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”的能力可能表明血液动力学弹性，这是一种不反映在静息BP或HR上的属性。扰动后阶段性逐搏BP和HR数据的高维响应-恢复曲线（RRC）可以帮助制定动态弹性指标（DIOR）。因此，BP和HR的随机昼夜波动可能是DIORs，反映了日常活动（微压力）期间小的自然扰动的微恢复。诱发不同血液动力学反应（心理任务、姿势改变和运动）的刺激后BP和HR的RRCs可以识别反映高血压（HTN）、BP敏感性靶器官损伤（TOD）、脑老化、认知受损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。血流动力学弹性降低与对压力源的BP和HR反应改变有关，其特征是自相关性更大、方差增加和刺激后恢复延迟; B. BP和HR弹性度量（DIOR）在家族内聚集，并且受到风险因素、动脉僵硬、普遍靶器官损伤（TOD）、脑老化、认知受损和临床前AD以及亚临床动脉粥样硬化的先前轨迹的影响; c. BP和HR的DIOR将增强对不良脑成像、神经认知（包括AD）和心血管结局的预测。我们将通过测量第三代（Gen 3）和少数（Omni 2）Fracket研究队列中3374名参与者对四种标准化、分级和补充压力源（精神压力[Stroop测试]、直立性;等张[握柄]和等长[3分钟步行]运动）的BP和HR反应来测试这些假设。我们有三个目标：目标1。描述3374名中年Frachial Gen 3/Omni 2参与者在第四次检查（2021-2024）时对四次最佳序列标准化扰动的阶段性逐搏BP和HR反应。我们将绘制每个刺激的动态RRC，并按年龄、性别和队列（白色与少数族裔）描述模式。我们将估计DIOR，制定特定年龄的参考界限，并量化其遗传力。目标二。评估血压和心率对四种标准化扰动反应的横截面关系。我们将RRC指标和相关的DIOR，和二进制BP响应以下：CVD危险因素;肾功能;静息BP和HR的纵向轨迹，动脉硬度，心脏质量;亚临床动脉粥样硬化;普遍BP敏感的TOD，包括MRI脑老化指数;神经认知测试评分，临床前阿尔茨海默病（AD）和相关疾病，和普遍的CVD。目标3：将BP和HR的RRC指标与HTN事件、轻度认知障碍、临床前/前驱AD和CVD相关。我们将确定一组简约的增量预测DIOR。总之，我们将在一个表型良好的基于社区的队列中描述血流动力学弹性的特征，并将DIOR与脑老化特征、临床前AD和CVD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.