CURRENT OPINION

How to use C-reactive protein in acutecoronary careLuigi M. Biasucci, Wolfgang Koenig, Johannes Mair, Christian Mueller, Mario Plebani,Bertil Lindahl, Nader Rifai, Per Venge, Christian Hamm, Evangelos Giannitsis,Kurt Huber, Marcello Galvani, Marco Tubaro, Paul Collinson, Joseph S. Alpert,Yonathan Hasin, Hugo Katus, Allan S. Jaffe, and Kristian Thygesen*, the Study Groupon Biomarkers in Cardiology of the Acute Cardiovascular Care Association of theEuropean Society of Cardiology

Department of Cardiology B, Aarhus University Hospital, Tage Hansens Gade 2, Aarhus DK-8000, Denmark

Received 26 May 2013; revised 17 September 2013; accepted 23 September 2013; online publish-ahead-of-print 7 November 2013

IntroductionC-reactive protein is an acute phase protein and an establishedmarker for detection, risk stratification, and monitoring of infectionsand inflammatory and necrotic processes. Because C-reactiveprotein is sensitive but not specific, its values must be interpretedin the clinical context. In patients with acute myocardial infarction(AMI), C-reactive protein increases within 46 h of symptoms,peaks 24 days later, and returns to baseline after 710 days.1

C-reactive protein has gained interest recently as a marker for riskstratification in acute coronary syndrome (ACS) when measured byhigh-sensitivity C-reactive protein assays. These assays have greateranalytical sensitivity and reliably measure C-reactive protein concen-trations within the reference range with low imprecision (510%).2

Because of evidence that atherosclerosis is an inflammatory disease,high-sensitivity C-reactive protein can be used as a biomarker of riskin primary prevention and in patients with known cardiovasculardisease.3 The aim of this review is to evaluate the use of C-reactiveprotein in patients with acute coronary disease.

Biochemical and analytical issuesC-reactive protein is a non-specific first-line host defence mechan-ism.4 With stimulation by cytokines (e.g. interleukins and tumour ne-crosis factor-alpha), C-reactive protein synthesis in hepatocytesoccurs within 46 h. Concentrations can rise 1000-fold or moreover 2448 h. C-reactive protein has been detected in atheroscler-otic plaques; its possible role in atherosclerogenesis is summarized inFigure 1, but is still a matter of debate.5 Genetic variants account for3540% of the variability in high-sensitivity C-reactive protein.6

The in vitro stability of high-sensitivity C-reactive protein is ex-cellent.2,7 Specific blood sampling conditions are not necessary.However, retesting may be necessary with some assays if there ismarked lipaemia. Baseline and subsequent measures are in goodagreement for risk stratification despite biological variability of3060%.2,7

The upper reference limit is method-dependent but usually,8 mg/L for standard assays.2,7 The distribution of high-sensitivityC-reactive protein concentrations is skewed in both genders with a50th percentile of 1.5 mg/L (excluding women on hormone re-placement therapy). Race differences have been reported.8 Moststudies have reported no relationship with age but circadian and sea-sonal variation.9 C-reactive protein concentrations are increased bysmoking, obesity, and hormone replacement therapy and reduced byexercise, moderate alcohol drinking, and statin use.2,3,7 Correctionfor these factors is essential in reference range studies.

C-reactive protein assays are not standardized.2 We recommendthe use of third-generation high-sensitivity C-reactive protein assaysthat combine features of standard and high-sensitivity C-reactiveprotein assays. Required assay precision should be ,10% in therange of 3 and 10 mg/L.

