Biomarkers of Ventricular and Vascular Remodeling

描述（由申请人提供）：CHF是一种以左心室（LV）结构和功能改变（LV重塑）为前兆的疾病。平行心室血管重构（VVR）随着年龄的增长，即更硬的心脏射入更硬的血管，更容易发生CHF。初步数据显示VVR存在性别差异。血管生长因子在VVR中起着基础作用，可以在血液中检测（称为VVR生物标志物）来评估这些过程。我们提出的主要假设有三个方面：(1)血管刚度是左室重构的关键决定因素；VVR随年龄、血压和性别而变化；(2) VVR生物标志物可以洞察左室和血管重构，以及相关的年龄和性别差异；(3) VVR生物标志物可以识别血管加速老化和高血压倾向增加的个体，可以识别亚临床左室收缩和舒张功能障碍，并可以预测CHF的发生。我们建议在三个弗雷明汉心脏研究（FHS）队列中通过测量中青年第三代（第3代，包括少数Omni队列）中选择的循环VVR生物标志物来验证这些假设：胰岛素样生长因子-1，IGF结合蛋白3；肝细胞生长因子；血管内皮生长因子及其可溶性受体；血管生成素1及其受体[Tie-2]此外，我们将验证两个与VVR最密切相关的VVR生物标志物，通过将它们与后代队列（Gen 2）中的高血压（HTN）和CHF发病率联系起来。我们建议的具体目标是：1。VVR：在第3代中选择超声心动图测量方法[echo]来检查动脉硬度测压测量的横截面关系，以表征年龄和性别相关的VVR差异。2. WR、生物标志物、LV和血管重构：研究VVR生物标志物的横断面临床和遗传（遗传力和连锁）相关性；它们与第三代回声和血管硬度的关系。3. VVR、生物标志物与临床转归：前瞻性探讨VVR、VVR生物标志物与纵向血压追踪包括HTN（第3代和第2代）和CHF发生率（第2代）的关系。FHS特别适合这项研究，因为它采用单地点、基于人群的设计、既往和当代风险因素数据的可用性、使用标准化的心力衰竭标准，以及对所有研究对象进行连续的纵向监测。我们的建议将促进对血管生长因子在启动和促进血管僵硬、左室功能障碍和HTN中的作用的理解。

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.