E. Neil Moore

Electrophysiologic and anatomic correlates of sustained ventricular tachyarrhythmias in a model of chronic myocardial infarction

Ten healthy adult mongrel dogs were subjected to two stage occlusions of the mid or distal left anterior descending coronary artery modified by a reperfusion stage. In 9 of 10 animals studied at 3 or more days after coronary occlusion, sustained reentrant ventricular tachyarrhythmias could be reproducibly initiated or terminated, or both, using routine methods of programmed electric stimulation. Plunge electrodes were inserted at multiple subepicardial, intramyocardial and subendocardial sites from areas of normal and infarcted myocardium to evaluate electrophysiologic properties of excitability and refractoriness. With use of constant current unipolar cathodal stimulation, strength-interval curves were measured at these sites and correlated with regional histopathologic findings. In this model, infarcts were mottled, with close interspersing of normal and abnormal myocardium. Although excitability thresholds and refractoriness tended to increase within areas of infarction, marked disparities in excitability thresholds, effective and relative refractory periods and duration of relative refractory periods (relative minus effective refractory period) were observed within areas of infarction at sites only 1 to 2 mm apart anatomically. This milieu of anatomic and electrophysiologic heterogeneity is apparently sufficient to predispose to the initiation of sustained reentrant ventricular tachyarrhythmias.

Functional Properties of the Atrioventricular Conduction System

Experiments were designed to study A-V transmission of premature atrial responses by recording electrical activity directly from selected parts of the conducting system. This experimental design permits a more exact interpretation of results than is the case when records are obtained only from the atria and ventricles. Two types of experiments have been conducted in studies of the response of the specialized conducting system of the mammalian heart to premature activation. Records of transmembrane potentials from single fibers of the A-V node and Purkinje system show that premature responses may show a reduced rate of rise and amplitude and thus may be conducted slowly or may decrement completely. Under other conditions, premature responses may show local delay or block because they arise from a local response of considerable duration. Records obtained directly from different parts of the in situ specialized conducting system show that the same phenomena probably occur in the intact, normal heart. These properties of the various fibers of the conducting system, in conjunction with the normal local differences in action potential duration, conduction velocity, and excitability, seem to account quite adequately for the variations which have been noted during A-V propagation of premature responses. On the basis of these results, it seems unnecessary to postulate a dual A-V conducting system in the mammalian heart.

Evidence for Propagation of Activation Across an Accessory Atrioventricular Connection in Types A and B Pre-excitation

The sequence of atrioventricular activation was studied in two human subjects with type B Wolff-Parkinson-White syndrome (WPW) and in a dog with spontaneous type A WPW. In all three subjects a focal spot of pre-excitation was demonstrated at the A-V margin of the right ventricle (RV). In the two human subjects with type B WPW, the area of pre-excitation was located on the anterior aspect of the RV and in the dog with type A the pre-excited area was located on the posterior aspect of the RV. A probable Kent bundle electrogram was recorded from the A-V margin in one of the human patients. Serial sections (7 &mgr;) of a block taken from the region of pre-excitation in the dog revealed an anomalous A-V communication (Kent bundle). Propagation velocity across this pathway was estimated to be 0.3 mm/msec. Electrophysiologic data recorded from one of the human subjects at the onset and during an episode of supraventricular tachycardia demonstrated an atrioventricular-atrial sequence of excitation. The mechanism of initiation of the tachycardia was a ventriculo-atrial echo following a premature atrial contraction blocked in the anomalous pathway. Surgical separation of right atrium and RV at the site of pre-excitation normalized the activation and ECG and abolished the tachycardia in both patients.Ventricular fibrillation occurred repeatedly in the dog as a direct result of the rapid ventricular rate permitted by the Kent bundle subsequent to induced atrial fibrillation. Correlation of the activation sequence with the body surface potentials suggests an updated conceptual model for electrocardiographic typing of WPW. In a third patient, who demonstrated an atypical form of WPW, the region of pre-excitation could not be precisely defined and interruption of an accessory pathway was unsuccessful.

Cellular electrophysiologic characteristics of chronically infarcted myocardium in dogs susceptible to sustained ventricular tachyarrhythmias

Standard microelectrode techniques were used to record transmembrane potentials and determine conduction characteristics in regions of mottled infarcts of canine epicardium, 3 to 5 days or 8 to 15 days after left anterior descending coronary artery occlusion and reperfusion. At 3 to 5 days, resting potential, action potential amplitude, maximal rate of depolarization and action potential duration at 30% repolarization were significantly reduced in the infarcted region. Cells on the epicardial surface showed improvement in resting potential, action potential amplitude and rate of depolarization between 3 to 5 days and 8 to 15 days after infarction. In normal noninfarcted tissues, conduction velocity parallel to fiber orientation was 0.54 +/- 0.06 m/s (mean +/- standard deviation). Slow conduction in infarcted regions ranged from 0.015 to 0.2 m/s. Action potentials recorded from slowly conducting regions tended to include cells with more depressed amplitude and rate of depolarization than other cells in infarcted regions; they also had inappropriately depressed overshoot relative to their resting potential. Action potentials in slowly conducting areas where local conduction block occurred were associated with prepotentials and notches on their depolarization and repolarization phases. The prepotentials and notches appeared to be caused by electrotonic interactions resulting from microcircuitous conduction around or across inexcitable areas. These findings demonstrate that areas of slow conduction are heterogenously distributed in the mottled infarct and suggest that disruptions in cell to cell electrical continuity and decreased excitability may contribute to this slow conduction.

