Continuous Concealed Ventricular Arrhythmias
RONALD R. HOPE, MB, FRACP BENJAMIN J. SCHERLAG, PhD, NABIL EL-SHERIF, MD RALPH
LAZZARA,
MD,
FACC
FACC
Miami, Florida
From the Section of Cardiology, Veterans Administration Hospital, and the Division of Cardiology, University of Miami School of Medicine, Miami, Florida. This study was supported in part by Grant ROI HL-18139 from the National Institutes of Health, Bethesda, Maryland. Manuscript received March 10, 1977; revised manuscript received May 9, 1977, accepted May 11, 1977. Address for reprints: Ronald R. Hope, MB, Veterans Administration Hospital, 1201 Northwest 16th Street, Miami, Florida 33125.
Twenty dogs were studied 3 to 9 days after myocardial infarction. None had ventricular arrhythmias during sinus rhythm, and ventricular automaticity (as revealed by sinus nodal crush procedure or vagai stimulation, or both) was within the normal range. With regular atriai pacing or pacing with long-short cycle sequences it was possible to induce ventricular arrhythmias in ail animals. Quadrigeminai and pentageminai rhythms (19 of 20 dogs) and trigeminai (17 of 20) and bigeminai ventricular rhythms (8 of 20) were observed. These rhythms which were manifest or partially or entirely concealed were always associated with delayed and fractionated electrical activity within the “infarcted” subepicardium. Continuous electrical activity (electrical activity that bridged the interval between two or more successive beats) was recorded from the infarct zone. Such activity either was manifest as ventricular arrhythmia during atrial pacing or remained concealed until atrial pacing was stopped and then was manifest as ventricular tachycardia.
Deductive analysis of electrocardiograms has provided circumstantial evidence of both manifest and concealed ventricular reentrant rhythms.i-5 Mathematical formulas have even been derived to describe various reentrant rhythms2y3s5 characterized by regular intermittent appearances of ventricular premature beats, that is, regular bigeminy or trigeminy. Continuous electrical activity during stable reentry has not been documented, and proof of reentry has been lacking. In recent studie&7 we described an experimental model using direct recording from potential reentry circuits. As previously postulated,s’l reentrant ventricular beats should be preceded by continuous electrical activity that bridges the interval from the initiating to the reentrant beat. In this study, dogs in the late postmyocardial infarction period (3 to 9 days after coronary arterial ligation) were studied using direct recordings from the “infarcted” epicardium. The study provides direct evidence for patterns of continuous activity in the infarct zone. This ischemic zone activity may be expressed in the surface electrocardiogram as ventricular arrhythmia or may remain concealed. Furthermore, direct recordings from the reentrant pathways provide possible explanations for the occurrence of intermittent ventricular ectopic beats or both manifest and concealed ventricular tachycardias. Materials
and Methods
Experiments were performed in 20 adult mongrel dogs weighing 10 to 30 kg and anesthetized with intravenously administered sodium pentobarbital (30 mg/kg body weight). A Harvard respirator provided mechanical ventilation of the lungs with room air through a cuffed endotracheal tube. A left thoracotomy in the fourth intercostal space was performed and the left anterior descending coronary artery exposed below the origin of the anterior septal branch. A silk ligature was placed around the artery and the artery occluded.
November 1977
The American Journal of CARDIOLOGY
Volume 40
733
CONTINUOUS CONCEALED REENTRY-HOPE
TABLE
ET AL
I
Types of Ventricular Arrhythmia in 20 Dogs
Bigeminy (2:l) Trigeminy (3: 1) Quadrigeminy (4: 1, 5: 1, etc.) Ventricular tachycardia Automaticity
a dogs 17 dogs 19 dogs 12 dogs 18-94 beatslmin (average 41 beats/min)
Instrumentation and recordings: Three to 10 days later, each animal underwent further surgery with use of the same anesthetic and ventilatory procedures. The heart was exposed through a right thoracotomy in the fourth intercostal space. The pericardium was opened. To obtain long diastolic intervals (slow heart rates) the sinus nodal area was crushed with a Satinsky clamp. The entire sinus node and the adjacent area were resected and the adjacent edges of the atrium sutured before the clamp was removed. The pericardium was then repaired, the incision closed and the animal placed on its right side, A left thoracotomy was performed and the pericardium incised. A large multipolar “paper” electrode12J3 was placed over the surface of the infarcted myocardium and held securely in place by the pericardium. Two to three pairs of fine Teflon@-coated stainless steel wires (diameter 0.005 inch [0.0127 cm]) were inserted into the epicardium through a 25 gauge needle 1 l/2 inches (3.81 cm) in length and positioned in subepicardial areas within and adjacent to the infarcted area. These were used to obtain local electrograms and to perform ventricular pacing from these sites. Atria1 pacing was achieved by delivery of electrical pulses of 2 to 10 volts and 2 msec duration 50 to 300 times/min through stainless steel wires (diameter 0.005 inch) inserted into the left atria1 appendage. An S88 Grass stimulator and SIU-5 isolation unit were used. A common carotid artery was exposed in the neck and a no. 5 French catheter with ring electrodes 10 mm apart used to obtain His bundle recordings at the aortic root.lO Vagal stimulation, used to stop temporarily supraventricular activity and to prevent atrioventricular (A-V) conduction, was accomplished with delivery of 0.05 msec rectangular wave pulses of 1 to 20 volts intensity at a frequency of 20 hertz through silver wire electrodes inserted into the left or right cervical vagosympathetic trunk, or both.14 All records were obtained on a multichannel oscilloscope photographic recorder (Electronics for Medicine, DR-12) at paper speeds of 50 to 200 mm/set with filter frequencies of 0.1 to 200 hertz for electrocardiographic leads and 40 to 200 hertz for electrographic recordings and the His bundle electrograms. All recordings were made on a magnetic tape recorder (Honeywell 5700) and replayed so that selected sections could be transferred to photographic paper for detailed analysis. Measurements were accurate up to f3 msec at a paper speed of 200 mm/set. Procedure: Control records were obtained during sinus rhythm before the sinus crush procedure, after the crush procedure and also during vagal slowing of the heart. Atria1 pacing was performed utilizing rates just faster than existing slow atria1 rates after sinus crush, up to rates that produced Wenckebach block within the A-V node. Over this wide range of heart rates (50 to 350 beats/min) several methods of atria1 stimulation were used. Regular pacing with (1) gradual changes in rate, and (2) abrupt asystolic pauses of variable duration was carried out in each animal. In addition, regular atria1 pacing with introduction of occasional atria1 premature beats was examined. Thus, of these three pacing methods, the
734
November
1977
The American Journal of CARDIOLOGY
FIGURE 1. Ventricular quadrigeminal rhythm in a dog 4 days after myocardial infarction. Electrocardiographic leads II (L2) and aVR in the upper panel are continuous with those tracings in the lower panel. The complete A-V block induced by vagal stimulation (VS) indicates that enhanced ventricular automaticity does not underly the supraventricular rhythm.
