled the ventricular

3 FIGURE 1. Electrocardiographic recordings from an open chest anesthetized dog 24 hours after ligation of the left anterior descending coronary artery. Panels A and B show spontaneous ventricular rhythm. Note that slowing of the sinus rhythm by vagal stimulation (VS) unravelled the presence of a pleomorphic ventricular rhythm (average rate, 155/min). The asterisks refer to ectopic ventricular beats that have a monomorphic QRS configuration and a fixed coupling interval. Panel C shows the induction of a fast monomorphic ventricular tachycardia (rate, 273/min) when four ventricular paced beats (S) were introduced during the spontaneous ventricular rhythm. Note the presence of fusion beats during the ventricular tachycardia. rhythm. Short periods of ventricular rhythms with a uniform QRS configuration were seen occasionally, but, generally, a multiform QRS configuration predominated. Figure 1, panel C, was obtained from the same animal. During the spontaneous multiform ventricular rhythm, a series of four ventricular paced beats were introduced at gradually shorter cycle lengths (360, 260, and 220 msec, respectively). This resulted in the induction of a long run of fast monomorphic ventricular tachycardia (cycle length 220 msec, rate, 273 beats/min). In all other experiments, short (3-10 beats) or long runs (>10 beats) of ventricular tachyarrhythmias could be induced by ventricular pacing. Pacing was introduced either in the form of short bursts (4-12 beats) of rapid stimulation at constant or shortening cycle lengths of 170 to 240 msec or programmed premature stimulation (S1-S2, S1-S2-S3, or S1-S2-S3-S4) at cycle lengths of msec applied during regular pacing (S1-S1 at cycle lengths of msec). The coupling intervals of premature stimuli varied from one experiment to the other but was usually 2-15 msec longer than the right ventricular effective refactory period. The rate of induced ventricular rhythms varied from 230 to 450 beats/min. Most monomorphic ventricular tachycardias and some short runs (4-7 beats) of pleomorphic ventricular tachycardias terminated spontaneously. However, 45% of pleomorphic tachycardias with rates >300/min degenerated into ventricular fibrillation. Spontaneous Focal Rhythms Figure 2 illustrates simultaneous endocardial and epicardial isochronal maps of three consecutive beats (labeled A to C) during a spontaneous ventricular rhythm from the experiment shown in Figure 1. The position of recording electrodes is indicated on the Circulation Research/Voi. 51, No. 2, August 1982 maps by the + signs. The anatomical outline of the infarction is indicated by interrupted lines. The isochronal maps were constructed by the computer at 7 and 8 msec/contour. The maps show that each of the three ventricular beats had a focal origin from a different site within the endocardial surface of the infarction zone, thus denoting a continuous shift of the pacemaker site. The earliest endocardial activation preceded by 4-14 msec the earliest epicardial activation. With the exception of the first ectopic beat, the earliest epicardial activation sites were located either on the border of the infarction zone or in the surrounding normal zone. Figure 3 illustrates selected epicardial and endocardial electrograms during the same three ventricular ectopic beats shown in Figure 2. The diagram on the lower right corner illustrates a transverse cross-section of the heart at approximately the level of the endocardial electrode at site E. It shows the presence of a surviving layer of normal myocardium on the epicardial surface of the infarction that varied in thickness from 2 to 3 mm at the border to a fraction of 1 mm at the center of the infarction. Most of the infarction extended all the way to the endocardial surface. However, there was a wedge of surviving myocardium 1-2 mm thick and 5-10 mm wide between the infarction and the endocardial surface. The sketch of the endocardial outline of the infarction illustrates the part of the infarction that reached the endocardial surface as a shaded area, whereas the larger grossly visible border of infarction is represented by the dotted lines. Histological examination confirmed that the infarction zone was made of myocardial fibers showing a wide variety of tissue damage ranging from massive necrosis with dense cellular infiltration to focal necrosis and cellular reaction in the less damaged parts of the tissue. On the other hand, both the surviving epicardial layer and the endocardial wedge contained myocardial cells that were normal in appearance with myofibrils, cross-striations, and nuclei clearly visible. At sites where the infarction extended to the endocardial site, only the most superficial subendocardial fibers (one to three cells in depth) were intact. This was similar to previously published data (Friedman et al., 1973a). Electrograms representing the earliest epicardial and endocardial activation sites are marked by asterisks. The epicardial electrograms including those recorded from the epicardial surface of the infarction were large biphasic or triphasic deflections of msec duration. On the other hand, the endocardial electrograms frequently showed two separate deflections a sharp brief deflection, 1-2 msec in duration, signifying Purkinje fiber activation, and a much broader larger amplitude deflection representing muscle activation. Endocardial electrograms A and E were recorded from an area where a few cell layers of Purkinje fibers were overlying a core of necrotic myocardium. They showed a Purkinje spike and a low amplitude slow potential lasting the duration of the surface QRS. The latter represented a far field potential and closely resembled cavity potentials