Observations on Concealed Conduction in Atrial Fibrillation

The mechanism of the ventricular dysrhythmia associated with atrial fibrillation in isolated rabbit heart was studied by recording electrograms from right atrium and ventricle simultaneously with transmembrane action potentials recorded from single fibers within the A-V node and right bundle branch. In most experiments, the variation in ventricular cycle length during experimentally initiated atrial fibrillation resulted from concealed conduction within the A-V node. The most frequently recorded ventricular interval during atrial fibrillation was found when a single response was concealed within the A-V node. In several experiments, as many as seven to nine consecutively concealed responses were recorded from the A-V node. When repetitive A-V nodal concealment occurred, the resulting ventricular cycle lengths were prolonged accordingly. In only a few experiments were conduction delay and block observed within the ventricular specialized conduction system (VSCS) during atrial fibrillation. Subsidiary pacemakers were never observed within the A-V node but were noted occasionally within the VSCS following epinephrine administration. Multiple A-V nodal concealments were usually associated with rapid atrial rates.

Electrophysiologic properties of a new antiarrhythmic drug--tocainide.

Abstract Tocainide (Astra W36095) is an orally active antiarrhythmic drug that is structurally related to lidocaine. This paper describes in vivo and in vitro studies undertaken to assay the electrophysiologic properties of this compound. Ouabain-induced ventricular ectopic activity was abolished by this drug in both isolated canine Purkinje fibers and in intact dogs. Similarly, the ventricular ectopic activity that occurs 24 hours after the two stage Harris coronary arterial ligation procedure also was abolished by tocainide. The amount of current necessary to evoke an action potential by intracell stimulation during diastole was Increased in direct relation to drug concentration. Similarly, in dogs anesthetized with pentobarbital sodium, tocainide increased the ventricular fibrillation threshold up to 150 percent above control values during normal supraventricular rhythm and up to 285 percent after premature ventricular beats. The transmembrane action potential duration and effective refractory period of isolated canine Purkinje fibers were shortened by tocainide. Tocainide depressed atrioventricular nodal conduction in anesthetized dogs, an effect that was magnified in the presence of premature atrial beats but had no effect on His, Purkinje or ventricular muscle conduction. These results Indicate that tocainide is a potentially effective antiarrhythmic agent and deserves further investigation in patients.

Electrocardiographic changes due to delayed activation of the wall of the right ventricle

Abstract The onset of activation of 20 to 30 right ventricular epicardial areas has been determined before and after sectioning of the right ventricular free-running false tendons, or the septal right bundle; the corresponding electrocardiogram and vectocardiogram are shown. It is postulated that many cases of incomplete right bundle branch block result from damage to the free-running false tendons in dogs (moderator band in man.) Delay in activation of the free right ventricular wall appears to be important in producing electrocardiographic changes in both conditions. Microelectrode experiments on isolated tissues demonstrated that the basilar part of the main right bundle branch located above the anterior papillary muscle does not excite the adjoining right septal musculature.

Modulation of quinidine-induced arrhythmias by temperature in perfused rabbit heart

We used low temperature to slow ion channel kinetics and studied the electrophysiological effects of quinidine at different pacing rates in isolated rabbit hearts. Fifteen epicardial electrograms together with an endocardial monophasic action potential were recorded. Epicardial activation and local recovery times were measured. Arrhythmias together with the characteristics of their mode of induction and rate were analyzed by epicardial activation sequence mapping. In the presence of quinidine, arrhythmias consistent with both triggered activity and reentry were observed. At baseline, triggered activity was not inducible, even though at 25°C the recovery time was greater than that in the presence of quinidine at 36°C. Also, with quinidine, the incidence of triggered activity decreased at 30 and 25°C. Therefore prolongation of the recovery time per se does not cause triggered activity. Quinidines use-dependent effects on conduction and reverse use-dependent effects on recovery time were amplified by low temperatures. These findings can be understood in terms of the known temperature sensitivities of the kinetics of the membrane ion channels responsible for activation and recovery. The results demonstrate that temperature can be used as a tool to elucidate mechanisms of drug action.

Effects of aminophylline on the threshold for initiating ventricular fibrillation during respiratory failure.

Cardiac arrhythmias have frequently been reported in association with respiratory failure. The possible additive role of pharmacologic agents in precipitating cardiac disturbances in patients with respiratory failure has only recently been emphasized. The effects of aminophylline on the ventricular fibrillation threshold during normal acid-base conditions and during respiratory failure were studied in anesthetized open chest dogs. The ventricular fibrillation threshold was measured by passing a gated train of 12 constant current pulses through the ventricular myocardium during the vulnerable period of the cardiac cycle. During the infusion of aminophylline, the ventricular fibrillation threshold was reduced by 30 to 40 percent of the control when pH and partial pressures of oxygen (PO2) and carbon dioxide (CO2) were kept within normal limits. When respiratory failure was produced by hypoventilation (pH 7.05 to 7.25; PC02 70 to 100 mm Hg: P02 20 to 40 mm Hg), infusion of aminophylline resulted in an even greater decrease in ventricular fibrillation threshold to 60 percent of the control level. These experiments suggest that although many factors may contribute to the increased incidence of ventricular arrhythmias in respiratory failure, pharmacologic agents, particularly aminophylline, may play a significant role.

Microelectrode Studies on Concealment of Multiple Premature Atrial Responses

Experiments employing microelectrodes to record from single cells within the AV node and ventricular specialized conduction system during conduction of serially evoked premature atrial responses have demonstrated AV conduction delays and block within both the AV node and ventricular specialized conduction system. The rapid decrease in functional refractory period of fibers within the ventricular specialized conduction system, following a decrease in preceding cycle length, resulted in block within the AV node of most serially concealed premature atrial responses. A one-millisecond change in the time of excitation of a premature atrial response could determine whether block or conduction occurred in the AV node.