last two had in common the presence of long-short cycle sequences. These same pacing methods were carried out with His bundle pacing instead of atria1 pacing in 8 of the 20 dogs. In those animals with A-V nodal Wenckebach block at rates of 200 to 240 beats/min, His bundle pacing achieved maximal stimulated heart rates comparable with those of the other dogs (up to 350 beats/min). During the procedure, areas of maximal epicardial activation delay were sought within the infarcted area. This was achieved by varying the position of either the multipolar paper electrode or the bipolar wire electrodes within the infarct zone. No animals were resuscitated from ventricular fibrillation during the course of these experiments.
Results The types of ventricular arrhythmias seen are listed in Table I. The dogs were studied 3 to 9 days (average 5 days) after myocardial infarction was induced. Underlying ventricular automaticity as revealed by sinus nodal crush procedure or vagal stimulation, or both, averaged 41 beats/min (range 18 to 94). No animal had ventricular arrhythmias during sinus rhythm. However, when the atria1 pacing techniques were used, ventricular arrthythmias were demonstrated in all cases. Detailed assessment of the variable responses to the different pacing procedures is the subject of other reports from this laboratory.6,7J5J6 Quadrigeminal and pentageminal ventricular rhythms were seen in 19 of 20 dogs (Table I). Trigeminal (17 of 20 dogs) and regular ventricular bigeminal rhythms (8 of 20 dogs) were less frequently observed. These rhythms were either concealed or manifest or, more often, variably manifest (and thus partially concealed). The terms “manifest” and “concealed” were respectively applied when recurring patterns of delayed electrical activity in the infarct zone were or were not accompanied by evidence of ventricular arrhythmias in the surface electrocardiogram. Evidence of continuous electrical activity was seen in the electrograms from the epicardium or subepicardium, or both, of the infarct zone in all animals. Continuous activity was defined as electrical activity that bridged the entire interval between two or more suc-
Volume 40
CONTINUOUS CONCEALED REENTRY-HOPE
A
ET AL.
B L2
Y:,
.‘-‘-i+L-,-‘w,p
L2
~$+Hb eg :~~~,~~,~,~~~~~,~~~~~~~,~~~~-~I~~,~~,~~~ A-
I2
egm-
-;-
IZ
eg
A--;
-
-.-+v~~~~‘~-~-..+~ c
I
Se‘
I
FIGURE 2. Bigeminal rhythm in a dog 5 days after myocardial infarction. A, surface electrocardiographic lead II (L2), His bundle electrogram (Hb eg) and two infarct zone electrograms (IZ eg) obtained during a relatively slow heart rate (R-R interval = 800 msec). B, same recordings have altered during a faster atrial pacing rate (R-R interval = 310 msec). See text for discussion.
cessive beats. That is, electrical activity as recorded by an electrogram was continuous if it persisted throughout one or more cardiac cycles.
Illustrative
Experiments
Figure 1 shows a ventricular quadrigeminal rhythm in a dog 4 days after myocardial infarction. The presence of complete A-V nodal block, induced by vagal stimulation, indicates that there was no enhanced ventricular automaticity underlying the supraventricular rhythm. Thus, increased ventricular automaticity induced by the infarct is an unlikely explanation for the quadrigeminal rhythm. The tracing is typical of those of all the dogs in that ventricular automaticity was not increased, a finding confirmed in each case with vagal stimulation (as in Fig. 1) or cessation of atria1 pacing, or both, in those animals with slow nodal escape rhythms after sinus crush. Previous reportss1°J7-I9 have documented the loss of potential, fractionation and delay of recorded electrical activity within the infarct zone. In our study, the extent of these changes was in part related to the effect of heart rate and abrupt rhythm changes in similar fashion to the responses after acute myocardial infarction.” Figure 2 shows the commencement of a bigeminal rhythm in a dog with a 5 day old myocardial infarction. Panel A illustrates the surface electrocardiographic lead II, His bundle electrogram and two ischemic zone electrograms obtained during a relatively slow heart rate (R-R interval = 800 msec). In panel B both ischemic zone electrograms have altered as a function of the faster pacing rate (R-R interval = 310 msec). The sharply inscribed electrograms of panel A contrast with the decreased amplitude, fractionation and marked delay of activation in panel B. The heterogeneous nature of the ischemit zone is illustrated by the difference in electrical activation of the two bipolar recordings within the infarct zone. There is a 2:l variation of these patterns of fractionation and delay in the lower recording. In addition, a superimposed alternating Wenckebach-like behavior is seen with increasing fractionation and delay of alternate cycles. Electrical activity as manifested in the lower recording becomes continuous between alternate beats. This pattern of underlying electrical activity, initially concealed, eventually is expressed in the electrocardiogram as an emerging ventricular bigeminal rhythm. Similar patterns of underlying electrical activity accounted for other forms of ventricular rhythms, such as trigeminy and quadrigeminy.