4 El-Sherif et al. /Ventricular Activation Patterns 155 T TT* A, ECG LJUULL ^ FIGURE 2. Computer-generated simu/taneous endocardial and epicardial isochronal maps of three consecutive beats (labeled A to C) during a spontaneous ventricular rhythm from the experiment shown in Figure I. See text for details, /n this and subsequent maps, the threedimensional heart is represented as a two-dimensional surface. On the epicardial map, the total epicardial surface is depicted as if the ventricles were folded out after a cut was made from the crux to apex along the posterior interventricular groove. The top right and left borders represent the right and left atrioventricular junctions, respectively. The two curvilinear surfaces on the right and left are contiguous with each other and extend from the posterior base to the apex of the heart. The endocardial map has the same layout as the epicardial map with the endocardial surface being viewed through the ventricular wall. The map on the upper left comer of the figure illustrates the position of the left anterior descending artery (LAD). The site of LAD ligation is represented by the double bar. RV and LV refer to the right and left ventricles, respectively. The visible borders of the infarction on both the endocardial and epicardial surfaces are represented by the dotted line. The position of recording electrodes is indicated on the maps by the + signs. The solid triangles represent the earliest sites of endocardial and epicardial activations. In all three beats, the earliest endocardial activation sites preceded the earliest epicardial activation sites by 4-14 msec. The times of activation in msec at various sites on the endocardial and epicardial maps are shown, with activation depicted to start at the earliest endocardial sites at 0 msec. The earliest epicardial site was located within the infarction zone for beat A and in the border and normal zones for beats B and C. Both endocardial and epicardial maps show activation in the form of radial spread from a "focus" with no evidence of a "reentrant" activation pattern. (Durrer et al., 1964). During the first and second ectopic beats, a Purkinje spike from a different site (sites A and B, respectively) preceded all other recorded endocardial and epicardial potentials as well as the surface QRS by at least 7 to 14 msec. During the third ectopic beat, the earliest Purkinje spike at site C was superimposed on the initial part of the muscle potential but it still preceded the earliest epicardial electrogram by 4 msec. In electrograms recorded from endocardial sites not close to the origin of the ectopic beat, Purkinje spikes could be identified superimposed on the muscle potentials (marked by arrows). Purkinje spikes could be identified in 40 to 60% of electrograms obtained from the endocardial surface of the infarction during spontaneous ventricular rhythms from different experiments. In 55% of spontaneous ventricular beats that were analyzed, an endocardial electrogram with a Purkinje spike could be identified that preceded all other recorded endocardial and epicardial potentials. The failure to record an early Purkinje spike in other beats could be attributed in part to the relatively sparse density of endocardial recording sites and the possible failure to.obtain a recording close to the Purkinje site of origin. It is also possible that some brief Purkinje spikes were missed because of the limitations imposed by the sampling rate of the multiplexer system of 1.0 khz (Barr and Spach, 1977). Ventricular activation patterns during spontaneous ventricular rhythms were invariably consistent with a focal site of origin, i.e., origin from a very small region with radial spread of activation wavefronts. On the other hand, no single spontaneous ventricular beat showed an endocardial or epicardial isochronal map consistent with reentrant activation in the form of a circulating wave front around an arc of conduction block, as in the case of pacing-induced ventricular rhythms. Pacing-Induced Reentrant Rhythms Figure 4 illustrates simultaneous epicardial and endocardial isochronal maps during the pacing-induced ventricular tachycardia shown in Figure lc. Isochronal lines were constructed manually at 20-msec intervals. The cycle length of the tachycardia was 220 msec (11 isochrones). Both isochronal maps show

5 156 Circulation Research/Vol. 51, No. 2, August 1982 Epicardial FIGURE 3. Selected epicardial and endocardial electrograms during the same three venticular ectopic beats shown in Figure 2. Electrograms representing the earliest epicardial and endocardial activation sites are marked by asterisks. The arrows point to Purkinje spikes that may precede or are superimposed on muscle potentials. Time markers for the electrographic recording (T) are set at 100-msec intervals. The diagram on the lower right corner illustrates a transverse cross-section of the heart at the level of the endocardial electrode at site E. The infarcted zone is represented by the shaded area. A surviving myocardial layer is seen on the epicardial surface of the infarction, and in the form of a wedge, 5 to 10 mm wide, between the infarction and the endocardial surface. See text for more details. evidence of reentrant activation in the form of two synchronous wavefronts that circulated in opposite directions around areas of conduction block. The two circulating wavefronts were completely depicted on the endocardial map (isochrones at 100 and 180 msec were interpolated in the absence of actual recordings). On the other hand, only eight isochrones were rep-, resented on the epicardial map. The zones of conduction block in the endocardial map were made of both an anatomical block (the area of infarction in which myocardial necrosis extended to the endocardial surface as represented by the stippled area) and two arcs of functional conduction block (reperesented by the heavy solid lines). The arcs of functional block developed during reentrant activation in areas of viable myocardium that showed relatively normal conduction during slower cardiac rhythms (both the sinus and spontaneous ventricular rhythms). Both the arcs of functional conduction block and the slow activation wavefronts were anatomically located in the subendocardial wedge of viable myocardium that surrounded the core of infarcted myocardium as shown in Figure 3. The selected electrograms in Figure 4 illustrate activation along different parts of the circulating wave fronts. Endocardial electrogram G was recorded approximately 20 msec before the inscription of the surface QRS comlex and for descriptive purposes was taken to represent the first isochrone of the reentrant circuit. From the area on the endocardial surface marked by an asterisk, two circulating wavefronts advanced in clockwise and counterclockwise directions. The counterclockwise wavefront circulated between a central island of infarcted myocardium and a continuous arc of functional conduction block that surrounded this zone. The arc of block separated myocardial areas that were activated rapidly on the outside of the arc from slowly activated myocardial areas on the inside. The endocardial isochronal map shows a second shorter arc of functional block that extended from the central area of anatomical block and separated the 20-msec isochrone from isochrones at 160 to 220 msec. The clockwise directed wavefront is depicted to start at the site represented by the asterisk, circulate on the outside of the long arc of functional block and rejoin the counterclockwise circuit at the 100-msec isochrone. Activation appeared simultaneously on the endocardial and epicardial surface at the 20-msec isochrone. After the epicardial breakthrough at the site represented by the asterisk, epicardial activation proceeded in the form of two circulating wavefronts, in clockwise and counterclockwise directions, around two arcs of functional conduction block. The two wavefronts fused into one at the 160-msec isochrone located at the cardiac apex. The remaining three isochrones of the reentrant circuit could not be identified on the epicardial surface. Ventricular activation continued during this time on the endocardial surface and possibly within intramural regions where no measurements were made. The two epicardial arcs of functional block were anatomically located in the epicardial layer of surviving myocardium overlying the infarction zone as shown diagramatically in Figure 3. The selected epicardial and endocardial electrograms in Figure 4 show the presence of diastolic

