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，这一特性不反映在静息血压或HR上。关于人类血压和心率恢复能力的信息缺乏。扰动后的相位BP和HR数据的高维响应恢复曲线（RRCs）有助于弹性动态指标（DIORs）的制定。因此，血压和心率的随机日波动可能是反映日常活动（微应激源）中小的自然扰动的微恢复的DIORs。刺激引起不同的血流动力学反应（精神任务、姿势改变和运动）后的血压和HR RRCs可以识别反映高血压（HTN）、BP敏感靶器官损伤（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DIORs。我们假设：a.血流动力学弹性的降低与压力源的血压和心率反应的改变有关，其特征是自相关性更强，方差增加，刺激后恢复延迟；b.血压和心率恢复指标（DIORs）在家庭中聚集，并受到危险因素、动脉硬度、普遍靶器官损伤（TOD）、脑衰老、认知障碍、临床前AD和亚临床动脉粥样硬化的事前轨迹的影响；c. BP和HR的DIORs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。我们将在第三代（Gen3）和少数族裔（Omni2） Framingham研究队列的3374名参与者中，通过测量血压和心率对四种标准化、等级化和互补的压力源（精神压力[Stroop测试]、直立性；等张力[握力]和等长[3分钟步行]运动）的反应来检验这些假设。我们的目标有三个方面：描述3374名中年Framingham Gen3/Omni2参与者在第四次考试（2021-2024）中对四种最佳顺序的标准化扰动的阶段性心跳和心率反应。我们将绘制每个刺激的动态RRCs，并按年龄、性别和队列（白人与少数民族）描述模式。我们将估算DIORs，制定特定年龄的参考限制，并量化其遗传性。目标2。评估四种标准化扰动下BP和HR响应的横截面关系。我们将把RRC指标、相关DIORs和BP二元反应与以下因素联系起来：心血管疾病危险因素；肾功能;静息血压和心率、动脉僵硬度和心脏质量的纵向轨迹；亚临床动脉粥样硬化;常见的bp敏感TOD包括MRI脑老化指标；神经认知测试分数，临床前阿尔茨海默病（AD）和相关疾病，以及流行的心血管疾病。目标3。将RRC血压和HR指标与HTN、轻度认知障碍、临床前/前驱AD和CVD的发生率联系起来。我们将确定一组简洁的增量预测dior。总之，我们将在一个表型良好的社区队列中描述血液动力学恢复能力，并将DIORs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.