NEJM: Cholesterol efflux capacity is inversely related to CIMT, CAD risk

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Cholesterol efflux capacity from macrophages has a sizeable inverse association with carotid intima-media thickness (CIMT) and the risk of angiographic coronary artery disease (CAD) that is independent of HDL cholesterol, according to a study published in the Jan. 12 issue of the New England Journal of Medicine.

Measurements of HDL cholesterol may have several limitations and assays of HDL function must be validated through better research. “HDL-mediated atheroprotection is most likely pleiotropic in nature, but the ability of HDL to promote reverse cholesterol transport by accepting cholesterol from lipid-laden macrophages (termed “cholesterol efflux capacity”) is thought to play a key role,” the authors wrote.

Amit V. Khera, MD, from the University of Pennsylvania in Philadelphia, and colleagues evaluated cholesterol efflux in 203 volunteers who underwent CIMT ultrasound measurement, 442 patients who had coronary artery disease confirmed by angiography and 351 patients who were without angiographically confirmed disease to assess whether or not the capacity of HDL to accept cholesterol from macrophages could predict atherosclerosis.

Within the patient cohort, the values for systolic blood pressure and glycated hemoglobin were 124 mm Hg and 5.5 percent, respectively. Thirty-three percent of the patients had previously smoked. In addition, the mean values for cholesterol efflux capacity were 11 percent prior to normalization and 0.77 percent after. Mean carotid intima-media thickness was 0.66 mm.

Khera et al found that while HDL cholesterol and apolipoprotein A-I were determinants of cholesterol efflux capacity, they accounted for less than 40 percent of the observed variation.

In addition, the study showed that patients with coronary artery disease had lower levels of HDL cholesterol and apolipoprotein A-I. HDL cholesterol levels were also found to be the strongest predictor of efflux capacity, but only accounted for 26 percent of the observed variation. And men and current smokers had a decreased efflux capacity.

After adjusting for age, sex and cardiovascular risk factors, the authors found an increased efflux capacity associated with a decreased risk of CAD. The researchers divided patients into quartiles according to efflux capacity and found evidence of an inverse association between the efflux capacity and CAD.

Lastly, the researchers found that treating patients with pioglitazone (Actos, Takeda Pharmaceuticals) for 12 weeks increased efflux capacity, particularly compared with the baseline value and with the change viewed within the placebo group. However, the authors noted no change when patients were treated with statins for 16 weeks.

“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,” the authors wrote.

The researchers noted that the findings are important in regard to the assessment of new therapies that target HDL metabolism and reverse cholesterol transport.

“In conclusion, cholesterol efflux capacity, a key metric of HDL function, is not explained simply by circulating levels of HDL cholesterol or apolipoprotein A-I and is independently related to both the presence and the extent of atherosclerosis,” the researchers concluded. “These findings reinforce the concept that assessment of HDL function may prove informative in refining our understanding of HDL-mediated atheroprotection.”