San Diego, CA - Elevated levels of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), an enzyme involved in the proatherogenic process, are associated with coronary heart disease (CHD) events independent of traditional risk factors, according to the results of a new study [1]. Despite strong associations between Lp-PLA₂ and traditional risk factors, including LDL, HDL, and total cholesterol, as well as triglycerides, Lp-PLA₂ was a "strong and independent predictor of fatal and nonfatal CHD events over and above other traditional risk factors," say investigators.

With these findings, published in the February 25, 2008 issue of the Journal of the American College of Cardiology, investigators, led by Dr Lori Daniels (University of California, San Diego), write that by adding information to lipid and lipoprotein prediction for future events, Lp-PLA₂ "may identify subpopulations at risk for CHD who would not be identified otherwise."

Lp-PLA₂ is a novel enzyme that is believed to be involved in the formation of vulnerable, rupture-prone plaque and circulates in the blood attached to LDL cholesterol. It is found alongside and is highly expressed by macrophages within the necrotic core and the fibrous cap of these advanced plaques, say investigators, and Lp-PLA₂'s primary enzymatic role is to hydrolyze oxidized phospholipids, which yield proinflammatory and proatherogenic products.

In this analysis, investigators sought to study the association between Lp-PLA₂ and CHD in apparently healthy older men, a population where Lp-PLA₂ might not contribute anything to risk prediction on account of age already being a strong predictor of risk. Included in the analysis were 1077 men and women, mean age 72 years, who had no known CHD at baseline and who were followed for an average of 16 years.

In terms of associations with other risk factors, Lp-PLA₂ levels positively correlated with total cholesterol, LDL cholesterol, and triglycerides and negatively correlated with HDL cholesterol. Weaker but still significant correlations between Lp-PLA₂ and systolic blood pressure, CRP, and body-mass index were also observed. After adjustment for age and gender only, elevated Lp-PLA₂ levels were significantly associated with risk of incident CHD, an association that held after adjustment for various other risk factors, including LDL and HDL cholesterol, as well as triglycerides.

When the analysis was limited to those who had CRP levels measured at baseline, the adjustment for CRP levels had minimal effect on the relationship between Lp-PLA₂ and the incidence of CHD. Among 815 subjects with measured CRP levels, the association between incident CHD and Lp-PLA₂ was significant for those with Lp-PLA₂ levels >488.5 ng/mL (those in the third and fourth quartiles).

"The addition of CRP to the fully adjusted model did not diminish the predictive capability of Lp-PLA₂, evidence that the two markers are not codependent," write Daniels and colleagues.

Previous epidemiologic studies—including the West of Scotland Coronary Prevention Study (WOSCOPS) and the Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA)—have also shown that higher levels of Lp-PLA₂ levels were associated with an increased risk of coronary disease, even after adjustment for traditional risk factors and C-reactive protein (CRP) levels. While the Atherosclerosis Risk in Communities (ARIC) study reported a similar positive association between Lp-PLA₂ and events, an analysis in the Women's Health Study found no association after adjustment for other risk factors, a finding that suggested that maybe the enzyme is not predictive of CHD in women.

In 2003, the Food and Drug Administration granted market clearance to an Lp-PLA₂ test for coronary heart disease (diaDexus Inc). Also, GlaxoSmithKline is currently conducting studies with various Lp-PLA₂ inhibitors.