Lipoprotein-Associated Phospholipase A2 as a Novel Risk Marker for Cardiovascular Disease: A Systematic Review of the Literature

We sought to critically assess the role of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) in the prediction of cardiovascular events in primary and secondary prevention settings. The inclusion criteria for our study included population-based epidemiologic studies and the presence of clinical outcomes of interest, including atherosclerotic disease, coronary events, stroke, and cardiovascular death. Studies that lacked clinical outcomes or that involved animals were excluded. We included primary and secondary prevention studies of subjects in all ethnic groups and of either sex, with no age limitation. We searched MEDLINE, Google Scholar, and the Cochrane Library for studies with publication dates from January 1970 through July 2009, and we searched major cardiology meeting abstracts from 2000 through 2009. From each study, we used predictive ability—including relative risk, hazard ratio, odds ratio, and prevalence of high Lp-PLA₂ levels, with adjustment—along with baseline population characteristics.Of 33 studies that met our inclusion criteria, 30 showed a significant association between Lp-PLA₂ and cardiovascular events. Most of the studies had been adjusted for major Framingham risk factors and other variables that might influence the effect under question. After multivariate adjustments in cohort and nested case-control studies, increased levels of Lp-PLA₂ remained a significant predictor of cardiovascular events. The available body of evidence suggests that Lp-PLA₂ is a reliable marker of risk for cardiovascular events.Key words: Atherosclerosis/prevention & control, biological markers/blood, case-control studies, cohort studies, C-reactive protein, epidemiology, inflammation, lipoprotein-associated phospholipase A2, phospholipases A2, treatment outcomeTraditional risk factors can predict the risk of cardiovascular (CV) disease in many, but not all, patients. About 10% to 20% of persons with coronary heart disease (CHD) have no identifiable risk factor,¹ and 35% of CHD deaths occur in patients who have total serum cholesterol levels of less than 200 mg/dL.²Current risk-prediction methods (such as the Framingham risk table) are not able to accurately pinpoint which patient will develop a CV event, or at what time. Exhaustive research is under way to improve our ability to determine individuals'' CV risks. Inflammation plays an important causal role in the development of atherosclerosis and its clinical complications³ (such as acute coronary syndrome [ACS], sudden cardiac death, acute myocardial infarction, unstable angina, and stroke). New diagnostic tests are being developed to identify individuals who are at high risk of inflammation.⁴ Several inflammatory markers, notably high-sensitivity C-reactive protein (hs-CRP)⁵ and white blood cells,⁶ have been studied as predictors of future CV events.Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a novel inflammatory marker that has been the recent focus of multiple epidemiologic studies involving primary and secondary prevention populations.⁷ A growing body of evidence suggests that Lp-PLA₂ is a CV risk marker independent of traditional risk factors like high-density-lipoprotein cholesterol (HDL-c), low-density-lipoprotein cholesterol (LDL-c), and hs-CRP. Lipoprotein-associated phospholipase A₂, a 45-kDa protein with 441 amino acids, was cloned in 1995.⁸ The gene for Lp-PLA₂ is located on chromosome 6p 21.2 to 12. Also known as platelet-activating factor acetylhydrolase (PAF-AH), Lp-PLA₂ hydrolyzes the short acyl group at the Sn-2 position of the phospholipids in oxidized LDL, which leads to production of the pro-inflammatory compounds lyso-phosphatidylcholine and oxidized nonesterified fatty acids.⁹ Lipoprotein-associated phospholipase A₂ is produced by several inflammatory cells (for example, monocytes, macrophages, T cells, hepatic Kupffer cells, and mast cells). In human plasma, it is associated mainly (70%–80%) with LDL particles, due to its affinity for the C-terminus of apolipoprotein B; the remaining 20%–30% is associated with HDL and other lipoproteins.¹⁰ Within LDL fractions, it shows more predilection for the denser LDL-4 and LDL-5, which are believed to be highly proatherogenic.¹¹ Studies have also shown that oxidized phospholipids are chemotactic and promote monocyte–endothelial-cell interaction.^12,13 A high level of circulating oxidized LDL has been shown to increase plaque vulnerability and mediate endothelial dysfunction, which can partly explain its higher levels in ACS patients.^14,15Recent reports suggest that human beings and rabbits with elevated Lp-PLA₂ have higher plaque burden in the coronary arteries.¹⁶ The reduction of atherosclerotic lesions in hyperlipidemic rabbits, by inhibiting Lp-PLA₂, supports the notion that Lp-PLA₂ enhances atherosclerosis.¹⁶ Lipoprotein-associated phospholipase A₂ is also expressed within the necrotic core and apoptotic macrophages of vulnerable and ruptured plaque in human coronary atheroma, which suggests its active role in acute coronary syndrome.¹⁷ Moreover, high levels of Lp-PLA₂ mRNA have been noted in carotid plaque.During myocardial ischemia, membrane phospholipids may undergo hydrolysis under stress, leading to accumulation of arachidonic acid and lysophophatidylcholine.^18,19 Lipoprotein-associated phospholipase A₂ levels are shown to be up-regulated by endotoxins.^20,21 The proatherogenic contribution of Lp-PLA₂ has been much studied; however, its anti-inflammatory and antiatherogenic potential should not go unnoticed.⁷Platelet-activating factor is prothrombotic and a mediator of inflammation; platelet-activating factor acetylhydrolase hydrolyzes PAF, thereby negating its proinflammatory and prothrombotic effects.²² The opposing actions of Lp-PLA₂ (PAF-AH) have led to a debate concerning which action is more potent and therefore warrants more attention. Initially, PAF-AH was thought to be atheroprotective by reducing platelet-activating factor.^23,24 However, subsequent studies have shown its role in inflammation: lysophosphatidyl choline stimulates macrophage proliferation, up--regulates cytokines and CD40 ligands, and increases the expression of vascular adhesion molecules.^25,26 This has led most researchers to believe that the proatherogenic effect of Lp-PLA₂ has a greater importance in CV disease prevention and management.Because of its low biologic fluctuation, high vascular specificity, and indication (at elevated levels) of plaque inflammation and endothelial dysfunction, Lp-PLA₂ is useful in identifying patients at high risk of CHD. A recent report²⁷ suggests that an Lp-PLA₂ level >235 ng/mL in healthy populations and >225 ng/mL in clinical populations is a high-risk marker for CV events, and that Lp-PLA₂ should be measured in patients who are at moderate to very high risk of CV events. An elevated Lp-PLA₂ level also predicts increased risk of myocardial infarction and stroke in population studies that are fully adjusted for other CV risk factors. More epidemiologic and clinical studies in the future can help clarify the effect of Lp-PLA₂ on atherosclerosis-related CV risk.

Secretory PLA₂

Secretory PLA₂ (sPLA₂)—another enzyme from the phospholipase A₂ family—has been the focus of many studies for its role in predicting coronary artery disease (CAD).²⁸ Secretory PLA₂ is an acute-phase reactant, the activity of which is up-regulated by other inflammatory markers.²⁶ Unlike Lp-PLA₂, its levels correlate with hs-CRP. Secretory PLA₂ is not widely used in clinical practice; one explanation for this could be its nonspecific predictive ability. However, ongoing and future studies will help shed more light on the predictive potential of sPLA₂ and its potential in comparison with Lp-PLA₂.The purpose of this particular review is to critically assess the role of Lp-PLA₂ in the prediction of CV events (with a focus on coronary heart disease) in primary and secondary prevention settings.