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

项目摘要/摘要 大的弹性中央动脉(例如，主动脉和颈动脉)的僵硬程度随着前进而增加。 年龄，是老年人心血管疾病(CVD)事件的有力预测因素 成年人。与年龄相关的中央动脉僵硬增加与随之而来的增加有关 在收缩压(BP)和脉压(PP)以及随后的发展中 许多老年人的单纯收缩期高血压(ISH)。因此，较高的PP会导致 更大的脉动压力和血流渗透到高血流器官，如大脑 造成亚临床靶器官损害。交感神经活动(SNA)也随着 增龄并与心血管靶器官损害有关，包括左 心肌肥厚与外周管道动脉内膜中层厚度(IMT)呈正相关，但 目前尚不清楚增强的SNA是否调节与年龄相关的中央动脉的增加 僵硬和相关的颈动脉压力和血流搏动增加，以及IMT增加。 因此，本申请的目标是：1)确定国民账户体系对 与年龄相关的主动脉僵硬增加、颈动脉顺应性降低和颈动脉增厚 老年ISH患者的压力、血流搏动性和IMT，以及2)决定 慢性抑制SNA对降低大动脉僵硬、颈动脉压的疗效 老年ISH患者的血流搏动性和IMT。在目标1中，我们将招收30名老年人(年龄 60-85岁)成人(50%女性/50%男性)，未经治疗的1期或2期ISH(收缩压 130-159毫米汞柱；舒张压和舒张压90毫米汞柱)重复测量实验研究 主动脉僵硬(颈动脉-股动脉脉搏波速度，PWV)和颈动脉顺应性 负值时下体压力搏动指数-15和-30 压力。我们假设SNA的急性实验性升高将导致一过性 颈动脉-股动脉PWV增加和颈动脉顺应性降低导致 颈动脉压力和血流搏动性。在目标2中，我们将招募78名健康的老年男性和女性 (60-85岁)未治疗或治疗的ISH在随机、安慰剂对照的双重试验中 盲目学习。我们推测口服可乐定会导致4周的慢性SNA抑制。 在临床上有意义的主动脉僵硬的减少和颈动脉顺应性的增加， 导致颈动脉压力和血流搏动指数及IMT显著降低。这个 拟议的研究将从根本上促进我们对大型银行监管的理解 SNA在老年ISH患者中的弹性动脉硬化，并提供了有价值的洞察 SNA可作为老年ISH患者降低心血管风险的新治疗靶点。

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.