Editorial
Lp-PLA2
A novel marker of atherosclerosis: To treat or not to treat?
Dimitris Tousoulis
, Nikolaos Papageorgiou, Emmanuel Androulakis, Christodoulos Stefanadis
1st Cardiology Department, Athens University Medical School, Hippokration Hospital, Greece
a r t i c l e i n f o
 Article history:
Received 14 August 2012Accepted 26 September 2012Available online 24 October 2012
Keywords:
AtherosclerosisLipoprotein-associated phospholipase A2In
ammationCardiovascular disease
1. Introduction
In
ammatory process contributes signi
cantly to the initiation,progression and rupture of atherosclerotic plaques [1]. A numberof classicalongwithnovel,whicharestillunderinvestigation,in
amma-tory biomarkers, have been proposed during the last years, evaluatingthecontributionofin
ammationinatherogenesis[2].Datahavedemon-stratedalsothatin
ammatorybiomarkersmaybeabletopredictcardio-vascular disease (CVD) events [2]. Thus, apart from the widely studiedC-reactiveprotein(CRP)andamongseveralnovelbiomarkersexaminedfortheirroleinCVD,lipoprotein-associatedphospholipaseA2(Lp-PLA2)is an emerging in
ammatory marker playing a key role in vascular in-
ammation and importantly in atherosclerosis evolution (Fig. 1). Morespeci
cally,Lp-PLA2isanenzymethathydrolyzesphospholipidstogen-eratelysophospholipidsaswellasoxidizedfreefattyacids,whilehavingapredictiveroleforfutureCVDevents.Althoughthereisanencouragingamount of Lp-PLA2-associated data, little is known about the involve-ment of Lp-PLA2 in the pathophysiology of atherosclerosis, CVD riskprediction, its association with cardiovascular indices and its poten-tial as a therapeutic target for future medical treatments.In this issue of the
 Journal
 Charniot et al. [3] aimed to assess rela-tionshipsbetween Lp-PLA2levels,cardiac disease and treatmentsandto evaluate the association of Lp-PLA2 levels with the severity of angiographic coronary artery disease (CAD) and the extracoronaryatherosclerosis. They reported that interpretation of Lp-PLA2 levelsneeds a good assessment of cardiac parameters and treatments, espe-cially statins and ACEi/ARA2. In addition, Lp-PLA2 levels are signi
-cantly associated with coronary heart disease and with the extension
ofextracoronarydiseaseafteradjustmentforageandgender.However,the exact role of Lp-PLA2 as a prognostic biomarker and as a targetbiomarker is not well elucidated.
2. Lp-PLA2, a novel marker 
Lipoprotein-associated phospholipase A2 is a 45.4-kDa protein andalso a calcium-associated member of the phospholipase A2 family.This in
ammatory biomarker is secreted mainly by macrophages,T-lymphocytes and monocytes as well as mast cells and data haveshownthatitisenhancedinatheroscleroticlesions,especiallyincomplexvulnerableplaquesandimportantlyinthincapcoronarylesionspronetorupture [4].Two-thirds of the Lp-PLA2 plasma isoform primarily bound tolow-density lipoprotein cholesterol (LDL-c), while the other third isdistributed between high-density lipoprotein cholesterol (HDL-c) HDL and very low-density lipoprotein (VLDL) [4]. Low-density lipoproteincholesterolappearstobeacirculatingreservoir,inwhichLp-PLA2isin-active until the oxidative modi
cation of LDL. Following LDL oxidation,Lp-PLA2 cleaves an oxidized phosphatidylcholine component of the li-poprotein particle generating lysophosphatidylcholine and oxidizedfattyacid,whichare pro-in
ammatory andpro-atherogenic mediators.
3. Evidence from large scale studies
SeveralstudieshaveexaminedthepredictiveroleofLp-PLA2incor-onary events (Table 1). In the ARIC trial [5], the authors prospectively found that Lp-PLA2 levels were increased in subjects who developedCAD. In addition to the classic risk factors, both levels of Lp-PLA2 andhighsensitivityCRPwerehigherinpatientswithCVDeventscomparedtothosewhodidnotexperienceCVDevents.ItwasshownthatLp-PLA2was independent of CRP and body mass index, thus being superiorin terms of speci
city to CRP as subjects presenting with abdominaladiposity had enhanced expression of CRP and pro-in
ammatory cyto-kines. Interestingly, increased Lp-PLA2 was signi
cantly related to adouble risk of CVD event, implicating that that Lp-PLA2 may be usefulin classifying intermediate risk individuals in high or low risk status.According to the data derived from the MONICA study [6] enhancedconcentrations of Lp-PLA2 and CRP were additional risk factors forCAD events.Of great importance were the scienti
c data coming from theWOSCOPS study [7]. Prior to the aforementioned studies, the WOSCOPSreported that Lp-PLA2 is a potential biomarker for CVD risk assessment.In addition, increased Lp-PLA2 levels have a predictive value for cardio-vasculareventsindependentlyofotherin
ammatorymarkersinahigherrisk population of men with hyperlipidemia [8]. Thus, a 60% statistically
 Corresponding authorat:Athens University Medical School, Hippokration Hospital,VasilissisSo
as114,11528,Athens,Greece.Tel.:+302132088099;fax:+302132088676.