FIGURE 3. Concealed trigeminal rhythm in a dog 6 days after myocardial infarction. Electrocardiographic lead II (L2), His bundle electrogram (Hb eg) and two infarct zone electrograms (IZ eg) recorded during sinus rhythm (R-R interval = 320 msec; first two beats of figure), during atrial pacing at a faster rate (R-R interval = 220 msec) and after cessation of atrial pacing. Arrowheads indicate Wenckebach-like sequence of atrial activation delay; VT = ventricular tachycardia. See text for discussion.
Figure 3 shows a concealed trigeminal rhythm in a dog studied 6 days after myocardial infarction. The electrographic recordings are neither appreciably delayed nor fractionated during sinus rhythm (R-R interval = 320 msec). The commencement of atria1 pacing at a faster rate (R-R interval = 220 msec) induces fractionation and delay of the electrographic potential.6 A stable and recurring Wenckebach-like sequence of delayed electrical activity recorded from a portion of the infarct zone is seen in the upper ischemic zone electrocardiogram. Simultaneously, another area of the ischemic zone (lower tracing) demonstrates minimal delay of activation. Cessation of pacing after any beat with maximal electrographic fractionation consistently resulted in one or more ventricular ectopic beats. In this case, cessation of atria1 pacing at the time of maximal electrographic fractionation and delay results in a reentrant ventricular ectopic beat. Ventricular tachycardia follows. During ventricular tachycardia low level electrical activity continues between electrograms but has a different wave form from that seen during the concealed trigeminy. As expected, ventricular ectopic beats did not occur when pacing was stopped after the first (minimal electro-
*
li i ***il
I**
li i
FIGURE 4. At a specific atrial pacing rate (R-R interval = 155 msec), there are irregular changes in the configuration of many beats (asterisks) suggesting fusion with a partly concealed ventricular rhythm (A through C). D, recorded during cessation of atrial pacing in this animal with myocardial infarction and sinus crush, reveals a normal slow ventricular automacity (49 beats/min) with escape beats of a different configuration from that of the ectopic beats of A through C.
November 1977
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735
CONTINUOUS CONCEALED REENTRY-HOPE ET AL.
ventricular premature beats. Two examples are shown in this study (Fig. 2 and 3), and intermittent concealment of the extrasystoles has been demonstrated. Others”,29 have suggested that block in reentrant pathways may produce concealment. A recent report from our laboratory15 has shown that this is not always true and suggested that excitation of the terminal part of the reentrant circuit by normal antegrade impulses prevents the reentrant beats from penetrating into the normal myocardium. That this is one likely explanation is shown in Figure 3, in which concealment occurs during pacing but reentry is manifest after abrupt termination of pacing after a beat showing delayed activation. Forms of ventricular ectopic rhythms: Two forms were seen in our study: intermittent ventricular premature beats, usually in regular coupled sequences or groups (trigeminy, quadrigeminy, and so forth), and short or sustained runs of ventricular tachycardia. Electrophysiologically these two forms of arrhythmia were related to different observations. In the former, the terminal component of each electrogram recorded from the “infarcted” zone showed progressive fractionation and delay into the S-T segment, T wave and beyond.6*7 At a given heart rate, this regular delay in a Wenckebach fashion correlated with the regular appearance of a ventricular premature beat that occurred when portions of the electrogram showed maximal delay. On the other hand, at rapid heart rates the terminal portion of the ischemic zone potential was delayed and blocked, usually in a 2:l fashion.6v7 However, at these rates the initial part of the ischemic zone potential also showed fractionation and delay. A Wenckebach form of delay leading to block was not evident in these instances. Instead, the fractionated activity appeared relatively constant in each cardiac cycle but extended throughout the diastolic interval and resulted in sustained ventricular tachycardia when the initiating heart rate reached a critical level (Fig. 5 and 6). The supraventricular rhythm suppressed or masked the ventricular
tachycardia although the characteristic fractionated activity persisted throughout each cardiac cycle. Thus, electrical activity was continuous but concealed in the electrocardiogram. The basis of this concealment may be due to the ability of the supraventricular impulse to depolarize a portion of the reentrant pathway before its exit to normal tissue or to the low safety factor of the fractionated wave front, or both. In a previous reporti we demonstrated that premature stimulation (atria1 or ventricular) can more completely depolarize the reentrant pathway, thus terminating the ventricular tachycardia and the continuous electrical activity. Implications: From a basic electrophysiologic standpoint these studies suggest that the “infarcted” epicardium is composed of at least two populations of abnormal cells. One group demonstrates electrical activity that fractionates in a Wenckebach cycle at relatively slow rates producing coupled ventricular ectopic beats. The other shows activity that fractionates extensively without progressive delay and block and can provide the basis of a sustained ventricular tachycardia. This postulate is consonant with recent in vitro findings from our laboratory. Lazzara et al. (unpublished data), in studies of infarcted epicardium taken from hearts 3 to 10 days after myocardial infarction, showed different responsiveness of “sick” cells to hypoxia, potassium and lidocaine. Various degrees of membrane response and postrepolarization refractoriness were associated with reentrant activity. The continuous concealed electrical activity recorded in our studies resembles that described by Waldo et a1.g during the early phase arrhythmia soon after ligation of a major coronary artery. However, unlike the induced localized ventricular fibrillation suggested by Moe et a1.30 and monitored by Waldo et a1.,g the continuous epicardial electrical activity we have described may be less chaotic and more organized. The latter would account for the occurrence of associated sustained ventricular arrhythmias rather than the appearance of ventricular fibrillation.
