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

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 question
How 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.

Hypothesis
Cocoa 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).