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Cholesterol efflux capacity inversely associated with CV events

Issue: December 2014

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CHICAGO — Cholesterol efflux capacity, a biomarker of reverse cholesterol transport, was inversely associated with CV events in participants of the Dallas Heart Study.

Previous research demonstrated no clinical benefit to increasing HDL levels. Anand Rohatgi, MD, from the division of cardiology at the University of Texas Southwestern Medical Center, Dallas, and colleagues investigated whether higher HDL efflux capacity might confer better clinical outcomes.

Anand Rohatgi*

“A key function of HDL that is not readily reflected by HDL levels is the ability to promote reverse cholesterol transport from the periphery to the liver and out the body,” Rohatgi said at the American Heart Association Scientific Sessions. “Cholesterol efflux from the macrophage to HDL is the key initial step in reverse cholesterol transport and has been directly and causally linked to the prevention of atherosclerosis in animal models. Recent strategies to measure efflux capacity in humans have been employed, revealing inverse associations between efflux capacity and prevalent coronary disease independent of HDL levels.”

The researchers assessed whether efflux capacity was associated with incident CV events in a cohort from the Dallas Heart Study free of CVD at baseline (n=2,924; median age, 42 years; 57% women; 49% black). Participants had their lipids measured at baseline, including measurement of cholesterol efflux by a BODIPY-cholesterol assay.

The primary endpoint was a composite of nonfatal MI, nonfatal stroke, PCI or CABG and CV death. A secondary endpoint was total CVD, defined as the primary endpoint events plus peripheral revascularization and hospitalization for HF or atrial fibrillation. Median follow-up was 9.4 years.

Rohatgi and colleagues observed 132 primary atherosclerotic CVD events during the study period in the 2,416 participants with complete follow-up data. In an adjusted analysis, baseline HDL level was not associated with CV events (HR=1.08; 95% CI, 0.59-1.99).

However, in a model adjusted for traditional risk factors, HDL level and HDL particle concentration, those in the highest quartile of cholesterol efflux capacity had reduced risk for the primary outcome compared with those in the lowest quartile (HR=0.33; 95% CI, 0.19-0.55).

The results were similar for total CVD (HR=0.42; 95% CI, 0.27-0.65) and hard atherosclerotic CVD events (HR=0.4; 95% CI, 0.21-0.74).

The addition of cholesterol efflux capacity to traditional risk factors improved all risk-prediction indexes for the primary endpoint, including C-statistic (from 0.827 to 0.841; P=.02), integrated-discrimination-improvement index (0.02; P<.0001) and net reclassification index (0.37; 95% CI, 0.18-0.56), according to the researchers.

The cholesterol efflux assay “may facilitate interrogation of key mechanisms linked to [CVD] in humans,” Rohatgi said. “Our findings suggest that the HDL-cholesterol hypothesis should instead be focused on the HDL-function hypothesis. We now have the ability to measure cholesterol efflux and HDL function in an efficient, high-throughput manner. Further studies are warranted to measure the clinical relevance of HDL function with regard to risk prediction across the spectrum of atherosclerotic disease.”

In an invited commentary at the presentation, Daniel J. Rader, MD, director of the preventive cardiovascular program at University of Pennsylvania, said, “I think it’s basically time [for the HDL-cholesterol hypothesis] to be retired.” – by Erik Swain

For more information:

Rohatgi A and Rader DJ. CS.04: Trials and Cardiovascular Registries. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Rohatgi A. N Engl J Med. 2014;doi:10.1056/NEJMoa1409065.

Disclosure: The study was supported by grants from the Donald W. Reynolds Foundation, the NIH, the NHLBI, the AHA and Merck Sharpe & Dohme. Rohatgi reports receiving a research grant from Merck and speaking for AstraZeneca. Rader reports no relevant financial disclosures.