REVIEWControversies in cardiovascular medicineC-reactive protein is a mediator of cardiovasculardiseaseRadjesh J. Bisoendial1, S. Matthijs Boekholdt1,2, Menno Vergeer1, Erik S.G. Stroes1,and John J.P. Kastelein1*1Department of Vascular Medicine, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands; and2Department of Cardiology, Academic Medical Center,Amsterdam, The NetherlandsReceived 7 September 2009;revised 5 December 2009;accepted 29 June 2010;online publish-ahead-of-print 3 August 2010C-reactive protein is postulatedto embody an index that can reect cardiovascular risk and can be used to independentlypredict majorcardiovascular events and mortality. On the other hand, credible experimental data have become available that demonstrate the abundantpresence of C-reactive protein in atherosclerotic lesions and, moreover, identify C-reactive protein as an initiator of several pathogenic path-ways that can cause atherogenic changes. Consequently, there has been a paradigm shift in which C-reactive protein is no longer regarded asmerely an indicator of cardiovascular risk, but increasingly considered a direct partaker in the pathogenesis of atherosclerotic cardiovasculardisease. These data underscore the need to explore risk-reducing interventions that selectively inhibit C-reactive protein activity as a novelstrategy to prevent clinical manifestations of atherosclerosis.-----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords C-reactive proteinIntroductionC-reactive protein, among other systemic inammatory mediators,has been widely accepted as a potent risk indicator, independentlypredictingfuturecardiovascularevents. Theimpactof C-reactiveproteinoncardiovascularoutcomehasbeencorroboratedbyalargenumberof observational studiesandmeta-analyses. Thesestudies show that an elevated C-reactive protein has a clear prog-nostic value for major cardiovascular events and mortality,whereastheloweringof C-reactiveproteinisassociatedwithareductionincardiovascular risk. Combining thesendings withexperimental observationshasleadtoaparadigmshiftinwhichC-reactive protein is no longer merely a marker, but is increasinglyconsidered as a mediator of cardiovascular disease. In the presentissue of controversies in cardiovascular medicine, we will focus onthe emerging evidence supporting a potentially causal role ofC-reactive protein in cardiovascular disease (Figure 1).EpidemiologyEvidence has cumulated to show that C-reactive protein levels areassociated with different aspects of the cardiovascular riskspectrum. For instance, C-reactive protein levels were higheramong people who were physically inactive,14had worse cardior-espiratorytness,5,6andweremoreobese.7C-reactiveproteinlevelswerealsoassociatedwiththepresenceandextentof themetabolic syndrome,810with the presence of subclinical athero-sclerosis,11and with the progression of atherosclerosis.12,13Besides these cross-sectional associations, C-reactive proteinlevels werealsoassociatedprospectivelywiththeriskof new-onset diabetes mellitus14,15and hypertension.16Moreover,plasmalevelsof C-reactiveproteinhavebeenacknowledgedtohave a predictive value for the development of future cardiovascu-lar events. Among the rst studies to show this association was astudyof patients hospitalizedfor unstableangina.17Thosewithelevated C-reactive protein levels at the time of hospital admissionweremoreproneforrevascularization, myocardial infarction, ormortalityduringhospitalization. Anotherstudyinvolvedpatientswitheither stableor unstableangina, revealing that patients inthe highest quintile of the C-reactive protein distribution(.3.6 mg/L) hadatwo-foldincreasedriskof acoronaryeventcompared with those in the lower quintiles.18These observationswere soon followed by a range of prospective studies in differentpopulations. Although heterogeneity exists in the predictive value* Corresponding author.Tel: +31 20 566 6612,Fax: +31 20 566 9343,Email: j.j.kastelein@amc.uva.nlPublished on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010.For permissions please email: journals.permissions@oxfordjournals.org.European Heart Journal (2010) 31, 20872095doi:10.1093/eurheartj/ehq238by guest on August 4, 2015Downloaded from of C-reactive protein between individual studies, general consensushas emerged acknowledging a relation between C-reactive proteinand cardiovascular disease. Some studies were performed inpatients with established cardiovascular disease including coronaryheart disease19and peripheral artery disease.20In addition, a widerange of prospective studies showed that C-reactive protein levelspredict future vascular events among people without clinicallymanifestcardiovasculardiseaseatthetimeof C-reactiveproteinmeasurement. InthePhysicians HealthStudy, apparentlyhealthymeninthehighestquartileoftheC-reactiveproteindistributionhad a 2.9-fold increased risk of future myocardial infarction, com-paredwiththoseinthelowest quartile.21This associationwasindependent of established cardiovascular risk factors. Accordingly,asymptomatic womenintheWomens HealthStudy whohadbaseline C-reactive protein levels in the top quartile had a4.8-foldincreased risk of vascular eventscomparedwith those inthe bottom quartile.22After that, many prospective studies includ-ing the Womens Health Initiative,23the Framingham HeartStudy,24the EPIC-Norfolk cohort,25the Cardiovascular HealthStudy,26the MONICA-Augsburg cohort,27and the ReykjavikStudy28have reported similar ndings. In addition, a meta-analysisestimated that the odds ratio for future coronary heart disease was1.58[95%condenceinterval (CI), 1.481.68]forpeopleinthetop tertile vs. those in the bottomtertile of the C-reactiveprotein distribution. The study population in which the predictivevalueof C-reactiveproteinlevelswasconsistentlyshowntobelimited were the elderly.2931Another set of studies havefocused on the association between C-reactive protein levelsand other vascular diseases including stroke and peripheralartery disease. The majority of these studies revealed that elevatedC-reactive protein levels were associated with an increased risk offuture stroke,3237although not all were in agreement.38C-reactiveproteinlevelswerealsoshowntobeassociatedwiththe risk of developing new-onset peripheral artery disease.3941On the basis of the strong evidence for a prospective associationbetween C-reactive protein levels and cardiovascular risk, a state-ment fromtheCenters of DiseaseControl andtheAmericanHeart Association suggested that