Understanding the mechanism of cardiovascular disease reduction and cognitive enhancement by dietary flavanols: the impact of flavanols on blood rheol

英国有超过750万人患有心血管疾病（CVD）。治疗疾病给NHS和更广泛的英国经济带来了巨大的负担，个人的生活质量也因此下降。以饮食为基础的心血管疾病一级和二级预防方法正被广泛接受，并可能获得多方面的好处。植物生物活性物质，如多酚，可以降低心血管疾病的风险，但对其潜在机制知之甚少。黄烷醇是多酚的一个亚类，因其降低非传染性疾病风险和发病率的能力而受到特别关注；即通过诱导血管改善和显示认知改善（作者在初步数据集中显示）。这些发现最近在开创性的COSMOS试验中得到了证实；一项随机对照试验（RCT），约2.2万名参与者接受可可黄烷醇治疗约4.5年；500毫克/天的黄烷醇补充剂可将心血管事件（包括心脏病发作、中风、心血管手术和死亡）减少多达40%。然而，这些膳食黄烷醇发挥这些保护作用的机制尚不清楚。核心研究问题：可可黄烷醇如何降低中风和其他心血管疾病的风险？COSMOS试验血液样本对黄烷醇生理功能的机制研究及其对脑卒中康复患者疗效的RCT调查。假设：可可黄烷醇通过调节血液动力学和血液流变学（血液流变学）降低中风风险并诱导认知改善。目的:1。探讨长期摄入黄烷醇对COSMOS试验血液样本血液流变学标志物的影响。在COSMOS试验中，卒中发生率为237例；缺血性194例，出血性29例，未分类14例。通过分析这些参与者以及没有中风的参与者的血液样本，血液流变学标志物，包括血液粘度、血浆粘度、红细胞压积和红细胞的机械特性，如红细胞变形性和红细胞聚集性，我们希望揭示黄烷醇预防中风和其他形式心血管疾病的机制。评价可可黄烷醇干预脑卒中治疗及二级预防的疗效。一项随机对照试验将在参加中风康复诊所的患者中进行。该试验将调查可可黄烷醇干预（与COSMOS试验相同）对中风风险标志物（血压、动脉硬度、血管功能和生化参数）、血液流变学和认知能力的影响。主要方法：本项目将采用实验室和临床两种方法。简而言之，这些将包括基本的生化分析（例如，ELISA）以及更先进的分析技术，如LCMS，以评估黄烷醇相关代谢物。COSMOS血液样本将进行全面的血液流变学评估（包括黄烷醇组和对照组），包括1)血浆粘度、血液粘度和血液粘弹性的测量；2)红细胞聚集；3)红细胞变形性；4)白细胞流变学。随机对照试验将使用基本的血流动力学评估（如血压）以及更新颖的技术，如颈-股脉波速度（通过血压计）来测量动脉硬度和血流介导的扩张（使用超声波）内皮功能，并结合专注于中风和脑血管疾病的相关认知测试电池（即测试情景和工作记忆、执行功能和处理速度）。

Over 7.5 million people in UK are living with a cardiovascular disease (CVD). Treating morbidity places a huge burden on the NHS and the wider UK economy with additional costs to the individual of reduced quality of life. Dietary-based approaches for primary and secondary prevention of CVD are becoming widely accepted and could reap multifaceted benefits. Plant bioactives, such as polyphenols, reduce the risk of CVD but there is little understanding of their underlying mechanisms.Flavanols, a sub-class of polyphenol have been specifically noted for their ability to reduce non-communicative disease risk and morbidity; namely by inducing vascular improvements and exhibiting improvements in cognition (shown by the authors in preliminary datasets). These findings have recently been confirmed in the seminal COSMOS trial; a randomised controlled trial (RCT) with ~22k participants treated with cocoa flavanols ~4.5 years; 500 mg/d of flavanol supplement reduced total cardiovascular events (including heart attacks, strokes, cardiovascular surgery and deaths) by up to 40%. However, the mechanism by which these dietary flavanols exert these protective effects remain unknown.Central research questionHow do cocoa flavanols reduce stroke, and other CVD risk? A mechanistic investigation into flavanol physiological function using COSMOS trial blood samples and an RCT investigation into their efficacy in stroke rehabilitation patients. HypothesisCocoa flavanols reduce the risk of stroke and induce improvements in cognition through modulation of blood haemodynamics and blood rheology (haemorheology). Objectives:1. To explore the impact of long-term flavanol intake on haemorheology markers in blood samples from the COSMOS trial. In the COSMOS trial there were 237 incidences of stroke; 194 were ischemic, 29 were haemorrhagic and 14 were not classified. By analysing blood samples from these participants, as well as participants without stroke, for haemorheology markers, including blood viscosity, plasma viscosity, haematocrit, and mechanical properties of red blood cells, such as erythrocyte deformability and erythrocyte aggregation, we hope to shed significant light on the mechanism by which flavanols protect against stroke and other forms of cardiovascular disease.2. To assess the efficacy of cocoa flavanol intervention in stroke treatment and secondary prevention. A randomised controlled trial will be performed in patients attending the stroke rehabilitation clinic. The trial will investigate the impact of cocoa flavanol intervention (identical to the COSMOS trial) on markers of stroke risk, (blood pressure, arterial stiffness, vascular function, and biochemical parameters), on blood haemorheology, and on cognitive performance.Key methods:Both laboratory and clinical methodology will be employed in the project. Briefly, these will include basic biochemical assays (e.g., ELISA) as well as more advanced analytical techniques such as LCMS to assess flavanol-related metabolites. COSMOS blood samples will undergo full haemorheology assessment (both flavanol and control group) and will include measures of 1) plasma viscosity, blood viscosity and blood viscoelasticity; 2) red blood cell aggregation; 3) red blood cell deformability; and 4) white cell rheology. The randomised controlled trial will use basic haemodynamic assessment (e.g., blood pressure) as well as more novel techniques such as carotid-femoral pulse wave velocity (by tonometry) to measure arterial stiffness and flow mediated dilatation (using ultrasound) for endothelial function in combination with relevant cognitive test batteries focused on stroke and cerebrovascular disease (i.e., to test episodic and working memory, executive function, and processing speed).