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。衰老还与脑血流量(CBF)调节的变化有关，这种变化可能会威胁到脑灌流，最终影响日常生活能力，导致功能障碍和认知障碍。在所有这些情况下，都是内皮功能障碍的受损血管。潜在的矫正疗法尚不清楚。这项研究的目的是在两个不同的循环中广泛研究富含黄烷醇的可可对血管的益处，这与NHLBI在审查心脑血管疾病的潜在预防和治疗方面的任务直接相关，也与NCCAM通过在严谨科学的背景下探索植物衍生生物制剂的任务直接相关。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。可可含有大量的黄酮亚单位黄烷醇，可以激活一氧化氮合酶。在外围，我们发现可可诱导血管扩张，改善健康人的内皮功能。通过输注特异的一氧化氮合酶抑制剂L-NAME，我们证明了其作用机制是NO依赖的。在一项对健康老年人的研究中，我们记录了在喝了两周富含黄烷醇的可可后，脑血流--通过经颅多普勒测量--的增加。我们建议进行生理学研究，以确定脑血流反应性的机制，以及它是否也是非依赖性的。我们还将通过核磁共振研究脑血流，包括区域研究和灰质和白质血流的测量，预计富含黄烷醇的可可会特别增加。我们将进一步研究MRI和超声波这两种方法在测量脑血流量方面的一致性。功能性经颅多普勒反应将评估神经血管偶联的潜在增强。这些试验将包括摄入一种质量受控的富含黄烷醇的可可产品和作为对照的模拟物，以及在外围循环中进行的平行研究。作为心脑血管疾病领域的一名独立临床研究员，费希尔博士将继续她的新奇工作，研究具有创新性、耐人寻味和广泛适用的内皮功能障碍的治疗方法。旨在恢复血管内皮细胞功能的治疗干预措施，特别是从自然产生的生物活性物质中提取的治疗措施，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一种普遍补充。这项研究探讨了富含黄烷醇的可可增加大脑血流量的机制。最终，这些数据可能会为预防认知衰退的试验奠定基础。

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.