References 1. Schamroth L, Marriott HJL: Intermittent ventricular parasystole with observations on its relationship to extrasystolic bigeminy. Am J Cardiol 7:799-809, 1961 Schamroth L, Marriott HJL: Concealed ventricular extrasystoles. Circulation 27:1043-1049, 1963 Schamroth L: Genesis and evolution of ectopic ventricular rhythm. Br Heart J 28:244-257, 1966 Levy MN, Adler DS, Levy JR: Three variants of concealed bigeminy. Circulation 51:646-655, 1975 Kerin N, Mori I, Levy MN: Ventricular quadrigeminy as a manifestation of concealed bigeminy. Circulation 52:1023-1029, 1975 6. Hope RR, Scherlag BJ, Lazzara R: The induction of ventricular arrhythmias in acute myocardial ischemia by atrial pacing with long-short cycle sequences. Chest 71:651-658. 1977 7. Hope RR, Scherlag BJ, El-Shertf N, et al: Ventricular arrhythmias in subacute myocardial infarction. Am Heart J, in press 8. Harris AS, Rojas AG: The initiation of ventricular fibrillation due to coronary occlusion. Exp Med Surg 1:105-121, 1943 9. Waldo AL, Kaiser GA: A study of ventricular arrhythmias associated with acute myocardial infarction in the canine heart. Circulation
47:1222-1228, 1973 10. Boineau JP, Cox JL: Slow ventricular activation in acute myocardial infarction. A source of reentrant premature contractions. Circulation 48:702-713, 1973 11. Wit AL, Cranefleld PF, Hoffman BF: Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res 3O:l l-22, 1972 12. Hope RR, Williams DO, El-SherTf N, et al: The efficacy of antiarrhythmic agents during acute myocardial ischemia and the role of heart rate. Circulation 50:507-514, 1974 13. Williams DO, Scherlag BJ, Hope RR, et al: The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 50:1163-i 172, 1974 14. Lazzara R, Scherlag BJ, Robinson MJ, et al: Selective in situ parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res 32:393-401, 1973 15. El-Sherif N, Scherlag BJ, Lazrara R, et al: Reentrant ventricular arrhythmias in the late myocardial infarction period. I. The conduction characteristics in the infarction zone. Circulation 55: 686-701, 1977
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16. El-Sherif N, Hope RR, Scherlag BJ, et al: Reentrant ventricular arrhythmias in the late myocardial infarction period. II.Patterns of initiation and termination of reentry. Circulation 55702-718, 1977 17. Durrer D, VanLier AAW, Buller J: Epicardial and intramural excitation in chronic myocardial infarction. Am Heart J 68:765-776, 1964 18. Durrer D, Van Dam RTH, Freud GE, et al: Re-entry and ventricular arrhythmias in local ischemia and infarction of the intact dog heart. Proc Kron Nedrl Akad Van Wetersch, Amsterdam C73:321-334, 1971 19. Scherlag BJ, Helfant RH, Haft JI, et al: Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol 219:1665-1671, 1970 20. Han J, Moe GK: Nonuniform recovery of excitability in ventricular muscle. Circ Res 14:44-60, 1964 21. Scherlag BJ, El-Sherif N, Hope RR, et al: Characteristics and localization of ventricular arrhythmias due to myocardial ischemia and infarction. Circ Res 35372-383, 1974 22. El-Sherif N, Scherlag BJ, Lazzara R: Electrode catheter recordings during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Circulation 51:1003-1014, 1975
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23. DeSoyza N, Bissett JJ, Kane JJ, et al: Ectopic ventricular prematurity and its relationship to ventricular tachycardia in acute myocardial infarction in man. Circulation 50:529-533, 1974 24. Lie KI, Wellens HJJ, Downar E, et al: Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation 52:755-759, 1975 25. El-Sherif N, Myerburg RJ, Scherlag BJ, et al: Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction. Br Heart J 38:415-422. 1976 26. Winkle RA, Derrington DC, Schroeder JS: Characteristics of ventricular tachycardia in ambulatory patients (abstr). Am J Cardiol 37:183, 1976 27. Hoffman BF: The genesis of cardiac arrhythmias. Prog Cardiovasc Dis 8:319-329, 1966 28. Cranefield PF: Ventricular fibrillation. N Engl J Med 289:732-736, 1973 29. Cranefield PF: The Conduction of the Cardiac Impulse. Mt Kisco, New York, Futura, 1975, p 163 30 Moe GK, Harris AS, Wiggers CJ: Analysis of the initiation of fibrillation by electrographic studies. Am J Physiol 134:473-492, 1941
Volume 40
RONALD R. HOPE, MB, FRACP BENJAMIN J. SCHERLAG, PhD, NABIL EL-SHERIF, MD RALPH
LAZZARA,
MD,
FACC
FACC
Miami, Florida
From the Section of Cardiology, Veterans Administration Hospital, and the Division of Cardiology, University of Miami School of Medicine, Miami, Florida. This study was supported in part by Grant ROI HL-18139 from the National Institutes of Health, Bethesda, Maryland. Manuscript received March 10, 1977; revised manuscript received May 9, 1977, accepted May 11, 1977. Address for reprints: Ronald R. Hope, MB, Veterans Administration Hospital, 1201 Northwest 16th Street, Miami, Florida 33125.
