Application) The long-term objective of this renewal project is to understand, at a more cellular/subcellular level, the electrical abnormalities defined in myocytes 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 life threatening ventricular arrhythmias post myocardial infarction.
The specific aims are as follows: 1) to determine the function of specific ionic currents in cells dispersed from the central common pathway versus the peripheral tissues of mapped reentrant the central common pathway versus the peripheral tissues of mapped reentrant circuits of the epicardial border zone of the 5 day infarcted heart, 2) to determine the function of specific ion currents of cells dispersed from the border zone of the 14 day and 2 month infarcted heart, 3) to determine what changes in the cardiac sodium channel at the level of the single channel underlie the observed reduced amplitude and altered kinetics of the Na current in 5 day border zone cells, 4) to determine the role of altered tyrosine kinase function in altered Ca2+ and K+ currents and their pharmacology in 5 day border zone cells, and 5) to determine the function and pharmacology of delayed rectified K+ currents in border zone cells in particular to identify Kvl1.5 channel proteins. Studies will be completed using whole cell and cell border zone of hearts post coronary artery occlusion. The results of these studies will provide a more detailed understanding of the ionic basis of electrical remodeling in cells surviving in the healing and healed hearts post infarction and in so doing will help identify new molecular targets for treatment of reentrant ventricular arrhythmias that occur during these times.
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