6 El-Sherif et al. /Ventricular Activation Patterns 157 1/ FIGURE 4. The right side of the figure illustrates simultaneous epicardial and endocardial isochronal maps during the pacing-induced ventricular tachycardia shown in Figure lc. The left side shows selected simultaneous electrograms from epicardial and endocardia! sites during ventricular activation. Both maps show evidence of reentrant activation in the form of two synchronous wavefronts that circulate in opposite directions around areas of conduction block. See text for more details. The zones of conduction block in the endocardial map are made of both the infarcted zone that extended to the endocardial surface (represented by the stippled area) and two arcs of functional conduction block. In this and subsequent figures, the arcs of functional conduction block are represented by heavy solid lines and are depicted to separate contiguous areas that are activated at least 40 msec apart. This point is illustrated by the two epicardial electrograms at sites D and E which were recorded 8 mm apart. Conduction block is represented here by a straight line with double bars. bridging during the reentrant tachycardia and should be contrasted with the electrograms recorded during the spontaneous ventricular rhythm from the same experiment shown in Figure 3. Epicardial electrograms D and E recorded on each side of the arc of functional block were 8 mm apart. Electrogram E shows two separate potentials: one is a relatively sharp multiphasic deflection that represents the moment of activation at site E. The other deflection is a low amplitude slow potential that is simultaneous with the sharp activation potential in electrogram D. It represents the passive far field or electrotonic potential of electrical activation at site D. The electrotonic potential in electrogram E was not present during the relatively slow ventricular rhythm in Figure 3 (compare epicardial electrograms D and E in Figures 3 and 4 that were recorded from the same sites). In Figure 3, conduction delays between sites D and E were in the order of 5-20 msec while during the reentrant rhythm in Figure 4 the delay measured 120 msec. Purkinje spikes that were evident in endocardial electrograms during the spontaneous ventricular rhythm could not, as a rule, be identified during reentrant activation (compare electrogram E in Figs. 3 and 4 that was recorded from the same site). The failure to identify Purkinje spikes during reentrant activation may have been due to superimposition on larger muscle potentials and/or to the occurrence of muscleto-purkinje block. A subendocardial reentrant circuit around a zone of block made largely by an anatomical obstacle such as the apical infarction shown in Figure 4 was uncommon and could only be identified in one experiment. In six of 11 experiments, induced reentrant beats that were analyzed had reentrant circuits that were mainly located in the surviving epicardial layer and the arcs of conduction block were commonly functional in nature. In four other experiments, there were gaps in the activation wavefront of varying duration that could not be accounted for by epicardial excitation. Multiple intramural recordings failed to bridge the gaps in these experiments, mainly because the insertion of multiple needles usually resulted in alteration of a stable reproducible activation pattern. In these experiments, a reentrant mechanism could not be adequately documented. Figure 5 illustrates an experiment in which reentrant activation was localized in the epicardial layer overlying the infarction. The figure also examines in detail the mechanism of induction of reentrant activation by programmed premature stimulation. The surface ECG shows that during a spontaneous ventricular rhythm (the first few beats in the recording) regular ventricular pacing (Si) was applied at a cycle length of 320 msec and resulted in

7 158 Circulation Research/Voi. 51, No. 2, August 1982 ECG 300 MSEC J L Si S 2 S 3 V,^ V 3 FIGURE 5. Induction of reentrant activation by programmed premature stimulation. The electrocardiographs recording (ECC) shows overdriving of spontaneous ventricular rhythm (the first two beats) by regular ventricular pacing at a faster rate (51). Two premature beats (S2 and S3) were then introduced and were followed by several spontaneous beats (V\ - V4). The epicardial isochronal maps show that the first two non-stimulated beats (V, and V?) are due to reentrant activation initiated by the S3 stimulated beat. On the other hand, V 3 shows a focal activation pattern. The same was true for V 4 (not shown in the figure). See text for more details. The shaded area on the Si map represents the epicardial outline of the infarction. The Vi map shows an area of conduction delay and block along the posterior interventricular septum unrelated to the reentrant circuit. overdriving the spontaneous rhythm. Two premature beats (S2 and S3) were introduced at coupling intervals of 215 and 190 msec, respectively, and were followed by several spontaneous beats, the first four of which are labeled Vi to V 4. The epicardial isochronal maps of the Si, S2, and S3 stimulated beats and the first three nonstimulated beats are shown. The shaded area on the Si map represents the epicardial outline of the infarction. Pacing was applied to the anterior wall of the right ventricle. During Si, the entire epicardial surface was activated within 80 msec (four isochrones) with the last isochrone located in the central part of the epicardial surface of the infarction. During S2, the activation wavefront was more irregular and slower (120 msec were required to activate the entire epicardial surface). Again, the last part to be activated was an area in the central zone of the epicardial surface of the infarction. During S3, however, the activation front proceeding from the right ventricle was blocked along an irregular but continuous arc of functional conduction block (represented by the heavy solid line) that was contained entirely within the infarction zone. The activation wavefront circulated around both the upper and lower ends of the arc of block, coalesced, and then advanced slowly in a direction from the lateral to the septal border of the infarction. The slow wavefront reached a site on the distal side of the arc of block 180 msec from the

