High Resolution Optical Imaging of Electrical Activity in the Heart

David S. Rosenbaum, M.D. (Principal Investigator), Kenneth R. Laurita, Ph.D.

High resolution optical imaging is relatively new technology that is used to "image" electrical activity in the heart. Cardiac action potentials are recorded using voltage-sensitive dyes to monitor cellular potential, cell to cell interactions, and propagation and repolarization "patterns" underlying cardiac arrhythmias. In addition, our center has developed techniques using other fluorescent probes and optical techniques to "measurement" propagation of intracellular ions such as calcium, cell to cell coupling using space constant, and detailed assessment of heterogeneities of repolarization.

Molecular Determinants of Cardiac Excitability Isabelle Deschenes, Ph.D.

Potentially lethal arrhythmias in rare inherited syndromes (idiopathic ventricular fibrillation) and more common, acquired heart diseases (cardiac hypertrophy and failure) have been associated with an imbalance of depolarizing (Na current) and repolarizing (Ito) current early in the ventricular action potential and a down regulation of Ito respectively. Our previous work demonstrated that cardiac Ito and INa form a macromolecular complex. Delineation of the molecular basis of this macromolecular complex formed by Ito and INa is essential for an accurate understanding of cardiac ventricular depolarization and repolarization and its derangements that are associated with lethal ventricular arrhythmias.

In this project we combine the use of gene silencing (RNA interference) and Fluorescence Resonance Energy Transfer (FRET) to electrophysiological recordings to elucidate the molecular basis, structure and function of this macromolecular complex formed between channel subunits that comprise voltage-dependent Na channels and the transient outward K current Ito. This work will have broad appeal and important implications for cellular electrophysiology of cardiac muscle and its derangements in both congenital and acquired diseases associated with potentially lethal cardiac arrhythmias.