Nabil El-Sherif

Re-entrant ventricular arrhythmias in the late myocardial infarction period. 1. Conduction characteristics in the infarction zone.

Dogs 3–7 days following ligation of the anterior descending coronary artery represented a remarkably stable model for re-entrant ventricular arrhythmias (RVA) and allowed detailed electrophysiologic studies of the re-entrant mechanism. In these dogs, we could regularly illustrate the presence of continuous electrical activity originating from the infarction zone (IZ) and bridging the diastolic interval between the initiating and re-entrant beats as well as between consecutive re-entrant beats. Conduction in the IZ was highly complex, with multiple potentially re-entrant pathways, functionally dissociated areas, and areas of localized ventricular confibrillation. Conduction disorders in ischemic myocardium were consistently tachycardia-dependent with the spontaneous onset of RVA specifically associated with a Wenckebach-like conduction pattern in a potentially re-entrant pathway. Both manifest and concealed reentry, as well as re-entrant beats with regular extrasystolic grouping, constant or variable coupling, uniform, multiform and bidirectional QRS configurations, were related to characteristic conduction patterns in the IZ. In summary, the study provides the first direct in vivo evidence of ventricular re-entry and demonstrates propensity for RVA and sudden death in the late myocardial infarction period.

Characterization and Localization of Ventricular Arrhythmias Resulting from Myocardial Ischemia and Infarction

Electrocardiograms and electrograms were recorded in 18 dogs anesthetized with sodium pentobarbital. Using endocardial and epicardial plunge wire electrodes in normal and ischemic or infarcted areas, activation of Purkinje and regular muscle tissue was studied within the first 20–30 minutes and 24 hours after anterior descending coronary artery ligation. The ventricular arrhythmias in the first 20 minutes were abolished during vagally induced atrial arrest, but ventricular automaticity was unchanged from that during the control period. These rate-related arrhythmias were uniformly associated with marked diminution and delay of epicardial activation in the ischemic zone. Slowing of the heart rate caused recovery of the timing, form, and duration of these epicardial potentials with the coincident disappearance of ventricular arrhythmias. The ventricular arrhythmias of the early phase spontaneously subsided with time 20–30 minutes after ligation; concurrently, epicardial activation in the ischemic zone improved. The ventricular arrhythmias noted 24 hours after coronary artery ligation were revealed by vagally induced atrial slowing and suppressed by rapid atrial pacing, indicating the existence of enhanced ventricular automaticity. There was a loss of endocardial muscle activation; Purkinje tissue was depressed but viable in the infarcted zone. The sequence of firing during many of the multifocal ventricular ectopic beats showed that the earliest activation arose from Purkinje tissue in the infarcted zone. However, other ectopic beats appeared to arise from infarcted epicardial muscle.

Re-entrant ventricular arrhythmias in the late myocardial infarction period. 2. Patterns of initiation and termination of re-entry.

The electrophysiologic mechanisms for the initiation and termination of re-entrant ventricular arrhythmias (RVA) were critically analyzed in dogs 3-7 days following ligation of the anterior descending coronary artery, utilizing direct recordings of the re-entrant pathway (RP) from the epicardial surface of the infarction zone. Re-entry could occur during a regular cardiac rhythm if the heart rate is within the narrow critical range during which conduction in a potentially RP exhibits a Wenckebach-like (W) pattem with a beat-to-beat increment of conduction delay until the activation wavefront is sufficiently delayed to re-excite normal myocardium. If a regular cardiac rhythm is associated with limited conduction delay in a potentially RP, premature beats within a critical range of coupling intervals could result in sufficient conduction delay to induce re-entry. Re-entrant ventricular arrhythmias may be unmasked on abrupt termination of a critical fast rate of cardiac pacing only if pacing was terminated during those beats of a W pattern associated with marked conduction delay in a RP. RVA could be ended by one or more properly timed premature beats that would pre-excite part of the RP. An electrophysiologic mechanism for Ron-T and its relationship to onset of ventricular fibrillation was shown, based on markedly delayed RP conduction of the beat prior to the one apparently coupled to the premature beat.

Ventricular arrhythmias and electrophysiological consequences of myocardial ischemia and infarction.

