Ion Channel Function in Arrhythmogenic Cardiac Cells

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DESCRIPTION (provided by applicant): The long term objective of the Boyden/Wit laboratories is to understand at a cellular/subcellular level the mechanisms of the electrical remodeling defined in myocytes that have survived in the infarcted heart. During the past period of support, our labs combined efforts developing a mapping/myocyte approach (e.g. EBZ cell pair experiments) to determine the electrophysiology of cells dispersed from select regions of mapped reentrant circuits. These findings have led to this series of highly focused, newly defined studies. Our specific aims are; 1)To determine if stretch, a component of the ischemic environment after coronary occlusion, is a stimulus that contributes to the occurrence of connexin43 gap junctional and sarcolemmal ion channel structural remodeling in the ischemic canine ventricle. 2) To determine the functional consequences of ion channel (gap junctional and ion channel) structural remodeling caused by myocardial stretch on electrophysiology (functional remodeling) and compare it to changes in the epicardial border zone after coronary occlusion. 3) To determine the contribution of stretch induced gap junction remodeling and ion channel remodeling to alterations in conduction and refractoriness of epicardial infarct border zone during infarct healing. 4) To determine the function and role of molecular components (subunits) of ion channels in the remodeling that occurs during ischemia/stretch. Studies will be completed using in situ mapping, molecular probing techniques, and voltage clamp techniques using single (pairs) cells dispersed from the reentrant circuits of the epicardial border zone of hearts post coronary artery occlusion and from stretched myocardium, computer simulations and in vitro and in situ gene expression techniques. Our results will provide a detailed understanding of the ionic basis of electrical remodeling in cells surviving in the healing and healed hearts post-infarction as well as the mechanism of the reentrant arrhythmias occurring during these times.