Dogs 3-7 days following ligation of the anterior descending coronary artery representing 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 fibrillation. 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 re-entry, 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.

We used cesium chloride (CsCI) for electrophysiologic studies in canine hearts in vivo and in vitro to examine the mechanisms underlying ventricular arrhythmias that are related to prolonged repolarization. Cesium is known to depress normal ventricular automaticity and some experimental arrhythmias by blocking delayed outward currents and prolonging action potential duration. In 10 dogs in normal sinus rhythm, 1 to 1.5 mM/kg iv CsCl prolonged the QT (QU) interval and induced ventricular ectopy in all, including multiform ventricular tachycardia. In 12 dogs with atrioventricular block, I to 1.5 mM/kg iv CsCl produced marked suppression of idioventricular rates (from 45 + 6 to 8 4 beats/min). These low rates were then associated with bigeminy or bursts of multiform ventricular arrhythmia. Pacing at rates of 60 beats/min or more suppressed these arrhythmias. Low doses of tetrodotoxin (1 ,ug/kg) also abolished these bradycardia-dependent arrhythmias without affecting the amplitude of ventricular electrograms. Tissue concentrations of cesium were determined by anatomic absorption spectroscopy in five dogs after injection of I mM/kg CsCl. Thirty minutes after the injection, cesium levels in Purkinje fibers were 5.3 ± 1.0 mM/kg, levels in ventricular muscle were 4.6 + 0.9 mM/kg, and levels in atrial muscle were 4.1 ± 0.8 mM/kg. In eight isolated endocardial preparations from canine ventricles, standard microelectrode techniques were used to study the effects of superfusion with 5 mM cesium. After 30 min, we observed early afterdepolarizations interrupting phase 3 of Purkinje fiber action potentials that already showed prolonged repolarization.' Slowing the rate generated single or multiple action potentials arising from partially repolarized levels of membrane potentials ( 80 to -65 mV). Pacing rates of 30 to 60 beats/min diminished the afterdepolarizations and suppressed the spontaneous beats. Tetrodotoxin at a concentration of 10-g/ml, which did not affect upstroke velocity, abolished'the afterpotentials. We conclude that cesium induced bradycardiadependent ventricular arrhythmias caused by early afterdepolarizations. These data suggest that an inward current, probably carried by sodium ions, appears to be essential for the occurrence of this phenomenon. The association of delayed repolarization, afterdepolarizations, and triggered activity has similarities to the phenomenon of drug-induced prolongation of the QTU interval associated with multiform ventricular tachycardia in humans, i.e. "torsades de pointes." Circulation 68, No. 4, 846-856, 1983. IN THE PAST DECADE, information has been accumulating on the occurrence of afterdepolarizations and triggered activity in cardiac tissue and their possible role in the generation of cardiac arrhythmias under various experimental conditions. A substantial amount of data concerning delayed afterdepolarizations has been acquired from experiments with preparations in From the

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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) pattern with a beat-to-beat increment of conduction delay until the activation waveform 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 R-on-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.

Historical PerspectivesThe 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 1 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, 2 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,3 in 1909, demonstrated the relationship of paroxysmal ventricular tachycardia to coronary occlusion in experimental animals; Robinson and Hermann, 4 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.There were two notable exceptions to this trend. Wiggers and associates' noted that a region of ischemia facilitated the induction of ventricular fibrillation by strong stimuli applied during the T wave. Ischemia lowered the "fibrillation threshold" i.e., the current requirement, and broadened the "vulnerable period," i.e., the time interval for the induction of fibrillation.Harris and associates 6 " 8 were distinctive in their attempts to determine the mechanisms for disorders of rhythm by directly recording from ischemic tissues in dogs with occluded coronary arteries. They concluded that ectopic beats are generated near the borders of infarct by automatic foci induced by potassium released from ischemic cells. They discounted the importance of the