BIOCHEMICAL ASPECTS OF ARRHYTHMOGENESIS AND VENTRICULAR-FIBRILLATION

The problem of arrhythmogenesis in acute myocardial infarction is approached by an analysis of the biochemical and metabolic factors causing abnormalities in the cardiac action potential. A fundamental change in acute ischemia is the abrupt increase in extracell potassium occurring within seconds of coronary occlusion. Localized hyperkalemia not only causes loss of resting membrane potential and shortening of the action potential duration but also can block the fast inward current to unmask the slow channel. If hyperkalemia is sufficiently severe, then normal phase 0 depolarization cannot occur. In such conditions, a slow response can be provoked by catecholamine activity, the cell effects of which are thought to be mediated by cyclic adenosine monophosphate (AMP). Increased cyclic AMP in ischemic tissue is circumstantially linked to the onset of ventricular arrhythmias and fibrillation after coronary occlusion in baboon, cat and pig preparations. More direct evidence for an arrhythmogenic role of cyclic AMP is provided by the demonstration in an isolated heart preparation of a decrease in the ventricular fibrillation threshold by perfusion with exogenous dibutyryl Cyclic AMP or by an increase in tissue cyclic AMP by beta agonists or theophylline, or both. Glycolytic adenosine triphosphate appears to play a special role in the maintenance of the action potential duration because lactate, free fatty acids or inhibition of glycolysis all shorten the action potential duration. Glucose is the substrate best able to maintain the action potential duration during hypoxia. Increased automaticity occurs in partially depolarized Purkinje fibers, especially when there is stimulation by catecholamines or cyclic AMP in the presence of a low external potassium level. These and other metabolic factors are thought to play an important role in the genesis of ischemic arrhythmias. An understanding of these effects contributes significantly to the elucidation of the mode of action of antiarrhythmic drugs. It remains to be determined whether the hypotheses derived from a variety of animal models can be extrapolated to the very complex setting of ischemic heart disease in man. © 1979.