Hearts with healed myocardial infarctions (HMI) have persistent regional electrophysiological abnormalities, in association with an enhanced risk for generating arrhythmias, particularly during recurrent episodes of ischemia. The overall goal of this study is to elucidate the relationships between ion channel properties, adrenergic receptors, and cellular electrophysiology in highly localized areas of hearts with prior HMIs. Since (1) areas adjacent to HMI scars have been shown to have regional hypertrophy (HYP) and alterations in adrenergic receptors compared to remote regions, and (2) subepicardial (EPI) and subendocardial (ENDO) muscle cells have inherent differences in specific ion channels and respond differently to simulated ischemia, a 2 x 2 matrix design of ADJACENT/REMOTE and EPI/ENDO regions will be studied to test the following hypotheses: (1) that regional changes in electrophysiologic characteristics after HMI result from permanent changes in specific ion channels; (2) that secondary changes in other characteristics of an HMI heart (regional HYP, alterations in autonomic receptors) regulate electrophysiology; and (3) that specific electrophysiologic responses to transient ischemia and reperfusion are conditioned by the pre-existing regional differences in specific ion channels. To test these hypotheses, patch clamp technology will be used to study ATP-sensitive K+ channel currents, inward Ca++ currents, and transient outward currents (l+o) in single isolated myocytes. The properties of the currents in each of the 4 regions in the 2 x 2 matrix (ADJACENT/REMOTE, ENDO/EPI) will be studied to determine their responses to simulated ischemia and reperfusion, and to channel modulation by alpha- and beta-adrenergic agonists. Since LV HYP also alters electrophysiological properties, including specific ion channel activities and responses to ischemia and reperfusion, the experimental design includes a study of the role of the regional HYP present adjacent to HMI in determining electrophysiologic abnormalities. These experiments will provide information on the mechanisms of persistent electrophysiologic abnormalities in hearts with HMI, and will clarify the understanding of the contribution of regional heterogeneity of ionic current properties, autonomic sensitivity, and responses to ischemia to modulation of the risk of potentially fatal arrhythmias after healing of myocardial infarction.
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