Cardiac resynchronization therapy (CRT) is the major new advance in heart failure treatment in the new millennium. It uses bi-ventricular pacing stimulation to offset conduction delay and thereby improve contraction coordination in affected patients. It is unique among treatments that acutely and chronically improve rest and reserve systolic function, as it also improves survival. The overall theme ofthis PPG is that by understanding how this is accomplished at the cellular and molecular level will yield important new insights into optimally using CRT, and for heart failure therapy more generally. Our recent work showed myocyte rest and beta-adrenergic stimulated function are markedly depressed in dyssynchronous heart failure (DHF) and both are greatly enhanced by CRT. Mechanisms included a modest rise in beta-1 receptor number, enhanced adenylate cyclase activity, and a marked suppression of inhibitory G-protein coupling potentially linked to negative modulation by regulator of G-coupled signaling protein 3. New data shows enhanced myofilament calcium responsiveness with CRT also contributes, and is accompanied by phosphorylation changes in several regulatory thin filament proteins. These changes are not observed in hearts that develop failure with always synchronous contraction either, but appear specific to having synchrony restored in a previously DHF heart. The goal of this project is to determine the mechanisms underlying improved contractile reserve mediated by myofilament-calcium and beta-adrenergic/Gi-coupled changes induced by CRT.
Aim 1 studies the mechanisms of altered myofilament sensitivity in our canine models, testing its coupling to ATP utilization, and role of post-translational changes in skinned muscle and myocyte-preparations.
Aims 2 and 3 test how CRT uniquely modulates beta-AR reserve, focusing on the role of RGS protein suppression of Gi signaling and changes in betai-beta2 activation effects. This work uses the dog model, as well as a new mouse model of DHF and CRT to enable studies of mice generically lacking RGS2, -3, or -4 to more directly test the impact of this regulation. These data may yield novel potential biomarkers for hearts amenable to CRT, and provide novel insights into a successful therapy that could impact heart failure treatment in the broader patient population.

Public Health Relevance

Our research will provide important new understanding regarding how cardiac resynchronization therapy improves systolic function yet still protects the heart against long-term adverse remodeling. We focus on myofilament-calcium interaction and beta-adrenergic signaling, as both undergo unique changes with CRT that could underlie its CRT benefits. Understanding these mechanisms will help develop biological markers for suitable patients, and potentially lead to novel treatments for the broader heart failure population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL077180-10
Application #
8686046
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
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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