Critical clinical concepts(1) C-reactive protein concentrations are reported in mg/L.(2) C-reactive protein test results are method-dependent, but clas-

sification of patients into risk categories is usually comparable.(3) Third-generation high-sensitivity C-reactive protein assays are

recommended.(4) Nospecific patient preparationbeforeblood sampling is necessary.(5) The in vitro stability of C-reactive protein is high.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

* Corresponding author. Tel: +45 78 46 7614, Fax: +45 78 46 7619, Email: kristhyg@rm.dkPublished on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com

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Clinical use of C-reactive proteinin acute coronary syndromeHigher C-reactive protein concentrations are associated withcomplex, vulnerable atherosclerotic plaques,10 suggesting thathigh-sensitivity C-reactive protein elevations represent a marker ofsystemic atherosclerotic plaque instability. Minor increases mightreflect inflammation in coronary plaques or injured coronary wallsafter stenting.5,11 However, there is no association betweenC-reactive protein and the extent of coronary artery disease, andC-reactive protein has not been causally related to coronaryevents.6 Nonetheless, C-reactive protein elevations are associatedwith mortality but only weakly with recurrent MI.12,13

C-reactive protein measurements have no value for the diagnosisof ST-segment elevation AMI (STEMI), since 41% of STEMI patientshave low (,2 mg/L) concentrations on admission. Furthermore, inmany, values are not significantly different in samples obtained ,2,

24, and 46 h afteronset of symptoms.14 However, high C-reactiveprotein concentrations before percutaneous coronary intervention(PCI) in STEMI are related to recurrent MI and death rates at 1-yearfollow-up.15 Moreover, C-reactive protein values correlate with infarctsize by magnetic resonance imaging,16 although markers of myocardialnecrosis, such as cardiac troponin (cTn), correlate more closely whileproviding similar predictive value for mortality.16,17

C-reactive protein measurements are not useful for the diagnosisof non-STEMI either. Its use has been advocated during the acutephase for risk stratification but conclusive evidence for its incremen-tal value is absent. C-reactiveprotein is a predictorof short- and long-term cardiovascular complications in ACS,10,13,14,17 and C-reactiveprotein levels contribute incremental information over and aboveclinical risk scores or other biomarkers in some but not all studies.1719 Inaddition, thereare fewstudiestodateofC-reactiveprotein togetherwith more sensitive cTn assays20 and none with high-sensitivity cTnassays.

Figure 1 Possible pathophysiological effects of C-reactive protein in atherosclerosis. Aggregated C-reactive protein selectively binds LDL andVLDL in serum, thereby potentially participating in the mechanisms involved in plaque formation and destabilization, and shows some of the keyproperties of antibodies and may contribute to immune responses by activation of antigen presenting cells. Procoagulant effects have been reportedin vitro as well. C-reactive protein induces increased expression of adhesion molecules and modulation of NO synthesis. Dashed arrow representsweak evidence, whereas continuous arrow denotes evidence confirmed by several studies. APC, antigen presenting cell; CRP, C-reactive protein;LDL, low-density lipoprotein; NO, nitric oxide; VLDL, very low-density lipoprotein; TF, tissue factor.

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C-reactive protein is not helpful in selecting an invasive or conser-vative strategy in ACS.21 However, an increased C-reactive proteinlevel is an independent prognostic indicator for death or non-fatalMI following PCI.22 It is difficult to advocate C-reactive protein as aprimary target for therapy since drugs that specifically influenceonly C-reactive protein alone do not exist. Nonetheless, in preven-tion studies post ACS, lower levels of C-reactive protein followingstatin therapy predict greater subsequent risk reductions.23 25

Based on early studies, a decision limit for risk stratification of10 mg/L was suggested although other limits have been proposedas well.20 C-reactive protein has usually been tested in samplesdrawn on admission, but the optimal time to assess risk has notbeen systematically investigated.

Critical clinical concepts(1) C-reactive protein is an established marker for diagnosing and

monitoring infection, inflammation, and tissue injury.(2) C-reactive protein measurement in primary prevention predicts

future cardiovascular events with significance similar to that oftotal and HDL cholesterol.

(3) C-reactive protein measurement in secondary prevention pre-dicts risk of recurrent MI, stroke, and cardiovascular death.

(4) C-reactive protein measurements have no value for diagnosingAMI.

(5) C-reactive protein release is related to infarct size and risk inSTEMI patients.

(6) C-reactive protein is not helpful for the choice of an invasive orconservative strategy in ACS.

(7) C-reactive protein measurement after ACS and after PCI can beused to identify patients in whom an intensive risk factor modifi-cation is useful.

