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Troponins and creatine kinase as biomarkers of cardiac injury

OfficialreprintfromUpToDate www.uptodate.com2013UpToDate

Troponinsandcreatinekinaseasbiomarkersofcardiacinjury Authors AllanSJaffe,MD DavidAMorrow,MD,MPH Disclosures Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete. Literaturereviewcurrentthrough:Mar2013.|Thistopiclastupdated:sep18,2012. INTRODUCTIONCardiacinjuryisdefinedasthedisruptionofnormalcardiacmyocytemembraneintegrity resultinginthelossintotheextracellularspace(includingblood)ofintracellularconstituentsincludingdetectable levelsofavarietyofbiologicallyactivecytosolicandstructuralproteinssuchastroponin,creatinekinase, myoglobin,hearttypefattyacidbindingprotein,andlactatedehydrogenase.Injuryisusuallyconsideredirreversible (celldeath),butdefinitiveproofthatcelldeathisaninevitableconsequenceoftheprocessisnotavailable.(See 'Ischemiaandenzymeelevations'below.) Causesofcardiacinjuryincludetrauma,toxins,andviralinfection,butischemiaorinfarctionconsequenttoan imbalancebetweenthesupplyanddemandofoxygen(andnutrients)isthemostcommoncause. Whenasufficientnumberofmyocyteshavedied(myocytenecrosis)orlostfunction,acuteclinicaldiseaseis apparentexamplesincludemyocardialinfarction(MI)ormyocarditis.(See"Criteriaforthediagnosisofacute myocardialinfarction"and"Clinicalmanifestationsanddiagnosisofmyocarditisinadults".) ThebiochemicalcharacteristicsandutilityoftroponinsandcreatinekinaseMBfraction(CKMB)forthediagnosis ofcardiacinjuryandacutemyocardialinfarction(MI)willbereviewedhere.Otherbiomarkersofcardiacinjuryand diseasestates,otherthananAMI,inwhichelevationofbiomarkersareseenarediscussedseparately.(See "Biomarkersofcardiacinjuryotherthantroponinsandcreatinekinase"and"Elevatedcardiactroponin concentrationintheabsenceofanacutecoronarysyndrome".) ISCHEMIAANDENZYMEELEVATIONSThereisconsiderabledebateaboutwhetherbiomarkerssuchas troponinsorCKMBarereleasedwithreversibleaswellasirreversibleinjury.Ifthisphenomenonoccurs,itshould beseenwithallcardiacbiomarkers,anditwouldnotbepossiblebiochemicallytodistinguishreversiblefrom irreversibleinjury[1]. Thoseinfavorofthehypothesisthatcardiacbiomarkerelevationsoccurwithreversibleinjurysuggestthatthe minorelevationsseenaftertriathlonsand/ormarathonsinsomeindividualsandwithseverepulmonaryembolism reflectreversibleinjurysincetheytendtobetransientanddonothavethepersistenceseenwithanacuteMI[24]. Thedevelopmentofmorehighlysensitiveassaysmayallowforabetterevaluationofthisissueinthefuturesince increasesfromnormalvaluesmaypersistbutnotbedetectedwithouthighlysensitiveassays.(See"Elevated cardiactroponinconcentrationintheabsenceofanacutecoronarysyndrome",sectionon'Myocardialstrain'.) Olderstudies(usinglesssensitivetests)thatevaluatedpatientswithischemiaduringstresstestingdidnotshow elevationsintroponinsorotherbiomarkersandthusdidnotsupportthehypothesis[5].However,areportfromthe PROMPTTIMI35study,whichevaluatedtroponinreleaseafterstresstestingusinganultrasensitive precommercialtroponin(I)assay,doessupporttheabovehypothesis[6].Inthisstudyof120patientsreferredfor SectionEditor JuanCarlosKaski,MD,DM,DSc, FRCP,FESC,FACC,FAHA DeputyEditor GordonMSaperia,MD,FACC