C-reactive protein measurementmay be used to direct further evaluation and therapy for those cate-gorized as intermediate risk by global risk assessment.42Evidencesupporting the concept that C-reactive protein is useful for reclassi-cation of people estimated to be at intermediate risk is based onstudies which show that risk algorithms including C-reactiveproteincanmore oftenclassify people correctly intoclinicallyuseful risk categories, than models without C-reactive protein.4347Epidemiological evidence for a causal roleof C-reactive protein?Whereas the status of C-reactive protein as risk marker is beyondreasonabledoubt, thereisanongoingdebatewhetherC-reactiveprotein is an active participant in atherogenesis or merely an innocentbystander. Besidesarangeof experimental studiesaddressingthepotentially causal role of C-reactive protein (see further), epidemio-logical studieshavepredominantlyfocusedontheMendelianran-domization. Thisapproachassumesthatif causalityindeedexists,geneticvariants in theC-reactiveprotein genethatareassociatedwith altered C-reactive protein plasma levels should also be associ-atedwithaconsistentlyandproportionallyalteredcardiovascularrisk. Several single-nucleotide polymorphisms in the C-reactiveprotein gene with a consistent impact on baseline C-reactiveproteinlevelshavebeenidentied; forinstance, rs18000947andrs7553007beingassociatedwithlower C-reactiveproteinlevelsand rs3093077 and rs3093059 with higher C-reactive proteinlevels.10,4866Few studies have found consistent associations amonggenetic C-reactive protein variants, C-reactive protein levels, and car-diovascular risk;51,59however, the majority of studies using this designwere negative.52,54,55,57,62,63Whether the latter implies a true lack ofassociation or result fromthe lack of statistical power is unknown. Ofnote, it has been acknowledged that this type of studies requires atleast 15 000 cases to have sufcient statistical power to detect suchassociations.67Arecentlarge-scaleanalysisachievedthisstatisticalpower and showed that rs7553007 in the C-reactive protein locuswasassociatedwith20.7%(95%CI, 17.923.4; P 1.3 10238)lower C-reactiveproteinlevels, whichyieldeda predictedoddsratio for coronary heart disease of 0.94 (95% CI, 0.940.95).66Theobserved odds ratio was 1.00 (95%CI, 0.971.02), providing an argu-ment against a causal role for C-reactiveproteininthe development ofcoronary heart disease.BiologyThere is convincing experimental evidence linking C-reactive proteinto plaque disruption and the onset of cardiovascular events.C-reactive protein mRNAand protein is abundantly present in ather-osclerotic lesions,6871whereas the level of C-reactive protein cor-relates with the extent of atherosclerotic disease.7274At the sametime, C-reactive protein itself elicits a wide array of pro-atherogeniceffects in a majority of cell types involved in atherogenesis, mostlymediated via Fcg receptor-dependent pathways.7581Followingreceptor engagement, various signalling cascades are activated,including NFkB, p38 MAPK, and Jun N-terminal kinase signalling path-waysaswell astheCD40/CD40ligandsignallingdyad.8286Acti-vation of these pathways elicit a series of pro-atherogenic changes.Figure 1Molecular structure of C-reactive protein. C-reactiveproteinconstitutes apentamericmoleculewithaC1q-bindingsitelocatedontheeffectorface, andontheoppositearecog-nition face that binds calcium ions and phosphocholine.R.J.Bisoendial et al. 2088by guest on August 4, 2015Downloaded from Vascular endotheliumC-reactive protein stimulates leucocyteendothelium interactionsvia the modulation of endothelium-derived molecules and chemo-kines in various cultured endotheliumcells.85,8790C-reactiveprotein decreases endothelial nitric oxide synthase (eNOS)mRNAproteinaswell asbioactivity.90,91Underlyingmechanismscomprisedecreasedstabilityof eNOSmRNA,90bluntedeNOSphosphorylationat Ser1179,81uncouplingof eNOS,92andsuper-oxide anion release from NAD(P)H oxidase.93,94C-reactiveprotein also increases LOX-1 expression, crucial for oxidized(ox)LDLs detrimental effects on endothelial function95andenhances angiotensin II-induced pro-inammatory effects.96C-reactive protein also impairs the number and function of endo-thelial progenitor cells97by promoting apoptosis98and attenuatingtheir migration and adherence capacities.99More recently,C-reactiveproteinhasbeenobservedtodamagetheendothelialglycocalyx, furtherpromotingthesensitivityof theendotheliumtowards pro-atherogenic insults.100In experimental animal models overexpressing human C-reactiveprotein, data have been conicting.93,101Since animals, however, donot express C-reactive protein, it is difcult to weigh the relevanceof theseobservations. Incontrast, werecentlyconrmeddirectharmful effects of C-reactive protein on endothelium-derived vaso-motor function in humans. Thus, systemic infusion of recombinanthuman C-reactive protein raising C-reactive protein levels to24 mg/L activated the vascular endothelium as attested by signi-cant elevation in circulating vWFAg and E-selectin. Concomitantly,endothelium-derived vasorelaxation was impaired, particularlyunder hypercholesterolaemic conditions.102,103Coagulation pathwaysC-reactive proteininduces a prothrombotic stateby stimulatingtissue factor release frommononuclear,104,105endothelial, andsmoothmusclecells.106Inaddition, C-reactiveproteinincreasesplasminogen activator inhibitor-1 activity in human aortic endothelialcells107with a concomitant reduction in tissue plasminogen activatoractivity,108resultinginanoverall impairedbrinolyticcapacity. Inline, humanvolunteersalsoexhibitincreasedthrombingenerationand impaired brinolysis upon C-reactive protein challenge.102Plaque remodellingRecentreportshavedemonstratedC-reactiveproteinsabilitytoincreasematrixmetalloproteinase(MMP) synthesiswithensuingcollagen-degradingactivityin monocytesmacrophagesaswell ascultured endothelia.84,86,109,110In parallel, interleukin (IL)-8 isstimulated, which has been suggested to further enhance the disba-lancebetweenMMPsandtissueinhibitorsof metalloproteinaseswithintheatheroscleroticplaqueinfavourof anunstableplaquephenotype.111,112Recently,C-reactiveprotein was also shown toelicit the activation of peripheral leucocytes with ensuing secretionof plaque-destabilizing mediators including MMP-9, monocyte che-moattractant protein-1, and plasminogen activator urokinase.113ComplementC-reactiveprotein activates thecomplementsystem,114whichhasbeenshowntoresult ina signicant increaseininfarct sizeinvariousmyocardial infarctionmodels.115118Incontrast, theinhi-bition of C-reactive protein binding (Figure 2) using a small-moleculeinhibitor was able to attenuate the increase in infarct size in rats.119Figure 2Specic inhibitor of C-reactive protein. This small molecule, termed bis(PC)H, is designed to interact with calcium ions bound toC-reactiveprotein, preventingC-reactiveproteinfrominteractingwithligands. ReprintedwithpermissionfromMacmillanPublishersLtd,& 2010 Nature Publishing Group, a division of Macmillan Publishers Limited (2006).131C-reactive protein marker or mediator? 