8 El-Sherif et al. /Ventricular Activation Patterns 159 onset of right ventricular activation, then reactivated an area on the proximal side of the arc to initiate the first reentrant beat (Vi). The reactivation of an area on the proximal side of the arc of block resulted in splitting of the arc of block into two separate arcs. Epicardial activation during Vi continued in the form of two simultaneous circulating wavefronts a clockwise circuit around the upper arc and a counterclockwise circuit around the lower arc. The two circuits combined into a slow wavefront that conducted over a long circuitous pathway bordered on each side by the two arcs of functional block. The wavefront reactivated once more a site on the right side of the two arcs of block thus initiating the second reentrant beat (V2). The longer circuitous pathway of the activation front preceding V2 explains the longer V1-V2 interval in the ECG of 260 msec compared to an S3-V1 interval of 200 msec. Epicardial activation during V2 continued as two circulating wavefronts. However, both wavefronts probably met refractory tissue that resulted in rejoining of the two separate arcs of block into one arc, thus interrupting the reentrant activation. Following termination of reentry, 380 msec elapsed before activation appeared on the epicardial surface as a focal site of origin. The entire epicardial surface was rapidly activated within 100 msec in a radial fashion giving rise to the third ectopic beat (V3). The epicardial activation map of V4 was identical to that of V3, suggesting that the two beats had the same focal site of origin. As a rule, arcs of functional block developed 2 to 15 mm within the anatomically visible border of the infarction. In six of 11 dogs, multiple intramural recordings obtained during a stable and reproducible reentrant rhythm have shown that both the arcs of functional block and the conduction delay necesary to establish a reentrant circuit occurred in the surviving epicardial layer. This is illustrated in Figure 6, which was obtained from a different experiment in which a reentrant rhythm was initiated by programmed premature stimulation in a fashion similar to the experiment shown in Figure 5. A diagramatic illustration of the visible epicardial border of the infarction (the dotted line) and the arcs of functional conduction block during S 2 and S3 stimulation (the heavy solid lines) is shown. Intramural needle recordings are shown from two sites, A and B, that were 6 mm apart. Site A was located at the visible anatomical border of the infarction, whereas site B was immediately to the left side of the arc of functional block. A transverse cross-section of the heart at the level of intramural recordings shows that the infarction extended to the endocardial surface, but there was an epicardial layer of viable myocardium. The epicardial layer varied in thickness from a fraction of 1 mm to 2 V2 mm. Examination of other cross-sections of the heart showed that the surviving epicardial layer was generally wedge shaped being wide (1-4 mm) at the border of the infarction compared to that over the central part of the infarction. Intramural recordings at site A showed relatively sharp and narrow multiphasic S 7 S FIGURE 6. Reentrant beat (Vi) initiated by programmed stimulation (S1-S2-S3J in the surviving epicardial layer overlying the infarction. The two diagrams on the lower right corner of the figure illustrate the visible epicardial border of the infarction (the dotted line) and the arcs of functional conduction block during 52 and S3 stimulation (the heavy solid lines). Intramural needle recordings are shown from two sites A and B located 6 mm apart on each side of the arc of functional block. A black and white print of a transverse crosssection of the heart at the level of intramural recordings stained by the NBT technique is shown in the lower left corner. The position of intramural needles is indicated by arrows. The dark staining region represents normal myocardium, while the pale, non-staining region represents irreversibly damaged tissue. The section shows that the infarction extended to the endocardial surface but there was a surviving epicardial layer that varied in thickness from a fraction of 1 mm to 2 V2 mm. Eiectrograms denoting local activation are recorded from the epicardial surface and intramural electrodes at site A and from the 2-mm surviving epicardial layer at site B. On the other hand, intramural recordings at 4 and 8 mm below the epicardial surface at site B show only far field potentials. The arrows point to far field (electrotonic) potentials at recording site B, 2 mm deep to the epicardial surface. These deflections are simultaneous with local activation at the 2-mm level in site A. See text for more details. The? points to a possible electrotonic potential. potentials (12-25 msec in duration). The intramural potential recorded 8 mm below the epicardial surface slightly preceded the epicardial potential by 7-15 msec during Si to S3 stimulations, respectively. On the other hand, intramural recordings 4 and 8 mm below the epicardial surface at site B show the presence of broad low amplitude slow deflections simultaneous with the surface QRS (not shown in the figure). These deflections represented far field potentials and were recorded from necrotic myocardial tissue. Cardiac potentials denoting myocardial activation were recorded up to 2 mm below the epicardial surface. Analysis of the eiectrograms at the 2-mm level showed the presence of two deflections. The first, a low amplitude slow potential simultaneous V,

