Elsevier

Clinica Chimica Acta

Volume 465, February 2017, Pages 22-29
Clinica Chimica Acta

Review
Lipoprotein-associated phospholipase A2 in coronary heart disease: Review and meta-analysis

https://doi.org/10.1016/j.cca.2016.12.006Get rights and content

Highlights

  • Lp-PLA2 was not related to all-cause mortality in coronary heart disease (CHD).

  • Higher Lp-PLA2 was significantly associated with increased cardiovascular events risk in (CHD).

  • It was superior for Lp-PLA2 predicting cardiovascular events in patients with stable (CHD) or without receiving therapies of inhibiting Lp-PLA2.

  • Lp-PLA2 was a vascular-specific inflammatory biomarker to stratify the high-risk patients with (CHD).

Abstract

Background

Risk associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) and adverse outcomes in patients with coronary heart disease (CHD) remain unclear. The aim of the meta-analysis was to investigate the association between Lp-PLA2 and prognosis of CHD.

Methods

PubMed and Embase were examined for prospective studies published before June 2016. Multivariate-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of adverse outcomes according to Lp-PLA2 activity or mass were extracted, pooled, and weighted using generic inverse-variance and random-effect modeling.

Results

Fifteen studies with 30,857 participants were included. Overall, higher Lp-PLA2 activity or mass was not significantly related to increased risk of long-term all-cause mortality. However, higher Lp-PLA2 activity or mass was independently associated with an increased risk of long-term cardiovascular events, with pooled HR for cardiovascular events of 1.55 (95% CI, 1.08–2.23; P = 0.018) and 1.62 (95% CI, 1.09–2.41; P = 0.017), respectively. The prognostic value of Lp-PLA2 in predicting cardiovascular events was observed in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2.

Conclusions

Greater Lp-PLA2 activity or mass was independently associated with cardiovascular events in patients with CHD, particularly in patients with stable CHD who were not receiving therapies for inhibiting Lp-PLA2.

Introduction

Coronary heart disease (CHD) remains the leading cause of death and functional impairment worldwide. There is intense interest in stratifying high-risk patients with CHD for targeted therapy. The traditional factors that make up the Framingham Risk Score (age, sex, blood pressure, serum total cholesterol or low-density lipoprotein (LDL) cholesterol levels, high-density lipoprotein cholesterol levels, cigarette smoking, and diabetes) account for most of the excess risk for incident CHD [1]. However, these factors do not explain the entire excess risk, and approximately 40% of CHD deaths occur in individuals with cholesterol levels lower than the population average [2]. Therefore, such an obvious gap has fueled the search for additional novel tools to provide more accurate risk stratification. Biomarkers are good tools to estimate the systemic severity level of cardiovascular diseases. Inflammation and oxidative stress play an important role in the progression and destabilization of atherosclerosis, and they are involved in all stages of initial plaque formation, destabilization, and subsequent rupture [3], [4]. Several serum markers such as C-reactive protein (CRP), interleukin-6, matrix metalloproteinases, myeloperoxidase, and neutrophil-to-lymphocyte ratio have been identified as independent predictors of adverse clinical outcomes in CHD [5], [6]. However, a variety of inflammatory biomarkers are also involved in the atherothrombotic process, and many of these belong to different pathophysiological processes; thus, identifying a biomarker that is involved in several pathophysiological events underpinning CHD may further improve risk prediction.

Lipoprotein-associated phospholipase A2 (Lp-PLA2), a vascular-specific inflammatory biomarker, is a highly expressed enzyme by macrophages, T-lymphocytes, monocytes as well as mast cells in atherosclerotic lesions, particularly within the necrotic core and fibrotic cap of rupture-prone plaques [7], [8], [9]. Lp-PLA2 hydrolyzes oxidized phospholipids in plaques to yield pro-inflammatory and pro-atherogenic products that are implicated in endothelial dysfunction, plaque inflammation, and formation of necrotic core in plaques. Moreover, Lp-PLA2 is postulated to link oxidative modification of LDL and development of inflammatory responses in the arterial intima [9], [10], [11]. Therefore, Lp-PLA2 is involved in multiple stages of atherosclerosis and may be a good biomarker to predict clinical outcomes of patients with CHD independent of traditional (e.g. LDL-C, blood pressure, smoking) and emerging (e.g. CRP) risk factors.

A meta-analysis by the Lp-PLA2 Studies Collaboration showed that higher levels of Lp-PLA2 activity and mass increased the risk of CHD, but not of ischemic stroke, over a median follow-up of 6 years [12]. Furthermore, the Lp-PLA2 Studies Collaboration included research pertaining to both CVD patients and the general population, with the aim of identifying the predictive value of Lp-PLA2 for CVD. However, they did not analyze the association between Lp-PLA2 and risk of adverse outcomes in CHD patients. A growing body of evidence has demonstrated that Lp-PLA2 activity or mass was independently associated with the risk of adverse outcomes in patients with CHD [13], [14], [15], [16], [17], [18], [19]. However, other studies with large samples have shown that Lp-PLA2 activity or mass was not a predictor of mortality or cardiovascular events in patients with CHD [8], [20], [21], [22], [23], [24]. Therefore, the relationship between Lp-PLA2 and risk of adverse outcomes of CHD is not evident. To further clarify the evidence, we performed a meta-analysis of eligible prospective observational studies to evaluate the association between Lp-PLA2 and risks of all-cause mortality or cardiovascular events in patients with CHD.

Section snippets

Methods

This systematic review and meta-analysis was conducted in accordance with the Meta-Analysis of Observational Studies in Epidemiology Guidelines [25].

Study selection and characteristics

A detailed description of literature search is presented in Fig. 1. A total of 2838 abstracts was identified through the literature search, with 7 of these studies identified through the manual search of reference lists in these articles. Finally, 15 prospective observational studies were included in this systemic review and meta-analysis.

The basic characteristics of the included studies are shown in Table 1, Table 2. Among the 15 studies, 9 were prospective cohort studies, 5 were randomized

Discussion

The meta-analysis of 15 prospective studies indicated that Lp-PLA2 was independently associated with long-term cardiovascular events in patients with CHD. However, no sufficient evidence supported that Lp-PLA2 activity or mass is an independent predictor of long-term all-cause mortality in patients with CHD. Further, compared to the lowest category of Lp-PLA2 activity or mass, the highest category did not experience a significantly increased risk of cardiovascular events in the subgroups of ACS

Limitations

This study has several limitations. First, the meta-analysis included a limited number of eligible studies, which made it more difficult to conduct a rigorous subgroup analysis based on influencing factors; it is possible that the subgroup analysis lacked statistical power for this reason. It was also difficult to detect heterogeneity among studies related to the association between Lp-PLA2 and the risk of CVD, CHD, and ischemic stroke. In addition, we could not conduct sensitivity analysis on

Conclusions

In conclusion, our meta-analysis indicated that greater Lp-PLA2 activity or mass was an independent predictor of cardiovascular events in patients with CHD, particularly in patients with stable CHD or who did not receive therapies for inhibiting Lp-PLA2. However, no evidence confirmed this association between higher Lp-PLA2 activities or mass and increased risk of long-term all-cause mortality in CHD patients. This observation supports that Lp-PLA2 is a vascular-specific inflammatory biomarker

Disclosures

None.

Acknowledgments

This work was supported financially by grants from the Science and Technology Department of Sichuan Province, China (No. 2016SZ0020), National Natural Science Foundation of China (No. 81471836), and Chinese Ministry of health (No. 201302003)

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    These authors contributed equally to this work.

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