CELLULAR ELECTROPHYSIOLOGY OF REPOLARIZATION

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The overall objective of this project is to obtain new insight concerning the cellular aspects of ventricular repolarization and their relationship to intracellular Ca2_ regulation and electronic interactions. Studies will be performed on left ventricular myocytes from both normal and disease hearts. Project 3 contains three subprojects. Subproject 3.1 focuses on repolarization abnormalities in myocytes surviving chronic myocardial infarction (post-MI myocytes). The experiments are designed to determine the ionic basis of post-MI-induced changes in repolarization and their reversal by the thyroid hormone analogue, DITPA. The central hypothesis is that repolarization abnormalities and their recovery are mediated by changes in I/Kp Ca2+ uptake by the sarcoplasmic reticulum (SR), I/Ca and I/NaCa. Voltage clamping and fluorescence measurements of intracellular Ca2+ (Ca/i) (confocal and conventional epifluorescence) will be used to test this hypothesis. Subject 3.2 focuses on the relationship between Ca+ influx and triggered Ca2+ release from SR. The central hypotheses is that conditions which promote Na+ entry, as occur in one inherited form of the long QT syndrome, will increase the gain of excitation-contradiction coupling and thus promote Cai-induced arrhythmias. Voltage clamp and fluorescence techniques will be used to test this hypothesis in myocytes exposed to anthopleurin-A which prolongs I/Na inactivation. Subproject 3.3 focuses on the relationship between intercellular communication and repolarization. The central hypothesis is that cell-cell electrical coupling during repolarization modulation action potential propagation and the formation of early after-depolarizations. This hypothesis will be tested with an electronic circuit which enables us to electrically connect physically separate myocytes with a variable resistance and thus simulate in vitro change in gap functional resistance.