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并获得认证，目前正在攻读博士学位。在约翰霍普金斯卫生与公共卫生学院的临床研究。她的长期目标是成为一名临床研究者，专注于血管功能的年龄相关变化以及它们如何与老年人心血管疾病的发展，表现和治疗相关。为了实现这一目标，她制定了一个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）血管评估技术和3）作为独立研究者开展职业生涯所需的专业技能。这个教学和结构化的培训计划补充了以下研究建议，重点是血管硬度的研究。使年龄成为心血管（CV）疾病最显著风险因素的生理变化尚不清楚。尽管动脉僵硬度增加和内皮功能障碍伴随着衰老，并与CV风险增加相关，但它们增加CV风险的机制及其关系的因果性质尚不清楚。最近开发的通过改变血管壁的结构成分来增加血管扩张性（VD）的新药物现在允许探索这些关系。该建议的指导性假设是血管扩张性降低本身损害内皮功能。特定目标1测试VD降低是否与健康年轻和老年志愿者肱动脉中内皮血流介导的血管舒张（FMD）受损相关。特定目标2测试下肢运动后血管内皮对脉动性增加的反应是否在扩张性降低的动脉中减弱。具体目标3检验了以下假设：在血管僵硬度增加的老年人中，增加动脉扩张性可改善FMD和运动诱导的脉冲灌注介导的血管舒张（PPMV）。将在一项为期2个月的前瞻性、随机、双盲、安慰剂对照试验中对一种新型晚期糖基化终产物交联破坏剂进行测试，研究血管扩张性增加对内皮功能（静息时FMD和运动诱导PPMV）的影响。总的目标是确定一种新的，重要的机制，血管硬化有助于动脉粥样硬化的风险，从而有针对性的努力，以治疗这种风险，通过提高血管扩张性。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，Zieman博士将作为独立的临床研究者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.