2089by guest on August 4, 2015Downloaded from C-reactive protein or contamination?Critics haveclaimedthat all these convincing pro-atherogeniceffectsshouldinfactbeattributedtocontaminating endotoxinspresent in commercially available preparations.120However,using carefully designed control experiments,several groups haveshown thatC-reactiveproteinitselfisamajor contributor. Thus,Jialal and Devaraj100,108showed that heat-induced C-reactiveprotein denaturation, which should have no effect on endotoxins,abolished the pro-atherogenic effects. In line, Bisoendial et al.121,122showedthatthetraceamountofendotoxinpresentinrecombi-nant humanC-reactiveprotein(followingadditional puricationsteps) does not contribute to the pro-atherogenic effects. Insummary,C-reactiveproteinitselfexertspro-atherogeniceffects,both in vitro and in vivo in humans.InterventionWith C-reactive protein being a strong risk factor for cardiovascu-lar disease (Figure 3), and in light of evidence that C-reactiveprotein may play a biological role in atherosclerosis,the questionarisesastowhetheraninterventiontolowerC-reactiveproteinlevelsmayconstituteaviabletherapeuticstrategy. Insupportofthis hypothesis, several knownanti-atheroscleroticinterventionshave been reported to reduce C-reactive protein.Weight lossAn example of a lifestyle intervention that reduces C-reactiveprotein levels, as well as cardiovascular risk, is weight loss. In a ran-domized, controlled trial consisting of 120 obese women, half theparticipantsreceiveddetailedadviceabout howtoachieve10%weightreductionusingdietandexercise, whereastheotherhalfwere given general information regarding a healthy lifestyle.After2 years, women in the intervention group had a stronger decreasein body mass index (24.2, P , 0.001), as well as a strongerreduction in C-reactive protein levels (21.6 mg/L, P 0.008),than women in the control group.123Similarly, weight loss in mor-bidly obese patients has been shown to induce a signicantdecreaseinC-reactiveproteinandIL-6concentrationsinassoci-ation with animprovement of insulinresistance.124Inanotherstudy, baselinemeasuresof obesityweresignicantlyassociatedwithC-reactiveproteinlevels andsubsequent weight loss wasshown to result in a proportionate reduction in C-reactiveprotein.125Statin therapyStatintherapy, besides loweringLDLcholesterol (LDL-C), rep-resents a pharmacological intervention that reduces bothC-reactiveproteinlevelsandcardiovascularrisk. Pravastatinhasprospectively beenshowntoreduce C-reactiveprotein levelsbyFigure 3C-reactive protein can be considered a long-term risk factor for cardiovascular events throughout the entire spectrum of ather-ogenesis, ranging from fatty streak formation to atherothrombosis and tissue injury of ischaemic regions.R.J.Bisoendial et al. 2090by guest on August 4, 2015Downloaded from more than 15% within 12 weeks, in a largely LDL-C-independentmanner.126Along-termstudy yielded even more pronouncedresults: after5yearsof pravastatintreatment, C-reactiveproteinlevelswerereducedbyover35%comparedwithplacebo, againunrelated to the magnitude of the lipid alterations.127In addition,measurements of C-reactiveproteinintheAFCAPS/TEXCAPSsuggested that patients with above-median baseline C-reactiveprotein levels still had cardiovascular benet fromlovastatintherapy, evenintheabsenceof overt dyslipidaemia.128Alsointhis trial,lovastatin reduced C-reactive protein by almost 15%.128It was mostly this nding that prompted the design of theJUPITER trial: a prospective evaluation of the efcacy of rosuvasta-tinintheprimarypreventionof majorcardiovasculareventsinpersons with elevated C-reactive protein, but low LDL-Clevels.129This trial thus employedaknownC-reactiveprotein-lowering agent130toreduce cardiovascular risk in a group ofpeoplewhoseriskwasconsideredtobemainlydeterminedbytheirhighC-reactiveproteinlevels. RosuvastatinreducedLDL-Cby 50% and C-reactive protein levels by 37%, and very effectivelydecreased cardiovascular events vs.placebo.The hazard ratio fortheprimary endpoint (non-fatal myocardial infarction, non-fatalstroke, hospitalization for unstable angina, arterial revascularizationprocedure, orconrmeddeathfromcardiovascularevents)was0.56(95%CI, 0.460.69; P , 0.00001), afteramedianfollow-upof 1.9 years. Pre-specied analyses showed that patients benetedparticularlyfromthisdrugif lowconcentrationsof bothLDL-CandC-reactiveproteinwereachieved.131,132Inaddition, lower-achievedvalues of C-reactiveproteinwereassociatedwiththelargest riskreduction(Figure4). Heretoo, theLDL-Cdecreasehardly correlated with the C-reactive protein decrease (r 0.15), at least suggesting that theC-reactiveproteinreductionmay have contributed to the reduction in cardiovascular risk.131,132What can we learn from these two examples? Both weight lossandstatintherapyapparentlyresult inareductioninlow-gradeinammation, underlying a reduction in cardiovascular diseaserisk. Thebigquestionis: isthisanti-atherogeniceffect (partially)mediated by C-reactive protein reduction, or are the lowerC-reactiveproteinlevels a merereectionof thereductionininammatory status? To answer this question, the impact ofspecicinhibitorsof C-reactiveproteinshouldbetested. Arstcluethat specicC-reactiveproteininhibitionmaybebenecialcamein2006, whenPepyset al. reportedthatasmall-moleculeinhibitor of C-reactive protein was able toreduce myocardialinfarct sizeaswell ascardiacdysfunctionproducedbyinjectionof human C-reactive protein in rats.119ConclusionCurrently available evidence indicates that C-reactiveprotein isapro-atherogenic factor throughout the entire spectrum of cardio-vascular disease, ranging fromfatty streak formationtoclinicalevents. Thus, C-reactiveproteinistobeconsideredasanestab-lished risk factor for cardiovascular risk, comparable to establishedcardiovascular risk factors such as hypertension and diabetes.Besides its roleas abystander, C-reactiveproteinhas