AUTONOMIC MODULATION OF ISCHEMIC ARRHYTHMIAS

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Many clinical and animal studies implicate the autonomic nervous system in the genesis of some of the arrhythmias responsible for sudden cardiac death, an event that accounts for almost 25% of all deaths annually in the U.S. The long-term objective of our studies is to investigate the mechanism(s) by which the autonomic nervous system modulates cardiac excitable properties and is in turn modulated by the ischemia/infarction, to promote, precipitate or prevent the development of cardiac arrhythmias after coronary occlusion. Although much is known about the physiological and biochemical consequences of stimulating autonomic receptors, and indeed, several of the receptors have been cloned, data integrating and linking findings from cellular and subcellular research to the development of cardiac arrhythmias in animal models in vivo and in patients with cardiac arrhythmias are lacking. We plan a series of studies based on the overall hypothesis that the myocardial infarction and/or ischemia alters the function of nerve axons passing through the ischemic/infarcted area, producing acute (functional) and then chronic (anatomical) denervation, denervation supersensitivity and reinnervation. These autonomic influences modulate cardiac excitable properties, resulting in suppression, facilitation or initiation of cardiac arrhythmias. The specific aims are to investigate mechanisms responsible for the functional denervation following acute myocardial ischemia, determine whether preconditioning ischemia alters the subsequent degree and time course of acute denervation, determine the concordance of afferent and efferent ischemic denervation, determine whether some types of myocardial infarction are more arrhythmogenic than others, determine whether after depolarizations are responsible for some arrhythmias, determine whether exposure to quinidine and digitalis is more arrhythmogenic in hearts with sympathetic denervation and supersensitivity, determine the mechanisms of adrenergic and cholinergic supersensitivity and determine whether sympathetic or vagal denervation occurs in patients following myocardial infarction and is arrhythmogenic. Autonomic stimulation will be produced by electrical stimulation of efferent vagal and sympathetic nerves, provocation of afferent myocardial reflexes with bradykinin and nicotine and infusion of various drugs. Noninvasive imaging with metaiodobenzylguanidine will be done to determine efferent myocardial sympathetic innervation in patients with coronary artery disease.