HDL function and atherosclerosis

There is a strong inverse relationship between serum levels of HDL and the risk of developing atherosclerotic cardiovascular disease.  This has fostered the search for pharmacological agents that raise HDL, but while several therapies have shown biochemical benefit – including nicotinic acid, fibrates and CETP inhibitors – there are little convincing data to associate these rises with significant reductions in clinical risk.  Indeed, there are increasing questions regarding the benefit of HDL increases per se, with HDL particle composition and biological activity being increasingly recognised as key metrics which static measurements are too blunt to identify.

One of HDL’s central atheroprotective properties is its ability to promote reverse cholesterol transport by accepting cholesterol from lipid laden macrophages, termed cholesterol efflux capacity.  Using a technically complex assay involving the use of radiolabelled cholesterol and scintillation counts, the authors recruited 442 patients with angiographically confirmed coronary artery disease, 351 patients without confirmed disease and 203 age-matched healthy volunteers (who also underwent assessment of carotid artery intima-media thickness (CIMT)), and quantified efflux capacity. In healthy volunteers an inverse relationship was noted between efflux capacity and CIMT even after adjustment for the HDL cholesterol level.  Furthermore, in the comparison between patients with and without coronary disease, efflux capacity was a strong inverse predictor of coronary disease status (adjusted OR for coronary disease, 0.70; 95% CI, 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (OR, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (OR, 0.74; 95% CI, 0.61 to 0.89; P=0.002).


Cholesterol efflux capacity from macrophages has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independent of the HDL cholesterol level.  Use of this more sophisticated assay of HDL may better inform future trials of the efficacy of HDL raising pharmacotherapies.

  • Khera AV, Cuchel M, de la Llera-Moya M et al.  Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011 Jan 13;364(2):127-35.