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Unravelling the conflicting results of HDL’s atheroprotective effect
Until recently it was undisputed dogma that high-density lipoprotein cholesterol (HDL-C) has solely atheroprotective properties. This notion was based on population studies and meta-analyses showing an association of high HDL-C plasma levels with a decreased risk for cardiovascular disease.
Recently, however, this view has been challenged, mainly by clinical studies showing that HDL-C levels predicted cardiovascular death only in individuals without CAD. Several lipid-lowering trials showed no or only a weak impact of low HDL-C levels on cardiovascular risk. For example, in the PROVE IT-TIMI 22 trial the levels of HDL-C reached had no predictive value in ACS patients under aggressive atorvastatin therapy. However, in the COURAGE trial an association of cardiovascular risk with HDL-C plasma levels was seen in patients with stable CAD in which target levels of LDL-C of 60-58 mg/dl were reached through intensive lipid lowering therapy.
Further doubts on the exclusively atheroprotective role of HDL-C were raised by trials aiming to raise HDL-C levels. These studies using nicotinic acid or cholesteryl ester transfer protein inhibitors were largely unsuccessful as no additional risk reduction on top of statins could be seen.
These conflicting and controversial results have led to the concept of dysfunctional HDL by which the atheroprotective role of HDL-C does not depend on the transported cholesterol but rather on properties of the HDL particles themselves.
Addressing this concept, recent intensive research has shed some light on the heterogeneity of HDL particles possibly responsible for the contradictory findings. HDL particles can be divided in various sub-fractions or subpopulations depending on their size, composition, density, charge and physiological function. This heterogeneity is a result of the varying contents of lipids and proteins of the respective LDL particles in which size and density show an inverse correlation. According to density, HDL particles can be classified as HDL2, which are large and less dense, and as HDL3, which are small and dense.
Another property of HDL particles is their respective shape. Discoidal HDL particles are poor in lipids and contain mainly apolipoprotein A-1 (apo A-1), whereas spherical HDL particles are larger and contain cholesteryl ester and some triglycerides. The most abundant protein in HDL particles is apo A-1 followed by apo A-II which together make up close to 90% of the total protein content. HDL particles also contain proteins involved in lipid transfer such as cholesteryl ester transfer protein (CTEP) and phospholipid transfer protein (PLTP) and lipolytic proteins such as lecithin cholesteryl acyl transferase (LCAT). The varying content and/or impaired function of these proteins might be related to the anti- or pro-atherogenic effects observed for HDL particles in various setting.
The major atheroprotective effect of HDL is thought to be associated with its function in reverse cholesterol transport. Anti-inflammatory, anticoagulant and antioxidative effects have also been described. The anti-inflammatory and antioxidant effects are brought about by PON-1, whereas the anticoagulant properties of HDL seem to be related to its ability to reduce platelet activation and decrease expression of tissue factor.
These atheroprotective effects are lost in dysfunctional HDL. Current knowledge on the transition from functional to dysfunctional HDL is still fragmentary and mainly based on in vitro findings. However, it is generally believed that systemic inflammation seen in pathologies such as metabolic syndrome, diabetes, CAD and infections contribute to the conversion of HDL-C from an antiatherogenic to a proatherogenic molecule.
In summary, the controversy of the atheroprotective role of HDL-C fuelled by conflicting clinical data might be explained by the fact that the exact function of HDL-C and thus its role in the development of cardiovascular pathologies depends not so much on its quantity but more on its lipid and protein composition, with the small dense fraction having the highest antiatherogenic activity.
It thus seems likely that the concept of dysfunctional HDL-C will lead to assays with greater sensitivity and specificity and will shape future therapies, which will not only be based on quantitative but more so on qualitative modifications to change or modulate functions of HDL-C.
Don’t miss: Is HDL atheroprotective? Current controversies 29 August 08:30-10:00 Baku - Village 1
By Johann Wojta
Medical University of Vienna, Austria
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