HDL cholesterol's efflux capacity, a measure of its ability to promote cholesterol efflux from lipid-laden macrophages, was strongly inversely correlated with atherosclerotic burden in a study of two independent groups of subjects.
In a study assessing HDL cholesterol efflux capacity in two independent populations, this key measure of HDL function was a stronger predictor of both subclinical atherosclerosis disease (as assessed by carotid intima-media thickness) and coronary artery disease than was HDL level itself.
“These results could be important in the assessment of new therapies targeting HDL metabolism and reverse cholesterol transport,” and may even guide the development of new treatments, said Dr. Amit V. Khera of the cardiovascular institute at the University of Pennsylvania, Philadelphia, and his associates.
They first tested efflux capacity in serum samples from a cohort of 203 healthy white adults participating in a study of HDL-related biomarkers and atherosclerosis. These subjects underwent measurement of carotid artery intima-media thickness as part of that study.
There was no association between HDL level and subclinical CAD. In contrast, there was a significant inverse correlation between HDL cholesterol efflux capacity and subclinical CAD, which remained robust after the data were adjusted for HDL and apolipoprotein A-1 levels.
The investigators then assessed efflux capacity using serum samples from 793 white participants in a case-control cohort who underwent cardiac catheterization. The 442 patients found to have CAD showed significantly lower efflux capacity than did the 351 control subjects who were free of CAD.
In a further analysis, the proportion of patients with CAD decreased consistently with increasing efflux capacity. When the cohort was divided into quartiles of efflux capacity, the quartile with the highest efflux capacity showed a distinct decrease in CAD compared with the quartile with the lowest capacity.
All of these correlations remained robust after adjustment for subject age, sex, and traditional cardiovascular disease risk factors, Dr. Khera and his colleagues said (N. Engl. J. Med. 2010;364:127-35).
“Although cholesterol efflux from macrophages represents only a small fraction of overall flux through the reverse-cholesterol-transport pathway, it is probably the component that is most relevant to atheroprotection,” they noted.
“These findings reinforce the concept that assessment of HDL function” – not just HDL levels – “may prove informative in refining our understanding of HDL-mediated atheroprotection,” the researchers added.
This study was supported by the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the Doris Duke Charitable Foundation; and the Howard Hughes Medical Institute. Dr. Khera's associates reported ties to Kinemed, Vascular Strategies, and GlaxoSmithKline, as well as involvement with a patent on cell culture systems for determining cholesterol efflux potential in serum.
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HDL Function Deserves Further Study
The central hypothesis of the study, which was based on findings from studies in animals and cell cultures, was that HDL promotes cholesterol efflux from macrophage foam cells in atheromatous vessels, thus decreasing both the cholesterol burden and macrophage-driven inflammation, said Dr. Jay Heinecke.
The results thus “provide important evidence that the ability of HDL to promote cholesterol efflux from macrophage foam cells is a key property that explains in part the inverse relationship between HDL and the risk of atherosclerotic coronary artery disease in humans.”
Measuring efflux capacity thus may become a useful tool in further investigation of HDL function as well as in developing treatments for CAD, he said.
DR. HEINECKE is with the University of Washington, Seattle. He reported ties to several drug and biomedical technology companies. These comments are taken from his editorial accompanying Dr. Khera's report (N. Engl. J. Med. 2010;364:170-1).