FLAVANOL-RICH COCOA TO REVERSE VASCULAR DISEASE OF AGING

描述（由申请人提供）：研究目的：心血管衰老年龄的增加伴随着心血管疾病的患病率增加，包括动脉粥样硬化，心肌梗死和中风。所有这些疾病的基础是血管老化，内皮功能障碍。有证据表明，衰老是内皮功能障碍的一个强有力的预测因素，但潜在的治疗方法尚不清楚。 饮用富含类黄酮的饮料，包括茶和红酒，与冠状动脉事件的减少有关。可可中含有大量的类黄酮，在体外可以激活一氧化氮合酶（NOS）。我们已经证明，可可富含这些类黄酮诱导外周血管舒张，改善健康人的内皮功能。此外，通过输注特异性NOS抑制剂L-NAME，我们已经证明了该机制是一氧化氮依赖性的。我们认为，这些类黄酮的反应，即通过激活NOS，是年龄依赖性的，随着年龄的增长而增加。具体来说，我们计划扩展初步观察，即富含类黄酮的可可对增强内皮功能的有益作用在老年人中比在年轻人中更大。脉搏波振幅将在手指中测量，以响应富含黄烷醇的可可，并以黄烷醇贫乏的可可作为对照。为了检验这些作用依赖于NO合成的假设，我们将在老年受试者服用富含黄烷醇的可可一周之前和之后测量对天然底物L-精氨酸的反应。我们预计，精氨酸的血管扩张作用将增强后，富含黄烷醇的可可，L-NAME将抑制反应。通过这项提议，Fisher博士将进入心血管衰老临床研究的新领域，研究内皮功能的改善，这是新颖的，有趣的和广泛适用的。她将全权负责规划、指导和执行布里格姆妇女医院GCRC拟议的两年期项目。她将能够很好地提交具有本研究结果的RO 1申请。旨在恢复血管内皮功能的治疗干预具有巨大的临床前景。

DESCRIPTION (provided by applicant): Research Objective: Cardiovascular Aging Advancing age is accompanied by an increased prevalence of cardiovascular disease, including atherosclerosis, myocardial infarction, and stroke. Underlying all of these conditions lies the aging blood vessel, damaged with a dysfunctional endothelium. Evidence has secured aging as a strong predictor of endothelial dysfunction, yet potential therapies are unknown. Consumption of flavonoid-rich beverages, including tea and red wine, is associated with a reduction in coronary events. Cocoa can contain extraordinary concentrations of flavonoids, shown to activate nitric oxide synthase (NOS) in vitro. We have demonstrated that cocoa rich in these flavonoids induced peripheral vasodilation, improving endothelial function in healthy people. Furthermore, through infusion of the specific NOS inhibitor L-NAME, we have demonstrated that the mechanism is nitric-oxide dependent. We propose that responsiveness to these flavonoids, namely via activation of NOS, is age-dependent, increasing with advancing age. Specifically, we plan to extend preliminary observations that the beneficial effects of flavonoid-rich cocoa on augmenting endothelial function are greater in the elderly than in the young. Pulse wave amplitude will be measured in the finger in response to flavanol-rich cocoa, with flavanol-poor cocoa as a control. To test the hypothesis that these actions are dependent upon NO synthesis, we will measure responsiveness to the naturally occurring substrate L-arginine before and after one week of flavanol-rich cocoa in elderly subjects. We anticipate that the vasodilator effects of arginine will be enhanced after flavanol-rich cocoa, and that L-NAME will inhibit the response. With this proposal Dr. Fisher will enter a new area of clinical research in cardiovascular aging, with investigations into improvement of endothelial function that are novel, intriguing and broadly applicable. She will be solely responsible for planning, directing and executing the proposed two-year project on the GCRC of the Brigham and Women's Hospital. She will be well-positioned to submit an application for an RO1 with results from this study. Therapeutic interventions aimed at restoring vascular endothelial function hold tremendous clinical promise.