Effect of Vascular Stiffness on Endothelial Function.

描述(由申请人提供)： 候选人苏珊·J·齐曼医学博士是约翰·霍普金斯大学心脏病学部的医学助理教授。她接受过老年医学和心脏病学的培训和认证，目前正在约翰·霍普金斯卫生与公共卫生学院攻读临床调查博士学位。她的长期目标是成为一名临床研究员，专注于血管功能与年龄相关的变化，以及它们与老年人心血管疾病的发展、表现和治疗的关系。为了实现这一目标，她制定了基于导师的研究职业发展计划，提供3个领域的培训：1)临床试验设计、管理和分析；2)血管评估技术；3)作为一名独立研究人员开始职业生涯所需的专业技能。这一教学和有组织的培训计划补充了以下侧重于血管僵硬研究的研究方案。使年龄成为心血管(CV)疾病最重要危险因素的生理变化尚不清楚。尽管动脉僵硬和内皮功能障碍伴随着年龄的增长，并与心血管风险增加有关，但它们导致心血管风险增加的机制和它们之间的因果关系尚不清楚。通过改变血管壁的结构成分来增加血管扩张性(VD)的新型药物的最新发展现在使得对这些关系的探索成为可能。这一建议的指导性假设是血管扩张性降低本身会损害内皮功能。特定目的1测试血管性痴呆降低是否与健康的年轻和老年志愿者的肱动脉内皮血流介导的血管扩张(FMD)受损有关。特定目的2测试在扩张性降低的动脉中，血管内皮细胞对下肢运动后搏动性增加的反应是否减弱。特定目标3测试了这样的假设：在血管僵硬增加的老年人中，增加动脉扩张性可以改善FMD和运动诱导的脉冲灌流介导的血管扩张(Ppmv)。一种新型的高级糖基化终产物交联剂将在一项为期两个月的前瞻性、随机、双盲、安慰剂对照试验中进行测试，调查血管扩张性增加对内皮功能(静息和运动诱导的PPMV)的影响。总的目标是确定一种新的、重要的机制，使血管僵硬有助于动脉粥样硬化的风险，从而通过增强血管扩张性来针对治疗这种风险的努力。这些项目和职业发展计划将提供资源、合作关系和学术基础，齐曼博士将在此基础上作为一名独立的临床研究员建立成功的职业生涯。

DESCRIPTION (provided by applicant): The candidate, Susan J. Zieman, M.D., is an Assistant Professor of Medicine in the Cardiology Division at Johns Hopkins. She is trained and certified in Geriatric Medicine and Cardiology and is pursuing a Ph.D. in Clinical Investigation at the Johns Hopkins School of Hygiene and Public Health. Her long-term goal is to become a clinical investigator focusing on age-associated changes in vascular function and how they relate to the development, manifestations and treatment of cardiovascular disease in older adults. To realize this goal, she has developed a mentor-based research career development plan which provides training in 3 realms: 1) clinical trial design, management and analysis 2) vascular assessment techniques and 3) professional skills needed to launch a career as an independent investigator. This didactic and structured training program complements the following research proposal focused on the study of vascular stiffness. The physiologic changes that render age the most significant risk factor for cardiovascular (CV) disease are unclear. Although increased arterial stiffness and endothelial dysfunction accompany aging and are associated with increased CV risk, the mechanisms by which they impart increased CV risk and the causal nature of their relationship are unknown. The recent development of novel agents which increase vascular distensibility (VD) by altering structural components of the vessel wall now allows exploration of these relationships. The guiding hypothesis of this proposal is that decreased vascular distensibility itself impairs endothelial function. Specific Aim 1 tests whether decreased VD is associated with impaired endothelial flow-mediated vasodilation (FMD) in the brachial arteries of healthy young and older volunteers. Specific Aim 2 tests whether the endothelial vasoactive response to increased pulsatility following lower limb exercise is diminished in arteries with reduced distensibility. Specific Aim 3 tests the hypothesis that increasing arterial distensibility improves FMD and exercise-induced pulse perfusion-mediated vasodilation (PPMV) in older adults with increased vascular stiffness. A novel advanced glycation end-product crosslink breaker will be tested in a prospective, randomized, double-blind, placebo-controlled two-month trial investigating the effect of increased vascular distensibility on endothelial function (FMD at rest and exercise-induced PPMV). The overall goal is to identify a novel, important mechanism whereby vascular stiffening contributes to atherosclerotic risk, and thereby target efforts to treat such risks by enhancing vascular distensibility. These projects and career development plans will provide the resources, collaborative relationships, and academic foundation on which Dr. Zieman will build a successful career as an independent clinical investigator.