9 160 Circulation Research/Voi. 51, No. 2, August 1982 with the sharp potential recorded at the 2 mm level at site A, represented a distant field or electrotonic potential. The second was a relatively sharp multiphasic deflection and represented myocardial activation at site B. During Si stimulation, the myocardical activation potential at B followed the activation at A by 20 msec, reflecting a slight conduction delay. However, during S2 and S3 stimulations, activation at B occurred 80 and 120 msec, respectively, after activation at A. Recording of the electrotonic potential still was simultaneous with the activation at A. This represented a functional conduction block between sites A and B induced by the premature stimulation. Myocardial activations at both the epicardial surface and the 2-mm level at site B were almost synchronous. However, the electrotonic potential that could be discerned at the 2-mm level was not depicted on the surface. A tridimensional diagrammatic illustration of the ventricular activation pattern during the reentrant beat (Vi) is shown in Figure 7. It was based on analysis of epicardial as well as several intramural recordings obtained from the infarction and border zones. The diagram shows a 1-2 mm thick surviving epicardial layer (dotted zone) overlying a core of necrotic myocardium (wavy zone) that extended to the endocardial surface. The surviving layer of Purkinje cells that normally underlies the infarction is not represented. Two arcs of functional conduction block occurred within the epicardial layer and extended from the epicardial surface to the nectrotic zone. Activation advanced within the epicardial layer in the form of two circulating wavefronts around the two arcs of block. The two wavefronts coalesced into a common reentrant wavefront that conducted slowly between the two arcs of block to reactivate areas on the proximal side of the two arcs, thus perpetuating the reentrant process. Because conduction across the perpendicular axis of the epicardial layer was synchronous or showed only slight dispersion (less than 20 msec), the bidimensional map of epicardial activation during Vi (lower left corner of Figure 7) accurately reflects the reentrant process. Torsades de Pointes Tachycardia and Ventricular Fibrillation Pleomorphic ventricular tachycardias could be induced in eight of 11 experiments. Forty-five percent of pleomorphic tachycardias with rates greater than 300/min degenerated into ventricular fibrillation. Some of these tachycardias showed the characteristic QRS configuration of torsades de pointes with alternating polarity in an undulating pattern. Figures 8 and 9 illustrate epicardial isochronal maps during pacing-induced ventricular tachycardia of the torsades de pointes type that rapidly degenerated into ventricular fibrillation. The surface ECG shows the initiation of ventricular tachycardia by a burst of rapid ventricular stimulation at a cycle length of 185 msec. The first 11 beats of the tachycardia were remarkably monomorphic and had an ectopic cycle length of 200 EPI END FlCURE 7. A tridimensional diagrammatic illustration of the ventricular activation pattern during the reentrant beat fv\) in Figure 6. See text for details. A bidimensional map of epicardial activation during V, is also shown in the lower left corner. msec. These were followed by a gradual shift in the QRS polarity characteristic of torsades de pointes. A few beats were omitted between the upper and lower ECG recordings, with the lower recording showing a more disorganized configuration compatible with ventricular fibrillation. Figures 8 and 9 show the epicardial isochronal maps of nine consecutive beats (labeled A to I) that cover the transition of QRS configuration in the upper rhythm strip. The isochronal maps of the first six beats of the tachycardia were remarkably similar to that of beats A and B. The isochronal map of beat A shows the earliest epicardial activation to occur at a site within the central part of the epicardial surface of the infarction (outlined by dotted lines). From that site, activation spread initially in a radial fashion. There was, however, a long continuous arc of functional conduction block that extended beyond the right and left visible borders of the infarction. Two incomplete circulating wavefronts advanced in a clockwise and counterclockwise fashion around the two borders of the arc of block. An epicardial reentrant circuit was not completed because the last 200-msec isochrone located at the right side of the cardiac apex was not continuous with the first isochrone in beat B at 220 msec. This isochrone was again located on the central part of the epicardial surface of the infarction and similarly showed initial spreading in a radial fashion. The same process continued in beats C and D but with the early epicardial activation site moving closer to the cardiac apex. The last activation wavefront in beat D was able to break through the arc of conduction block and reactivate myocardial sites on the other side of the block. This established an epicardial reentrant activation in the form of two circulating wavefronts around two separate arcs of conduction block. Two synchronous epicardial circuits were seen during beats E and F. The isochronal maps of the four transitional QRS complexes F to I are shown in Figure 9. Reentrant activation continued between beats F and G. However, the epicardial activation pattern of beat G was significantly different from that in F. The left arc of con-

10 El-Sherif et al. /Ventricular Activation Patterns 161 _u A BC DE FGH I FIGURE 8. Epicardial isochronal maps of six consecutive beats (labeled A to F) during a ventricular tachycardia of the torsades de pointes type that degenerated into ventricular fibrillation. The arrhythmia was induced by a burst of rapid ventricular pacing (the first 6 beats in the upper electrocardiographic recording). See text for details. duction block extended on the left ventricular wall close to the posterior interventricular groove, and a new arc of functional block developed on the anterior surface of the right ventricle. During beats F and G, some isochrones showed a peculiar amoeboid configuration (see isochrones at 1120 and 1280 msec). This was attributed, in part, to nonhomogeneous shortening of refractoriness at certain myocardial sites from 200 msec during the early tachycardia to msec. Between beats G and H, another gap in the activation wavefront developed not accounted for by epicardial spread. Within 20 msec, activation jumped from epicardial sites close to the cardiac apex (the 1400-msec isochrone) to a site near the center of the epicardial surface of the infarction (the 1420-msec isochrone). Conduction was markedly slowed from this epicardial site in the direction of the left ventricle (some of the crowded isochronal lines were interpolated). In contrast, the activation wavefront spread much faster to the right ventricle. This resulted in the creation of new arcs of functional conduction block and a new circulating wavefront over the right ventricle. Si addition to this reentrant circuit, two additional circuits could be identified, one of which was in the form of a dead end incomplete circuit. The isochronal map of beat I shows the simultaneous presence of three complete reentrant circuits in addition to the fourth incomplete circuit. The three asterisks denote three separate sites on the epicardial surface at which reactivation occurred simultaneously at 1800 msec. Epicardial maps of subsequent beats of the tachyarrhythmia showed constant change in the configuration and anatomical location of the arcs of conduction block and the circulating wavefronts. There was always three or more asynchronous reentrant circuits. This sharply contrasted with the two synchronous circuits considered as the hallmark of a stable reentrant tachycardia. Although epicardial reentrant activation was clearly demonstrated several beats after the initiation of ven-

