Sympathetic Regulation of Large Artery Stiffness in Humans with Age-Related Isolated Systolic Hypertension

年龄相关性单纯性收缩期高血压患者大动脉僵硬度的交感调节

• 批准号: 10620643
• 负责人: Gary L. Pierce
• 金额: $ 34.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620643
• 关键词: Acute; Adult; Age; Aging; Aorta; Arteries; Attenuated; Blood Pressure; Blood flow; Brain; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Central Artery; Cessation of life; Chronic; Clinical; Clonidine; Collagen; Data; Development; Diastolic blood pressure; Double-Blind Method; Elasticity; Elastin; Elderly; Enrollment; Event; Femur; Goals; Human; Hypertension; Isolated systolic hypertension; Left Ventricular Hypertrophy; Lower Body Negative Pressure; Measures; Medial; Mediating; Myocardial Infarction; Nerve; Oral; Organ; Penetration; Peripheral; Pharmaceutical Preparations; Physiologic pulse; Placebo Control; Publishing; Pulse Pressure; Randomized; Regulation; Research; Smooth Muscle; Stroke; Thick; Woman; age related; aged; arterial stiffness; arteriole; calcification; cardiovascular disorder risk; cerebrovascular; effectiveness evaluation; experimental study; hemodynamics; human old age (65+); hypoperfusion; indexing; insight; men; middle age; muscle hypertrophy; new therapeutic target; novel therapeutic intervention; older men; older women; pharmacologic; prehypertension; pressure; therapeutic target; white matter damage

Project Summary/Abstract Stiffness of the large elastic central arteries (e.g., aorta and carotids) increases with advancing age and is a robust predictor of incident cardiovascular disease (CVD) events among older adults. The age-related increase in central artery stiffness is associated with a concomitant rise in systolic blood pressure (BP) and pulse pressure (PP) and subsequently the development of isolated systolic hypertension (ISH) in many older adults. Consequently, higher PP results in greater pulsatile pressure and flow penetrating into high blood flow organs such as the brain causing subclinical target organ damage. Sympathetic nerve activity (SNA) also increases with advancing age and is associated with cardiovascular target organ damage including left ventricular hypertrophy and intima-medial thickness (IMT) of peripheral conduit arteries, but it remains unclear whether enhanced SNA modulates the age-related increase in central artery stiffness and associated augmented carotid pressure and flow pulsatility and increased IMT. Therefore, the objectives of this application are to 1) determine the contribution of SNA to the age-related increase in aortic stiffness and reduced carotid compliance, and augmented carotid pressure and flow pulsatility and IMT among older adults with ISH, and 2) determine the effectiveness of chronic inhibition of SNA for reducing large artery stiffness, carotid pressure and flow pulsatility and IMT among older adults with ISH. In Aim 1, we will enroll 30 older (age 60-85 years) adults (50% women/50% men) with untreated stage 1 or stage 2 ISH (systolic BP 130-159 mmHg; diastolic BP <90mmHg) in a repeated measures experimental study assessing aortic stiffness (carotid-femoral pulse wave velocity, PWV) and carotid artery compliance and pressure pulsatility index at baseline and during -15 and -30 mmHg of lower body negative pressure. We hypothesize that acute experimental elevations in SNA will result in transient increases in carotid-femoral PWV and decreases in carotid compliance resulting in higher carotid pressure and flow pulsatility. In Aim 2, we will enroll 78 healthy older men and women (age 60-85 years) with untreated or treated ISH in a randomized, placebo-controlled double blind study. We hypothesize that 4 weeks of chronic SNA inhibition with oral clonidine will result in clinically meaningful decreases in aortic stiffness and increases in carotid artery compliance, causing significant reductions in carotid pressure and flow pulsatility index and IMT. The proposed research will fundamentally advance our understanding of the regulation of large elastic artery stiffness by SNA among older humans with ISH, and provide valuable insight into SNA as a novel therapeutic target among older adults with ISH for lowering CVD risk.

项目摘要/摘要 大型弹性中央动脉的刚度（例如主动脉和颈动脉）随着前进而增加 年龄，是老年人事件心血管疾病（CVD）事件的强大预测指标 成年人。中央动脉刚度与年龄相关的增加与伴随的上升有关 在收缩压（BP）和脉压（PP）中，随后发展 许多老年人中分离的收缩压（ISH）。因此，较高的PP导致 更大的脉冲压力和渗透到高血流器官（例如大脑）的流动 引起亚临床目标器官损伤。交感神经活动（SNA）也随着 增长年龄，与心血管靶器官损伤有关，包括左 周围导管动脉的心室肥大和内膜中内厚度（IMT），但 尚不清楚增强的SNA是否调节了中央动脉的年龄相关增加 刚度和相关的增强颈动脉压力和流动性脉动和IMT增加。 因此，本申请的目标是1）确定SNA对 与年龄相关的主动脉僵硬度和颈动脉依从性降低并增加颈动脉 ISH老年人的压力和流动性脉动和IMT，2）确定 慢性抑制SNA可降低大动脉刚度，颈动脉压力的有效性 以及具有ISH的老年人的流动性脉动和IMT。在AIM 1中，我们将注册30岁（年龄 60 - 85年）成人（50％女性/50％男性），未经治疗的第1阶段或第2阶段（收缩BP） 130-159 mmhg;舒张期BP <90mmHg）在重复测量中进行实验研究评估 主动脉刚度（颈动脉脉搏波速度，PWV）和颈动脉依从性 基线和-15和-30 mmHg的压力脉动指数负阴性 压力。我们假设SNA中的急性实验高程将导致短暂 颈动脉 - 股骨PWV的增加并减少颈动脉依从性，从而提高 颈动脉压力和流动脉动。在AIM 2中，我们将注册78个健康的老年男女 （60-85岁）在一个随机的，安慰剂对照双重的双重治疗或处理的ISH 盲目研究。我们假设用口服可乐定的4周慢性SNA抑制作用将导致 在临床上有意义的降低主动脉僵硬度和颈动脉依从性的增加中， 导致颈动脉压力和流动脉动指数和IMT的显着降低。这 拟议的研究将从根本上促进我们对大型调节的理解 SNA的弹性动脉僵硬在具有ISH的老年人中，并提供了宝贵的见解 SNA是具有ISH的老年人的新型治疗靶标，用于降低CVD风险。