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。治疗发病率给NHS和更广泛的英国经济带来了巨大的负担，给个人带来了额外的成本，降低了生活质量。以饮食为基础的心血管疾病一级和二级预防方法正在被广泛接受，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。黄香酚，多酚的一个亚类，因其具有降低非传递性疾病风险和发病率的能力而被特别注意；即通过诱导血管改善和表现出认知的改善(作者在初步数据集中显示)。这些发现最近在SENSING COSMOS试验中得到证实；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~4.5年；每天补充500毫克黄烷醇，可将总心血管事件(包括心脏病发作、中风、心血管手术和死亡)减少高达40%。然而，这些饮食黄烷醇发挥这些保护作用的机制尚不清楚。中心研究问题可可黄烷醇如何降低中风和其他心血管疾病风险？使用COSMOS试验血液样本对黄烷醇生理功能的机制研究以及对中风康复患者进行随机对照试验的疗效调查。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)降低中风风险并改善认知能力。目的：1.探讨长期摄入黄烷醇对COSMOS试验中血液流变学指标的影响。在COSMOS试验中，有237例中风；194例是缺血性的，29例是出血性的，14例没有分类。通过分析这些参与者以及没有中风的参与者的血液样本，包括血液粘度、血浆粘度、红细胞压积和红细胞机械性能，如红细胞变形性和红细胞聚集性，我们希望对黄烷醇预防中风和其他形式的心血管疾病的机制提供重要的信息。目的：评价可可黄醇干预在卒中治疗和二级预防中的疗效。将在中风康复诊所的患者中进行随机对照试验。这项试验将调查可可黄醇干预(与COSMOS试验相同)对中风风险标记物(血压、动脉僵硬、血管功能和生化参数)、血液流变学和认知能力的影响。关键方法：该项目将采用实验室和临床方法。简而言之，这些将包括基本的生化分析(例如，酶联免疫吸附试验)以及更先进的分析技术，如用于评估与黄烷醇相关的代谢物的LC MS。COSMOS血液样本将接受全面的血液流变学评估(黄烷醇和对照组)，包括1)血浆粘度、血液粘度和血液粘弹性；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液动力学评估(例如血压)以及更新的技术，如颈动脉-股动脉脉搏波速度(通过眼压计)来测量动脉僵硬和血流介导的内皮功能扩张(使用超声波)，并结合专注于中风和脑血管疾病的相关认知测试组件(即测试情景记忆和工作记忆、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).