Flavanol-Rich Cocoa, Vascular Responses and Mechanisms

描述（由申请人提供）：内皮功能障碍几乎是年龄增长的普遍补充，表现为高血压、动脉粥样硬化和心血管疾病的高患病率。衰老还与脑血流（CBF）调节的变化有关，这可能威胁脑灌注并最终影响日常生活活动，导致功能障碍以及认知受损。所有这些疾病的基础是血管受损和内皮功能障碍。潜在的纠正治疗尚不清楚。这项研究的目的是广泛研究富含黄烷醇的可可在两个独立的循环中对血管的益处，这与NHLBI的使命直接相关，NHLBI在研究心脏和脑血管疾病的潜在预防和治疗方面，NCCAM通过在严格的科学背景下探索植物来源的生物制剂。饮用富含类黄酮的饮料与冠状动脉事件的减少有关;我们的假设归功于它们的类黄酮含量。可可中含有大量的类黄酮亚类黄烷醇，可激活一氧化氮（NO）合酶。在外周，我们发现可可诱导血管舒张，改善健康人的内皮功能。通过输注特异性NO合酶抑制剂L-NAME，我们证明了该机制是NO依赖性的。在一项对健康老年人的研究中，我们记录了在食用富含黄烷醇的可可两周后，经颅多普勒测量的脑血流量的增加。我们建议进行生理学研究来确定脑血流反应性的机制，以及它是否也是NO依赖性的。我们还将通过MRI研究脑血流量，包括区域研究和灰色和白色物质的流量测量，预计富含黄烷醇的可可会增加。我们将进一步研究MRI和超声这两种方法在测量脑血流量方面的一致性。功能性TCD反应将评估神经血管耦合的潜在增强。这些试验将包括摄入质量受控的富含黄烷醇的可可产品和作为对照的模拟物，以及外周循环的平行研究。Fisher博士将继续她作为心脑血管疾病领域独立临床研究者的新工作，研究创新、有趣和广泛适用的内皮功能障碍治疗方法。旨在恢复血管内皮功能的治疗干预，特别是当来自天然存在的生物活性剂时，具有巨大的临床前景。 公共卫生相关性：内皮功能障碍几乎是年龄增长、潜在高血压、心血管疾病和频繁认知能力下降的普遍补充。这项研究探讨了富含黄烷醇的可可增加脑血流量的机制。最终，这些数据可能为预防认知能力下降的试验奠定基础。

DESCRIPTION (provided by applicant): Endothelial dysfunction is a nearly universal complement to advancing age, manifest by a high prevalence of hypertension, atherosclerosis, and cardiovascular disease. Aging is also associated with changes in cerebral blood flow (CBF) regulation which may threaten cerebral perfusion and ultimately affect activities of daily living, resulting in functional disabilities as well as impaired cognition. Underlying all of these conditions lies the damaged blood vessel with a dysfunctional endothelium. Potential corrective therapies are unknown. This research, aimed broadly at studying the vascular benefits of flavanol-rich cocoa in two separate circulations, is directly related to the missions of both the NHLBI, in examining a potential prevention and treatment for cardiac and cerebrovascular disease, and of the NCCAM, by exploring a botanically-derived biological agent in the context of rigorous science. Consumption of flavonoid-rich beverages has been associated with a reduction in coronary events; our hypothesis credits their flavonoid content. Cocoa can contain extraordinary amounts of the flavonoid subset flavanols, shown to activate nitric oxide (NO) synthase. In the periphery, we showed that cocoa induced vasodilation, improving endothelial function in healthy people. Through infusion of the specific NO synthase inhibitor L-NAME, we demonstrated that the mechanism is NO- dependent. In a study of healthy elderly, we documented a rise in cerebral blood flow -- measured by transcranial Doppler -- following two weeks of flavanol-rich cocoa. We propose physiologic studies to determine the mechanism underlying cerebral blood flow responsiveness and whether it, too, is NO- dependent. We will also study brain blood flow by MRI, including regional studies and measures of flow in gray and white matter, anticipating specific increases with flavanol-rich cocoa. We will further examine the two methodologies, MRI and ultrasound, for concordance in measuring cerebral blood flow. Functional TCD responses will assess potential enhancement of neurovascular coupling. The trials will involve ingestion of a quality-controlled flavanol-rich cocoa product and mimetic as control, as well as parallel studies in the peripheral circulation. Dr. Fisher will continue her novel work as an independent clinical investigator in the area of cardio- and cerebrovascular disease, studying treatments of endothelial dysfunction that are innovative, intriguing and broadly applicable. Therapeutic interventions aimed at restoring vascular endothelial function, especially when derived from a naturally occurring biologically active agent, hold tremendous clinical promise. PUBLIC HEALTH RELEVANCE: Endothelial dysfunction is a nearly universal complement to advancing age, underlying hypertension, cardiovascular disease and frequent cognitive decline. This research examines the mechanisms by which flavanol-rich cocoa increases cerebral blood flow. Ultimately these data might lay the foundation for a trial in the prevention of cognitive decline.