(8) For cardiovascular prevention, a C-reactive protein value of.3 mg/L is considered high risk but a limit 10 mg/L seemsmore appropriate in ACS patients.

Conclusions and outlookGiven the central role of inflammation in the pathogenesis of ather-othrombosis, this is an area of active research. There are many newinflammatory markers proposed for use, but at present none ofthem has emerged as clinically more useful than C-reactive protein.New ways of conceptualizing acute atherothrombotic diseases mayfacilitate new approaches in this critical field.26

Conflict of interest: LB has been consultant for Siemens Diagnos-tics, Roche Diagnostics and Abbott Diagnostics; WK has receivedlecture honoraria from AstraZeneca, Roche and Novartis and is amember of the Executive Steering Committee of CANTOS; JM hasreceived fees from Philipps Health Care Incubator; EG receivedlecture honoraria from Roche Diagnostics, Bayer Vital, MitsubishiChemicals and was consultant for Roche Diagnostics; CM receivedlecture honoraria from Abbott Diagnostics, Biosite, Brahms, RocheDiagnostics, Siemens Diagnostics and he has received support fromthe Swiss National Science Foundation (PP00B-102853), the SwissHeart Foundation, Abbott Diagnostics, Biosite, Brahms, Nano-sphere, Roche Diagnostics and Siemens Diagnostics; BL has received

research grants from Roche Diagnostics and Radiometer A/S, lecturefees from Roche Diagnostics and Siemens Healthcare Diagnosticsand has been member of the scientific advisory boards of PhilipsHealthcare, Siemens Healthcare, Beckman Coulter, FIOMI and bio-Merieux; HK holds a patent on the cardiac troponin T assay jointlywith Roche Diagnostics; ASJ has received consulting honorariafrom most of the major diagnostic companies including Beckman-Coulter and Siemens; MT has been member of the advisory boardsof Roche Diagnostics and Abbott Diagnostics and he has receivedlecture honoraria from Biosite/Inverness, Abbott Diagnostics andDade Behring; JA received lecture honoraria from Roche Diagnosticsand Siemens Diagnostics; PC is member of the Diagnostics AdvisoryCommittee of the National Institute of Clinical Excellence in the UK;CH has been consultant for Abbott Diagnostics and Roche Diagnos-tics; MG has been consultant for Roche Diagnostics and he hasreceived research grants from Roche Diagnostics, Siemens Diagnos-tics and Beckman Coulter; MP received consulting honoraria fromSiemens, Roche and Abbott Diagnostics; PV has received lecturehonoraria and research grants from Abbott, Beckman Coulter,Roche Diagnostics, Siemens and is currently consultant for Abbott,bioMerieux, Philips and Radiometer.

References1. de Beer FC, Hind CRX, Fox KM, Allan RM, Maseri A, Pepys MB. Measurement of

serum C-reactive protein in myocardial ischemia and infarction. Br Heart J 1982;47:239243.

2. Roberts WL, CDC; AHA. Workshop on markers of inflammation and cardiovascu-lar disease: application to clinical and public health practice laboratory tests availableto assess inflammation performance and standardization: a background paper.Circulation 2004;110:e572e576.

3. Smith SC Jr, Anderson JL, Cannon RO III, Fadl YY, Koenig W, Libby P, Lipshultz SE,Mensah GA, RidkerPM, Rosenson R. CDC/AHAworkshop on markersof inflamma-tion and cardiovascular disease: application to clinical and public health practice:report from the clinical practice discussion group. Circulation 2004;110:e550e553.

4. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem 2004;279:4848748490.

5. Devaraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombo-sis. Clin Chem 2009;55:229238.

6. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC),Wensley F, Gao P, Burgess S, Kaptoge S, Di Angelantonio E, Shah T, Engert JC,Clarke R, Davey-Smith G, Nordestgaard BG, Saleheen D, Samani NJ, Sandhu M,Anand S, Pepys MB, Smeeth L, Whittaker J, Casas JP, Thompson SG,Hingorani AD, Danesh J. Association between C reactive protein and coronaryheart disease: mendelian randomisation analysis based on individual participantdata. BMJ 2011;342:d548.