Twenty dogs were studied 3 to 9 days after myocardial infarction. None had ventricular arrhythmias during sinus rhythm, and ventricular automaticity (as revealed by sinus nodal crush procedure or vagai stimulation, or both) was within the normal range. With regular atriai pacing or pacing with long-short cycle sequences it was possible to induce ventricular arrhythmias in ail animals. Quadrigeminai and pentageminai rhythms (19 of 20 dogs) and trigeminai (17 of 20) and bigeminai ventricular rhythms (8 of 20) were observed. These rhythms which were manifest or partially or entirely concealed were always associated with delayed and fractionated electrical activity within the “infarcted” subepicardium. Continuous electrical activity (electrical activity that bridged the interval between two or more successive beats) was recorded from the infarct zone. Such activity either was manifest as ventricular arrhythmia during atrial pacing or remained concealed until atrial pacing was stopped and then was manifest as ventricular tachycardia.
Deductive analysis of electrocardiograms has provided circumstantial evidence of both manifest and concealed ventricular reentrant rhythms.i-5 Mathematical formulas have even been derived to describe various reentrant rhythms2y3s5 characterized by regular intermittent appearances of ventricular premature beats, that is, regular bigeminy or trigeminy. Continuous electrical activity during stable reentry has not been documented, and proof of reentry has been lacking. In recent studie&7 we described an experimental model using direct recording from potential reentry circuits. As previously postulated,s’l reentrant ventricular beats should be preceded by continuous electrical activity that bridges the interval from the initiating to the reentrant beat. In this study, dogs in the late postmyocardial infarction period (3 to 9 days after coronary arterial ligation) were studied using direct recordings from the “infarcted” epicardium. The study provides direct evidence for patterns of continuous activity in the infarct zone. This ischemic zone activity may be expressed in the surface electrocardiogram as ventricular arrhythmia or may remain concealed. Furthermore, direct recordings from the reentrant pathways provide possible explanations for the occurrence of intermittent ventricular ectopic beats or both manifest and concealed ventricular tachycardias. Materials
and Methods
Experiments were performed in 20 adult mongrel dogs weighing 10 to 30 kg and anesthetized with intravenously administered sodium pentobarbital (30 mg/kg body weight). A Harvard respirator provided mechanical ventilation of the lungs with room air through a cuffed endotracheal tube. A left thoracotomy in the fourth intercostal space was performed and the left anterior descending coronary artery exposed below the origin of the anterior septal branch. A silk ligature was placed around the artery and the artery occluded.
November 1977
The American Journal of CARDIOLOGY
Volume 40
733
CONTINUOUS CONCEALED REENTRY-HOPE
TABLE
ET AL
I
Types of Ventricular Arrhythmia in 20 Dogs
Bigeminy (2:l) Trigeminy (3: 1) Quadrigeminy (4: 1, 5: 1, etc.) Ventricular tachycardia Automaticity
a dogs 17 dogs 19 dogs 12 dogs 18-94 beatslmin (average 41 beats/min)
Instrumentation and recordings: Three to 10 days later, each animal underwent further surgery with use of the same anesthetic and ventilatory procedures. The heart was exposed through a right thoracotomy in the fourth intercostal space. The pericardium was opened. To obtain long diastolic intervals (slow heart rates) the sinus nodal area was crushed with a Satinsky clamp. The entire sinus node and the adjacent area were resected and the adjacent edges of the atrium sutured before the clamp was removed. The pericardium was then repaired, the incision closed and the animal placed on its right side, A left thoracotomy was performed and the pericardium incised. A large multipolar “paper” electrode12J3 was placed over the surface of the infarcted myocardium and held securely in place by the pericardium. Two to three pairs of fine Teflon@-coated stainless steel wires (diameter 0.005 inch [0.0127 cm]) were inserted into the epicardium through a 25 gauge needle 1 l/2 inches (3.81 cm) in length and positioned in subepicardial areas within and adjacent to the infarcted area. These were used to obtain local electrograms and to perform ventricular pacing from these sites. Atria1 pacing was achieved by delivery of electrical pulses of 2 to 10 volts and 2 msec duration 50 to 300 times/min through stainless steel wires (diameter 0.005 inch) inserted into the left atria1 appendage. An S88 Grass stimulator and SIU-5 isolation unit were used. A common carotid artery was exposed in the neck and a no. 5 French catheter with ring electrodes 10 mm apart used to obtain His bundle recordings at the aortic root.lO Vagal stimulation, used to stop temporarily supraventricular activity and to prevent atrioventricular (A-V) conduction, was accomplished with delivery of 0.05 msec rectangular wave pulses of 1 to 20 volts intensity at a frequency of 20 hertz through silver wire electrodes inserted into the left or right cervical vagosympathetic trunk, or both.14 All records were obtained on a multichannel oscilloscope photographic recorder (Electronics for Medicine, DR-12) at paper speeds of 50 to 200 mm/set with filter frequencies of 0.1 to 200 hertz for electrocardiographic leads and 40 to 200 hertz for electrographic recordings and the His bundle electrograms. All recordings were made on a magnetic tape recorder (Honeywell 5700) and replayed so that selected sections could be transferred to photographic paper for detailed analysis. Measurements were accurate up to f3 msec at a paper speed of 200 mm/set. Procedure: Control records were obtained during sinus rhythm before the sinus crush procedure, after the crush procedure and also during vagal slowing of the heart. Atria1 pacing was performed utilizing rates just faster than existing slow atria1 rates after sinus crush, up to rates that produced Wenckebach block within the A-V node. Over this wide range of heart rates (50 to 350 beats/min) several methods of atria1 stimulation were used. Regular pacing with (1) gradual changes in rate, and (2) abrupt asystolic pauses of variable duration was carried out in each animal. In addition, regular atria1 pacing with introduction of occasional atria1 premature beats was examined. Thus, of these three pacing methods, the
734
November
1977
The American Journal of CARDIOLOGY
FIGURE 1. Ventricular quadrigeminal rhythm in a dog 4 days after myocardial infarction. Electrocardiographic leads II (L2) and aVR in the upper panel are continuous with those tracings in the lower panel. The complete A-V block induced by vagal stimulation (VS) indicates that enhanced ventricular automaticity does not underly the supraventricular rhythm.
