Dymott, Jane Alison
Cardiovascular disease and type 2 diabetes mellitus: Investigation of underlying mechanisms.
MD thesis, University of Glasgow.
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Cardiovascular disease (CVD) remains the leading cause of death in the United Kingdom and is associated with a huge burden of morbidity. Within the group of cardiovascular diseases coronary artery disease (CAD) is the single largest cause of death. Death rates from CAD have been falling since the 1970s predominantly due to a reduction in the prevalence in major risk factors such as cigarette smoking. Type 2 diabetes mellitus (DM) is an important risk factor for CVD. Type 2 DM is increasing in prevalence and there is concern that this will contribute to an increase in the burden of CVD. Reducing cardiovascular risk in patients with type 2 DM has to date focussed on tight blood pressure and glycaemic control together with statin therapy to achieve tight low density lipoprotein cholesterol (LDL) targets. Recent studies such as ADVANCE and ACCORD have highlighted some of the limitations with this approach. Important vascular abnormalities underlying the development of CAD include endothelial dysfunction and increased arterial stiffness. Some of the mechanisms underlying these abnormalities are thought to include increased oxidative stress, inflammation, insulin resistance and dyslipidaemia. These processes in patients with type 2 DM are currently not fully understood. It is hoped that through increased understanding of these processes new strategies for reducing cardiovascular risk in patients with type 2 DM can be identified.
This study aimed to investigate some of the processes thought to underlie CVD in patients with type 2 DM namely endothelial dysfunction, arterial stiffness, oxidative stress and dyslipidaemia. Finally this study aimed to assess the impact of two cardiovascular prevention strategies (statin therapy and increased physical activity) on these processes believed to underlie the development of CVD.
One hundred and twenty six patients with CAD (36 patients with type 2 DM, 90 patients without diabetes) and 80 controls (64 healthy controls and 16 varicose vein controls) were recruited as part of the VASCAB study. In these patients in vivo and ex vivo endothelial function studies were performed. Indicators of arterial stiffness were measured using pulse wave velocity and pulse wave analysis techniques. Superoxide levels were assessed in vascular tissue, mononuclear cells and whole blood. LDL and high density lipoprotein cholesterol (HDL) subfractions were analysed in patients with CAD. To assess the impact of intensive statin therapy and tight LDL targets, endothelial function and vascular superoxide levels were compared in patients recruited as part of the VASCAB study (2007 cohort) to a group of patients recruited in 2003. Finally patients attending the cardiac rehabilitation programme following surgical revascularisation were recruited to assess the impact of increased physical activity on endothelial function and oxidative stress.
Endothelial function was impaired in patients with CAD compared to controls. In patients with CAD, type 2 DM was associated with greater impairment of endothelial function compared to patients with CAD alone. Superoxide levels in the vasculature, mononuclear cells and whole blood were similar in patients with and without type 2 DM. Type 2 DM was associated with significantly lower HDL levels and a preponderance to small dense LDL compared to patients without diabetes. Arterial stiffness was increased in patients with CAD compared to controls. There was however no significant difference in arterial stiffness in patients with type 2 DM and CAD compared to patients with CAD alone. Intensive statin therapy was associated with lower LDL levels and improved endothelial function but no change in vascular superoxide levels. Following the cardiac rehabilitation programme endothelial function was improved and HDL levels increased. There were no changes in levels of oxidative stress.
Endothelial dysfunction in patients with type 2 DM may partly account for the increased cardiovascular risk and worse cardiovascular outcomes seen in this group of patients. Increased oxidative stress did not explain the endothelial dysfunction associated with type 2 DM. The dyslipidaemia that was associated with type 2 DM (low HLD and small dense LDL levels) may partly explain the increased endothelial dysfunction observed. Targeting endothelial dysfunction may therefore be a strategy for reducing cardiovascular risk in patients with type 2 DM. Intensive statin therapy and increased physical activity were both associated with improvements in endothelial function. The lack of evidence for increased arterial stiffness in patients with type 2 DM may reflect deficiencies in the methods used for assessing arterial stiffness. However this study highlights the difficulties of assessing arterial stiffness clinically and raises questions regarding the impact of type 2 DM on commonly used measures of arterial stiffness.
Future prospective studies assessing the impact of improving endothelial function in patients with type 2 DM on cardiovascular outcomes are required.
||cardiovascular disease, coronary artery bypass graft, type 2 diabetes mellitus, oxidative stress, endothelial function, arterial stiffness,dyslipidaemia,low density lipoprotein cholesterol (LDL),cardiac rehabilitation.
||R Medicine > RC Internal medicine
||College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
||Delles, Dr. Christian and Dominiczak, Professor Anna
|Date of Award:
Dr Jane Alison Dymott
||Copyright of this thesis is held by the author.
||21 Sep 2011
||10 Dec 2012 14:00
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