Biomarkers of Ventricular and Vascular Remodeling

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DESCRIPTION (provided by applicant): CHF is a condition that is predated by changes in left ventricular (LV) structure and function (LV remodeling). Parallel ventricular-vascular remodeling (VVR) with age, i.e., a stiffer heart ejecting into stiffer vessels, predisposes to CHF. Preliminary data indicate gender differences in VVR. Vascular growth factors play a fundamental role in VVR and can be assayed in blood (referred to as VVR biomarkers) to assess these processes. The major hypotheses of our proposal are three-fold: (1) Vascular stiffness is a key determinant of LV remodeling; VVR varies with age, blood pressure, and by gender; (2) VVR biomarkers can provide insights into LV and vascular remodeling, and related age and gender differences; (3) VVR biomarkers can identify individuals with accelerated vascular aging and consequent greater propensity to hypertension, can identify subclinical LV systolic and diastolic dysfunction, and can predict incident CHF. We propose to test these hypotheses in three Framingham Heart Study (FHS) cohorts by measuring select circulating VVR biomarkers in the young-to-middle aged third generation (Gen 3, minority Omni cohort included): insulin-like growth factor-1, IGF binding protein 3; hepatocyte growth factor; vascular endothelial growth factor and its soluble receptor [sFlt-1]; angiopoietin-1 and its receptor [Tie-2]. Additionally, we will validate two VVR biomarkers most closely implicated in VVR in Gen 3 by relating them to hypertension (HTN) and CHF incidence in the Offspring cohort (Gen 2). The specific aims of our proposal are: 1. VVR: To examine the cross-sectional relations of tonometric measures of arterial stiffness to select echocardiographic measures [echo] in Gen 3, to characterize age- and gender-related differences in VVR. 2. WR, biomarkers, LV and vascular remodeling: To examine the cross-sectional clinical and genetic (heritability & linkage) correlates of VVR biomarkers; their relations to echo and vascular stiffness in Gen 3. 3. VVR, biomarkers and clinical outcome: To investigate prospectively the relations of VVR, VVR biomarkers to longitudinal blood pressure tracking including HTN (Gen 3 and 2), and incidence of CHF (Gen 2). The FHS 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. Our proposal will advance understanding of the role of vascular growth factors in initiating and promoting vascular stiffness, LV dysfunction and HTN.