7. Ledue TB, Rifai N. Preanalytic and analytic sources of variations in C-reactive proteinmeasurement: implications for cardiovascular disease risk assessment. Clin Chem2003;49:12581271.

8. Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, Wians FHJr, Grundy SM, de Lemos JA. Raceand gender differences in C-reactiveprotein levels.J Am Coll Cardiol 2005;46:464469.

9. Rudnicka AR, Rumley A, Lowe GD, Strachan DP. Diurnal, seasonal and blood-processing patterns in levels of circulating fibrinogen, fibrin D-dimer, C-reactiveprotein, tissue plasminogen activator and von Willebrand factor in a 45-years oldpopulation. Circulation 2007;115:9961003.

10. Monaco C, Rossi E, Milazzo D, Citterio F, Ginnetti F, DOnofrio G, Cianflone D,Crea F, Biasucci LM, Maseri A. Persistent systemic inflammation in unstable anginais largely unrelated to the atherothrombotic burden. J Am Coll Cardiol 2005;45:238243.

11. Inoue T, Kato T, Uchida T, Sakuma M, Nakajima A, Shibazaki M, Imoto Y, Saito M,Hashimoto S, Hikichi Y, Node K. Local release of C-reactive protein from vulnerableplaque or coronary arterial wall injured by stenting. J Am Coll Cardiol 2005;46:239245.

12. Lindahl B,TossH, Siegbagn A,VengeP, Wallentin K. Markersof myocardial injury andinflammation in relation to long-term mortality in unstable coronary artery disease.FRISC study group. Fragmin during instability in coronary artery. N Engl J Med 2000;343:11391147.

Use of C-reactive protein in acute coronary care 3689

by guest on September 22, 2014

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13. James SK, Armstrong P, Barnathan E, Califf R, Lindahl B, Siegbahn A, Simoons ML,Topol EJ, Venge P, Wallentin L, GUSTO-IV-ACS Investigators. Troponin andC-reactive protein have different relations to subsequent mortality and myocardialinfarction after acute coronary syndrome: a GUSTO-IV substudy. J Am Coll Cardiol2003;41:916924.

14. Cristell N, Cianflone D, Durante A, Ammirati E, Vanuzzo D, Banfi M, Calori G,Latib A, Crea F, Marenzi G, De Metrio M, Moretti L, Li H, Uren NG, Hu D,Maseri A. FAMI Study Investigators. High-sensitivity C-reactive protein is withinnormal levels at the veryonset of first ST-segment elevation acute myocardial infarc-tion in 41% of cases: a multiethnic case-control study. J Am Coll Cardiol 2011;58:26542661.

15. Ohlmann P, Jaquemin L, Morel O, El Behlgiti R, Faure A, Michotey MO, Beranger N,Roul G, Schneider F, Bareiss P, Monassier JP. Prognostic value of C-reactive proteinand cardiac troponin I in primary percutaneous interventions for ST-elevation myo-cardial infarction. Am Heart J 2006;152:11611167.

16. Mayr A, Klug G, Schocke M, Trieb T, Mair J, Padernig K, Pachinger O, Jaschke W,Metzler B. Late microvascular obstruction after acute myocardial infarction: relationwith cardiac and inflammatory markers. Int J Cardiol 2012;157:391396.

17. Tello-Montoliu A, Marin F, Roldan V, Mainar L, Lopez MT, Sogorb F, Vicente V,Lip GY. A multimarker risk stratification approach to non-ST elevation acute coron-ary syndrome: implications of troponin T, CRP, NT-proBNP, and fibrin D-dimerlevels. J Intern Med 2007;262:651658.

18. Foussas SG, Zairis MN, Lyras AG, Patsourakos NG, Tsirimpis VG, Katsaros K,Beldekos DJ, Handanis SM, Mytas DZ, Karidis KS, Tselioti PG, Prekates AA,Ambrose JA. Early prognostic usefulness of C-reactive protein added to theThrombolysis In Myocardial Infarction risk score in acute coronary syndromes.Am J Cardiol 2005;96:533537.