The derangements of cardiac rhythm that result from occlusion of coronary arteries caught the attention of the earliest experimenters in the field. By the time of the studies of Porter in 1894, it was known that fibrillar contractions often were the end result of coronary occlusion and that irregularities of cardiac rhythm commonly preceded terminal ventricular fibrillation. Porter remarked that the pioneer investigator, Erichsen, in 1842, saw a slight tremulous motion after cessation of the regular heart beat following coronary occlusion. To Porter, disturbance of the cardiac rhythm was the salient feature of coronary occlusion. Thomas Lewis, in 1909, demonstrated the relationship of paroxysmal ventricular tachycardia to coronary occlusion in experimental animals; Robinson and Hermann, in 1921, established this relationship in man. Clinicians observed a multitude of arrhythmias resulting from ischemia and infarction but the fascination of experimenters with ischemic rhythm disorders waned. During the first half of the 20th century, the attention of researchers was focused more on the effects of ischemia and infarction on the configuration of the ventricular complexes, the QRS and T waves, than on rhythm.

The Pathophysiology of Malignant Ventricular Arrhythmias During Acute Myocardial Ischemia

In 20 anesthetized open-chest dogs, epicardial electrograms were recorded from ischemic and nonischemic zones of the left ventricle during acute occlusion of the left anterior descending artery. The average time to onset of ventricular tachycardia during atrial pacing (150-200 beats/min) was 4 min, 18 sec. In 18 dogs, ventricular ectopic beats were induced in normal and ischemic zones after every tenth atrial stimulus. Those induced in the ischemic zone consistently caused ventricular tachycardia earlier (mean: 3 min, 22 sec) than those in the normal zone (mean: 4 min, 11 sec) (P < 0.01). This arrhythmia, whether spontaneous or induced, always followed the complex which demonstrated the greatest delay of the ischemic zone potential and increased ventricular activation time. Ventricular tachycardia was repeatedly produced by ectopic beats with late diastolic coupling. Analysis of the episodes of tachycardia leading to fibrillation revealed a progressive increase in the ventricular activation time of the successive beats, whereas in those self-terminating episodes ventricular activation time progressively decreased. These data suggest that the major determinant of malignant ventricular arrhythmias in acute ischemia may be the related abnormalities of ventricular activation rather than the coupling of the premature ectopic beats.

Re-entrant ventricular arrhythmias in the late myocardial infarction period. 4. Mechanism of action of lidocaine.

The effect of lidocaine on re-entrant ventricular arrhythmias (RVA) was studied in dogs 3-7 days following ligation of the anterior descending coronary artery; direct recordings were made of the re-entrant pathway (RP) from the epicardial surface of the infarction zone (IZ). Lidocaine in a therapeutic dose consistently prolonged refractoriness of potentially RP(s) in the IZ and produced a higher degree of conduction block at a constant heart rate. Conduction in the adjacent normal zone was not affected. The impairment of conduction induced by lidocaine in the RP was directly related to its ability to abolish re-entrant ventricular beats and tachycardia. Gradual slowing of conduction in the RP consistently developed before abolition: lengthening of coupling of extrasystolic beats in surface leads and gradual slowing of ventricular tachycardia rate occurred. The termination of re-entry was characteristically associated with complete block in the RP. A “selectivity hypothesis” for the antiarrhythmic action of lidocaine is proposed.

The Efficacy of Antiarrhythmic Agents During Acute Myocardial Ischemia and the Role of Heart Rate

The influence of lidocaine, procaine amide, and propranolol on ventricular arrhythmias during acute myocardial ischemia in the dog was examined. Ischemic zone epicardial (IZE) activation delay and the time of onset of ventricular tachycardia (VTt) were studied. Progressive IZE delay always preceded ventricular tachycardia (VT). Ventricular tachycardia occurred when IZE delay extended into the T wave of the standard electrocardiogram but areas of ischemic epicardium were found in which activation delayed beyond the T wave. Fast heart rates during acute ischemia were associated with an accelerated time course of IZE delay and early VT. Slow heart rates resulted in minimal IZE delay and delayed onset or absence of VT. Sympathectomized dogs with heart rates 32% slower than normal dogs did not develop significant IZE delay or VT during ischemia. When heart rates were increased by atrial pacing, these dogs behaved in the same fashion as the normal dogs with respect to IZE delay and VTt. Lidocaine was found to hasten the time course of IZE delay but to have no significant effect on VTt. Procaine amide did not influence IZE delay nor VTt during ischemia. Propranolol slowed the mean heart rate by 20% and appeared to protect against arrhythmia. When the heart rate (115 ± 10 beats/min; mean ± standard deviation) was increased by atrial pacing (184 ± 9 beats/min), propranolol did not significantly influence IZE delay or VTt as compared to the untreated controls. The clinical counterpart of our experiments during acute ischemia may relate to the prehospitalization phase of myocardial infarction.

Re-entrant ventricular arrhythmias in the late myocardial infarction period. 3. Manifest and concealed extrasystolic grouping.

