Midlife cardiovascular stress physiology and preclinical cerebrovascular disease

中年心血管应激生理学与临床前脑血管疾病

• 批准号: 10720054
• 负责人: Peter J Gianaros
• 金额: $ 77.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720054
• 关键词: Accounting; Acute; Adult; Alzheimer' s Disease; Baroreflex; Behavioral; Biological; Biological Testing; Blood Pressure; Blood Vessels; Blood flow; Brain; Brain imaging; Cardiac Output; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cerebrovascular Disorders; Cerebrum; Clinical; Communities; Coronary heart disease; Data; Dementia; Disease Marker; Elderly; Endothelium; Equation; Exhibits; Failure; Future; Goals; Hippocampus; Hypertension; Impaired cognition; Impairment; Individual; Individual Differences; Ischemic Stroke; Knowledge; Lesion; Link; Liquid substance; Measures; Medial; Mediating; Mediation; Mediator; Modeling; National Heart, Lung, and Blood Institute; Outcome; Pathway interactions; Penetration; Peripheral; Peripheral Resistance; Persons; Phenotype; Physiologic pulse; Physiology; Prevention; Protocols documentation; Public Health; Reaction; Reproducibility; Research; Risk; Robin bird; Role; Sampling; Severities; Site-Directed Mutagenesis; Source; Specific qualifier value; Strategic vision; Stress; Temporal Lobe; Testing; Tissues; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Vascular remodeling; Visit; Visual; Woman; aged; arterial stiffness; cardiovascular health; cardiovascular risk factor; cerebrovascular; cerebrovascular health; cohort; dementia risk; endothelial dysfunction; hemodynamics; male; middle age; neurovascular injury; pre-clinical; pressure; psychological stressor; reactive hyperemia; risk stratification; sex; social; stem; stress reactivity; stressor; transmission process; volunteer; white matter

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.

抽象的 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。该目标与 NOT-HL-23-002 和 NHLBI 一致 战略愿景，强调需要了解中年心血管对晚年生活的贡献 痴呆症。根据累积的证据，关注中年心血管应激生理学 表明具有对急性心理压力源做出反应的表型倾向的个体 血压相对大幅升高（压力源诱发的血压反应性）有以下风险： 高血压和不良心血管结局，它们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症。应激源诱发的机制途径 血压反应性可能带来的脑血管风险尚不清楚。他们在此假设 项目包括外周血管重塑和功能障碍，表现为动脉僵硬， 内皮功能障碍和逐搏血流动力学控制受损。后者更进一步 假设通过神经血管损伤的基质促进临床前脑血管疾病； 即脑搏动。为了测试这些尚未评估的假设的预测，3 个具体目标 在 538 名中年成年人（年龄 40-59 岁；约 60% 为女性，约 40% 认定为非白人；最终分析 N=450（预计在自然减员后），无临床症状 心血管疾病和认知障碍。在 2 次访问协议中，志愿者将完成经过验证的 和可靠的评估方案：心血管和心血管疾病的行为、社会和生物决定因素 脑血管健康；动脉僵硬度、内皮功能和逐搏血流动力学控制； 心血管应激反应；并且，脑搏动和临床前脑血管疾病。目标 1 测试 是否有较大的应激源诱发心血管（血压、心输出量和总外周血 抵抗）反应与临床前脑血管疾病标志物（更大的脑搏动， 白质病变负担增加，海马体积减少，大脑增大 多元结构方程模型中的血管周围空间）。目标 2 测试之间是否存在关联 应激诱发的心血管反应和临床前脑血管疾病标志物部分是 可以通过动脉僵硬度、内皮功能障碍和逐搏血流动力学控制来解释。第三 目标 3 探讨目标 1-2 的影响是否会受到已知的心血管风险和性别作为生物因素的调节。 多变的。拟议的项目旨在描述心血管应激反应的程度 中年是脑血管疾病风险的一个特定心血管来源。这样，新的 该项目的信息可能会识别中年时期潜在的可改变且与压力相关的因素， 可以帮助预测和减少晚年痴呆风险的血管来源。