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

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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.