Recent studies have established that cardiac extracellular matrix (ECM) remodeling is a major determinant of pathologic LV hypertrophy (LVH) and progressive LV dilatation, and as a result, contributes to the development of LV dysfunction and overt congestive heart failure (CHF). The recent development of reliable serologic assays for procollagen peptides, metalloproteinases (MMP) and their tissue inhibitors (TIMP), and cytokines permits the in vivo assessment of LV ECM remodeling, and raises the possibility of expanding the utility of these markers 'from the bench to the bedside.' Prior studies of ECM biomarkers in CHF have been limited to cross-sectional investigations of small samples of highly selected patients with advanced disease. The fundamental question whether serum markers of ECM remodeling are important correlates of LV dilatation or LVH, or are independent predictors of incident CHF in the community remains unanswered. We propose to assess the diagnostic and prognostic value of serum markers of LV remodeling (ECM markers: procollagen peptides, MMP-9, TIMP-1; and aldosterone, TNF-alpha) in a stratified sample of 1244 subjects from the community-based Framingham Study.
The aims of this proposal are to: 1. Determine the relations between serum markers of ECM remodeling and traditional CHF risk factors. 2. Analyze the cross-sectional relations between markers of ECM remodeling and : echocardiographic LVH and LV dilatation; Doppler indices of LV filling; serum natriuretic peptides. 3. Investigate prospectively the relations between ECM remodeling markers and: progressive LV dilatation and LVH, and CHF incidence, adjusting for standard risk factors. We hypothesize that biomarkers of ECM remodeling will permit us to identify individuals with LVH and LV dilatation, and will improve our ability to predict CHF risk beyond that already achievable through use of known risk factors. The Framingham Study is uniquely suited for this research by virtue of the single-site, population-based design, availability of antecedent and contemporary risk factor data, use of standardized criteria for CHF, and the continuous longitudinal surveillance of all study subjects. The proposed translational research will likely yield seminal information that could directly improve our efforts to prevent CHF through the biochemical assessment of cardiac ECM remodeling.
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