11 162 Circulation Research/Voi. 51, No. 2, August 1982 FIGURE 9. The same experiment shown in Figure 8. Epicardial isochronal maps of beats F to 1 during which gradual change in QRS polarity of the torsades de pointes tachycardia occurred. Note the transition from an activation pattern with two synchronous reentrant circuits (F and G) to a more complicated activation pattern in 1. The latter shows two synchronous reentrant circuits and a third asynchronous one. In addition, there is a fourth incomplete circuit. The asterisks denote three separate sites on the epicardial surface at which activation occurred simultaneously at 1800 msec. tricular tachycardia in Figure 8, the mechanism of the first several beats is less certain. These beats could be attributed to pacing-induced fast ectopic activity that later initiated reentrant activation. However, as an alternative explanation, these beats could be due to FIGURE 10. Initiation of a ventricular tachyarrhythmia that rapidly degenerated into ventricular fibrillation by a burst of rapid ventricular pacing. The arrhythmia started before the termination of pacing and the fifth QRS complex was a non-stimulated beat. The figure illustrates the epicardial isochronal maps during a 360-msec interval (marked by arrows on the ECG) that started only 1 second after the first non-stimulated beat. Note that epicardial activation is already chaotic with continuously changing multiple asynchronous reentrant circuits several of which are incomplete (or dead end) circuits. reentrant activation with the specialized conduction system forming part of the reentrant circuit. Fast conduction in the bundle branch-purkinje system may explain the abrupt gaps in epicardial activation within a short period of time. Because recordings were not obtained from the specialized conduction system, its contribution to reentrant activation could not be ascertained. Analysis of other episodes of pacing-induced ventricular tachyarrhythmias that degenerated into ventricular fibrillation showed that a prefibrillatory stage developed when three or more asynchronous reentrant circuits could be identified. This is illustrated in Figure 10 which was obtained from an experiment in which ventricular fibrillation was initiated by a burst of rapid stimulation. The surface ECG shows that only the first four QRS complexes showing electrical altemans followed the pacing stimulus and thus represented paced beats. A spontaneous ventricular rhythm was initiated before the termination of stimulation. The fifth QRS complex was inscribed before the fifth pacing artifact and was rapidly followed by a chaotic fast activity consistent with ventricular fibrillation. The figure illustrates isochronal mapping during a 360-msec interval (marked by arrows on the ECG) that started 1 second after the first non-stimulated beat (the fifth QRS complex). Epicardial mapping of the first 140 msec already showed the presence of multiple irregular arcs of block and at least three complete and one incomplete reentrant circuits. Map-

12 El-Sherifet al./ventricular Activation Patterns 163 ping of the following msec interval revealed marked change in the geometry of the arcs of functional conduction block and the circulating wavefronts. Several circuits were incomplete including two circuits that terminated in a "functional" dead end enclave on the anteroseptal region of the left ventricle. During both prefibrillatory and fibrillatory states, functional arcs of conduction block and reentrant circuits frequently developed in normal myocardium outside the anatomical border of the infarction, and several of these arcs extended to the atrioventricular junction (see Fig. 10). The dimension of reentrant circuits during stable reentrant rhythms varied widely from 3 to 11 cm in circumference. During ventricular fibrillatior,. smaller circuits of cm could be identified, particularly on the right ventricular wall (Fig. 10). However, precise mapping of activation during ventricular fibrillation could not always be accomplished because of rapid deterioration of extracellular electrograms, particularly on the epicardial surface of the infarction, making exact determination of the moment of local activation difficult. Also, it was sometimes difficult to decide whether a certain deflection represented local activation or a passive electrotonic potential. Discussion Spontaneous Focal Ventricular Rhythms The present study confirms previous observations that showed that spontaneous ventricular rhythms in canine 1-day-old infarction arise from the surviving subendocardial network underlying the infarction (Friedman et al., 1973a, 1973b; Lazzara et al., 1973a; Scherlag et al., 1974, Horowitz et al., 1975). Our study showed a focal origin of these rhythms in the sense that they arose from a very small region of the endocardial surface of the infarction from which activation spread in a radial fashion. Because of the limited resolution of our endocardial maps, a small reentrant circuit (less than 10 mm in dimension) could not be excluded. However, we have conducted isochronal mapping studies of small endocardial preparations (5X6 mm) from canine 1-day-old infarction utilizing an electrode grid with 1.5-mm interelectrode distance. This study has confirmed the focal origin of the ventricular rhythm from surviving Purkinje fibers and found no evidence of reentrant activation (El- Sherif et al., 1981b). Although previous in vitro studies have suggested that spontaneous ventricular rhythms may be due to "enhanced" automaticity of ischemic Purkinje fibers (Friedman et al., 1973b; Lazzara et al., 1973a), our recent studies strongly suggest that these