Vascular Stiffness as a Precursor of Hypertension in a Middle-aged Cohort

 描述(由申请人提供)：随着年龄的增长，异常主动脉僵硬的患病率急剧增加，呈非线性增长，从50岁前的1%上升到70岁后的60%以上。我们以前已经证明了年龄和主要血流动力学指标如脉压(PP)之间存在明显的非线性横截面关系。我们证明，主动脉壁变硬和主动脉血流与直径不匹配是导致脉压后期升高的原因。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。我们对这一应用的假设有3个方面：1)早期主动脉对环境应激源(如肥胖)的适应性降低了脉压，尽管主动脉壁变硬，但有助于日后主动脉结构和功能的恶化；2)随之而来的脉动血流动力学应力增加导致宽幅脉压、收缩和舒张期高血压、左室重构并伴有收缩和舒张期功能障碍以及异常的小血管结构和功能，导致脑部和肾脏的微血管损伤；以及3)动脉特性的变化与亚临床和临床事件发生的风险增加相关。我们将通过以下具体目标来检验这些假说：目的1.前瞻性地研究压力波正向波幅从年轻时随年龄下降到中年后随年龄增加的非线性转变的血流动力学机制和危险因素。我们将在下一个检查周期对约3800名Framingham第三代和少数Omni-II队列参与者进行动脉血压测量和超声心动图，以表征压力搏动性下降阶段(2001-2005)、最低点(2007-2011)和上升阶段(2015-2018)动脉僵硬的纵向变化；目的2.检查关键中心血流动力学指标的变化与12年来左室舒张功能指标之间的关系。目的3.将基线值和主动脉功能指标的非线性变化与基线、靶器官损害和涉及心、脑、肾的临床事件的指标的变化联系起来。我们的应用程序将评估在关键年龄范围内社区动脉硬度的个人非线性纵向(三个时间点)变化，为高血压的发病机制和心、脑和肾脏的靶器官损害提供新的见解。

 DESCRIPTION (provided by applicant): The prevalence of abnormal aortic stiffness increases dramatically and nonlinearly with age, from <1% prior to 50 years of age to over 60% after 70 years. We have previously demonstrated markedly nonlinear cross-sectional relations between age and key hemodynamic measures such as pulse pressure (PP). We demonstrated that aortic wall stiffening and mismatch between aortic flow and diameter contribute to the late increase in PP. Whether longitudinal changes in hemodynamics will mirror these cross-sectional relations is unknown. Our hypotheses for this application are 3 fold: 1) early aortic adaptations to environmental stressors (such as obesity) reduce PP despite aortic wall stiffening, but contribute to later life deterioration in aortic structure and function; 2) the consequent increasein pulsatile hemodynamic stress contributes to the development of wide PP, systolic hypertension, left ventricular remodeling with systolic and diastolic dysfunction and abnormal small vessel structure and function, resulting in microvascular damage in the brain and kidneys; and 3) changes in arterial properties are associated with increased risk for incident subclinical and clinical events. We will test these hypotheses with the following specific aims: Aim 1. To examine prospectively hemodynamic mechanisms of and risk factors for nonlinear transition in forward pressure wave amplitude from falling with age in young adults to increasing with age after midlife. We will perform arterial tonometry and echocardiography in ~3800 Framingham third generation and minority Omni-II cohort participants at their next exam cycle to characterize longitudinal changes in arterial stiffness during the falling phase (2001-2005), nadir (2007-2011) and rising phase (2015-2018) of pressure pulsatility; Aim 2. To examine relations between change in key central hemodynamic measures and measures of left ventricular diastolic function over a 12-year interval. Aim 3. To relate baseline values and nonlinear change in measures of aortic function to baseline and change in measures of target organ damage and clinical events involving the heart, brain, and kidneys. Our application will evaluate individual nonlinear longitudinal (three time points) changes in arterial stiffness in the community during a critical age range, providing novel insights into the pathogenesis of hypertension and target organ damage in the heart, brain and kidneys.