Cholesterol-overloaded HDL particles help predict atherosclerosis risk

By Anne Harding

Adults with a higher ratio of high-density lipoprotein (HDL) cholesterol to HDL particles (HDL-P) -- indicating that these particles are more heavily loaded with cholesterol -- are at greater risk of progression of carotid atherosclerosis, new research shows.

"Cholesterol-overloaded HDL-P may be a strong predictor of carotid atherosclerosis risk, implying that in cases of high levels of cholesterol-overloaded HDL-P, an individual may be more prone to atherosclerosis risk despite high HDL-C levels," Dr. Yue Qi and colleagues from the Beijing Institute of Heart, Lung and Blood Vessel Diseases in China write in their report, published in the February issue of the Journal of the American College of Cardiology.

Observational studies have linked higher HDL-C levels to lower risk of atherosclerosis, Dr. Qi and colleagues note, but trials of drugs that raise HDL-C have not found protective effects. Evidence from experimental research, they add, suggests that when HDL-P are overloaded, they are less able to help clear excess cholesterol from the body.

To investigate whether something similar occurs in humans, the researchers used nuclear magnetic resonance (NMR) spectroscopy to measure baseline HDL-P number in 930 patients who ranged in age from 45 to 74. They calculated the number of molecules of cholesterol per HDL particle as the ratio of HDL-C to HDL-P.

The average HDL-C/P ratio was 46.4, and ranged from 23.8 to 86.9. Study participants with the highest HDL-C/P ratio (53 or above) had 1.56 times greater progression of carotid atherosclerosis over the next five years compared to those with the lowest HDL-C/P ratio (below 41).

When the researchers re-evaluated study participants who were plaque-free at baseline five years later, they found total plaque area was 9.4 mm2 larger in the patients with the highest versus the lowest HDL-C/P ratio.

At any level of HDL-C, the researchers found, the risk of atherosclerotic progression increased as the number of HDL-P decreased.

"The field is very confused at this point in time," Dr. Alan Remaley of the National Institutes of Health in Bethesda, Maryland, who wrote an editorial accompanying the study, told Reuters Health in a telephone interview. "In the last few years, people have realized that HDL is a transport vehicle for many different things."

Dr. Remaley said he is convinced that the HDL particle number is a better predictor of cardiovascular disease risk than HDL-C. "It will take more papers and more investigations and people to confirm this, but if it's true then this could be an alternative measure of HDL cholesterol, and that would help the field in many ways. About half the people who have heart attacks, based on our current lipoprotein tests, don't seem to be at risk."

The NMR test for HDL-P used in the study, developed by LipoScience (Raleigh, North Carolina), has not been cleared by the U.S. Food and Drug Administration, Dr. Remaley notes in his commentary, although several large studies suggest that HDL-P is a better negative cardiovascular disease risk marker than HDL-C. Dr. Remaley has a Cooperative Research and Development Agreement research grant from LipoScience.

Future investigations will need to address whether the HDL-C/HDL-P ratio has independent predictive value in addition to currently used biomarkers for cardiovascular disease, "particularly for those subjects at intermediate CVD risk, a population on which the test is most likely to be first used," he writes.

Also, Dr. Remaley added, it will be important to determine whether HDL-C/HDL-P ratio can predict the likelihood of clinical events, such as myocardial infarction and stroke.

"It's bad news to have very high HDL cholesterol in the setting of low HDL particle number," Dr. Jim Otvos of LipoScience, who developed the NMR method for quantifying lipoproteins used in the study, told Reuters Health. He noted that the current findings replicate those of the MESA (Multi-Ethnic Study of Atherosclerosis), published in 2012.

"The main takeaway for clinicians at this stage is less about what's the best information to use for getting a handle on the HDL-related cardiovascular risk of patients, and more that they shouldn't be too invested in HDL cholesterol," Dr. Otvos added in a telephone interview. "It's really looking like the more cholesterol-poor, smaller particles are more functionally relevant for lots of activities of HDL."

SOURCE: http://bit.ly/1A7eWRd

J Am Coll Cardiol 2015;65:355-363.

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