beenshowntoexertawidearrayof pro-atherogeniceffects, therebyimplying acausal rolefor C-reactiveproteinby driving inam-mationas well asthrombosis. Thesedataunderscoretheneedtoexploretheimpactof selectivelytargetingC-reactiveproteinas a novel approach to prevent clinical manifestations ofatherosclerosis.Conict of interest: J.J.P.K. has receivedgrant support fromAstraZeneca, Pzer, Roche, Novartis, Merck, MerckSchering-Plough, Isis, Genzyme, and sano-aventis; lecture fees fromAstraZeneca,GlaxoSmithKline,Pzer,Novartis,MerckSchering-Plough,Roche, Isis, and Boehringer Ingelheim;and consulting feesfrom AstraZeneca, Abbott, Pzer, Isis, Genzyme, Roche, Novartis,Merck, MerckSchering-Plough, and sano-aventis. E.S.G.S. hasreceived consulting fees from Novartis, Isis Pharmaceuticals,AstraZeneca, and Roche; and lecture fees fromAstraZeneca,Merck, and Isis Pharmaceuticals.Figure 4Hazard ratios for incident cardiovascular events in JUPITER according to achieved concentrations of low-density lipoprotein (LDL)cholesteroland high-sensitivityC-reactive protein(hsCRP)after initiation of rosuvastatin.Data areadjustedfor age,baselinelow- and high-density lipoprotein cholesterol, baseline hsCRP, blood pressure, sex, body mass index, smoking status, and parental history of premature cor-onary heart disease.Event rates are per 100 person-years. Reprinted with permission from Ridker et al.132C-reactive protein marker or mediator? 2091by guest on August 4, 2015Downloaded from References1. FordES. Doesexercisereduceinammation? Physical activityandC-reactiveprotein among U.S.adults.Epidemiology 2002;13:561568.2. Geffken DF, Cushman M, Burke GL, Polak JF, Sakkinen PA, Tracy RP. Associationbetween physical activity and markers of inammation in a healthy elderly popu-lation. Am J Epidemiol2001;1:242250.3. Reuben DB, Judd-Hamilton L, Harris TB, Seeman TE, MacArthur Studies of Suc-cessful Aging. The associations between physical activity and inammatorymarkers inhigh-functioning older persons: MacArthur Studies of SuccessfulAging.J Am Geriatr Soc 2003;51:11251130.4. WannametheeSG, LoweGD, WhincupPH, RumleyA, WalkerM, LennonL.Physical activity and hemostatic and inammatory variables in elderly men.Circulation 2002;105:17851790.5. Church TS, Barlow CE, Earnest CP, Kampert JB, Priest EL, Blair SN. Associationsbetweencardiorespiratorytness andC-reactiveproteininmen. ArteriosclerThromb Vasc Biol 2002;22:18691876.6. LaMonte MJ, Durstine JL, Yanowitz FG, Lim T, DuBose KD, Davis P,Ainsworth BE. Cardiorespiratory tness and C-reactive protein among atri-ethnic sample of women.Circulation 2002;106:403406.7. Hak AE, Stehouwer CD, Bots ML, Polderman KH, Schalkwijk CG,WestendorpIC, HofmanA, WittemanJC. Associationsof C-reactiveproteinwithmeasuresof obesity, insulinresistance, andsubclinical atherosclerosisinhealthy, middle-aged women.Arterioscler Thromb Vasc Biol 1999;19:19861991.8. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syn-drome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719initially healthy American women.Circulation 2003;107:391397.9. Rutter MK, Meigs JB, Sullivan LM, DAgostino RB, Wilson PW. C-reactiveprotein, themetabolicsyndrome, andpredictionof cardiovascular events inthe Framingham Offspring Study. Circulation 2004;110:380385.10. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, Palmer LJ,HattersleyAT, EbrahimS, LoweGD, RumleyA, DaveySmithG. C-reactiveproteinandits roleinmetabolicsyndrome: Mendelianrandomisationstudy.Lancet 2005;366:19541959.11. Khera A, De Lemos JA, Peshock RM, Lo HS, Stanek HG, Murphy SA, Wians FHJr, Grundy SM, McGuire DK. Relationship between C-reactive protein and sub-clinical atherosclerosis: the Dallas Heart Study. Circulation 2006;113:3843.12. Tzoulaki I, MurrayGD, LeeAJ, RumleyA, LoweGD, FowkesFG. C-reactiveprotein, interleukin-6, and soluble adhesion molecules as predictors of progress-ive peripheral atherosclerosis in the general population: Edinburgh Artery Study.Circulation 2005;112:976983.13. van der Meer IM, de Maat MP, Hak AE, Kiliaan AJ, Del Sol AI, van der Kuip DA,Nijhuis RL, Hofman A, Witteman JC. C-reactive protein predicts progression ofatherosclerosismeasuredat varioussitesinthearterial tree: theRotterdamStudy. Stroke 2002;33:27502755.14. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, inter-leukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327334.15. Hu G, Jousilahti P, Tuomilehto J, Antikainen R, Sundvall J, Salomaa V. Associationof serum C-reactive protein level with sex-specic type 2 diabetes risk:a pro-spective Finnish study. J Clin Endocrinol Metab 2009;94:20992105.16. SessoHD, Buring JE, Rifai N, BlakeGJ, GazianoJM, Ridker PM. C-reactiveprotein and the risk of developing hypertension.JAMA 2003;290:29452951.17. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A.Theprognosticvalueof C-reactiveproteinandserumamyloidaproteininsevere unstable angina. N Engl J Med 1994;331:417424.18. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB, European Con-certedActiononThrombosis, DisabilitiesAnginaPectorisStudyGroup. Pro-duction of C-reactive protein and risk of coronary events in stable andunstable angina. Lancet 1997;349:462466.19. Lindahl B, Toss H, SiegbahnA, VengeP, WallentinL, FRISCStudy Group.Markers of myocardial damage and inammation in relation to long-term mor-tality in unstable coronary artery disease. N Engl J Med 2000;343:11391147.20. Vidula H, TianL, LiuK, Criqui MH, Ferrucci L, Pearce WH, GreenlandP,GreenD, TanJ, GarsideDB, GuralnikJ, RidkerPM, Rifai N, McDermottMM.Biomarkersof inammationandthrombosisaspredictorsof near-termmor-tality inpatients withperipheral arterial disease: a cohort study. Ann InternMed 2008;148:8593.21. Ridker PM, Cushman M,Stampfer MJ, Tracy RP, Hennekens CH. Inammation,aspirin, and the risk of cardiovascular disease in apparently healthy men.N Engl J Med 1997;336:973979.22. RidkerPM, BuringJE, ShihJ, MatiasM, HennekensCH. ProspectivestudyofC-reactive protein and the risk of future cardiovascular events among apparentlyhealthy women. Circulation 1998;98:731733.23. Pradhan AD, Manson JE, RossouwJE, Siscovick DS, Mouton CP, Rifai N,WallaceRB, JacksonRD, PettingerMB, RidkerPM. Inammatorybiomarkers,hormone replacement therapy, and incident coronary heart disease: prospectiveanalysis from the Womens Health Initiative observational study. JAMA 2002;288:980987.24. WilsonPW, NamBH, PencinaM, DAgostinoRB, BenjaminEJ, ODonnell CJ.C-reactiveprotein andrisk of cardiovascular diseaseinmenandwomenfromthe Framingham Heart Study. Arch Intern Med 2005;165:24732478.25. Boekholdt SM, HackCE, SandhuMS, LubenR, BinghamSA, WarehamNJ,Peters RJ, Jukema JW, Day NE, Kastelein JJ, KhawKT. C-reactive proteinlevels and coronary artery disease incidence and mortality in apparentlyhealthy men and women: the EPIC-Norfolk prospective population study19932003.Atherosclerosis 2006;2006:415422.26. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL, Polak JF,Tracy RP. C-reactive protein and the 10-year incidence of coronary heartdisease in older men and women. The Cardiovascular Health Study.Circulation2005;112:2531.27. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A,HutchinsonWL, PepysMB. C-reactiveprotein, asensitivemarkerof inam-mation, predicts future risk of coronary heart disease in initially healthymiddle-aged men: results from the MONICA (Monitoring Trends and Determi-nants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circula-tion 1999;99:237242.28. Danesh J, Wheeler JG, Hirscheld GM, Eda S, Eiriksdottir G, Rumley A,LoweGD, Pepys MB, GudnasonV. C-reactiveproteinandother circulatingmarkersof inammationinthepredictionof coronaryheartdisease. NEngl JMed 2004;350:13871397.29. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P.N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinaryalbuminlevels as predictors of mortalityandcardiovascular events inolderadults.JAMA 2005;293:16091616.30. Sattar N, Murray HM, McConnachie A, BlauwGJ, Bollen EL, Buckley BM,Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM,Macfarlane PW, Murphy MB, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ,TwomeyC, WestendorpRG, ShepherdJ, PROSPERStudyGroup. C-reactiveprotein andpredictionofcoronaryheartdiseaseandglobal vascular eventsinthe Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation2007;11:981989.31. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ,Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M. Inamma-tory markers and onset of cardiovascular events: results from the Health ABCstudy. Circulation 2003;108:23172322.32. GusseklooJ, SchaapMC, FrohlichM, BlauwGJ, WestendorpRG. C-reactiveprotein is a strong but nonspecic risk factor of fatal stroke in elderlypersons. Arterioscler Thromb Vasc Biol 2000;20:10471051.33. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM,DAgostinoRB, FranzblauC, WilsonPW. Plasmaconcentrationof C-reactiveprotein and risk of ischemicstroke andtransient ischemic attack:the Framing-ham study. Stroke 2001;32:25752579.34. DiNapoli M,PapaF,BocolaV.C-reactive protein in ischemic stroke:an inde-pendent prognostic factor. Stroke 2001;32:917924.35. CurbJD, AbbottRD, RodriguezBL, SakkinenP, PopperJS, YanoK, Tracy RP.C-reactiveproteinandthefutureriskof thromboembolicstrokeinhealthymen.Circulation 2003;107:20162020.36. CaoJJ, Thach C, ManolioTA, Psaty BM, Kuller LH, Chaves PH, Polak JF,Sutton-Tyrrell K, HerringtonDM, PriceTR, CushmanM. C-reactiveprotein,carotid intima-media thickness,and incidence of ischemic stroke in the elderly:the Cardiovascular Health Study. Circulation 2003;108:166170.37. BallantyneCM, HoogeveenRC, BangH, CoreshJ, FolsomAR, ChamblessLE,MyersonM, WuKK, SharrettAR, BoerwinkleE. Lipoprotein-associatedphos-pholipaseA2, high-sensitivity C-reactiveprotein,andrisk forincidentischemicstroke in middle-aged men and women in the Atherosclerosis Risk in Commu-nities (ARIC) study. Arch Intern Med 2005;165:24792484.38. Bos MJ, Schipper CM, Koudstaal PJ, Witteman JC, Hofman A, Breteler MM. Highserum C-reactive protein level is not an independent predictor for stroke;theRotterdam study. Circulation 2006;114:15911598.39. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG. Inammatory,haemostatic, andrheological markers for incident peripheral arterial disease:Edinburgh Artery Study. Eur Heart J 2007;28:354362.40. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concen-tration of C-reactive protein and risk of developing peripheral vascular disease.Circulation 1998;97:425428.41. Ridker PM, Stampfer MR, Rifai N. Novel risk factors for systemic atherosclerosis.Acomparisonof C-reactiveprotein, brinogen, homocysteine, lipoprotein(a),andstandardcholesterol screening aspredictorsofperipheral arterial disease.JAMA 2001;285:24812485.R.J.Bisoendial et al. 2091aby guest on August 4, 2015Downloaded from 42. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO3rd,Criqui M, Fadl YY, FortmannSP, Hong Y, Myers GL, Rifai N, SmithSCJr,TaubertK, TracyRP, VinicorF. CentersforDiseaseControl andPrevention,American Heart Association. Markers of inammation and cardiovasculardisease: application to clinical and public health practice: a statement for health-care professionals from the Centers for Disease Control and Prevention and theAmerican Heart Association. Circulation 2003;107:499511.43. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates riskprediction based on the Framingham Score:implications forfuture risk assess-ment: results froma large cohort study in southern Germany. Circulation2004;109:13491353.44. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in car-diovascular risk prediction models for women. Ann Intern Med 2006;145:2129.45. WilsonPW, PencinaM, JacquesP, SelhubJ, DAgostinoRBSr, ODonnell CJ.C-reactive protein and reclassication of cardiovascular risk in the FraminghamHeart Study. Circ Cardiovasc Qual Outcomes 2008;1:9297.46. RanaJS, CoteM, DespresJP, SandhuMS, TalmudPJ, NinioE, WarehamNJ,Kastelein JJ, Zwinderman AH, KhawKT, Boekholdt MS. Inammatory bio-markersandthepredictionof coronaryeventsamongpeopleatintermediaterisk; the EPIC-Norfolk prospective population study. Heart 2009;95:16821687.47. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G,Persson M, Smith JG, Magnusson M, Christensson A, Struck J, Morgenthaler NG,Bergmann A, Pencina MJ, Wang TJ. Novel and conventional biomarkers for pre-dictionof incident cardiovascular events inthecommunity. JAMA2009;302:4957.48. Verzilli C, Shah T, Casas JP, Chapman J, Sandhu M, Debenham SL, Boekholdt MS,Khaw KT, Wareham NJ, Judson R, Benjamin EJ, Kathiresan S, Larson MG, Rong J,Sofat R, HumphriesSE, SmeethL, Cavalleri G, WhittakerJC, Hingorani AD.Bayesian meta-analysis of genetic association studies with different sets ofmarkers. Am J Hum Genet 2008;82:859872.49. Crawford DC,Sanders CL,Qin X, Smith JD,ShephardC,Wong M,Witrak L,Rieder MJ, Nickerson DA. Genetic variation is associated with C-reactiveprotein levelsintheThirdNational HealthandNutritionExaminationSurvey.Circulation 2006;114:24582465.50. Kathiresan S, Larson MG, Vasan RS, Guo CY, Gona P, Keaney JF Jr, Wilson PW,Newton-ChehC, MusoneSL, CamargoAL, DrakeJA, LevyD, ODonnell CJ,Hirschhorn JN, Benjamin EJ. Contribution of clinical correlates and 13 C-reactiveproteingenepolymorphismstointerindividual variabilityinserumC-reactiveprotein level. Circulation 2006;113:14151423.51. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, Cushman M,Bis JC, Zeng D, Lin D, Kuller LH, Nickerson DA, Psaty BM, Tracy RP, Reiner AP.Association of polymorphisms in the CRP gene with circulating C-reactiveprotein levels and cardiovascular events. JAMA 2006;296:27032711.52. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG.Genetically elevated C-reactiveprotein andischemic vascular disease.NEngl JMed 2008;359:18971908.53. Brull DJ, SerranoN, ZitoF, JonesL, MontgomeryHE, RumleyA, SharmaP,LoweGD, WorldMJ, HumphriesSE, Hingorani AD. HumanCRPgenepoly-morphism inuences CRP levels: implications for the prediction and pathogen-esis of coronary heart disease. Arterioscler Thromb Vasc Biol 2003;23:20632069.54. CasasJP, ShahT, CooperJ, HaweE, McMahonAD, GaffneyD, PackardCJ,OReillyDS, Juhan-VagueI, YudkinJS, Tremoli E, MargaglioneM, Di MinnoG,HamstenA, KooistraT, StephensJW, Hurel SJ, LivingstoneS, ColhounHM,Miller GJ, Bautista LE, Meade T, Sattar N, Humphries SE, Hingorani AD.Insight into the nature of the CRP - coronary event association using Mendelianrandomization. Int J Epidemiol 2006;35:922931.55. Pai JK, Mukamal KJ, Rexrode KM, Rimm EB. C-reactive protein (CRP) gene poly-morphisms, CRP levels, and risk of incident coronary heart disease in two nestedcase-control studies. PLoS ONE 2008;3:e1395.56. Russell AI, Cunninghame Graham DS, Shepherd C, Robertson CA, Whittaker J,MeeksJ, Powell RJ, IsenbergDA, Walport MJ, VyseTJ. PolymorphismattheC-reactive protein locus inuences gene expression and predisposes to systemiclupus erythematosus. Hum Mol Genet 2004;13:137147.57. Zee RY, Ridker PM. Polymorphism in the human C-reactive protein (CRP) gene,plasma concentrations of CRP, and the risk of future arterial thrombosis. Athero-sclerosis 2002;162:217219.58. Suk HJ, Ridker PM, Cook NR, Zee RY. Relation of polymorphism within the C-reactive protein gene and plasma CRP levels. Atherosclerosis 2005;178:139145.59. Balistreri CR, Vasto S, Listi F, Grimaldi MP, Lio D, Colonna-Romano G,Caruso M,CaimiG, Hoffmann E,Caruso C,Candore G.Association between+1059G/CCRPpolymorphism andacute myocardial infarction ina cohortofpatients from Sicily:a pilot study. Ann N Y Acad Sci2006;1067:276281.60. Eklund C, Kivimaki M, Islam MS, Juonala M, Kahonen M, Marniemi J, Lehtimaki T,Viikari J, Raitakari OT, Hurme M. C-reactive protein genetics is associated withcarotidarterycomplianceinmeninTheCardiovascularRiskinYoungFinnsStudy. Atherosclerosis 2008;196:841848.61. Kovacs A, Green F, Hansson LO, Lundman P, Samnegard A, Boquist S,Ericsson CG, Watkins H, Hamsten A, Tornvall P. Anovel common singlenucleotidepolymorphisminthepromoter regionof theC-reactiveproteingeneassociatedwiththeplasmaconcentrationof C-reactiveprotein. Athero-sclerosis 2005;178:193198.62. Lawlor DA, Harbord RM, Timpson NJ, Lowe GD, Rumley A, Gaunt TR, Baker I,Yarnell JW, Kivimaki M, Kumari M, Norman PE, Jamrozik K, Hankey GJ,AlmeidaOP, FlickerL, WarringtonN, MarmotMG, Ben-ShlomoY, PalmerLJ,Day IN, EbrahimS, SmithGD. TheassociationofC-reactive protein andCRPgenotypewithcoronaryheart disease: ndings fromvestudies with4,610cases amongst 18,637 participants.PLoS ONE 2008;3:e3011.63. Miller DT, Zee RY, Suk Danik J, Kozlowski P, Chasman DI, Lazarus R, Cook NR,RidkerPM, Kwiatkowski DJ. Associationof commonCRPgenevariantswithCRP levels and cardiovascular events. Ann Hum Genet 2005;69:623638.64. Szalai AJ, McCroryMA, CooperGS, WuJ, KimberlyRP. Associationbetweenbaselinelevels of C-reactiveprotein(CRP) anda dinucleotiderepeat poly-morphism in the intron of the CRP gene.Genes Immun 2002;3:1419.65. Szalai AJ, Wu J, Lange EM, McCrory MA, Langefeld CD, Williams A,ZakharkinSO, GeorgeV, AllisonDB, CooperGS, XieF, FanZ, EdbergJC,Kimberly RP. Single-nucleotide polymorphisms in the C-reactive protein(CRP) genepromoterthat affect transcriptionfactorbinding, altertranscrip-tional activity, and associate with differences in baseline serumCRP level.J Mol Med 2005;83:440447.66. Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, Erdmann J,Braund P, Engert JC, Bennett D, Coin L, Ashby D, Tzoulaki I, Brown IJ, Mt-Isa S,McCarthyMI, PeltonenL, Freimer NB, Farrall M, RuokonenA, HamstenA,LimN, Froguel P, WaterworthDM, VollenweideP, WaeberG, JarvelinMR,Mooser V, Scott J, Hall AS, Schunkert H, AnandSS, Collins R, Samani NJ,WatkinsH, KoonerJS. Geneticloci associatedwithC-reactiveproteinlevelsand risk of coronary heart disease.JAMA 2009;302:3748.67. CRPCHDGenetics Collaboration. Collaborativepooledanalysis of dataonC-reactive protein gene variants and coronary disease: judging causality byMendelian randomisation. Eur J Epidemiol 2008;23:531540.68. Kobayashi S, InoueN, Ohashi Y, Terashima M, Matsui K, Mori T, Fujita H,AwanoK, Kobayashi K, Azumi H, Ejiri J, HirataK, KawashimaS, Hayashi Y,Yokozaki H, Itoh H, Yokoyama M. Interaction of oxidative stress and inamma-tory response in coronary plaque instability: important role of C-reactiveprotein. Arterioscler Thromb Vasc Biol 2003;23:13981404.69. Sattler KJ, WoodrumJE, Galili O, OlsonM, Samee S, Meyer FB, ZhuXY,LermanLO, LermanA. Concurrent treatment withrenin-angiotensinsystemblockersandacetylsalicylicacidreducesnuclearfactorkappaBactivationandC-reactiveproteinexpressioninhumancarotidarteryplaques. Stroke2005;36:1420.70. Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J,Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with theterminalcomplementcomplex inthe intimaofearly atheroscleroticlesionsofhuman coronary arteries.Arterioscler Thromb Vasc Biol 1998;18:13861392.71. Yasojima K, SchwabC, McGeer EG, McGeer PL. Generationof C-reactiveproteinandcomplement components inatheroscleroticplaques. AmJ Pathol2001;158:10391051.72. TurkJR, Carroll JA, LaughlinMH, ThomasTR, Casati J, BowlesDK, SturekM.C-reactive protein correlates with macrophage accumulation in coronaryarteries of hypercholesterolemic pigs.J Appl Physiol 2003;95:13011304.73. SunH, KoikeT, IchikawaT, HatakeyamaK, Shiomi M, ZhangB, KitajimaS,Morimoto M, Watanabe T, Asada Y, Chen YE, Fan J. C-reactive protein in ather-osclerotic lesions: its origin and pathophysiological signicance. Am J Pathol 2005;167:11391148.74. InoueT, KatoT, Uchida T, Sakuma M, Nakajima A, Shibazaki M, ImotoY,SaitoM, HashimotoS, Hikichi Y, NodeK. Local releaseof C-reactiveproteinfromvulnerableplaqueorcoronaryarterial wall injuredbystenting. J AmCollCardiol 2005;46:239245.75. Bodman-SmithKB, GregoryRE, HarrisonPT, Raynes JG. FcgRIIaexpressionwith FcgRI results in C-reactive protein- and IgG-mediated phagocytosis.J Leukoc Biol 2004;75:10291035.76. Bodman-Smith KB, Melendez AJ, Campbell I, Harrison PT, Allen JM, Raynes JG.C-reactive protein-mediated phagocytosis and phospholipase D signallingthroughthehigh-afnityreceptorforimmunoglobulinG(FcgRI). Immunology2002;107:252260.77. Tebo JM,Mortensen RF. Characterization and isolation of a C-reactive proteinreceptor fromthe human monocytic cell line U-937. J Immunol 1990;144:231238.C-reactive protein marker or mediator? 