The proposed research is designed around the concept that the evolution of arrhythmias occurs in the setting of a changing substrate that must be studied in light of its dynamic properties. The goal is to study the molecular, ionic and signal transduction mechanisms of electrical remodeling of ventricle, as well as its phenotypic expression in the T wave and effective refractory period. The applicant hypothesizes that (1) the cardiac renin-angiotensin II system is vital to the evolution of short-term (lasting minutes) and long-term (last weeks) electrical remodeling; (2) the sympathetic nervous system is an important modulator of this; (3) short-term remodeling induces specific changes in ion channels via alterations in phosphorylation, and long-term remodeling induces changes in channels via altered message and/or expression; and (4) remodeling induces potentially antiarrhythmic or arrhythmic changes in repolarization and refractoriness that have important implications as well, for antiarrhythmic drug actions. The hypotheses will be tested in a multidimensional fashion, via electrophysiologic, biophysical and molecular studies. Short-term pacing and resultant electrical remodeling will be used as surrogates of sustained arrhythmias. The approach will be integrative, incorporating the T wave, the effective refractory period, antiarrhythmic drugs and pertinent signal transduction systems in electrophysiologic studies of the intact heart and isolated tissues, and studying underling mechanisms and expression molecular and biophysical experiments on ion channels. The applicant anticipates that the results will enhance our understanding of the plasticity of and control of the events that determine cardiac repolarization, and with this, identify new strategies for arrhythmia prevention.
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