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.
|Hall, Gentzon; Rowell, Janelle; Farinelli, Federica et al. (2014) Phosphodiesterase 5 inhibition ameliorates angiontensin II-induced podocyte dysmotility via the protein kinase G-mediated downregulation of TRPC6 activity. Am J Physiol Renal Physiol 306:F1442-50|
|Rainer, Peter P; Hao, Scarlett; Vanhoutte, Davy et al. (2014) Cardiomyocyte-specific transforming growth factor ? suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction. Circ Res 114:1246-57|
|Del Monte, Federica; Agnetti, Giulio (2014) Protein post-translational modifications and misfolding: new concepts in heart failure. Proteomics Clin Appl 8:534-42|
|Kooij, Viola; Venkatraman, Vidya; Kirk, Jonathan A et al. (2014) Identification of cardiac myofilament protein isoforms using multiple mass spectrometry based approaches. Proteomics Clin Appl 8:578-89|
|Sharma, Kavita; Kass, David A (2014) Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115:79-96|
|Kooij, Viola; Venkatraman, Vidya; Tra, John et al. (2014) Sizing up models of heart failure: Proteomics from flies to humans. Proteomics Clin Appl 8:653-64|
|Chow, Grant V; Silverman, Michael G; Tunin, Richard S et al. (2014) Efficacy of cardiac resynchronization in acutely infarcted canine hearts with electromechanical dyssynchrony. Heart Rhythm 11:1819-26|
|Agnetti, Giulio; Halperin, Victoria L; Kirk, Jonathan A et al. (2014) Desmin modifications associate with amyloid-like oligomers deposition in heart failure. Cardiovasc Res 102:24-34|
|Lichter, Justin G; Carruth, Eric; Mitchell, Chelsea et al. (2014) Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy. J Mol Cell Cardiol 72:186-95|
|Kirk, Jonathan A; Holewinski, Ronald J; Kooij, Viola et al. (2014) Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3*. J Clin Invest 124:129-38|
Showing the most recent 10 out of 99 publications