Most deaths from coronary artery disease occur suddenly, apparently early after the onset of an acute attack of ischemia. These deaths appear to be due primarily to electrophysiological derangements rapidly progressing to ventricular fibrillation. We have recently demonstrated increased Alpha-adrenergic receptor number and function in ischemic myocardium. The research proposed is designed to determine the relative influences of Alpha- and Beta-adrenergic mediated sympathetic input on the electrophysiological alterations which occur during early ischemia and reperfusion. Computer reconstructed isochronic mapping of the activation of the ventricular wall will be performed to detect specific alterations in conduction time and changes in the pattern of activation before, during and after dysrhythmia dependent on either Alpha- or Beta-adrenergic input during ischemia and reperfusion. Additional studies will be performed to determine whether the electrophysiological alterations induced by either Alpha- or Beta-adrenergic stimulation or blockade is related to the concentrations of two types of arrhythmogenic metabolites previously detected in ischemic tissue and venous effluents, lysophosphoglycerides and long-chain acyl carnitines. Correlative experiments will be performed in vitro with membrane preparations derived from normal myocardium to assess the influence of these biochemical factors on Alpha 1-adrenergic receptor number and affinity. If they induce increases in Alpha 1-receptor number, electrophysiological studies will be performed in vitro to determine whether the same factors also alter Alpha-adrenergic responsivity. Delineation of the role of the adrenergic nervous system in the generation of arrhythmogenic metabolites and their effects on the electrophysiological derangements during ischemia appears to be promising for ultimately developing means to protect the ischemic heart against malignant ventricular dysrhythmia and possibly defining useful prophylactic approaches to reducing sudden death in man.
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