Re-entrant beats with regular extrasystolic grouping were seen in 44% of dogs 3-7 days following ligation of the anterior descending coronary artery. Utilizing direct recordings of the re-entrant pathway (RP) from the epicardial surface of the infarction zone, we found extrasystolic grouping to be based on characteristic tachycardia-dependent conduction disorders in a potentially RP. Trigeminy and quadrigeminy were related, respectively, to a 3:2 and 4:3 Wenckebach-like conduction cycle in a RP. However, quadrigeminy could also be due to an underlying bigeminal rhythm with concealment of alternate re-entrant beats, i.e., concealed bigeminy. A bigeminal rhythm was the result of a 2: 1 conduction pattern in a reentrant pathway with a sufficient degree of conduction delay during the conducted beat of the 2:1 cycle to result in re-entry. A trigeminal or quadrigeminal rhythm could change to a bigeminal rhythm on critical shortening of the cardiac cycle. Fixed and variable coupling were related, respectively, to stable and changing conduction pattern in a re-entrant pathway. On the other hand, extrasystolic grouping could be concealed due to either block in the re-entrant pathway or entrapment in a small area of the closely bordering normal zone.

Disorders of cellular electrophysiology produced by ischemia of the canine His bundle.

In the first 4 hours after occlusion of the anterior septal coronary artery, 18 dogs developed bundle branch block, heart block, or both. The hearts were then excised, and preparations were dissected to expose the His bundle and the bundle branches, which were superfused with modified Tyrodes solution at 37°C. In the His bundle and the most proximal bundle branches, resting potentials were reduced and diminutive action potentials had slow upstrokes, often with notches or steps. Action potentials were generated by fibers that had resting potentials between prime40 and prime50 mv. Conduction was impaired; conduction velocities less than 0.01 m/sec were sometimes observed. In more severely affected cells, refractoriness outlasted repolarization. Encroachment on the prolonged refractory period resulted in further diminution of the upstroke velocity and the amplitude of the action potentials. Rapid stimulation sometimes produced repetitive diminution of action potentials and continuous rather than intermittent block. More commonly, the response to rapid rate took the form of intermittent block with progressive conduction delay in the series of conducted beats, culminating in a blocked beat (Wenckebach sequence). There was a fatigue factor that accumulated at short cycle lengths and depressed the action potential. Automaticity was not enhanced, but pacemaker function was abnormal. The threshold potential shifted erratically, and pacemaker potentials sometimes were intermittently diminished, resulting in intermittent failure to propagate. During prolonged superfusion, there was a tendency to recover with a drift of the maximum diastolic potentials toward more negative levels. None of these changes were found in ten hearts excised from dogs in which the coronary artery had not been ligated.

Conduction Disorders in the Canine Proximal His-Purkinje System Following Acute Myocardial Ischemia I. The Pathophysiology of Intra-His Bundle Block

An intra-His bundle lesion developed in 26 out of 38 dogs (68%) that survived the initial period of arrhythmias that followed ligation of the anterior septal artery. The lesion was isolated in the His bundle in ten experiments and was associated with bundle branch block in 16. The evolution of intra-His bundle block (IHBB) was evaluated utilizing standard ECG leads, catheter electrode, and plunge wire recordings from the His bundle and bundle branches. In all experiments the His bundle potential recorded by the catheter electrode was split into at least two distinct deflections (H1 and H2). This was always associated with a progressive increase of the H1-V interval and represented “first degree IHBB.’ A “second degree IHBB,’ characterized by intermittent block of the atrial impulse between the two His deflections, consistently developed either spontaneously or in response to atrial pacing. The first “stage’ of second degree IHBB had a Mobitz type II pattern with a constant P-R, H1-V, and H1-H2 intervals of the beats preceding and following the block. In 20 of 26 observations, this stage merged into the second stage of second degree IHBB characterized by a progressive increment of the H1-H2 intervals prior to failure of a ventricular response. The increment of conduction time, which was at first in the range of a few msec, would not be recognized in standard ECG recordings. This increment could increase up to 180 msec, giving rise to an obvious Wenckebach periodicity that would be recognized at the usual 25 mm/sec paper speed. Complete (third degree) IHBB was observed either in the form of paroxysmal or persistent block. Paroxysmal block occurred spontaneously or could be induced by a critical rate of rapid atrial pacing during early stages of second degree IHBB. Complete IHBB that developed later was persistent and usually associated with a slow idioventricular rhythm. The study suggests that Mobitz type II and the Wenckebach patterns of conduction disturbance in the His bundle are different stages of the same electrophysiological disturbance, with Mobitz type II block representing the initial stages of failure of impulse propagation.