last two had in common the presence of long-short cycle sequences. These same pacing methods were carried out with His bundle pacing instead of atria1 pacing in 8 of the 20 dogs. In those animals with A-V nodal Wenckebach block at rates of 200 to 240 beats/min, His bundle pacing achieved maximal stimulated heart rates comparable with those of the other dogs (up to 350 beats/min). During the procedure, areas of maximal epicardial activation delay were sought within the infarcted area. This was achieved by varying the position of either the multipolar paper electrode or the bipolar wire electrodes within the infarct zone. No animals were resuscitated from ventricular fibrillation during the course of these experiments.
Results The types of ventricular arrhythmias seen are listed in Table I. The dogs were studied 3 to 9 days (average 5 days) after myocardial infarction was induced. Underlying ventricular automaticity as revealed by sinus nodal crush procedure or vagal stimulation, or both, averaged 41 beats/min (range 18 to 94). No animal had ventricular arrhythmias during sinus rhythm. However, when the atria1 pacing techniques were used, ventricular arrthythmias were demonstrated in all cases. Detailed assessment of the variable responses to the different pacing procedures is the subject of other reports from this laboratory.6,7J5J6 Quadrigeminal and pentageminal ventricular rhythms were seen in 19 of 20 dogs (Table I). Trigeminal (17 of 20 dogs) and regular ventricular bigeminal rhythms (8 of 20 dogs) were less frequently observed. These rhythms were either concealed or manifest or, more often, variably manifest (and thus partially concealed). The terms “manifest” and “concealed” were respectively applied when recurring patterns of delayed electrical activity in the infarct zone were or were not accompanied by evidence of ventricular arrhythmias in the surface electrocardiogram. Evidence of continuous electrical activity was seen in the electrograms from the epicardium or subepicardium, or both, of the infarct zone in all animals. Continuous activity was defined as electrical activity that bridged the entire interval between two or more suc-
Volume 40
CONTINUOUS CONCEALED REENTRY-HOPE
A
ET AL.
B L2
Y:,
.‘-‘-i+L-,-‘w,p
L2
~$+Hb eg :~~~,~~,~,~~~~~,~~~~~~~,~~~~-~I~~,~~,~~~ A-
I2
egm-
-;-
IZ
eg
A--;
-
-.-+v~~~~‘~-~-..+~ c
I
Se‘
I
FIGURE 2. Bigeminal rhythm in a dog 5 days after myocardial infarction. A, surface electrocardiographic lead II (L2), His bundle electrogram (Hb eg) and two infarct zone electrograms (IZ eg) obtained during a relatively slow heart rate (R-R interval = 800 msec). B, same recordings have altered during a faster atrial pacing rate (R-R interval = 310 msec). See text for discussion.
cessive beats. That is, electrical activity as recorded by an electrogram was continuous if it persisted throughout one or more cardiac cycles.
Illustrative
Experiments
Figure 1 shows a ventricular quadrigeminal rhythm in a dog 4 days after myocardial infarction. The presence of complete A-V nodal block, induced by vagal stimulation, indicates that there was no enhanced ventricular automaticity underlying the supraventricular rhythm. Thus, increased ventricular automaticity induced by the infarct is an unlikely explanation for the quadrigeminal rhythm. The tracing is typical of those of all the dogs in that ventricular automaticity was not increased, a finding confirmed in each case with vagal stimulation (as in Fig. 1) or cessation of atria1 pacing, or both, in those animals with slow nodal escape rhythms after sinus crush. Previous reportss1°J7-I9 have documented the loss of potential, fractionation and delay of recorded electrical activity within the infarct zone. In our study, the extent of these changes was in part related to the effect of heart rate and abrupt rhythm changes in similar fashion to the responses after acute myocardial infarction.” Figure 2 shows the commencement of a bigeminal rhythm in a dog with a 5 day old myocardial infarction. Panel A illustrates the surface electrocardiographic lead II, His bundle electrogram and two ischemic zone electrograms obtained during a relatively slow heart rate (R-R interval = 800 msec). In panel B both ischemic zone electrograms have altered as a function of the faster pacing rate (R-R interval = 310 msec). The sharply inscribed electrograms of panel A contrast with the decreased amplitude, fractionation and marked delay of activation in panel B. The heterogeneous nature of the ischemit zone is illustrated by the difference in electrical activation of the two bipolar recordings within the infarct zone. There is a 2:l variation of these patterns of fractionation and delay in the lower recording. In addition, a superimposed alternating Wenckebach-like behavior is seen with increasing fractionation and delay of alternate cycles. Electrical activity as manifested in the lower recording becomes continuous between alternate beats. This pattern of underlying electrical activity, initially concealed, eventually is expressed in the electrocardiogram as an emerging ventricular bigeminal rhythm. Similar patterns of underlying electrical activity accounted for other forms of ventricular rhythms, such as trigeminy and quadrigeminy.