rhythms are due to triggered activity arising from a delayed afterdepolarization in depolarized Purkinje fibers (El- Sherif et al., 1980). Pacing-Induced Reentrant Rhythms The present study confirms our recent observations on the electrophysiological determinants of reentrant activation in canine 3- to 5-day ischemic ventricular myocardium (El-Sherif et al., 1981a). Both studies show that the length of the arc of functional conduction block which defines the length of the reentrant circuit and the degree of slow conduction are crucial factors for the creation of a reentrant circuit. A premature beat that successfully initiates reentry results in a longer arc of conduction block and slower conduction compared to one that fails to induce reentry. The slower activation travels around a longer, more circuitous route, thus providing sufficient time for refractoriness along the side of unidirectional block to expire at one site. Reexcitation of this site will complete the reentrant circuit. The present study emphasizes a hitherto unrecognized characteristic of reentrant activation in the present canine model. This is the fact that reentrant activation consistently occurred in the form of two wavefronts that circulated around two separate arcs of functional conduction block before coalescing into a slow common reentrant wavefront. The beat that initiates reentry results in a continuous arc of conduction block. The activation front circulates around both ends of the arc of block and rejoins on the distal side of the arc of block before breaking through the arc to reactivate an area proximal to the block. This results in splitting of the initial single arc of block into two separate arcs. Reentrant activation subsequently continues as two synchronous circulating wavefronts, a clockwise circuit around one arc and a counterclockwise circuit around the other arc (Fig. 7). During a monomorphic reentrant tachycardia, the two arcs of block and the two circulating wavefronts remain fairly stable (Fig. 4). On the other hand, during a pleomorphic reentrant rhythm, both arcs of block and the circulating wavefronts can change their geometrical configuration while maintaining their synchrony. Reentrant activation spontaneously terminates when the leading edge of both reentrant circuits encounters refractory tissue and fails to conduct. This results in coalescence of the two arcs of block into a single arc and termination of reentrant activation (Fig. 5). The presence of two synchronous reentrant circuits around two separate arcs of conduction block is not an essential requirement to maintain reentrant activation. One possible situation where reentrant activation could be maintained in the in vivo heart by one reentrant circuit around a single arc of block is when the second arc of block joins the atrioventricular junction so that the second circuit is aborted. This could be seen in some published examples of induced atrial flutter in the in vivo canine heart (Boineau et al., 1980). A similar situation is seen when reentrant activation is initiated in vitro in isolated pieces of cardiac tissue. Analysis of the reentrant activation induced in small pieces of rabbit atrial tissue by Allessie et al. (1973, 1976, 1977) reveals that, besides the main circulating wavefront around a single arc of block, frequently there was a second arc of block that joined the cut edge of the preparation, sometimes, with a diminutive incomplete circuit around it.

13 164 Circulation Research/Voi. 51, No. 2, August 1982 The present study confirms our recent observations on electrogram analysis at sites of functional conduction block (El-Sherif et al., 1981a). Bipolar electrograms on both sides of the arc of functional conduction block may exhibit two separate potentials. One, a low amplitude slow deflection that is simultaneous with the moment of activation at a site on the other side of the arc of block, represents a far field or electrotonic potential. The second potential has a rapid intrinsic deflection and reflects the moment of activation at the recording site (see Fig. 6). It should be emphasized, however, that configurational analysis of bipolar electrograms is sometimes fraught with difficulty, particularly during complex excitation sequences, because any number of combinations of unipolar deflections could occur at each point but produce the same bipolar shape on subtraction one from the other. On the other hand, several elegant studies by Spach et al. (1979, 1981, 1982) have shown that unipolar extracellular electrograms provide a sensitive index of intracellular current flow, especially in multidimensional anisotropic tissue and during discontinuous propagation. In the present study, it was sometimes difficult to discern local activation from electrotonic potentials, particularly during unstable reentrant activation patterns. Similar difficulties were also reported during mapping studies that utilized unipolar electrograms (Janse et al., 1980). However, if temporal relationship between contiguous sites are taken into consideration, possible slight inaccuracies in the identification of the moment of activation at one or more sites may not significantly interfere with satisfactory mapping of activation fronts (Janse et al., 1980; El-Sherif et al., 1981a). Anatomical Substrate of Reentrant Circuits After ligation of the left anterior descending artery, blood flow is reduced more in the subendocardium, and resistance to flow in the infarcting tissue causes a redistribution of flow to the epicardial layer. Combined with the enlargement of collateral vessels, this results in sufficient flow to the epicardial layer that it usually survives (Hirzel et al., 1976). Twenty-four hours after occlusion, the surviving epicardial layer, although grossly intact on microscopic examination, has a myocardial blood flow which is 55% of control (Hirzel et al., 1976). In vitro recordings from the surviving "ischemic" epicardial layer showed cells with variable degrees of partial depolarization, reduced action potential amplitude, and decreased upstroke velocity (El-Sherif et al., 1979). Full recovery of responsiveness frequently outlasted the action potential duration reflecting the presence of post-repolarization refractoriness. In these cells, premature stimuli would elicit graded responses over a wide range of coupling intervals. Slowed conduction, Wenckebach periodicity, 2:1 and higher degrees of conduction block could easily be induced by fast pacing or premature stimulation. The present study showed that both the arcs of functional conduction block and the slow activation fronts of reentrant