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Title: Impact of diet on vascular and biomarkers of injury : role of non invasive vascular assessment in quantifying risk and the effect of Metformin in addressing risk
Author: Varma, Madhusudham Chittari
ISNI:       0000 0004 5992 8014
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Cardiovascular disease (CVD) continues to be a significant cause of mortality in Western society despite improvement in medicine and clinical management. Both CVD and coronary artery disease (CAD) are caused by a pathological process known as atherosclerosis which occurs due to deposition of lipid rich cholesterol material into the arterial inner lining, the endothelium. The endothelium is a thin mononuclear layer that covers the inner surface of all the blood vessels. It acts an athero-protective organ which mediates its actions through vasoactive mediators, such as nitric oxide (NO). Endothelium derived nitric oxide is synthesised from the amino acid L-arginine by the endothelial nitric oxide synthase (eNOS). The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone which is essential for the regulation of blood pressure and flow. The eNOS enzyme is constitutive, calcium- and calmodulin-dependent, and releases pico-moles of nitric oxide in response to receptor stimulation. A physiologic vaso-dilator tone mediated by nitric oxide is in part maintained through the physical activation of endothelial cells by stimuli such as pulsatile flow and shear stress. This current thesis, as a first stage, investigated vascular function of the endothelium, following a physiological stress, at the macrovascular level (flow mediated dilatation of brachial artery-FMD) in healthy subjects and other CVD risk groups - type 2 diabetes (T2DM), obesity and impaired glucose tolerance (IGT). Oral glucose and high fat meal were used for inducing physiological stress. On the application of a physiological glucose stress, the mean FMD significantly and profoundly reduced in all CVD groups revealing the acute effects of post-prandial stress on the endothelium (p<0.05). This thesis, further evaluated the microvascular function at the level of retina (using a retinal vessel analyser, RVA) in all risk groups concurrent with macrovascular function assessment. Such analysis identified that microvascular function, in contrast to FMD, at 1 and 2 hour post glucose stress, appeared not to reveal significant reduction in healthy population compared with T2DM; This thesis also explored the impact of high fat diet on markers of endothelial dysfunction, inflammatory markers including TNF-α and endotoxin; which are known to be increased in conditions of CVD and CAD. Studies determined that endotoxin levels increased over time post a high fat meal. Specifically circulating endotoxin levels remained significantly and exponentially high in T2DM even 4 hours after ingesting high fat diet (p<0.05);whilst endotoxin levels in healthy subjects revealed only mild raise over time. This thesis explored the role of high endotoxin levels not only in T2DM subjects but also in obese children to demonstrate its association with subclinical inflammation and CVD risk. As a lipid meal appeared to affect vascular function which was most pronounced in T2DM subjects, this thesis further assessed the potential influence of medication to protect or reduce vascular damage. As such this thesis investigated whether metformin treatment had protective effect on lipoprotein damage and in turn on endothelial function on the high risk group of T2DM compared with control subjects. Glycation, oxidation and nitration reactions lead to significant damage of the apoB100 of LDL increasing atherogenicity and plasma residence times (p<0.01). Metformin appeared to reduce this damage (P<0.05 for all AGE (advanced glycation end) products and methionine sulphoxide) and thereby protect against endothelial dysfunction. This thesis determined the relevance of post-prandial stressors on vascular function at different levels. It investigated the impact such stress could exert on different CVD risk groups and how medication such as metformin may have protective effects. Microvascular reactivity measurements using Retinal vascular analyser appears to demonstrate potential to reliably study acute changes in endothelial function with potential long-term benefits for providing individualized medicine to “at risk”patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine