Lipoprotein-Associated Phospholipase A2 Activity Predicts Cardiovascular Events in High Risk Coronary Artery Disease Patients

Giuseppe Maiolino,Mario Zanchetta,Robert L Wolfert,Gian Paolo Rossi,Leopoldo Pagliani,Luigi Pedon,Maurizio Cesari,Teresa Maria Seccia,Anna Chiara Frigo,Marlena Barisa,Giacomo Rossitto,Gerard Pasterkamp

doi:10.1371/journal.pone.0048171

Abstract

ObjectiveLipoprotein-associated phospholipase A2 (Lp-PLA2) is deemed to play a role in atherosclerosis and plaque destabilization as demonstrated in animal models and in prospective clinical studies. However, most of the literature is either focused on high-risk, apparently healthy patients, or is based on cross sectional studies. Therefore, we tested the hypothesis that serum Lp-PLA2 mass and activity are useful for predicting cardiovascular (CV) events over the coronary atherosclerotic burden and conventional risk factors in high-risk coronary artery disease patients.Methods and ResultsIn a prospective cohort study of 712 Caucasian patients, who underwent coronary angiography and measurement of both Lp-PLA2 mass and activity at baseline, we determined incident CV events at follow-up after splitting the patients into a high and a low Lp-PLA2 mass and activity groups based on ROC analysis and Youden index. Kaplan-Meier and propensity score matching analysis were used to compare CV event-free survival between groups. Follow-up data were obtained in 75% of the cohort after a median of 7.2 years (range 1–12.7 years) during which 129 (25.5%) CV events were observed. The high Lp-PLA2 activity patients showed worse CV event-free survival (66.7% vs. 79.5%, p = 0.023) and acute coronary syndrome-free survival (75.4% vs. 85.6%, p = 0.04) than those in low Lp-PLA2 group.ConclusionsA high Lp-PLA2 activity implies a worse CV prognosis at long term follow up in high-risk Caucasian patients referred for coronary angiography.

Highlights

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a Ca2+independent protein produced by monocytes/macrophages [1], which acts by hydrolyzing the sn-2 acyl chain of the phospholipid substrate [2]
A high Lp-PLA2 activity implies a worse CV prognosis at long term follow up in high-risk Caucasian patients referred for coronary angiography
Clinical Characteristics According to the ATP III NCEP criteria 96% of the patients enrolled in the GENICA Study were considered to be at high CV risk, e.g. to have a 20% risk of major CV events at 10 years [41]

Summary

Introduction

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a Ca2+independent protein produced by monocytes/macrophages [1], which acts by hydrolyzing the sn-2 acyl chain of the phospholipid substrate [2]. The pro-atherogenic mechanism of Lp-PLA2 could be related to the hydrolysis of oxidized phospholipids on the LDL surface [7], forming oxidized fatty acids and lysophosphatidylcholine, two important triggers of the inflammation cascade [7,8,9]. These substances stimulate the expression of adhesion molecules and cytokines by endothelial cells, macrophages, and leukocytes; they down-regulate the endothelial nitric oxide, enhance the production of reactive oxygen species and oxidative stress, and induce endothelial cell apoptosis [10,11,12]. It is conceivable that raised Lp-PLA2 activity could predict cardiovascular (CV) events

Methods

Results

Discussion

Conclusion