E-mail address:
 drtousoulis@hotmail.com (D. Tousoulis).0167-5273/$
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signi
cantincreaseinriskbetweenthehighestandthelowestquintileof Lp-PLA2 was found. Despite the signi
cant relations of Lp-PLA2 withtotal and LDL, Lp-PLA2 levels were independent of age, body massindex, blood pressure or smoking.Several other studies have reported the predictive value of Lp-PLA2to identify residual risk in high risk individuals [9]. However, Lp-PLA2levels during the early phase of the acute coronary syndromes werenot associated with the risk for recurrent events [10]. Moreover, meta-analyses have tried to enlighten the role of this in
ammatory molecule.In a cohort of more than 20,000 patients from large epidemiologicalstudies [11], increased Lp-PLA2 levels were independently associatedwith CVD events, while from the early studies it was shown thatLp-PLA2 may be also an attractive novel therapeutic target [12].
4. Recent data highlighting the role of Lp-PLA2 in atherosclerosis
Apartfromthepromisingresultsfromlargeepidemiologicalstudies,recent studies have aimed to examine the potential pathophysiologicalrole of Lp-PLA2 in CVD and the potential agents aiming to that. Whileevaluating the known results of previous large scale studies Kleber etal. [13] demonstrated that Lp-PLA2 levels predict risk for total and CVDmortality independently from established risk factors and indicatedrisk for CVD death even in patients with high CRP levels. Recently,otherstudiesaimedtoinvestigatetherole ofLp-PLA2intransient ische-mic attack patients and to examine their association with recurrentstroke [14]. The authors found that Lp-PLA2 mass and activity werehigher in transient ischemic patients in the control group. Duringfollow-up Lp-PLA2 activity of >207 nmol/ml/min was a signi
cant pre-dictorforrecurrentstroke[14]implyingapotentialroleintheearlyeval-uationofsuchpatients.Furtherstudieshavedemonstratedthatintype1diabetes Lp-PLA2 mass was marginally higher and Lp-PLA2 activitywas signi
cantly lower than in those without diabetes as well as agreaterproportion ofthose withprogression of coronarycalci
cationin type 1 diabetes compared with those without diabetes. Lp-PLA2 ac-tivitywasindependentlyassociated withprogressionofcoronarycalci-
cation in multivariate analysis. However, LpPLA2 mass was notsigni
cantly associated with progression of coronary calci
cationin this cohort [15]. Moreover, other studies have shown thatLp-PLA2 expression increases dramatically during human monocyte tomacrophage differentiation and further in in
ammatory macrophagesand foam like cells [16]. Despite only a marginal association of singlenucleotide polymorphisms in PLA2G7 with Lp-PLA2 activity or mass,numerous PLA2G7 single nucleotide polymorphisms were associatedwith coronary artery calci
cation [16]. Charniot et al. [3] reported that in healthy controls, mean Lp-PLA2 level correlated with age, bodymass index, smoking, history of hypertension but not with diabetes,gender,creatinineorNewYorkHeartAssociationstatus.Inmultivariateanalysis Lp-PLA2 was associated with total cholesterol, LDL-cholesteroland apoB but not with Lp(a).AsmorestudieshighlightfurthertheroleofLp-PLA2inatherosclero-sistheaimofthecurrentandfuturestudiesistoevaluatetheroleofthisin
ammatory marker in hypolipidemic therapy. Statins and darapladibare the most potent agents targeting Lp-PLA2. High-dose atorvastatinsigni
cantly reduced sPLA2 and Lp-PLA2 mass and activity after acutecoronary syndromes and mitigated the risk of death associated withsPLA2 mass suggesting that atorvastatin may exert antiin
ammatoryeffects on phospholipases which contribute to its therapeutic bene
tafter acute coronary syndromes [17]. Importantly, the relationship be-tween circulating Lp-PLA2 levels and coronary plaque volume has not
Ox-LDL
      L     p   -      P      L      A      2
Lyso-PCT-cell activationleukocyte recruitment Plaque destabilizationVSMC proliferation and migrationPlatelet recruitment and activation
Fig. 1.
 Lp-PLA2 mediates in
ammatory process.
 Table 1
Major large scale studies evaluating the predictive value of Lp-PLA2.Study Subjects Events OR/HR or RR (95% CI)Ballantyne et al. [5] Healthy subjects CAD events 1.15 (0.8
1.6)2.08 (1.2
3.6)Koenig et al. [6] Hypercholesterolemia CAD events 1.21 (1.01
1.5)Packard et al. [7] Hyperlipidemia CAD events 1.80 (1.3
2.6)Winkler et al. [20] DM II CAD 2.09 (1.0
4.2)Persson et al. [21] Healthy MI 1.54 (1.1
2.2)Kiechl et al. [22] Healthy CAD events 1.4 (1.1
1.4)Khuseyinova [23] CAD CAD 1.91 (1.12
3.28)Koenig et al. [24] ACS CAD 2.09 (1.10
3.96)Gerber et al. [25] ACS Death 4.93 (2.10
11.6)O'Donoghueetal.[10] ACS CAD events 1.33 (1.01
1.74)Sabatine et al. [26] CAD MI 1.41 (1.17
1.70)Mockel et al. [27] ACS CAD events 2.60 (1.1
6.6)Oldgren et al. [28] ACS CAD events 1.40 (0.77
2.5)Abbreviations: DM: diabetes mellitus; MI: myocardial infarction; ACS: acute coronarysyndromes; OR: odds ratio; RR: relative risk; HR: hazard ratio; CI: con
dence intervals;CAD: coronary artery disease.214
 Editorial
 
been well clari
ed in patients with acute coronary syndromes [18].Therefore,Dohietal.[18]demonstratedthatLp-PLA2levelssigni
cantlydecreased between baseline and six months of follow-up, while the ab-solute change in plaque volume also signi
cantly correlated with thechange in Lp-PLA2 levels. In the study of Charniot et al. [3] it was foundthat Lp-PLA2 levels were signi
cantly higher in patients with CAD thanin patients without CAD and signi
cantly higher in patients with themost extensive angiographic CAD. Patients with heart failure, sepsis oraortic aneurysm had increased Lp-PLA2 levels compared to controlsand interestingly, in patients with carotid artery disease, Lp-PLA2 signif-icantly increased with the severity of atherosclerosis.Furthermore, experimental data have shown that administrationof darapladib daily for 6 weeks, although not affecting body weightand serum lipids levels, reduced serum Lp-PLA2 activity signi
cantly aswellasCRPandinterleukin-6[19].Interestingly,theplaqueareathroughthe arch to the abdominal aorta was reduced in the darapladib group,while the macrophage content was decreased and collagen content wasincreased in atherosclerotic lesions at the aortic sinus in the darapladibgroup compared with the vehicle group. It is also worth mentioningthat the samestudy revealed lowerexpressionof monocyte chemotacticprotein-1, vascular cell adhesion molecule 1 and tumor necrosis factoralpha after darapladib [19]. Additional data to the current knowledgehave been provided by Charniot et al. [3] as Lp-PLA2 was signi
cantlyassociated with treatments such as statins and ACEi/ARA2 but not withb-blockers, antiaggregant drugs or diuretics.
5. Challenging role of novel biomarkers: time for Lp-PLA2?
Thereis a continuous seek of new riskfactorsthat predictCVD andcan be incorporated into risk assessment algorithms. Although sever-al molecules seem to play a central pathogenic role in atherogenesis,this does not necessarily mean that they are suitable parameters forrisk prediction. Moreover, a proposed biomarker should not only pro-vide independentinformation on CVD risk, but alsobe easyto measureusing inexpensive and standardized commercial assays that have lowvariability,arerelativelystable,andexhibitminimalcircadianvariation.Lp-PLA2isnotyetwellvalidatedtobeusedindailyclinicalpracticeandfurther studies are required to con
rm its clinical utility as a predictorbiomarker. Furthermore, in
ammatory process is multifactorial andthus, inhibiting just one mediator does not warrant the achievementof a signi
cant total antiin
ammatory improvement.
6. Conclusions
Recent evidence suggests that Lp-PLA2 plays an important role in thepathophysiology of atherosclerosis and may have predictive value forfuture cardiovascular events. The available data suggest that Lp-PLA2couldbeamorevascular-speci
cmarkercomparedtoC-reactiveprotein,but there are still issues pending as regards to the available assays/measurements of this protein, especially at low plasma concentrations.The studies already conducted have demonstrated that Lp-PLA2 may bea target of lipid-lowering drugs such as statins and novel includingdarapladib aiming further to plaque formation. Although the majorityoftheresultsareinfavortothesigni
cantroleofLp-PLA2incardiovas-cular disease, the available data remain limited. Therefore, more welldesigned large scale randomized trials, especially in humans are re-quired to investigate further and evaluate the atherosclerotic mecha-nisms associated with Lp-PLA2 and its potential role as a therapeutictarget for cardiovascular agents.
 Acknowledgments
The authors of this manuscript have certi
ed that they complywith the Principles of Ethical Publishing in the International Journalof Cardiology.
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