FIGURE 3. Concealed trigeminal rhythm in a dog 6 days after myocardial infarction. Electrocardiographic lead II (L2), His bundle electrogram (Hb eg) and two infarct zone electrograms (IZ eg) recorded during sinus rhythm (R-R interval = 320 msec; first two beats of figure), during atrial pacing at a faster rate (R-R interval = 220 msec) and after cessation of atrial pacing. Arrowheads indicate Wenckebach-like sequence of atrial activation delay; VT = ventricular tachycardia. See text for discussion.
Figure 3 shows a concealed trigeminal rhythm in a dog studied 6 days after myocardial infarction. The electrographic recordings are neither appreciably delayed nor fractionated during sinus rhythm (R-R interval = 320 msec). The commencement of atria1 pacing at a faster rate (R-R interval = 220 msec) induces fractionation and delay of the electrographic potential.6 A stable and recurring Wenckebach-like sequence of delayed electrical activity recorded from a portion of the infarct zone is seen in the upper ischemic zone electrocardiogram. Simultaneously, another area of the ischemic zone (lower tracing) demonstrates minimal delay of activation. Cessation of pacing after any beat with maximal electrographic fractionation consistently resulted in one or more ventricular ectopic beats. In this case, cessation of atria1 pacing at the time of maximal electrographic fractionation and delay results in a reentrant ventricular ectopic beat. Ventricular tachycardia follows. During ventricular tachycardia low level electrical activity continues between electrograms but has a different wave form from that seen during the concealed trigeminy. As expected, ventricular ectopic beats did not occur when pacing was stopped after the first (minimal electro-
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FIGURE 4. At a specific atrial pacing rate (R-R interval = 155 msec), there are irregular changes in the configuration of many beats (asterisks) suggesting fusion with a partly concealed ventricular rhythm (A through C). D, recorded during cessation of atrial pacing in this animal with myocardial infarction and sinus crush, reveals a normal slow ventricular automacity (49 beats/min) with escape beats of a different configuration from that of the ectopic beats of A through C.
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ventricular premature beats. Two examples are shown in this study (Fig. 2 and 3), and intermittent concealment of the extrasystoles has been demonstrated. Others”,29 have suggested that block in reentrant pathways may produce concealment. A recent report from our laboratory15 has shown that this is not always true and suggested that excitation of the terminal part of the reentrant circuit by normal antegrade impulses prevents the reentrant beats from penetrating into the normal myocardium. That this is one likely explanation is shown in Figure 3, in which concealment occurs during pacing but reentry is manifest after abrupt termination of pacing after a beat showing delayed activation. Forms of ventricular ectopic rhythms: Two forms were seen in our study: intermittent ventricular premature beats, usually in regular coupled sequences or groups (trigeminy, quadrigeminy, and so forth), and short or sustained runs of ventricular tachycardia. Electrophysiologically these two forms of arrhythmia were related to different observations. In the former, the terminal component of each electrogram recorded from the “infarcted” zone showed progressive fractionation and delay into the S-T segment, T wave and beyond.6*7 At a given heart rate, this regular delay in a Wenckebach fashion correlated with the regular appearance of a ventricular premature beat that occurred when portions of the electrogram showed maximal delay. On the other hand, at rapid heart rates the terminal portion of the ischemic zone potential was delayed and blocked, usually in a 2:l fashion.6v7 However, at these rates the initial part of the ischemic zone potential also showed fractionation and delay. A Wenckebach form of delay leading to block was not evident in these instances. Instead, the fractionated activity appeared relatively constant in each cardiac cycle but extended throughout the diastolic interval and resulted in sustained ventricular tachycardia when the initiating heart rate reached a critical level (Fig. 5 and 6). The supraventricular rhythm suppressed or masked the ventricular
tachycardia although the characteristic fractionated activity persisted throughout each cardiac cycle. Thus, electrical activity was continuous but concealed in the electrocardiogram. The basis of this concealment may be due to the ability of the supraventricular impulse to depolarize a portion of the reentrant pathway before its exit to normal tissue or to the low safety factor of the fractionated wave front, or both. In a previous reporti we demonstrated that premature stimulation (atria1 or ventricular) can more completely depolarize the reentrant pathway, thus terminating the ventricular tachycardia and the continuous electrical activity. Implications: From a basic electrophysiologic standpoint these studies suggest that the “infarcted” epicardium is composed of at least two populations of abnormal cells. One group demonstrates electrical activity that fractionates in a Wenckebach cycle at relatively slow rates producing coupled ventricular ectopic beats. The other shows activity that fractionates extensively without progressive delay and block and can provide the basis of a sustained ventricular tachycardia. This postulate is consonant with recent in vitro findings from our laboratory. Lazzara et al. (unpublished data), in studies of infarcted epicardium taken from hearts 3 to 10 days after myocardial infarction, showed different responsiveness of “sick” cells to hypoxia, potassium and lidocaine. Various degrees of membrane response and postrepolarization refractoriness were associated with reentrant activity. The continuous concealed electrical activity recorded in our studies resembles that described by Waldo et a1.g during the early phase arrhythmia soon after ligation of a major coronary artery. However, unlike the induced localized ventricular fibrillation suggested by Moe et a1.30 and monitored by Waldo et a1.,g the continuous epicardial electrical activity we have described may be less chaotic and more organized. The latter would account for the occurrence of associated sustained ventricular arrhythmias rather than the appearance of ventricular fibrillation.