19. Bogaty P, Boyer L, Simard S, Dauwe F, Dupuis R, Verret B, Huynh T, Bertrand F,DagenaisGR, Brophy JM. Clinical utiliryofC-reactiveproteinmeasuredat admission,hospital discharge, and 1 month later to predict outcome in patients with acute

coronary artery disease. The RISCA (recurrence and inflammation in the acute cor-onary syndromes) study. J Am Coll Cardiol 2008;51:23392346.

20. Eggers KM, Lagerqvist B, Venge P, Wallentin L, Lindahl B. Prognostic value of biomar-kers during and after non-ST-segment elevation acute coronary syndrome. J Am CollCardiol 2009;54:357364.

21. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactiveprotein and troponin T in patients with unstable angina: a comparative analysis.CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstableangina REfractory to standard treatment trial. J Am Coll Cardiol 2000;35:15351542.

22. Park DW, Lee SW, Yun SC, Song HG, Ahn JM, Lee JY, Kim WJ, Kang SJ, Kim YH,Lee CW, Park SW, Park SJ. A point-of-care platelet function assay and C-reactiveprotein for prediction of major cardiovascular events after drug-eluting stent im-plantation. J Am Coll Cardiol 2011;58:26302639.

23. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA,Braunwald E. the Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22 (PROVE ITTIMI 22) Investigators.C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:2028.

24. Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, Rifai N,Califf RM, Braunwald E. Clinical relevance of C-reactive protein during follow-upof patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circula-tion 2006;114:281288.

25. Braunwald E. Creating controversy where none exists: the important role ofC-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A toZ, JUPITER, HEART PROTECTION, and ASCOT trials. Eur Heart J 2012;33:430432.

26. Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am Coll Cardiol 2013;61:111.

CARDIOVASCULAR FLASHLIGHT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

doi:10.1093/eurheartj/eht413Online publish-ahead-of-print 3 October 2013

Acute myocardial infarction caused by coronary tumour embolismShuhei Kushiyama, Yoshihiro Ikura*, and Yasuhiro Iwai

Department of Pathology, Takatsuki General Hospital, Takatsuki 569-1192, Japan

* Corresponding author. Tel: +81 726813801, Fax: +81 726823834, Email: ikura@ajk.takatsuki-hp.or.jp

A 78-year-old male patient with advanced lung cancer and liver metas-tasis was admitted to our hospital because of persistent and criticalhyperkalaemia (5.17.1 mEq/L), probably caused by tumour lysis syn-drome. He had a history of myocardial infarction and arteriosclerosisobliterans. Echocardiography showed akinesis of the cardiac apex, andsevere hypokinesis of the inferior wall, reflecting old infarction. Hishyperkalaemia was accompanied by elevated levels of aminotrans-ferases and lactate dehydrogenase. Because his disease was an incur-able malignancy, palliative care was chosen for his treatment.Although no electrocardiographic abnormalities associated withhyperkalaemia were detected during hospitalization, he sufferedsudden death due to ventricular fibrillation. The clinicians suspectedthat the uncontrolled hyperkalaemia had induced this fatal arrhythmia.

An autopsy was performed in which the lung cancer (pleomorphiccarcinoma) with extensive blood-borne metastases was confirmed.Fresh myocardial necrosis was found to be superimposed on an areaof fibrosis corresponding to old infarction in the left anterior wall(Panel A, arrowheads). This finding suggested that the precise causeof death was not hyperkalaemia but rather acute myocardial infarction.We then investigated the coronary arteries thoroughly to identify a culprit vascular lesion (Panel B). Surprisingly, a mixtureof blood clot andtumourcell aggregation (PanelsC andD) occluded the left anteriordescending artery (Panel B, asterisk). We surmised that coronary tumourembolism was a primary reason for his sudden death.

Tumour embolism is an extremely rare cause of acute myocardial infarction. However, clinicians should recognize it as a potentialaetiology of acute coronary syndrome.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com

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