Electrophysiological effects of Metabolic Stress and Calcium Handling by CRT

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Over 5 million Americans suffer from heart failure (HF) and more than 250,000 die annually. Cardiac resynchronization therapy (CRT) produces unprecedented improvement in the efficiency of myocardial energy utilization and a number of clinical trials demonstrate the efficacy of this therapy in improving symptoms, reducing HF hospitalizations and overall mortality. The mechanisms by which CRT improves cardiac function are only beginning to be unraveled. The failing heart exhibits remodeling of structure, metabolism, electrophysiology and ion homeostasis with maladaptive consequences. However, the causes of acute mechanical decompensation and lethal ventricular arrhythmias in the failing heart are often obscure. The failing heart exhibits altered energy utilization and redox balance that affects ionic curtents, ion homeostasis, and Ca2+ handling, each of which in turn will modulate the action potential (AP) and arrhythmia susceptibility. CRT resynchronizes mechanical contraction and alters ventricular activation. Work from our previous period of funding demonstrates that remodeling of electrophysiology and Ca 2+ handling is regionally heterogeneous and distinct in failing hearts with (DHF) and without dyssynchronous contraction. The improvement in LV performance with CRT is linked to remarkable cellular and molecular regional restitution of cardiac electrophysiology and Ca 2+ handling, even in the context of ongoing HF. This project will examine the mechanisms by which CRT improves global and regional maladaptive changes in metabolism, and Ca 2+ handling in DHF and the consequences for the electrophysiology of the heart. Examination of different variants of HF and resynchronization will permit determine the contributions of synchronization of contraction and biventricular pacing to the beneficial effects of CRT. The hypotheses underlying this project are that 1. CRT is an antioxidant therapy that antagonizes maladaptive ion homeostatic remodeling and exaggerated responses to acute metabolic stress by improving mitochondrial function, energy regulation and redox balance in DHF. 2. CRT reverses the functional defects that contribute to defective Ca2+ handling by improving Na"" homeostasis and reversal of maladaptive adrenergic, CaMK and ROS signaling.