Antiarrhythmic versus antifibrillatory actions: Inference from experimental studies

Pathophysiology of the coronary circulation is a major contributor to altering the myocardial substrate, rendering the heart susceptible to the onset of arrhythmias associated with sudden cardiac death. Antiarrhythmic drug therapy for the prevention of sudden cardiac death has been provided primarily on the basis of trial and error and in some instances based on ill-suited preclinical evaluations. The findings of the Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before entering into clinical testing. The major deficiency in this area of experimental investigation has been the lack of animal models that would permit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distinguish between pharmacologic interventions that suppresses nonlethal disturbances of cardiac rhythm as opposed to those agents capable of preventing lethal ventricular tachycardia or ventricular fibrillation. Preclinical models for the testing of antifibrillatory agents must consider the fact that the superimposition of transient ischemic events on an underlying pathophysiologic substrate makes the heart susceptible to lethal arrhythmias. Proarrhythmic events, not observed in the normal heart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more closely simulate the clinical state in humans who are at risk. The experimental results show a good correlation with clinical data regarding agents known to reduce the incidence of lethal arrhythmias as well as those showing proarrhythmic actions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30443/1/0000066.pd

Comparative effects of antiarrhythmic drugs on enhanced ventricular automaticity in endocardial preparations obtained from infarcted canine hearts

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Electrophysiological effects of quinidine in ventricular preparations from infarcted hearts

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The inter-rater reliability of a diagnostic shoulder arthroscopy

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Electrophysiological effects or procainamide in acute and healed experimental ischemic injury of cat myocardium.

We studied the effects of a membrane-active antiarrhythmic agent, procainamide (PA), on cellular electrophysiological consequences of ischemic injury to cat ventricular muscle. The left ventricles of 90- to 120-minute acute myocardial infarctions (AMI) (n = 14), and 2- to 4-month healed myocardial infarctions (HMI) (n = 17), were studied by microelectrode techniques in isolated tissue bath. Control action potential duration at 90% repolarization (APD90) recorded from ventricular muscle cells in AMI areas were short (114 ± 4 msec) compared to recordings from cells in normal areas (136 ± 6 msec) (P < 0.001). In contrast, APD90 of cells surviving ischemia in HMI preparations were longer than normals (159 ± 5 vs. 140 ± 5 msec, P < 0.001). After 60 minutes of exposure to PA, the APD90 of all cells was prolonged, but the absolute and relative magnitudes of prolongation were greater in AMI cells (mean = +40 msec, +35%), than in HMI cells (mean = +19 msec, +13%), P < 0.001. The prolongation of APD90 of normal cells was intermediate. Local refractory period changes paralleled APD90 changes. In seven additional HMI preparations, sustained ventricular activity was induced by premature stimulation. APD90 of HMI cells prolonged less than APD90 of normal cells during exposure to PA in these preparations, and decreased differences of APD90 between normal and HMI cells was associated with loss of inducibility of sustained ventricular activity. The effect of tetrodotoxin (TTX) was compared to the effect of PA in four HMI preparations to determine whether impaired delivery of test substances caused only an apparent decreased responsiveness to PA in HMI zones. TTX caused nearly identical prolongations of conduction times in HMI zones and normal zones, whereas PA caused different effects on APD90 in the two zones. In conclusion, PA alters the time course of repolarization of AMI cells more than that of HMI cells, decreasing the dispersion of repolarization in a given AMI or HMI preparation. The decreased dispersion correlated with loss of ability to induce sustained ventricular activity. Finally, the decreased responsiveness of HMI cells to PA does not appear to be due to impaired delivery to cell membranes, but, rather, appears to be a membrane difference persisting in cells which have survived ischemic injury