circuits developed in the surviving electrophysiologically abnormal epicardial layer overlying the infarction. Conduction across the perpendicular axis of the thin epicardial layer usually was synchronous or showed only slight dispersion (up to 40 msec) compared to conduction in the horizontal axis (see Fig. 6). Thus a majority of reentrant circuits in the present canine model could be viewed to have essentially a "two-dimensional configuration." On the other hand, during induced ventricular rhythms in 4 of 11 experiments, there were gaps in the activation wavefront of varying duration that could not be accounted for by epicardial excitation. If these beats were reentrant, a variable degree of intramyocardial and/or subendocardial extension of the reentrant circuit, i.e., "a tridimensional configuration," cannot be excluded. Reentrant circuits in a surviving subendocardial myocardial rim surrounding an apical infarction was uncommonly identified in the present canine model (Fig. 4). However, it is of special interest because it simulates closely reentrant circuits described in the human heart around the scar of a ventricular aneurysm (Horowitz et al., 1980a). Our observations underscore the shortcomings of the clinical mapping studies where the true nature of the reentrant circuit was probably not fully appreciated. The present study clearly illustrates the fact that it is not possible to maintain reentrant activation around an anatomical obstacle in the absence of arcs of functional conduction block that separate the rim of slowly conducting wave fronts from the surrounding fast conducting "normal" myocardium (Fig. 4). Although a rim of slowly conducting wavefront was described in these studies, the arcs of functional conduction block were not identified (Horowitz et al., 1980a). In the present study, the myocardial wedge containing both the arcs of functional block and the slow activation wavefronts measured 5-10 mm in width. It is reasonable to assume that the incision around the anatomical obstacle should extend up to the functional arc of block if surgical interruption of reentrant activation is to succeed. In most recent clinical studies, extensive endocardial resection is performed around the visible border of the aneurysmal scar (Horowitz et al., 1980b). The high success rate of these surgical procedures in spite of incomplete mapping of the reentrant circuit may suggest that surgical incisions did indeed extend up to the arcs of functional conduction block. Torsades de Pointes Tachycardia and Ventricular Fibrillation In a computer-simulated model, Moe et al. (1964) have shown that, by dispersion of refractory periods, an arrhythmia akin to fibrillation could be induced in the form of continuously changing asynchronous reentrant circuits, many of which were incomplete or "dead" circuits. Mapping of a limited area of the epicardial surface during ventricular fibrillation following acute ischemia in the porcine heart showed the presence of multiple asynchronous reentrant circuits (Janse et al., 1980). In the present study, ventric-

14 El-Shehfet al. /Ventricular Activation Patterns 165 ular fibrillation was similarly associated with continuously changing multiple asynchronous circuits, some of which were incomplete circuits. Of special interest is our observation on the transition from regular reentrant tachycardia to ventricular fibrillation. We have shown that the presence of two synchronous reentrant circuits is the hallmark of a stable reentrant activation. Deviation from this situation with the development of three or more asynchronous circuits creates an activation pattern that could be regarded as "prefibrillatory." This pattern was seen to develop during the initial shift of QRS polarity in ventricular tachycardia of the torades de pointes type (Figs. 8 and 9). It was also seen, though with less telltale from surface QRS configurations, when a pleomorphic ventricular rhythm degenerated into ventricular fibrillation. One possible electrophysiological factor that underlined the transition from a stable activation pattern with two synchronous reentrant circuits into one with multiple asynchronous circuits was the nonhomogeneous shortening of refractory periods in different parts of the epicardial surface. Here, refractory periods were defined as the time between two successive activations at the same electrode site. This was based on the assumption that, during self-sustained activity, a wavefront will move at the maximum velocity permitted by the state of recovery of surrounding myocardium (Moe et al., 1964). We have observed irregular shortening of refractory periods particularly on the right ventricular epicardial surface during the few transitional beats into ventricular fibrillation (Fig. 9). The peculiar amoeboid isochronal activation seen during these transitional beats probably reflects this irregular shortening of refractoriness. Another related factor was the observed irregular slowing of conduction in the central zone of the epicardial surface of the infarction (Figs. 8 and 9). Although difference in refractory periods is one factor which decides whether conduction will occur or fail, recent studies emphasize the effect on propagation of cardiac anatomical complexities produced by the inhomogenous distribution of the connections between cells and between muscle bundles (Spach et al., 1982). The contribution of preferential fast conduction in the subendocardial His-Purkinje system was difficult to evaluate in the present study because of frequent absence of relevant direct recordings. In summary, the present study has presented evidence that spontaneous and pacing-induced ventricular rhythms in the canine 1-day-old myocardial infarction are due, respectively, to a focal and a reentrant mechanism. In addition, the study extends further our recent observations on electrophysiological determinants of reentrant activation in ischemic myocardium. This study was presented in part at the Annual Meeting of the American Heart Association, Dallas, Texas, November Supported by Veterans Administration Medical Research Funds. Address for reprints: Nabil El-Sherif, M.D., Veterans Administration Medical Center, 800 Poly Place, Brooklyn, New York Received January 22, 1982; accepted for publication May 13, References Allessie MA, Bonke FIM, Schopman FJG (1973) Circus movement in rabbit atrial muscle as a mechanism of tachycardia. Circ Res 33: Allessie MA, Bonke FIM, Schopman FJG (1976) Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional blocks, as studied with multiple microelectrodes. 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