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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1172.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A₂ and Low High-Density Lipoprotein-Cholesterol

The Veterans Affairs HDL Intervention Trial

Sander J. Robins; Dorothea Collins; Jeanenne J. Nelson; Hanna E. Bloomfield; Bela F. Asztalos

From the Department of Medicine (S.J.R.), Boston University School of Medicine, Boston, Mass; VA Medical Center Cooperative Studies Program Coordinating Center (D.C.), West Haven, Conn; Department of Worldwide Epidemiology (J.J.N.), GlaxoSmithKline, Research Triangle Park, NC; Center for Chronic Disease Outcomes Research (H.E.B.), VA Medical Center, Minneapolis, Minn; Lipid Metabolism Laboratory (B.F.A.), HNRCA at Tufts University School of Medicine, Boston, Mass.

Correspondence to Sander Robins, MD, Framingham Heart Study, 73 Mt Wayte Avenue, Framingham, MA 01702. E-mail sjrobins{at}bu.edu

Abstract

Objective— Lipoprotein-associated phospholipase A₂ (Lp-PLA₂), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA₂ would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C).

Methods and Results— Plasma Lp-PLA₂ activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA₂ there was a significant increase in LDL-C and decrease in HDL-C (P<0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA₂ was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA₂ only modestly (6.6%), at higher levels of Lp-PLA₂ gemfibrozil produced a significant reduction in CV events.

Conclusions— In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA₂ independently predicted CV events that were reduced by gemfibrozil.

The phospholipase, Lp-PLA₂ is known to be associated with LDL and an increase in cardiovascular events. We show in the VA-HIT population with both low HDL-C and low LDL-C that Lp-PLA2 was significantly increased, independently associated with increased cardiovascular events, and reduced by gemfibrozil therapy.

Key Words: cardiovascular events • lipoprotein-associated phospholipase A₂ • inflammation • high-density lipoproteins • gemfibrozil