U. ROCHESTER (US)—HDL cholesterol, long thought of as “good” cholesterol actually places certain patients at high risk for recurrent coronary events, including chest pain, heart attack, and death.

“It seems counterintuitive that increasing good cholesterol, which we’ve always thought of as protective, leads to negative consequences in some people,” says James Corsetti, professor of pathology and laboratory medicine at the University of Rochester.

“We’ve confirmed that high HDL cholesterol is in fact associated with risk in a certain group of patients.”

The findings, published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, could help explain disappointing results from a high-profile clinical trial testing an experimental drug designed to increase levels of HDL cholesterol, that some predicted would become a blockbuster medicine.

The trial was halted in 2006 due to a surprisingly excessive number of cardiovascular events and death. As in the current study, cardiovascular events in the earlier trial were associated with higher levels of “good” HDL cholesterol, though the reasons were unclear.

Using a graphical data mapping tool, Corsetti identified a group of patients in which elevated levels of HDL cholesterol place them in a high-risk category for coronary events.

“The ability to identify patients who will not benefit from efforts to increase HDL cholesterol is important because they can be excluded from trials testing medications that aim to raise HDL cholesterol,” explains Charles Sparks, professor of pathology and laboratory medicine and coauthor of the study.

“With these patients excluded, researchers may find that raising HDL cholesterol in the remaining population is effective in reducing cardiovascular disease risk.”

Patients in the high-risk subgroup were characterized as having high levels of C-reactive protein (CRP), a well-known marker of inflammation, in addition to high HDL cholesterol.

Genetics and environmental factors, particularly inflammation, influence whether high levels of HDL cholesterol are protective or if they increase cardiovascular risk in individual patients.

Given an inflammatory environment, an individual’s unique set of genes helps determine whether HDL cholesterol transforms from a good actor to a bad actor in the heart disease process.

In the high-risk subgroup of patients with elevated HDL cholesterol and CRP, researchers also identified two genetic factors associated with recurrent coronary events.

The activity of cholesterol ester transfer protein, which moves cholesterol away from the vascular system and is associated with HDL cholesterol, and p22phox, which influences inflammation-related processes and is associated with CRP, are both risk predictors in this subgroup of patients.

“Our research is oriented around the ability to better identify patients at high risk,” says Corsetti. “Identifying these patients and determining what puts them at high risk may be useful in choosing treatments tailored to the specific needs of particular patient subgroups. This gets us another step closer to achieving the goal of personalized medicine.”

Corsetti’s team identified individuals at high risk for recurrent coronary events among 767 non-diabetic patients who experienced at least one prior heart attack. About 20 percent of the total study population was in the subgroup having high-risk with high HDL cholesterol and CRP.

Outcome event maps plot risk over an area defined by high and low levels of two biomarkers, in this case HDL cholesterol and CRP. Peaks and valleys in the maps correspond to high- and low-risk patient subgroups.

Patients were followed for recurrent events for approximately two years and were part of the Thrombogenic Factors and Recurrent Coronary Events study led by cardiologist Arthur Moss, professor of medicine and study coauthor.

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