Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis

Abstract

Conclusion: Cholesterol efflux capacity has a strong inverse relationship with angiographic coronary artery disease and carotid intima-media thickness independent of high-density lipoprotein (HDL) cholesterol level. Summary: A strong inverse association exists between levels of HDL cholesterol and cardiovascular disease risk. Pharmacologic increases in HDL cholesterol have thus been postulated to reduce cardiovascular risk. However, an inhibitor of cholesteryl ester transfer protein (CETP) was found to result in a 72% increase in HDL cholesterol levels, but was associated with an increase in the number of cardiovascular events (Barter PJ [N Engl J Med 2007;357:2109-22]). This may be because HDL has marked heterogeneity in particle composition that affects its biologic properties. Emphasis has therefore shifted on not only measurement of HDL cholesterol levels but on the development of a validated measure of HDL function (Vaisar T [J Clin Invest 2007;117:746-56]). There may be many components of HDL-mediated atheroprotection. The ability of HDL to promote reverse cholesterol transport by accepting cholesterol from lipid-laden macrophages may be important. This is termed “cholesterol efflux capacity” (Tall AR [J Intern Med 2008;263:256-73]). The authors measured cholesterol efflux capacity in 203 healthy volunteers undergoing assessment of carotid artery intima-media thickness (CIMT). Efflux capacity was also measured in 442 patients with angiographically confirmed coronary artery disease and in 351 patients without angiographically confirmed disease. Efflux capacity was measured using a validated ex vivo system that used incubation of macrophages with apolipoprotein B-depleted serum from study participants. Levels of HDL cholesterol and apolipoprotein A-1 were significant determinants of cholesterol efflux capacity. However, these parameters accounted for <40% of observed variation. An inverse relationship was found between efflux capacity and CIMT, both before and after adjustment for the HDL cholesterol level. Efflux capacity was a strong inverse predictor of coronary disease (adjusted odds ratio [OR] for coronary disease per 1-SD increase in efflux capacity: 0.70; 95% confidence interval [CI], 0.59-0.83; P < .001). The relationship remained significant, although attenuated, after additional adjustment for HDL cholesterol level (OR per 1-SD increase: 0.75; 95% CI, 0.63-0.90, P = .002) or apolipoprotein A-1 level (OR per 1-SD increase, 0.74; 95% CI, 0.61-0.89; P = .002). Smoking was a significant inverse predictor of efflux capacity, even after adjustment for HDL cholesterol level and sex. Comment: The study addresses an important issue of why static measurements of HDL cholesterol have inherent limitations for predicting the functional affects of HDL. Clearly, a simple assessment of HDL levels and modulation of only HDL levels is not likely, according to these data, to result in predictable modification of cardiovascular risk factors. Drug therapy targeting cholesterol efflux capacity may be a more fruitful target for modulation of the antiatherogenic effects of HDL cholesterol.