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.
CRT is the most important and widely used invasive therapy for heart failure. Despite its demonstrated efficacy in selected patients the mechanism(s) by which it improves cardiac function is incompletely understood. The goal of the overall program is to understand the cellular and molecular effects of CRT in HF, this project in the is aimed at understanding the mechanism by which CRT improves calcium handling and the metabolic state of the ventricle and the implications for the improvement in heart's performance.
|Barth, Andreas S; Kumordzie, Ami; Tomaselli, Gordon F (2016) Orchestrated regulation of energy supply and energy expenditure: Transcriptional coexpression of metabolism, ion homeostasis, and sarcomeric genes in mammalian myocardium. Heart Rhythm 13:1131-9|
|Barth, Andreas S; Tomaselli, Gordon F (2016) Gene scanning and heart attack risk. Trends Cardiovasc Med 26:260-5|
|O'Rourke, Brian; Liu, Ting; Foster, D Brian (2016) Seeing the Forest for the Trees. Circ Res 119:1170-1172|
|DeMazumder, Deeptankar; Kass, David A; O'Rourke, Brian et al. (2015) Cardiac resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling. Circ Res 116:1691-9|
|Chung, Heaseung Sophia; Murray, Christopher I; Venkatraman, Vidya et al. (2015) Dual Labeling Biotin Switch Assay to Reduce Bias Derived From Different Cysteine Subpopulations: A Method to Maximize S-Nitrosylation Detection. Circ Res 117:846-57|
|Kaushik, Gaurav; Spenlehauer, Alice; Sessions, Ayla O et al. (2015) Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med 7:292ra99|
|Kwon, Chulan; Tomaselli, Gordon F (2015) Coins of the realm in atrioventricular junction development. Circ Res 116:386-8|
|Kirk, Jonathan A; Kass, David A (2015) Cellular and Molecular Aspects of Dyssynchrony and Resynchronization. Card Electrophysiol Clin 7:585-97|
|Melman, Yonathan F; Shah, Ravi; Danielson, Kirsty et al. (2015) Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study. Circulation 131:2202-2216|
|Tomaselli, Gordon F (2015) Introduction to a compendium on sudden cardiac death: epidemiology, mechanisms, and management. Circ Res 116:1883-6|
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