Recent epidemiological evidence suggests that although lowering low-density lipoprotein (LDL) cholesterol is important in decreasing cardiovascular disease morbidity and mortality, it accounts only for part of the coronary artery disease (CAD) improvement with lipid-lowering therapy. In the last decade, it has become evident that the atherogenicity of LDL particles is associated not only with their plasma levels, but also with their size and density. The presence of small, dense LDL particles is associated with a three fold increase in CAD risk. Hepatic lipase (HL), a key enzyme in the formation of small, dense LDL particles, modulates their phospholipid and triglyceride contents. The higher the HL activity, the smaller, denser, and more atherogenic the resulting lipoprotein particle. It is, therefore, plausible to hypothesize that at least part of the CAD benefits observed in the recent CAD-prevention pharmacological trials, which are not accounted for by the decrease in LDL-C (LDL-cholesterol), might be explained by a pharmacological effect on LDL size and density, possibly mediated by changes in hepatic lipase activity. By studying patients with dyslipidemia and CAD, we have been able to provide strong evidence that regression of coronary atherosclerosis results from at least two independent effects of lipid-lowering therapy on lipoprotein metabolism: the well known one that leads to changes in LDL-C and apo B levels, and a new pathway of HL-mediated improvement in LDL buoyancy. Finally, HL activity and LDL density appear to be significantly affected by the presence of a common C>T substitution at position -514 with respect to the transcription start site of the HL gene, raising the possibility that the -514 C>T polymorphism may significantly contribute to differences in individual CAD response to lipid-lowering treatment, as seen in the recent major primary and secondary CAD-prevention clinical trials.
- hepatic lipase
- LDL density
- coronary artery disease regression
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