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HDL cholesterol efflux capacity better lab test than HDL level

Posted Feb 05 2011 12:00am

The discovery that high levels of high-density lipoprotein HDL cholesterol (the “good cholesterol”) are associated with reduced cardiovascular risk has fostered intensive research to modify HDL levels for therapeutic gain. However, recent findings have called into question the notion that pharmacologic increases in HDL cholesterol levels are necessarily beneficial to patients.

Now, a study from researchers at the University of Pennsylvania School of Medicine shows that a different metric, a measure of HDL function called cholesterol efflux capacity, is more closely associated with protection against heart disease than HDL cholesterol levels themselves. Findings from the study could lead to improved understanding of the mechanism behind new therapeutic interventions in the fight against heart disease. The research was published in the January 13, 2011 issue of The New England Journal of Medicine.

Atherosclerosis, a major risk factor of heart disease, occurs with a buildup of fatty materials such as cholesterol along the artery wall. Cholesterol efflux capacity, one measure of HDL function, is a direct measure of the efficiency by which a person’s HDL removes cholesterol from cholesterol-loaded macrophages (a type of white blood cell), the sort that accumulate in arterial plaque. According to the new research, increasing efflux capacity decreased the atherosclerotic plaque development, hence decreasing the likelihood of having coronary artery disease.

“Ever since Torcetrapib failed to show protection against cardiovascular disease, several interesting hypotheses have been proposed as to why increased HDL-C levels do not protect against heart disease,” says Amar Sethi, MD, PhD, Vice President of Research and Development at Pacific Biomarkers, Inc. (PBI), a provider of biomarker laboratory services to the pharmaceutical, biotechnology and diagnostics industries. “Beside the obvious factors related to off-target effects of the drug, many scientists were attracted to the theory of HDL being dysfunctional and hence not cardioprotective, but on the contrary pro-inflammatory or dysfunctional. Following Torcetrapib, evidence has accumulated that HDL-C alone is not a satisfactory biomarker to predict cardiovascular disease.”

HDL, as Dr. Sethi notes, has multiple antiatherogenic functions: Besides removal of excess cholesterol through the reverse cholesterol transport, it is involved in inflammation, lipid oxidation, coagulation and endothelial activation.

“The Penn study examined one of these functions, namely the removal of excess cholesterol from the very atherogenic macrophages named foam cells,” Dr. Sethi says. “This was assessed by an in vitro method examining the HDL particle’s ability to accept cholesterol through the ABCAI transporters located in macrophages. This method has been published widely and is currently accepted as the best-understood biomarker for HDL function, although HDL functionality is much broader than cholesterol efflux.

“This paper is the first one to show that it is worthwhile assessing HDL function. The cholesterol efflux capacity was inversely related to carotid intima media thickness, independent of the HDL-C levels. Although evidence has accumulated over the past years in favor of assessing HDL function we did not, before now, have any clinical evidence that a biomarker for assessing HDL function could predict cardiovascular disease independent of the HDL-C levels.”

The study abstract notes that additional studies showed that pioglitazone improved efflux capacity in patients with metabolic syndrome and low HDL levels, but statins did not improve efflux in patients with hypercholesterolemia.

According to Dr. Sethi, the University of Pennsylvania study will spark further research into the usability of HDL function biomarkers aside from the cholesterol efflux method reported. He sees a clear need for new methods to assess as many of the HDL functions as possible, as future HDL therapeutics will modify HDL function differently. Sethi also notes that PBI is currently evaluating several HDL function assays, including the cholesterol efflux method for potential future inclusion into clinical trials (Newswise).

The abstract of the article is available free online here:

Reference: Amit V. Khera, M.D., et al. N Engl J Med 2011; 364:127-135. January 13, 2011.

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