2091bby guest on August 4, 2015Downloaded from 78. Stein MP, Edberg JC, Kimberly RP, ManganEK, Bharadwaj D, MoldC, DuClos TW. C-reactive protein binding to FcgRIIa on human monocytes and neu-trophils is allele-specic.J Clin Invest 2000;105:369376.79. Manolov DE, Rocker C, Hombach V, Nienhaus GU, Torzewski J. Ultrasensitiveconfocal uorescence microscopy of C-reactive protein interacting with FcgRIIa.Arterioscler Thromb Vasc Biol 2004;24:23722377.80. Devaraj S, Du Clos TW, Jialal I. Binding and internalization of C-reactive proteinby Fcg receptors on human aortic endothelial cells mediates biological effects.Arterioscler Thromb Vasc Biol 2005;25:13591363.81. Mineo C, Gormley AK, Yuhanna IS, Osborne-Lawrence S, Gibson LL, Hahner L,Shohet RV, BlackS, SalmonJE, SamolsD, KarpDR, ThomasGD, Shaul PW.FcgRIIBmediates C-reactive protein inhibition of endothelial NOsynthase.Circ Res 2005;97:11241131.82. LimMY, Wang H, Kapoun AM, Oconnell M, OYoung G, Brauer HA,LuedtkeGR, ChakravartyS, Dugar S, SchreinerGS, ProtterAA, Higgins LS.p38 inhibition attenuates the pro-inammatory response to C-reactive proteinby human peripheral blood mononuclear cells. J Mol Cell Cardiol 2004;37:11111114.83. Bharadwaj D, Stein MP, Volzer M, Mold C, Du Clos TW. The major receptor forC-reactiveproteinonleukocytesisfcgammareceptorII. J ExpMed1999;190:585590.84. Lin R, Liu J, Peng N, Yang G, Gan W, Wang W. Lovastatin reduces nuclear factorkappaBactivationinducedby C-reactive protein in human vascular endothelialcells.Biol Pharm Bull 2005;28:16301634.85. Devaraj S, DavisB, Simon SI, Jialal I. CRPpromotesmonocyte-endothelial celladhesionviaFcgreceptorsinhumanaorticendothelial cellsunderstaticandshear ow conditions.Am J Physiol Heart Circ Physiol 2006;291:H1170H1176.86. Williams TN, ZhangCX, GameBA, HeL, HuangY. C-reactiveprotein stimu-latesMMP-1expressioninU937histiocytesthroughFcgRII andextracellularsignal-regulatedkinasepathway:: animplicationof CRPinvolvementinplaquedestabilization. Arterioscler Thromb Vasc Biol 2004;24:6166.87. Pasceri V, WillersonJT, YehET. Direct proinammatoryeffect of C-reactiveprotein on human endothelial cells.Circulation 2000;102:21652168.88. Verma S, Li SH, Badiwala MV, Weisel RD, Fedak PW, Li RK, Dhillon B,MickleDA. Endothelinantagonismandinterleukin-6inhibitionattenuatetheproatherogenic effects of C-reactive protein. Circulation 2002;105:18901896.89. Devaraj S, KumaresanPR, Jialal I. Effect of C-reactiveproteinonchemokineexpression in human aortic endothelial cells. J Mol Cell Cardiol 2004;36:405410.90. Venugopal SK, Devaraj S, YuhannaI, Shaul P, Jialal I. Demonstrationthat C-reactiveproteindecreaseseNOSexpressionandbioactivityinhumanaorticendothelial cells. Circulation 2002;106:14391441.91. VermaS, WangCH, Li SH, DumontAS, FedakPW, BadiwalaMV, DhillonB,Weisel RD,Li RK,Mickle DA, Stewart DJ.A self-fullling prophecy: C-reactiveproteinattenuates nitricoxideproductionandinhibitsangiogenesis. Circulation2002;106:913919.92. Hein TW, Singh U, Vasquez-Vivar J, Devaraj S, Kuo L, Jialal I. Human C-reactiveprotein induces endothelial dysfunction and uncoupling of eNOS in vivo. Athero-sclerosis 2009;206:6168.93. Qamirani E, RenY, KuoL, HeinTW. C-reactiveprotein inhibitsendothelium-dependent NO-mediated dilation in coronary arterioles by activating p38kinase and NAD(P)H oxidase.Arterioscler Thromb Vasc Biol 2005;25:9951001.94. Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclinrelease from human aortic endothelial cells.Circulation 2003;108:16761678.95. Li L, Roumeliotis N, Sawamura T, Renier G. C-reactive protein enhances LOX-1expression in human aortic endothelial cells: relevance of LOX-1 to C-reactiveprotein-induced endothelial dysfunction.Circ Res 2004;95:877883.96. Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, SzmitkoP, Li RK,Mickle DA, Verma S. C-reactive protein upregulates angiotensintype1 recep-tors in vascular smooth muscle.Circulation 2003;107:17831790.97. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM,AsaharaT. Transplantation of ex vivoexpanded endothelial progenitor cellsfortherapeutic neovascularization. Proc Natl Acad Sci USA 2000;97:34223427.98. Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, Badiwala MV,MickleDA, Weisel RD, FedakPW, StewartDJ, KutrykMJ. C-reactiveproteinattenuates endothelial progenitor cell survival, differentiation, and function:further evidence of a mechanistic link between C-reactive protein and cardiovas-cular disease. Circulation 2004;109:20582067.99. Suh W, Kim KL, Choi JH, Lee YS, Lee JY, Kim JM, Jang HS, Shin IS, Lee JS, Byun J,Jeon ES, Kim DK. C-reactive protein impairs angiogenic functions and decreasesthe secretion of arteriogenic chemo-cytokines in human endothelial progenitorcells.Biochem Biophys Res Commun 2004;321:6571.100. Devaraj S, Yun JM, Adamson G, Galvez J, Jialal I. C-reactive protein impairs theendothelial glycocalyxresulting in endothelial dysfunction. Cardiovasc Res 2009;84:479484.101. Clapp BR, Hirscheld GM, Storry C, Gallimore JR, Stidwill RP, Singer M,Deaneld JE, MacAllister RJ, Pepys MB, Vallance P, Hingorani AD. Inammationand endothelial function: direct vascular effects of human C-reactive protein onnitric oxide bioavailability.Circulation 2005;111:15301536.102. Bisoendial RJ, Kastelein JJ, Peters SL, Levels JH, Birjmohun R, Rotmans JI,Hartman D, Meijers JC, Levi M, Stroes ES. Effects of CRP-infusion on endothelialfunctionandcoagulationinnormocholesterolemicandhypercholesterolemicsubjects.J Lipid Res 2007;48:952960.103. Bisoendial RJ, KasteleinJJ, Levels JH, Zwaginga JJ, vandenBB, Reitsma PH,Meijers JC, Hartman D, Levi M, Stroes ES. Activation of inammation and coagu-lation after infusion of C-reactive protein in humans. Circ Res 2005;96:714716.104. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive proteininduceshumanperipheral bloodmonocytestosynthesizetissuefactor. Blood1993;82:513520.105. Paffen E, Vos HL, Bertina RM. C-reactive protein does not directly induce tissuefactor in human monocytes.Arterioscler Thromb Vasc Biol 2004;24:975981.106. Cirillo P, Golino P, Calabro P, Cali G, Ragni M, DeRosa S, Cimmino G, Pacileo M,De Palma R, Forte L, Gargiulo A, Corigliano FG, Angri V, Spagnuolo R, Nitsch L,Chiariello M. C-reactive protein induces tissue factor expression and promotessmooth muscle and endothelial cell proliferation. Cardiovasc Res 2005;68:4755.107. Devaraj S, XuDY, Jialal I. C-reactiveproteinincreasesplasminogenactivatorinhibitor-1 expression and activity in human aortic endothelial cells: implicationsfor the metabolic syndrome and atherothrombosis. Circulation 2003;107:398404.108. Singh U, Devaraj S, Jialal I. C-reactive protein decreases tissue plasminogen acti-vator activity in human aortic endothelial cells. Evidence that C-reactive proteinis a procoagulant.Arterioscler Thromb Vasc Biol 2005;25:22162221.109. Abe N,OsanaiT,Fujiwara T,Kameda K,Matsunaga T,Okumura K.C-reactiveprotein-induced upregulationof extracellular matrix metalloproteinaseinducerin macrophages:inhibitory effect of uvastatin. Life Sci2006;78:10211028.110. Montero I, Orbe J, Varo N, Beloqui O, Monreal JI, Rodriguez JA, Diez J, Libby P,ParamoJA. C-reactiveproteininducesmatrixmetalloproteinase-1and-10inhuman endothelial cells: implications for clinical and subclinical atherosclerosis.J Am Coll Cardiol 2006;47:13691378.111. Moreau M,BrocheriouI, Petit L,NinioE,Chapman MJ, Rouis M.Interleukin-8mediatesdownregulationof tissueinhibitorof metalloproteinase-1expressionin cholesterol-loaded human macrophages: relevance tostability of athero-sclerotic plaque.Circulation 1999;99:420426.112. Devaraj S, KumaresanPR, Jialal I. Effect of C-reactiveproteinonchemokineexpression in human aortic endothelial cells. J Mol Cell Cardiol 2004;36:405410.113. Bisoendial RJ, Birjmohun RS, AkdimF, van V, Spek CA, Hartman D, deGroot ER, Bankaitis-Davis DM, Kastelein JJ, Stroes ES. C-reactive proteinelicits white blood cell activation in humans. Am J Med 2009;122:582589.114. Volanakis JE. Complement activation by C-reactive protein complexes. Ann N YAcad Sci1982;389:235250.115. Nijmeijer R, LagrandWK, Lubbers YT, Visser CA, Meijer CJ, NiessenHW,Hack CE. C-reactive protein activates complement in infarcted human myocar-dium.Am J Pathol 2003;163:269275.116. Kushner I, Kaplan MH. Studies of acute phase protein. I. An immunohistochem-ical methodforthelocalizationof Cx-reactiveproteininrabbits. Associationwith necrosis in local inammatory lesions.J Exp Med 1961;114:961974.117. Lagrand WK, Niessen HW, WolbinkGJ,JasparsLH,VisserCA,Verheugt FW,Meijer CJ, Hack CE. C-reactive protein colocalizes with complement inhuman hearts during acute myocardial infarction. Circulation 1997;95:97103.118. Griselli M, Herbert J, Hutchinson WL, Taylor KM, Sohail M, Krausz T, Pepys MB.C-reactive protein and complement are important mediators of tissue damage inacute myocardial infarction.J Exp Med 1999;190:17331740.119. PepysMB, HirscheldGM, TennentGA, GallimoreJR, KahanMC, Bellotti V,HawkinsPN, MyersRM, SmithMD, PolaraA, CobbAJ, LeySV, AquilinaJA,Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE,Thompson D, Wood SP. Targeting C-reactive protein for the treatment of car-diovascular disease. Nature 2006;440:12171221.120. Pepys MB, Hawkins PN, KahanMC, Tennent GA, GallimoreJR, GrahamD,Sabin CA, Zychlinsky A, de DJ. Proinammatory effects of bacterial recombinanthuman C-reactive protein are caused by contamination with bacterial products,not by C-reactive protein itself. Circ Res 2005;97:e97e103.121. Bisoendial R, KasteleinJ, StroesE. InresponsetovandenBergetal: onthedirect actions of CRP in humans. Circ Res 2005;97:e71.122. Bisoendial R, BirjmohunR, Keller T, vanLS, Levels H, Levi M, KasteleinJ,Stroes E.In vivo effects of C-reactive protein (CRP)-infusion into humans.CircRes 2005;97:e115e116.123. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R,Giugliano D. Effect of weight loss and lifestyle changes on vascular inammatorymarkers in obese women: a randomized trial. JAMA 2003;289:17991804.124. KoppHP, KoppCW, FestaA, KrzyzanowskaK, KriwanekS, MinarE, RokaR,Schernthaner G. Impact of weight loss oninammatory proteins andtheirR.J.Bisoendial et al. 2091cby guest on August 4, 2015Downloaded from associationwiththeinsulinresistancesyndromeinmorbidlyobesepatients.Arterioscler Thromb Vasc Biol 2003;23:10421047.125. Tchernof A, NolanA, SitesCK, AdesPA, PoehlmanET. WeightlossreducesC-reactiveproteinlevels inobesepostmenopausal women. Circulation2002;105:564569.126. Albert MA, DanielsonE, Rifai N, RidkerPM, PRINCEInvestigators. Effect ofstatintherapyonC-reactiveproteinlevels: thepravastatininammation/CRPevaluation(PRINCE): a randomizedtrial andcohort study. JAMA2001;286:6470.127. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pra-vastatinonplasmaconcentrationof C-reactiveprotein. TheCholesterol andRecurrent Events (CARE) Investigators. Circulation 1999;100:230235.128. Ridker PM, Rifai N, Cleareld M, Downs JR, Weis SE, Miles JS, Gotto AM Jr, AirForce/Texas Coronary Atherosclerosis Prevention Study Investigators. Measure-ment of C-reactive protein for the targeting of statin therapy in the primary pre-vention of acute coronary events. N Engl J Med 2001;344:19591965.129. Ridker PM, Danielson E, Fonseca FA, Genest J, GottoAMJr, Kastelein JJ,Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG,ShepherdJ, WillersonJT, GlynnRJ. RosuvastatintopreventvasculareventsinmenandwomenwithelevatedC-reactiveprotein. NEngl J Med2008;359:21952207.130. Verma A, Ranganna KM, Reddy RS, Verma M, Gordon NF. Effect of rosuvastatinon C-reactive protein and renal function in patients with chronic kidney disease.Am J Cardiol 2005;96:12901292.131. Heinecke JW. Chemical knockout of C-reactive protein in cardiovasculardisease. Nat Chem Biol 2006;2:300301.132. Ridker PM, Danielson E, Fonseca FA, Genest J, GottoAMJr, Kastelein JJ,Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BrG,ShepherdJ, WillersonJT, GlynnRJ. ReductioninC-reactiveproteinandLDLcholesterol and cardiovascular event rates after initiation of rosuvastatin: a pro-spective study of the JUPITER trial. Lancet 2009;373:11751182.C-reactive protein marker or mediator? 2091dby guest on August 4, 2015Downloaded from