Elevated Lp-PLA2 Levels Predict Incident CHD Independent of Traditional Risk Factors

Michael O'Riordan

February 27, 2008

February 27, 2008 (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."

Over and above traditional risk factors

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.

Hazard ratios for incident CHD by Lp-PLA2 quartilesa
Model 2nd quartile (409.9–488.4 ng/mL) 3rd quartile (488.5–625.2 ng/mL) 4th quartile (>625.2 ng/mL)
Model 1b 1.66 (1.09–2.54) 1.80 (1.19–2.72) 1.89 (1.26–2.86)
Model 2 1.54 (1.01–2.37) 1.71 (1.12–2.61) 1.61 (1.03–2.51)
a. Lowest quartile (<409.9 ng/mL) is the reference
b. Model 1 adjusted for age and gender; model 2 adjusted for age, gender, fasting plasma glucose, systolic blood pressure, hypertension, diabetes, LDL, HDL, and 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.

  1. Daniels LB, Laughlin GA, Sarno MJ, healthy older population. J Am Coll Cardiol 2008; 51:913-919.

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