FLAVANOL-RICH COCOA TO REVERSE VASCULAR DISEASE OF AGING

描述(由申请人提供)：研究目的：心血管衰老伴随着心血管疾病发病率的增加，包括动脉粥样硬化、心肌梗死和中风。在所有这些情况下，是老化的血管，内皮功能失调而受损。有证据表明，衰老是内皮功能障碍的有力预测指标，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。可可含有超常浓度的类黄酮类物质，在体外可以激活一氧化氮合酶(NOS)。我们已经证明，富含这些黄酮类化合物的可可诱导外周血管扩张，改善健康人的内皮功能。此外，通过注入特异性一氧化氮合酶抑制剂L-NAME，我们证明了其机制是一氧化氮依赖的。我们认为，对这些黄酮类化合物的反应性，即通过激活一氧化氮合酶，是年龄依赖的，随着年龄的增长而增加。具体地说，我们计划扩大初步观察结果，即富含类黄酮类的可可在增强内皮功能方面的有益效果在老年人比年轻人更大。脉搏波幅度将在手指上测量，以黄醇含量较低的可可为对照。为了验证这些活动依赖于NO合成的假设，我们将测量老年受试者在饮用富含黄烷醇的可可一周之前和一周后对自然产生的底物L精氨酸的反应性。我们预计富含黄烷醇的可可会增强精氨酸的血管扩张作用，而L会抑制这一反应。有了这项建议，费希尔博士将进入心血管衰老临床研究的一个新领域，对改善内皮功能的研究具有新颖性、耐人寻味和广泛适用的特点。她将单独负责规划、指导和执行布里格姆妇女医院GCRC拟议的两年项目。她将处于有利地位，可以根据这项研究的结果提交RO1的申请。旨在恢复血管内皮细胞功能的治疗干预措施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.