Heart failure is a leading cause of death world-wide, and despite advances in drug treatment, morbidity and mortality remain high. Cardiac resynchronization (CRT) a device-based therapy in which failing hearts are bi-ventricularly stimulated to offset a conduction delay and discoordinate motion, is the first new treatment advance of the millennium, and only therapy to date to acutely and chronically enhance systolic function, while reducing long-term mortality. Despite widespread clinical use of CRT, little is known about how it works at the basic level, contributing to ongoing difficulties in its optimal deployment. We developed a dog model of dyssynchronous heart failure (DHF) and CRT that has reveal marked effects of CRT on reversing regional stress signaling and genome-wide expression heterogeneity, improving cell survival, myocyte electrophysiology, contractile function, calcium homeostasis, mitochondrial function (greatly altering its subproteome), and reversing beta-adrenergic down-regulation at multiple levels of the cascade. New data shows CRT acts as a Ca2+-sensitizer, has novel anti-oxidant effects, improves energy status, and alters mitochondrial oxidative phosphorylation linked to novel post-translational modifications (PTM). Strikingly, we now show improved myocyte function and reserve with CRT is not replicated in cells from hearts that develop failure synchronously;i.e. CRT induces specific changes when implemented in DHF. The goal of this proposal is to elucidate the mechanisms for these changes. Project 1 focuses on myofilament-Ca2+ regulation, and beta-adrenergic signaling, particularly changes in inhibitory G-protein coupling. Project 2 tests the influence of CRT on oxidant-modulated electrical instability and elucidates mechanisms for improved calcium cycling. Project 3 uses state-of-the-art proteomic analysis to explore modifications in mitochondrial ATP synthetic and redox regulatory proteins and their impact on organelle function. Using state-of-the art methodologies, including a new mouse-model of DHF and CRT, proteomic approaches to assess tiny protein amounts, and comparisons between experimental data and human myocardial tissue results, we will advance our understanding of this therapy and the patients in which it is best used.

National Institute of Health (NIH)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Shah, Monica R
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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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

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