Midlife cardiovascular stress physiology and preclinical cerebrovascular disease

摘要 该项目的目标是确定中年心血管应激生理学的相关程度。 临床前脑血管疾病的严重程度。这一目标与NOT-HL-23-002和NHLBI一致 战略远景，强调需要了解中年心血管对晚年生活的贡献 痴呆症。对中年心血管应激生理的关注源于积累的证据 这表明具有表型倾向的个体对急性心理应激源的反应 血压相对较大的上升(应激源诱发的血压反应性)有患高血压的风险 高血压和不良心血管结局本身就是中年心血管危险因素 用于脑血管疾病和晚年痴呆。应激源诱发的机械性途径 血压的反应性可能使脑血管疾病的风险未知。他们是在这里假设的 项目包括外周血管重塑和功能障碍，表现为动脉僵硬， 内皮功能障碍，心跳与心跳血流动力学控制受损。后者则更进一步 假设通过神经血管损伤的底物促进临床前脑血管疾病； 也就是说，大脑的搏动性。为了测试这些尚未评估的假设的预测，有三个具体目标 在538名中年成年人(年龄40-59岁；约60%女性，约40%)的社区队列中进行追踪 确定为非白人；最终分析结果N=450，预计在磨损后)临床上没有症状 心血管疾病和认知障碍。在两次访问方案中，志愿者将完成验证 和可靠的方案来评估：心血管和 脑血管健康；动脉僵硬、内皮功能和节拍血流动力学控制； 心血管应激反应；以及脑搏动性和临床前脑血管疾病。AIM 1测试 较大的应激源诱发的心血管(血压、心输出量和总外周 抵抗力)反应与临床前脑血管疾病标记物(更大的脑搏动性， 脑白质损伤负荷增加，海马体体积减小，脑体积增大 血管周围空间)在多变量结构方程模型中。目标2测试两者之间的关联 应激源诱发的心血管反应和临床前脑血管疾病标记物是部分原因 可由动脉僵硬、内皮功能障碍和节律血流动力学控制所解释。三级 目标3探索目标1-2的影响是否被已知的心血管风险和性别作为生物学因素所缓和 变量。这项拟议的项目试图表征心血管应激反应在多大程度上 中年是脑血管疾病的一个特殊的心血管风险来源。这样一来，新的 来自该项目的信息可能会在中年确定一个潜在的可改变的和压力相关的因素， 有助于预测和减少晚年痴呆症风险的血管来源。

Abstract The goal of this project is to determine the extent to which cardiovascular stress physiology in midlife relates to the severity of preclinical cerebrovascular disease. This goal aligns with NOT-HL-23-002 and the NHLBI Strategic Vision, which emphasize a need to understand midlife cardiovascular contributions to later life dementias. Focusing on cardiovascular stress physiology in midlife follows from cumulative evidence indicating that individuals with a phenotypic tendency to react to acute psychological stressors with relatively large rises in blood pressure (stressor-evoked blood pressure reactivity) are at risk for hypertension and adverse cardiovascular outcomes, which themselves are midlife cardiovascular risk factors for cerebrovascular disease and later life dementias. The mechanistic pathways by which stressor-evoked blood pressure reactivity may confer cerebrovascular risk are unknown. They are hypothesized in this project to include peripheral vascular remodeling and dysfunction, manifesting as arterial stiffness, endothelial dysfunction, and impaired beat-to-beat hemodynamic control. The latter are further hypothesized to promote preclinical cerebrovascular disease via a substrate for neurovascular damage; namely, cerebral pulsatility. To test predictions from these as yet unevaluated hypotheses, 3 Specific Aims are pursued in a community cohort of 538 midlife adults (aged 40-59 years; ~60% women, ~40% identifying as nonwhite; final analytic N=450 expected after attrition) who are asymptomatic for clinical cardiovascular disease and cognitive impairment. In a 2-visit protocol, volunteers will complete validated and reliable protocols to assess: behavioral, social, and biological determinants of cardiovascular and cerebrovascular health; arterial stiffness, endothelial function, and beat-to-beat hemodynamic control; cardiovascular stress reactivity; and, cerebral pulsatility and preclinical cerebrovascular disease. Aim 1 tests whether larger stressor-evoked cardiovascular (blood pressure, cardiac output, and total peripheral resistance) reactions relate to preclinical cerebrovascular disease markers (greater cerebral pulsatility, higher white matter lesion burden, decreased hippocampal volume, and increased enlargement of brain perivascular spaces) in a multivariate structural equation model. Aim 2 tests whether associations between stressor-evoked cardiovascular reactions and preclinical cerebrovascular disease markers are partly explained by arterial stiffness, endothelial dysfunction, and beat-to-beat hemodynamic control. Tertiary Aim 3 explores whether Aim 1-2 effects are moderated by known cardiovascular risks and sex as a biological variable. The proposed project seeks to characterize the extent to which cardiovascular stress reactivity in midlife is a specific cardiovascular source of risk for cerebrovascular disease. In this way, the new information from this project may identify a potentially modifiable and stress-related factor in midlife that could aid efforts to predict and reduce vascular sources of later life dementia risk.