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Medical News: HDL Function Tied to Cardio Risk - Printable Version


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HDL Function Tied to Cardio Risk
By Todd Neale, Staff Writer, MedPage Today
January 13, 2011

MedPage Today Action Points

Note that this study identified an important relationship between cholesterol

efflux capacity and the presence of coronary heart disease.

Recognize that the atheroprotective effect of serum HDL to promote cholesterol

efflux from macrophages was not simply a function of HDL cholesterol levels
but rather reflects a functional capacity of normal HDL. Thus, dysfunctional
HDL would not be protective, even with elevated levels.

A measure of the ability of HDL to remove cholesterol from macrophages predicted
the likelihood that an individual undergoing cardiac catheterization had coronary
artery disease, a cross-sectional study showed.

As cholesterol efflux capacity increased, the odds of coronary disease dropped, an

effect independent of HDL cholesterol (P=0.002), according to Daniel Rader, MD, of
the University of Pennsylvania in Philadelphia, and colleagues.

Compared with patients with the lowest efflux capacity, those with the highest had a
52% reduced likelihood of having coronary disease after adjustment for
cardiovascular risk factors and HDL cholesterol level (OR 0.48, 95% CI 0.30 to 0.78),
the researchers reported in the Jan. 13 issue of the New England Journal of

Also, in a group of healthy volunteers, cholesterol efflux capacity was inversely

associated with carotid intima-media thickness, even after adjustment for HDL
cholesterol and apolipoprotein A-I levels (P<0.05).

"Our demonstration that cholesterol efflux capacity is associated with atherosclerosis

in humans helps support the use of this measure in guiding the development of new
HDL-targeted therapies for humans," Rader and his colleagues wrote.

In an accompanying editorial, Jay Heinecke, MD, of the University of Washington in

Seattle, wrote, "These observations suggest that HDL efflux capacity is a measure of
HDL function that is relevant to the pathogenesis of atherosclerosis. These
observations also support the proposal that dysfunctional HDL contributes to the risk
of coronary disease."

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Medical News: HDL Function Tied to Cardio Risk - Printable Version

Although HDL cholesterol levels are inversely related to risk of coronary disease,
studies have questioned whether raising HDL cholesterol with drugs is beneficial.

The function of HDL cholesterol may be more important than its level, according to
the researchers. HDL cholesterol may provide cardioprotection by promoting reverse
cholesterol transport by accepting cholesterol from macrophages loaded with lipids,
thereby decreasing inflammation.

To assess the relationship of cholesterol efflux capacity with atherosclerosis, Rader

and his colleagues recruited 203 healthy volunteers to have carotid artery
intima-media thickness measured by ultrasound, and also recruited 793 patients who
were undergoing cardiac catheterization. Of the latter group, 442 had
angiographically confirmed coronary disease and 351 had no evidence of disease.

All of the participants gave blood, and the researchers used an assay to quantify
cholesterol efflux capacity.

There were significant correlations between cholesterol efflux capacity and levels of
both HDL cholesterol and apolipoprotein A-I in all participants (P<0.0001).

In the healthy volunteers, lower efflux capacity was associated with increased carotid
intima-media thickness both before and after adjustment for cardiovascular risk
factors, HDL cholesterol level, and apolipoprotein A-I.

Efflux capacity was also a strong inverse predictor of coronary artery disease, with an
odds ratio per standard-deviation increase in capacity of 0.70 (95% CI 0.59 to 0.83)
after adjustment for cardiovascular risk factors. Additional adjustment for HDL
cholesterol and apolipoprotein A-I did not substantially change the results.

The researchers also performed the assay on samples from 39 patients with
metabolic syndrome who participated in a placebo-controlled trial of pioglitazone
(Actos) and from 99 patients with hypercholesterolemia who participated in a
placebo-controlled trial of statin therapy.

Cholesterol efflux capacity was enhanced by pioglitazone but not by statin therapy,
which "is consistent with the concept that statins most likely exert therapeutic benefit
by means of a mechanism that is distinct from the promotion of cholesterol efflux,"
according to the researchers.

They acknowledged that their study was limited by the cross-sectional design.

"Another limitation is that although our assessment of cholesterol efflux capacity

reflects the ability to mobilize free cholesterol from macrophages, it does not capture
variation in the reverse-cholesterol-transport pathway in terms of cellular
components (i.e., the hydrolysis of cholesteryl esters and the status of endogenous
macrophage cholesterol transporters) or terminal components (i.e., uptake into the
liver and biliary excretion)," they wrote.

The study was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) and the National
Center for Research Resources, and by a Distinguished Clinical Scientist Award from the Doris Duke Charitable

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Medical News: HDL Function Tied to Cardio Risk - Printable Version

Foundation. Rader's co-authors reported support from a medical student research fellowship from the Howard
Hughes Medical Institute and a K23 award from the NHLBI.

Rader reported that his institution received a grant from the NIH. He also reported being a founder of
VascularStrategies, which provides services related to the development of new therapeutics for atherosclerotic
cardiovascular disease, including, but not limited to, assessment of reverse cholesterol transport, cholesterol
efflux, and HDL function.

Heinecke reported receiving grants from the NIH and Merck and serving as a consultant for Merck, Schering-
Plough, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, and Corcept. He has received payment for lectures from
Merck and owns stock or stock options in Insilicos. Heinecke and a colleague, along with the University of
Washington, hold a patent that relates to diagnostic tests for measuring the quantity of one or more HDL
oxidation products, which may be useful in evaluating the risk for developing cardiovascular disease. The
Cleveland Heart Labs has a licensing agreement with the University of Washington based on the patent.

Primary source: New England Journal of Medicine

Source reference:
Khera A, et al "Cholesterol efflux capacity, high-density lipoprotein function, and
atherosclerosis" N Engl J Med 2011; 364: 127-135.

Additional source: New England Journal of Medicine

Source reference:
Heinecke J "HDL and cardiovascular disease risk -- Time for a new approach?" N
Engl J Med 2011; 364: 170-171.

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