Congestive heart failure (CHF) is the eventual endpoint of the adverse myocardial remodeling induced by chronic elevations in ventricular stress. Although the mechanisms involved in the transition from compensated myocardial remodeling to overt CHF have yet to be elucidated, recent findings in our laboratory have resulted in several novel observations implicating cardiac mast cells in the regulation of myocardial remodeling. These include: 1) cardiac mast cells are pivotal in initiating activation of matrix metalloproteinases, resulting in marked extracellular matrix (ECM) degradation and subsequent ventricular dilatation; 2) inhibition of mast cell degranulation prevents the adverse myocardial remodeling and significantly attenuates mortality due to CHF; 3) significant increases in TNF-alpha (TNF-a) and IL-6 occur prior to the development of CHF; and 4) antagonism of TNF-a significantly attenuated the myocardial remodeling. Other observations complementing these findings include the significant ventricular dilatation and structural alterations in the myocardium produced by chronic infusion of TNF-a and the observation that alterations in cellular function and protein expression mediated by cardiac mast cells was mirrored by treatment of fibroblast cultures with TNF-a. Also, constitutive expression of TNF-a is localized predominantly in mast cells in the heart. Thus, the overall hypothesis is that cardiac mast cell mediated elevations in TNF-a contribute to the pathologic ventricular remodeling ultimately resulting in the development of CHF. This proposal will utilize cytokine infusions, aortocaval fistula and mast cell deficient rat models to determine: 1) mast celt phenotype during the temporal course of myocardial remodeling and the ability of mast cell secretory products to regulate a) cardiac mast cell maturation and density, and b) cardiac myocyte and fibroblast interaction with the ECM in the progression to CHF; 2) the causal relationships between mast cell activation, induction of TNF-a and the initial myocardial remodeling associated with chronic volume overload; 3) the mechanisms by which chronic pathophysiologic elevations in TNF-a mediate the adverse myocardial remodeling responsible for the development of CHF; and 4) the efficacy of pharmacological inhibition of endothelin, mast cell degranulation and proinfiammatory cytokines in preventing the adverse myocardial remodeling and subsequent development of CHF. It is expected that these investigations will increase our understanding of the contributions of cardiac mast cells and TNF-a to ventricular remodeling and may potentially identify novel therapeutic approaches for the prevention of CHF. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-PTHA (02))
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Massicot-Fisher, Judith
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University of South Carolina at Columbia
Anatomy/Cell Biology
Schools of Medicine
United States
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