The plurimetabolic syndrome: qualitative lipoprotein abnormalities and atherosclerosis

Abstract

Hypercholesterolemia with increased LDL-C levels is associated with higher risk of coronary artery disease (CAD). However, over 50% of patients with CAD do not present with increased plasma LDL-C, but their lipoprotein profile is rather characterized by qualitative lipoprotein abnormalities such as LDL particles that are small, dense and more atherogenic, mild hypertriglyceridemia and low HDL-C, particularly HDL2-C. This lipoprotein profile is often found in patients with insulin resistance and increased intra-abdominal adipose tissue, hallmarks of the plurimetabolic syndrome. Smaller, denser LDL particles are more susceptible to oxidative modifications. Oxidized LDL are potent inflammatory agents when they reach the sub-endothelial space. In addition, low levels of HDL2-C may be a marker of an impaired reverse cholesterol transport. Indeed, this lipid profile is associated with a three- to six-fold increased risk of both cardiovascular and cerebrovascular disease. It is interesting to notice that patients with small, dense LDL and low HDL2-C are particularly susceptible to CAD improvement when treated with an aggressive lipid-lowering therapy. Changes in LDL density with therapy, mediated by a decrease in hepatic lipase (HL) activity, a key enzyme in LDL and HDL metabolism, account, at least partly, for this increased susceptibility to CAD clinical improvement seen in patients with a lipid profile peculiar of the plurimetabolic syndrome. A common polymorphism in the promoter region of the HL gene (−514 C–T) appears to predict CAD regression by modulating the effect of lipid-lowering therapy on HL activity and thereby on LDL and HDL density. Lipid-lowering therapy with fibrates results in increased HDL-C and HDL2-C and a significant improvement in both LDL and HDL size and density.