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 on-set of arrhythmias associated with sudden cardiac death. Antiar rhythmic drug therapy for the prevention of sudden cardiac death has b een provided primarily on the basis of trial and error and in some ins tances based on ill-suited preclinical evaluations. The findings of th e Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before ente ring into clinical testing. The major deficiency in this area of exper imental investigation has been the lack of animal models that would pe rmit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distingu ish between pharmacologic interventions that suppresses nonlethal dist urbances of cardiac rhythm as opposed to those agents capable of preve nting lethal ventricular tachycardia or ventricular fibrillation. Prec linical models for the testing of antifibrillatory agents must conside r 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 h eart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more clo sely simulate the clinical state in humans who are at risk. The experi mental results show a good correlation with clinical data regarding ag ents known to reduce the incidence of lethal arrhythmias as well as th ose showing proarrhythmic actions.