High levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) were an independent risk factor for non-vascular mortality as well as for cardiovascular death, stroke, and coronary heart disease in a large meta-analysis.
For each standard deviation above the mean for Lp-PLA2 among nearly 80,000 participants in 32 prospective studies, the risk of non-vascular death increased by 10% after adjusting for conventional risk factors, reported Alexander Thompson, of the University of Cambridge in England, and 14 other members of the Lp-PLA2 Studies Collaboration in the May 1 Lancet.
Similar risks associated with the inflammatory enzyme were seen for vascular mortality, coronary heart disease (nonfatal MI plus any cardiac death), and ischemic stroke, and were about the same whether Lp-PLA2 activity or mass was considered, the researchers found.
For coronary heart disease, the association's magnitude was similar to those seen with non-HDL cholesterol and systolic blood pressure.
Thompson and colleagues noted that Lp-PLA2 mass and activity aren't "materially correlated" with other circulating inflammatory markers such as fibrinogen and C-reactive protein.
As a result, they wrote, "Lp-PLA2 measurements could have the potential to provide distinct insight into the relation between inflammation and atherothrombosis."
Previous studies have linked Lp-PLA2 with cardiovascular events, particularly stroke. (See Inflammatory Biomarkers Improve Stroke Risk Prediction and Inflammatory Markers Refine Prognosis After Stroke)
The enzyme is produced by inflammatory cells within atherosclerotic plaques and appears in circulation bound to LDL-cholesterol. Its catalytic activity cleaves pro-inflammatory molecules from oxidized lipids, with such products implicated in several aspects of vascular disease, Thompson and colleagues explained.
The Lp-PLA2 Studies Collaboration comprises investigators from more than two dozen large trials, including ARIC, EPIC-Norfolk, PROVEIT-TIMI 22, PROSPER, and WOSCOPS. They pooled the patient-level data from 32 prospective trials in which Lp-PLA2 mass or activity was measured. A total of 79,036 patients were included in the analysis.
About 13% of the patients had suffered an acute ischemic event within 30 days of study entry. The remainder were divided evenly between those with no history of vascular disease at baseline and those considered to have stable vascular disease.
Thompson and colleagues reported the following relative risks associated with each standard deviation in Lp-PLA2 activity and mass measured in the study participants, after adjusting for smoking status, sex, age, baseline diabetes, and other standard risk factors:
- Coronary heart disease: activity, 1.10 (95% CI 1.05 to 1.16); mass, 1.11 (95% CO 1.07 to 1.17)
- Ischemic stroke: activity, 1.08 (95% CI 0.97 to 1.20); mass, 1.14 (95% CI 1.02 to 1.27)
- Vascular mortality: activity, 1.16 (95% CI 1.09 to 1.24); mass, 1.13 (95% CI 1.05 to 1.22)
- Non-vascular mortality: activity, 1.10 (95% CI 1.04 to 1.17); mass, 1.10 (95% CI 1.03 to 1.18)
Most of these risks did not differ in patients with stable vascular disease at baseline versus those without it.
For comparison, each standard deviation in non-HDL cholesterol carried a relative risk for coronary heart disease of 1.10 (95% CI 1.02 to 1.18). The relative risk associated with each standard deviation increase in systolic blood pressure was also 1.10 (95% CI 1.00 to 1.21).
Thompson and colleagues noted that the association between Lp-PLA2 levels and coronary heart disease was greater before adjusting for lipid parameters, with relative risks of 1.15 to 1.16. Lp-PLA2 was also a stronger predictor of disease in patients with relatively low levels of apoliprotein B.
"Since Lp-PLA2 is physically linked (through apolipoprotein B) with LDL, however, the validity of statistical attempts to distinguish the effects of Lp-PLA2 on risk of coronary heart disease from those of proatherogenic lipids remains uncertain," they wrote.
They added that the adjusted risks for coronary heart disease may not be entirely accurate because of possible residual confounding from measurement errors in lipid levels and lack of complete data on medications patients may have been taking.
Other limitations included "sparse and apparently divergent" serial measurements of Lp-PLA2 in the included studies and potential errors and omissions in records of non-vascular deaths.
A major open question is whether Lp-PLA2 is a modifiable risk factor, the researchers also suggested.
"Randomized trials of potent reversible pharmacological inhibitors of Lp-PLA2 activity should help to establish whether modification of Lp-PLA2 can reverse vascular risk," they wrote.
In an accompanying editorial, Robert S. Rosenson, MD, of Mount Sinai School of Medicine in New York City, commented that Lp-PLA2's value as a clinical biomarker of risk remains uncertain, even after this study.
"The predictive value [for coronary heart disease] is weaker with higher apoliprotein B concentrations," he wrote. "Future studies that evaluate the cardiovascular risks associated with Lp-PLA2 activity and/or mass should at least adjust for apolipoprotein B concentrations, and -- more relevant to the Lp-PLA2–LDL interaction -- small LDL-particle concentration."
Rosenson added that better data are available indicating that Lp-PLA2 and its sibling, secretory phospholipase A2, play a causal role in atherosclerosis and therefore are promising therapeutic targets.
The meta-analysis was funded by the UK Medical Research Council, GlaxoSmithKline, and the British Heart Foundation.
Thompson and colleagues reported relationships with a large number of commercial entities, including GlaxoSmithKline, Bristol-Myers Squibb, sanofi-aventis, Intekrin, Novartis, Takeda, AstraZeneca, Merck, Automedics Medical Systems, Roche, Solvay, and others.
Rosenson reported relationships with Anthera Pharmaceuticals and LipoScience.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
The LancetSource Reference: Lp-PLA2 Studies Collaboration, "Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies" Lancet 2010; 375: 1536-44.
The LancetSource Reference: Rosenson R, "Lp-PLA2 and risk of atherosclerotic vascular disease" Lancet 2010; 375: 1498-1500.