Ion Channel Function in Arrhythmogenic Cardiac Cells

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DESCRIPTION (provided by applicant): The long term objective of this application is to combine the expertise of the Boyden and Wit laboratories to understand at a more cellular/subcellular level the electrical abnormalities defined in myocytes that have survived in the epicardial border zone of the infarcted heart 5 days, 14 days and 2 months post coronary artery occlusion. These abnormalities contribute to the occurrence of serious life threatening ventricular arrhythmias post myocardial infarction. Our specific aims are as follows: 1) to determine the function of specific ionic currents in cells dispersed from the select regions of mapped reentrant circuits of the epicardial border zone of the 5 day infarcted heart and then by using these experimental data develop 1D and 2D computer models of the EBZ, 2) to determine the function of specific ionic currents (INa, ICaL and IK) of cells dispersed from select regions of the border zone of the 14 day and 2month infarcted heart, and 3) to determine the function and pharmacology of delayed rectifier K+ currents in border zone cells in particular to identify the electrical sequelae of observed cell surface redistribution pattern of Kvl.5 channel proteins. Studies will be completed using insitu mapping, whole cell voltage clamp techniques using single cells dispersed from the reentrant circuits of the epicardial border zone of hearts post coronary artery occlusion and computer simulation techniques. Our results will provide a more 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 this time. In so doing they will help to identify new molecular targets for treatment of reentrant ventricular arrhythmias in this remodeled substrate.