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 #
5P01HL077180-09
Application #
8545887
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$464,206
Indirect Cost
$153,384
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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