Mechanisms of Arrhythmias and Defibrillation in Ischemia

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Ischemia introduces arrhythmias and may increase defibrillation threshold. TO improve understanding and treatment of patients with ischemia, knowledge of the mechanisms for the arrhythmias and for defibrillation threshold changes during ischemia is needed. This project will test the hypotheses that 1) the gradient of transmembrane potential and curvature of the regional ischemic border induce extrasystoles, and 2) ischemia reduces the transmembrane voltage changes produced by an electrical shock. We will test these hypotheses using optical mapping and fluorescence emission ratiometry with voltage-sensitive dyes in isolated hearts and myocyte cultures, histological examination of the ischemic border, and mathematical modeling with a biodomain representation of cardiac tissue containing realistic ischemic tissue resistances and geometry of the border. We will produce global and regional ischemia and components of the ischemia with epinephrine, elevated potassium, an ATP-dependent potassium channel opener (cromakalim), and a cellular uncoupler (palmitoleic acid). We will determine the dependence of extrasystoles on regional hyperkalemia and ischemia by measuring gradients of transmembrane potential across the ischemic or hyperkalemic border on epicardium and endocardium. Studies will emphasize border curvature as an important variable for focusing injury current, and will consider modulation of extrasystole induction by cellular uncoupling. Transmembrane voltage changes produce by an electrical shock during ischemia will be considered in terms of membrane resistance modulation by elevated potassium and by ATP-dependent potassium channel opening. Separate studies will consider cellular uncoupling. The understanding of the mechanisms of extrasystoles and defibrillation during ischemia gained from this project will help in the diagnosis and emergency treatment of patients who undergo arrhythmias or sudden cardiac death soon after acute myocardial ischemia.