Aortic Dysfunction, Pulsatile Stress and Target Organ Damage in Framingham

描述(由申请人提供)：随着年龄的增长，主动脉僵硬显著增加，并与心血管疾病、中风、认知障碍、脑白质损伤和肾功能障碍有关。不幸的是，我们目前对动脉硬化和脉压升高(PP)的病理生理学的了解有限。来自我们小组的最新数据表明，由于周围血流与不适当的较小的主动脉直径之间的不匹配而导致的前向波幅度增加，是高血压患者和社区PP增加的主要原因。我们还发现，年龄与关键的中枢血流动力学指标如前向波振幅和脉压之间存在明显的非线性横截面关系。血流动力学的纵向变化是否会反映这些横断面关系尚不清楚。我们对这一建议的假设有三个方面：1)近端主动脉壁僵硬和主动脉内径与血流不匹配是老年人过度压力脉动的主要来源；2)随之而来的脉动性血流动力学应力增加有助于心脏、脑和肾脏的收缩期高血压和靶器官损害的发展；以及3)动脉特性的变化将预测发生的临床事件。我们将通过以下具体目标来检验这些假说：目的1.检验弗雷明翰子代和Omni-I参与者在6年间关键中心血流动力学指标变化的风险因素。我们将在他们的下一次常规心脏研究检查(2011-2014)中对约3000名Framingham子代和少数OMNI队列参与者进行动脉血压测量，以全面表征动脉僵硬及其与之前检查(2005-2008)相比的变化。目的2.检查关键中心血流动力学指标中观察到的和预测的纵向变化之间的关系，以确定与纵向和横断面年龄关系差异相关的因素。目的3.将基线和主动脉功能指标的变化与基线和靶器官损害指标的变化以及涉及心、脑和肾的临床疾病的变化联系起来。这项拟议的研究将表征动脉僵硬随年龄的纵向变化及其在社区心血管疾病、中风、认知障碍和肾功能障碍发展中的作用。

DESCRIPTION (provided by applicant): Aortic stiffness increases markedly with advancing age and is associated with incident CVD, stroke, cognitive impairment, white matter brain lesions, and kidney dysfunction. Unfortunately, our current understanding of arterial stiffening and the pathophysiology of elevated pulse pressure (PP) is limited. Recent data from our group suggests that increased forward wave amplitude due to mismatch between ambient flow and an inappropriately smaller aortic diameter accounts for a major component of increased PP in hypertensive individuals and in the community. We have also found markedly nonlinear cross-sectional relations between age and key central hemodynamic measures such as forward wave amplitude and PP. Whether longitudinal changes in hemodynamics will mirror these cross-sectional relations is unknown. Our hypotheses for this proposal are 3 fold: 1) that proximal aortic wall stiffening and mismatch between aortic diameter and flow are major sources of excessive pressure pulsatility in older people, 2) that the consequent increase in pulsatile hemodynamic stress contributes to development of systolic hypertension and target organ damage in the heart, brain and kidneys, and 3) that change in arterial properties will predict incident clinical events. We will test these hypotheses with the following specific aims: Aim 1. To examine risk factors for change in key central hemodynamic measures across an interval of 6 years in the Framingham Offspring and OMNI-I participants. We will perform arterial tonometry in ~3000 Framingham Offspring and minority Omni cohort participants at their next routine Heart Study exam (2011- 2014) to comprehensively characterize arterial stiffness and its change from their previous examination (2005- 2008). Aim 2. To examine relations between observed and predicted longitudinal change in key central hemodynamic measures in order to identify factors associated with discrepancies in longitudinal and cross-sectional age relations. Aim 3. To relate baseline and change in measures of aortic function to baseline and change in measures of target organ damage and incident clinical disease involving the heart, brain and kidneys. The proposed research will characterize longitudinal changes in arterial stiffness with aging and its contribution to the development of cardiovascular disease, stroke and cognitive impairment and renal dysfunction in the community.