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Clinical Evidence Supporting the Role of Lp-PLA2 in Stroke Risk Assessment

by: Richard B. Lanman, MD

Lp-PLA2 (lipoprotein-associated phospholipase A2) is an enzyme transported primarily in LDL.1Lp-PLA2 hydrolyzes oxidized phospholipids, generating lysophosphatidylcholine, which up-regulates adhesion molecules and cytokine expression. Lp-PLA2 is secreted by cells of the monocyte-macrophage series, T-lymphocytes and mast cells.2-4

Clinical studies have shown that elevated Lp-PLA2 levels are associated with increased risk of CHD and stroke. The PLAC test is an enzyme immunoassay developed for the quantitative determination of Lp-PLA2 in human plasma, for use in conjunction with clinical evaluation and patient risk assessment in predicting risk for coronary heart disease, and ischemic stroke associated with atherosclerosis.

The Atherosclerosis Risk in Communities (ARIC) study was an NIH-sponsored case cohort study in four U.S. communities on 12,773 African-American and Caucasian men and women with an approximate six-year follow-up period. A total of 194 cases of ischemic stroke were examined from this study. The ARIC study examined the relationship between Lp-PLA2, traditional risk factors and ischemic stroke. As seen in a number of other epidemiological studies, LDL cholesterol was not considerably different between stroke and non-stroke individuals in the ARIC cohort, but Lp-PLA2 was significantly higher in stroke cases than non-stroke subjects.5Elevated Lp-PLA2 levels conferred approximately a twofold increase in stroke risk, independent of other risk factors. Further analyses showed that individuals with the highest levels of Lp-PLA2 and systolic blood pressure were at the greatest risk of suffering an ischemic stroke, conferring an over sixfold increase in stroke risk compared to those with low levels of both.

The Rotterdam Study also supports an association between Lp-PLA2 levels and both CHD and stroke after adjustment for other risk factors. The Rotterdam Study is an ongoing population-based observational study of 7,983 men and women (begun in 1990) representing 78% of the inhabitants age 55 and older of a suburb of Rotterdam. A total of 110 cases of ischemic stroke were examined. The study investigated whether Lp-PLA2 is an independent predictor of coronary heart disease and ischemic stroke. In the Rotterdam analysis, the association of Lp-PLA2 with ischemic stroke was statistically significant and independent of other cardiovascular risk factors. Participants with the highest Lp-PLA2 activity had a 77 percent greater risk of ischemic stroke compared with those with the lowest Lp-PLA2 activity, after adjusting for other cardiovascular risk factors.6The results from these studies support the rationale that Lp-PLA2 may be useful to identify patients at increased risk for stroke or CHD, including those who have 'normal' LDL-C (<130 mg/dL) and are not targeted for drug therapy by the current guidelines.

The PLAC test for Lp-PLA2 is the first blood test cleared by the FDA as an aid in predicting risk for ischemic stroke associated with atherosclerosis. The PLAC test provides physicians critical information to help determine the right treatment program to prevent patients from suffering an ischemic stroke. The PLAC test is currently available through clinical laboratories nationwide. For more information, please visit www.plactest.com or call 1-877-PLACTEST.

References

1. Caslake MJ, Packard CJ, Suckling KE, et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. Atherosclerosis 2000;150:413-9.

2. Stafforini DM, Elstad MR, McIntyre TM, Zimmerman GA, Prescott SM. Human macrophages secrete platelet-activating factor acetylhydrolase. J Biol Chem 1990;265:9682-7.

3. Asano K, Okamoto S, Fukunaga K, et al. Cellular source(s) of plateletactivating-factor acetylhydrolase activity in plasma. Biochem Biophys Res Commun 1999;261:511-4.

4. Macphee CH. Lipoprotein-associated phospholipase A2: a potential new risk factor for coronary artery disease and a therapeutic target. Curr Opin Pharmacol 2001;1:121-5

5. Ballantyne CM, Hoogeveen RC, Heejung B, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study. [Abstract 2979, Scientific Sessions of the American Heart Association, Nov 2004. New Orleans, La.] Circulation.

6. Oei HH, van der Meer IM, Hofman A, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. irculation. 2005;111:570-75.

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