Elsevier

Atherosclerosis

Volume 182, Issue 1, September 2005, Pages 193-198
Atherosclerosis

Rapid communication
The effect of statin therapy on lipoprotein associated phospholipase A2 levels

https://doi.org/10.1016/j.atherosclerosis.2005.05.006Get rights and content

Abstract

Lipoprotein associated phospholipase A2 (Lp-PLA2), a biomarker of oxidation and inflammation, has been associated with increased coronary heart disease (CHD) risk. To date, data examining the effect of HMG CoA reductase inhibitors on Lp-PLA2 are few. We evaluated the effect of pravastatin 40 mg daily versus placebo on Lp-PLA2 levels among 481 subjects free of cardiovascular disease (pravastatin N = 246 and placebo N = 235) who participated in the Pravastatin Inflammation/CRP Study (PRINCE). After 12 weeks, Lp-PLA2 levels decreased by 22.1% among pravastatin treated participants and by 7.8% among those randomized to placebo (p < 0.001). These results were similar in all subgroups evaluated according to age, blood pressure, lipid parameters, diabetic status, smoking status, aspirin use, body mass index and gender. There were correlations between change in Lp-PLA2 levels and baseline Lp-PLA2 levels (r = −0.63, p < 0.001), total cholesterol change (r = −0.26, p < 0.001), LDL-C change (r = −0.32, p < 0.001) and C-reactive protein (CRP) change (r = −0.13, p = 0.05). Multivariate linear regression models that assessed the relationship between the log difference in Lp-PLA2 at 12 weeks and treatment revealed a beta-coefficient of 0.15 for the treatment variable (p < 0.01). However, adjustment for change in LDL-C substantially attenuated the beta-coefficient associated with treatment to 0.07 (P < 0.005) and after additional control for other potential confounders, the effect of treatment was no longer significant. Thus, Lp-PLA2 levels were significantly reduced at 12 weeks by pravastatin, an effect that was significantly related to LDL cholesterol reduction accounting for about 6% of the variability in this response. Moreover, pravastatin induced reduction in Lp-PLA2 was no longer significant after taking the latter into account.

Introduction

Lp-PLA2 is a calcium independent member (distinguished from secretory PLA2, a calcium dependent enzyme) of the phospholipase A2 enzyme family that is believed to play a role in the development of atherosclerosis. Also known as platelet activating factor acetylhyrolase, Lp-PLA2 is principally produced by hematopoietic cells including macrophages, monocytes and mast cells [1], [2]. Mechanistically, Lp-PLA2 hydrolyzes oxidatively altered phospholipids that have shortened sn2 fatty acids to produce oxidized fatty acids and lysophosphatidylcholine, a function that deems Lp-PLA2 a pro-atherogenic agent. Additionally, through its role in hydrolyzing and thus inactivating platelet activating factor, Lp-PLA2 also has an anti-inflammatory function [2], [3]. In plasma, most Lp-PLA2 is bound to pro-atherogenic small, dense, LDL particles while a small fraction is associated with high-density lipoprotein cholesterol (HDL-C).

At the population level, the association between risk of cardiovascular disease (CVD) and Lp-PLA2 remains the subject of ongoing evaluation. Both the West of Scotland Coronary Prevention (WOSCOPS) and the Atherosclerosis Risk in Communities (ARIC) studies suggest a relationship between elevated levels of Lp-PLA2 and increased risk of CVD [4], [5]. Also, a study by Koenig et al. indicated that elevated levels of Lp-PLA2 were associated with increased risk of coronary events [6]. By contrast, data from the Women's Health Study found little evidence of independent association between CVD and Lp-PLA2 levels [7], and in a Japanese study, deficiency of plasma Lp-PLA2 due to a point mutation in G994  T in the Lp-PLA2 gene resulted in decreased enzyme activity and a reported increase in risk of vascular disease [8].

Since Lp-PLA2 is primarily bound to LDL-C and probably influences the development of foam cells and other oxidatively charged molecules involved in atherosclerosis, it is of potential clinical importance to understand the effect of statin therapy on Lp-PLA2 levels. We, therefore, examined the role of statin treatment in reducing Lp-PLA2 levels among 481 individuals treated for 12 weeks with pravastatin.

Section snippets

Methods

The study population was derived from participants in the Pravastatin/CRP Evaluation (PRINCE) trial, a multicenter, community-based trial that examined the effect of pravastatin 40 mg daily on CRP levels among individuals with and without cardiovascular disease (history of myocardial infarction, stroke or coronary revascularization) [9]. Individuals with a history of a chronic inflammatory condition, need for anti-inflammatory therapy, use of statin therapy within 6 months prior to enrollment or

Results

Baseline clinical characteristics of the 481 study participants are shown in Table 1. With the exception of current smokers and diastolic blood pressure, no significant differences were observed at baseline between the pravastatin and placebo groups. Current smoking was somewhat more prevalent in the placebo group while those in the pravastatin group had higher diastolic blood pressure. There were no significant differences in baseline median Lp-PLA2 levels between the pravastatin treated (282.8

Discussion

In this randomized, placebo controlled study, we found that pravastatin resulted in a significant reduction in median Lp-PLA2 levels compared to placebo among individuals who were free of cardiovascular disease. This finding was consistent among all subgroups evaluated. As also shown in these data, much of this effect is mediated through statin effect on LDL-C. Our data adds to the emerging literature on Lp-PLA2 by demonstrating the noted effects of statin therapy in a sizable randomized

Acknowledgements

Dr. Albert is supported by an award from the Robert Wood Johnson Foundation. Both Drs. Albert and Ridker are supported by a grant from the Donald W. Reynolds Foundation.

The PRINCE trial was investigator initiated, coordinated and performed centrally within the Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, and was run with full independence. The research group wrote all the protocols and manuals, holds all the primary data forms, and

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    Statins have been shown to reduce the level of Lp-PLA2 activity. Data from the Pravastatin OR atorVastatin Evaluation and Infection Therapy study showed that treatment with atorvastatin 80 mg/d correlated with a 20% reduction in Lp-PLA2 activity at 30 days, whereas Lp-PLA2 increased by 3.6% with 40 mg/d pravastatin [35,36]. The Heart Protection Study (HPS) also showed that simvastatin reduced Lp-PLA2 activity by 25%, but the effects of simvastatin on vascular outcomes did not vary according to Lp-PLA2 levels.

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