References 1. Schamroth L, Marriott HJL: Intermittent ventricular parasystole with observations on its relationship to extrasystolic bigeminy. Am J Cardiol 7:799-809, 1961 Schamroth L, Marriott HJL: Concealed ventricular extrasystoles. Circulation 27:1043-1049, 1963 Schamroth L: Genesis and evolution of ectopic ventricular rhythm. Br Heart J 28:244-257, 1966 Levy MN, Adler DS, Levy JR: Three variants of concealed bigeminy. Circulation 51:646-655, 1975 Kerin N, Mori I, Levy MN: Ventricular quadrigeminy as a manifestation of concealed bigeminy. Circulation 52:1023-1029, 1975 6. Hope RR, Scherlag BJ, Lazzara R: The induction of ventricular arrhythmias in acute myocardial ischemia by atrial pacing with long-short cycle sequences. Chest 71:651-658. 1977 7. Hope RR, Scherlag BJ, El-Shertf N, et al: Ventricular arrhythmias in subacute myocardial infarction. Am Heart J, in press 8. Harris AS, Rojas AG: The initiation of ventricular fibrillation due to coronary occlusion. Exp Med Surg 1:105-121, 1943 9. Waldo AL, Kaiser GA: A study of ventricular arrhythmias associated with acute myocardial infarction in the canine heart. Circulation
47:1222-1228, 1973 10. Boineau JP, Cox JL: Slow ventricular activation in acute myocardial infarction. A source of reentrant premature contractions. Circulation 48:702-713, 1973 11. Wit AL, Cranefleld PF, Hoffman BF: Slow conduction and reentry in the ventricular conducting system. II. Single and sustained circus movement in networks of canine and bovine Purkinje fibers. Circ Res 3O:l l-22, 1972 12. Hope RR, Williams DO, El-SherTf N, et al: The efficacy of antiarrhythmic agents during acute myocardial ischemia and the role of heart rate. Circulation 50:507-514, 1974 13. Williams DO, Scherlag BJ, Hope RR, et al: The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 50:1163-i 172, 1974 14. Lazzara R, Scherlag BJ, Robinson MJ, et al: Selective in situ parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res 32:393-401, 1973 15. El-Sherif N, Scherlag BJ, Lazrara R, et al: Reentrant ventricular arrhythmias in the late myocardial infarction period. I. The conduction characteristics in the infarction zone. Circulation 55: 686-701, 1977
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16. El-Sherif N, Hope RR, Scherlag BJ, et al: Reentrant ventricular arrhythmias in the late myocardial infarction period. II.Patterns of initiation and termination of reentry. Circulation 55702-718, 1977 17. Durrer D, VanLier AAW, Buller J: Epicardial and intramural excitation in chronic myocardial infarction. Am Heart J 68:765-776, 1964 18. Durrer D, Van Dam RTH, Freud GE, et al: Re-entry and ventricular arrhythmias in local ischemia and infarction of the intact dog heart. Proc Kron Nedrl Akad Van Wetersch, Amsterdam C73:321-334, 1971 19. Scherlag BJ, Helfant RH, Haft JI, et al: Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol 219:1665-1671, 1970 20. Han J, Moe GK: Nonuniform recovery of excitability in ventricular muscle. Circ Res 14:44-60, 1964 21. Scherlag BJ, El-Sherif N, Hope RR, et al: Characteristics and localization of ventricular arrhythmias due to myocardial ischemia and infarction. Circ Res 35372-383, 1974 22. El-Sherif N, Scherlag BJ, Lazzara R: Electrode catheter recordings during malignant ventricular arrhythmia following experimental acute myocardial ischemia. Circulation 51:1003-1014, 1975
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23. DeSoyza N, Bissett JJ, Kane JJ, et al: Ectopic ventricular prematurity and its relationship to ventricular tachycardia in acute myocardial infarction in man. Circulation 50:529-533, 1974 24. Lie KI, Wellens HJJ, Downar E, et al: Observations on patients with primary ventricular fibrillation complicating acute myocardial infarction. Circulation 52:755-759, 1975 25. El-Sherif N, Myerburg RJ, Scherlag BJ, et al: Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction. Br Heart J 38:415-422. 1976 26. Winkle RA, Derrington DC, Schroeder JS: Characteristics of ventricular tachycardia in ambulatory patients (abstr). Am J Cardiol 37:183, 1976 27. Hoffman BF: The genesis of cardiac arrhythmias. Prog Cardiovasc Dis 8:319-329, 1966 28. Cranefield PF: Ventricular fibrillation. N Engl J Med 289:732-736, 1973 29. Cranefield PF: The Conduction of the Cardiac Impulse. Mt Kisco, New York, Futura, 1975, p 163 30 Moe GK, Harris AS, Wiggers CJ: Analysis of the initiation of fibrillation by electrographic studies. Am J Physiol 134:473-492, 1941
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