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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077180-09
Application #
8545886
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Shah, Monica R
Project Start
2004-09-15
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$2,192,403
Indirect Cost
$827,801
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Barth, Andreas S; Tomaselli, Gordon F (2016) Gene scanning and heart attack risk. Trends Cardiovasc Med 26:260-5
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
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
Li, Hui; Lichter, Justin G; Seidel, Thomas et al. (2015) Cardiac Resynchronization Therapy Reduces Subcellular Heterogeneity of Ryanodine Receptors, T-Tubules, and Ca2+ Sparks Produced by Dyssynchronous Heart Failure. Circ Heart Fail 8:1105-14
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 131:2202-16
Kirk, Jonathan A; Chakir, Khalid; Lee, Kyoung Hwan et al. (2015) Pacemaker-induced transient asynchrony suppresses heart failure progression. Sci Transl Med 7:319ra207
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
Tomaselli, Gordon F (2015) Introduction to a compendium on sudden cardiac death: epidemiology, mechanisms, and management. Circ Res 116:1883-6
Kwon, Chulan; Tomaselli, Gordon F (2015) Coins of the realm in atrioventricular junction development. Circ Res 116:386-8

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