Epidemiology of blood pressure responses to perturbations: Correlates and prognosis for vascular risk, end-organ damage, cognitive aging and preclinical Alzheimer's disease

血压(BP)和心率(HR)在刺激后“反弹”的能力可能表明血流动力学弹性，这一特性不能通过静息BP或HR反映出来。关于人类血压和心率弹性的信息还很缺乏。扰动后各相BP和HR数据的高维响应-恢复曲线(RRC)有助于制定动态恢复力指标(DIORS)。因此，血压和心率的随机日波动可能是反映日常活动期间微小自然扰动(微应激源)的微恢复的Diors。在刺激引起不同的血流动力学反应(心理任务、体位改变和运动)后，血压和心率的RRC可以确定反映高血压(HTN)、BP敏感的靶器官损伤(TOD)、脑老化、认知障碍和临床前阿尔茨海默病(AD)以及心血管疾病(CVD)风险的互补Dior。我们假设：a.血流动力学恢复力降低与BP和HR对应激源的反应改变相关；b.BP和HR恢复力指标(DIORS)在家庭内部聚集，并受风险因素的先期轨迹、动脉僵硬、普遍的靶器官损害(TOD)、脑老化、认知障碍和临床前AD以及亚临床动脉粥样硬化的影响；c.BP和HR的Diors将增强对不利的脑成像、神经认知(包括AD)和心血管结果的预测。我们将通过测量3374名第三代(Gen3)和少数民族(Omni2)Framingham研究队列中的参与者对四种标准化的、分级的和互补的应激源(精神应激[Stroop测试]、正位站立、等张[握手]和等长[3分钟步行]运动)的BP和HR反应来验证这些假设。我们的目标有三个：目标1.在3374名中年Framingham Gen3/Omni2参与者的第四次考试(2021-2024年)中，表征对四种最佳排序标准化扰动的BP和HR相性反应。我们将绘制每个刺激的动态RRC图，并按年龄、性别和队列(白人与少数族裔)描述模式。我们将评估迪奥，制定特定年龄的参考限值，并量化它们的遗传性。目的2.评估BP和HR对四种标准化扰动的响应的横截面关系。我们将把RRC指标和相关的Diors和二元BP反应与下列因素联系起来：心血管疾病风险因素；肾功能；静息血压和心率、动脉僵硬和心脏质量的纵向轨迹；亚临床动脉粥样硬化；普遍存在的BP敏感的TOD，包括MRI脑老化指数；神经认知测试分数、临床前阿尔茨海默病(AD)和相关疾病，以及流行的CVD。目的3.将血压和心率的RRC指标与HTN、轻度认知损害、临床前期/先兆AD和CVD联系起来。我们将确定一组节俭的增量预测迪奥。综上所述，我们将在一个表型良好的社区队列中表征血流动力学弹性，并将Diors与脑老化特征、临床前AD和心血管疾病联系起来。

The ability of blood pressure (BP) and heart rate (HR) to ‘bounce back’ after stimuli may indicate hemodynamic resilience, a property not reflected by resting BP or HR. Information on BP and HR resilience in humans is lacking. High-dimensional response-recovery curves (RRCs) for phasic beat-to-beat BP and HR data after perturbations can aid the formulation of dynamic indicators of resilience (DIORs). Thus, stochastic diurnal fluctuations in BP and HR may be DIORs reflecting micro-recoveries from small natural perturbations during daily activities (micro-stressors). RRCs for BP and HR after stimuli that evoke distinct hemodynamic responses (mental tasks, posture change, and exercise) may identify complementary DIORs that reflect risks of hypertension (HTN), BP-sensitive target organ damage (TOD), brain aging, impaired cognition and preclinical Alzheimer’s disease (AD), and cardiovascular disease (CVD). We hypothesize that: a. reduced hemodynamic resilience is associated with altered BP and HR responses to stressors marked by greater autocorrelation, increased variance and delayed recovery after a stimulus; b. BP and HR resilience metrics (DIORs) cluster within families and are influenced by antecedent trajectories of risk factors, arterial stiffness, prevalent target organ damage (TOD), brain aging, impaired cognition and preclinical AD, and subclinical atherosclerosis; c. DIORs of BP and HR will enhance prediction of adverse brain imaging, neurocognitive (including AD) and cardiovascular outcomes. We will test these hypotheses by measuring BP and HR responses to four standardized, graded and complementary stressors (mental stress [Stroop test], orthostasis; isotonic [handgrip] and isometric [3-minute walk] exercise) in 3374 participants in the third Generation (Gen3) and minority (Omni2) Framingham Study cohorts. Our aims are three-fold: Aim 1. Characterize the phasic beat-to-beat BP and HR responses to four optimally sequenced standardized perturbations in 3374 middle-aged Framingham Gen3/Omni2 participants at their fourth exam (2021-2024). We will plot dynamic RRCs for each stimulus and describe patterns by age, sex and cohort (white vs. minority). We will estimate DIORs, formulate age-specific reference limits and quantify their heritability. Aim 2. Evaluate the cross-sectional relations of BP and HR responses to the four standardized perturbations. We will relate RRC metrics and related DIORs, and binary BP responses to the following: CVD risk factors; renal function; longitudinal trajectories of resting BP and HR, arterial stiffness, and cardiac mass; subclinical atherosclerosis; prevalent BP-sensitive TOD including MRI brain aging indices; neurocognitive test scores, preclinical Alzheimer’s disease (AD) and related disorders, and prevalent CVD. Aim 3. Relate RRC metrics for BP and HR to incident HTN, mild cognitive impairment, pre-clinical/prodromal AD, and CVD. We will identify a parsimonious set of incrementally predictive DIORs. In summary, we will characterize hemodynamic resilience and relate DIORs to brain aging traits, preclinical AD and CVD in a well phenotyped community-based cohort.