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Vascular risk factors and adipocyte dysfunction in metabolic syndrome

By G.R. Hajer

Abstract

The cluster of vascular risk factors closely associated with obesity, consists of fasting and postprandial dyslipidemia, hypertension, and insulin resistance, also known as metabolic syndrome, is associated with an increased cardiovascular morbidity and mortality. In addition, adipose tissue in concordance with insulin resistance induces a pro-inflammatory and pro-atherogenic condition through the secretion of large quantities of pro-atherogenic, pro-inflammatory and pro-diabetic adipocytokines that influence lipid and carbohydrate metabolism, inflammatory and coagulation pathways and directly accelerate atherosclerosis. In this thesis the concept of ‘adipocyte dysfunction’ is presented. The work presented in this thesis is focused on 1] the relationship between metabolic risk factors associated with insulin resistance and adipocyte dysfunction and the occurrence of new cardiovascular events in patients with clinical manifest vascular disease, 2] the evaluation of the effect of lipid lowering therapy on postprandial lipid metabolism and endothelial function in obese patients with metabolic syndrome. Adiponectin is only produced by adipocytes and has potential anti-atherosclerotic properties and influences fatty acid and glucose metabolism (insulin resistance). We evaluated whether lower adiponectin plasma levels would also confer an increased vascular risk in a population of high-risk patients. It appeared that lower adiponectin plasma levels were associated with a decreased risk for vascular events in a large prospective cohort of patients with manifest vascular disease, even though the presence of metabolic syndrome was associated with lower adiponectin Low HDL-cholesterol plasma levels are a risk factor in healthy, non-treated subjects. In a large cohort of patients with manifest vascular diseases frequently using lipid-lowering therapy, low plasma HDL-cholesterol levels also confered an increased vascular risk. This relationship is irrespective of the localization of the disease or LDL-cholesterol levels, and independent of the use of lipid-lowering therapy. Obese metabolic syndrome patients have low fasting levels of HDL-cholesterol. We have shown that during an oral fat load, as a model of triglyceride-rich meal consumption, HDL-cholesterol levels further decrease. This dip is the result of high triglyceride levels and an increased synthesis of cholesteryl ester transfer protein, probably by dysfunctional adipocytes. This may contribute to the increased vascular risk seen in metabolic syndrome patients. In a randomized crossover trial, neither simvastatin nor simvastatin combined with ezetimibe could prevent this HDL-cholesterol dip. Postprandial hypertriglyceridemia is a key feature of metabolic syndrome due to reduced clearance of triglyceride-rich lipoproteins. As a result highly atherogenic small-dense lipoprotein particles are formed. In prevention the main focus is on lowering fasting LDL-cholesterol levels by either inhibiting cholesterol-synthesis (statin therapy), inhibition of intestinal cholesterol-absorption (ezetimibe) or by a combination of these two. Whether additional risk reduction can be achieved by preventing the development of this atherogenic postprandial lipoprotein profile by using ezetimibe in addition to a statin was unknown. As shown in the trial presented in this thesis, high-dose simvastatin and low dose simvastatin in combination with ezetimibe are equally effective in reducing postprandial lipoprotein concentrations and composition but show no effects on top of reduced fasting lipoprotein concentrations. Although no differences were observed between both treatment regimes in post fat load lipid levels or composition; simvastatin therapy combined with ezetimibe preserved endothelial function during the postprandial phase in contrast to high-dose of simvastatin alone

Publisher: Utrecht University
Year: 2008
OAI identifier: oai:dspace.library.uu.nl:1874/26271
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