The objective of this Program is to increase our understanding of the electrophysiological abnormalities that result in ventricular arrhythmias caused by ischemia and infarction and to determine how this pathophysiology influences the actions of antiarrhythmic drugs on ion channels of cardiac cells and on reentrant arrhythmias. Our focus in on the effects of prolonged ischemia that occurs while an infarct is healing. Prolonged ischemia causes changes in ion channel function that are not dependent on alterations in the extracellular environment as during acute ischemia but rather are dependent on the prolonged effects of the ischemia on intracellular ions and possibly alterations in the expression of ion channels. Our strategy is to coordinate membrane biophysical studies with studies on in situ arrhythmias so that the information from the different approaches can be integrated to develop new concepts for antiarrhythmic therapy. To accomplish the objectives, there are 4 Projects (A-D). Projects A and B will elucidate the physiological mechanisms of reentrant arrhythmias and the actions of drugs on these arrhythmias in the in situ infarcted heart during the healing stage of myocardial infarction caused by coronary occlusion. They utilize state of the art technology to map reentrant excitation with electrical and optical methods to define the effects of drugs that interact with different ion channels on initiation and perpetuation of reentrant excitation. The exact mechanism for the effects of these pharmacological agents on the in situ arrhythmias can be determined by Project C and D which investigate the interaction of drugs with ion channels of single ventricular myocytes. Project C investigates the altered ion channel function of myocytes that come from the arrhythmogenic region of the infarct and how this altered ion channel function modifies drug action. Project D uses intracellular dialysis of myocytes from normal ventricles to alter the intracellular environment in a way that is expected to occur in the ischemic heart to determine how ischemic changes influence ion channel function and drug interactions with the channels. To support the Projects, there are 3 Core facilities, and Administrative Core (A), and Electronic and Computer Core (B), and a Cell Disaggregation Core (C) that prepares the single myocytes. The program, therefore, provides a format for scientists with expertise in different methods and techniques for the study of electrophysiology to work together in a multifaceted approach for improving the pharmacological therapy os ischemic arrhythmias.
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