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evaluationofpossiblemyocardialischemia,significantchangesincirculatingtroponinweredetectedonlyinthe70 patientswithtransientstresstestinducedmyocardialischemiadocumentedonmyocardialperfusionimaging.The consistencyoftheresultswasimpressive,butthemagnitudeofthechangeswassmall(mean=0.002mcg/L), meaningthisapproachcannotbeusedinindividualpatientswithoutextremelyhighprecisionassays.Whetherthe increasesreflectreleaseduetoischemiaorminoramountsofdamageisunclear.Asimilarstudyusinganother highsensitivityprecommercialassayforcTnTcouldnotreplicatethesefindings[7]. AstudyusingpacingandcoronarysinussamplingwithanhscTnTassayalsofoundelevationsbothinthe coronarysinusandsystemicallywithandwithoutelevationsinlactateinthecoronarysinus[8].Thesefindings couldbeinterpretedassuggestingthatcTnisreleasedwithcardiacstressandthusduetoreversibleinjury. Alternatively,elevationscouldrepresentirreversiblemyocyteinjurysinceitisnowclearthatreparative mechanismsexistwithintheheart.However,fromtheclinicalperspective,thisissuemightbelesscritical. ElevationsofcTninmostsituations,saveshorttermafterextremeexertion,areassociatedwithadverse consequencesregardlessoftheirmechanismofrelease. TROPONINSCardiactroponinI(cTnI)andT(cTnT)arecardiacregulatoryproteinsthatcontrolthecalcium mediatedinteractionofactinandmyosin[9].Bothhavecytosolicorearlyreleasableandstructuralpools,withmost existinginthestructuralpool[10,11].(See"Excitationcontractioncouplinginmyocardium",sectionon'Roleof tropomyosinandtroponins'.) Theseproteinsareproductsofspecificgenesandthereforehavethepotentialtobeuniquefortheheart.Studies performedwithcTnIhavefailedtofindanycTnIoutsideoftheheartatanystageofneonataldevelopment[12,13]. Incontrast,cTnTisexpressedtoaminorextentinskeletalmuscle.However,thepresentcTnTassaywasnot thoughttodetecttheseforms[14].Dataindicatethatthereareatleastsomepatientswithskeletalmuscledisease whohaveproteinsthataredetectedbytheantibodiesinthecTnTandhscTnTassay.Thisimpliesthatskeletal musclecan,insomepatients,bethesourceforelevationsofcTnTdetectedintheblood[15].Definingthe frequencyofthisphenomenonwillrequireadditionalstudy.Thus,inmostclinicalsettings,itsspecificityshouldbe comparabletothatofcTnI. ItisthoughtthatearlytroponinreleaseduringMIcomesfromwhathasbeentermedthecytosolicpool,whichisof amagnitudethatissimilartotheamountofCKMBinthatpool.Inreality,abetternameforthispoolmightbethe earlyreleasablepool,sinceitscellularlocalizationisnotproven.Subsequentreleaseisprolongedwithdegradation oftheactinandmyosinfilamentsintheareaofdamage. VariationsinassaysAlthoughcTnIandcTnTarespecificmarkersformyocardialdamage,therearevariations inthesensitivityandspecificityofvariousimmunoassays[16,17].Thisisrelatedtoalackofstandardization,the presenceofmodifiedcTnIandcTnTintheserum,andvariationsinantibodycrossreactivitiestothevarious detectableformsofcTnIthatresultfromitsdegradation[14,1822].Pointofcaretestsareusuallylesssensitive thanlaboratorybasedtests[1,23].Newerassays,labeled'highsensitivity'orhighlysensitiveassaysarebeing developed.However,therehasbeensubstantialconfusionintheliteratureconcerningwhatassaysshouldbe definedashighsensitivity.(See'Highsensitivityassays'below.)Intheabsenceofsuchaspecificdesignation, theassaysreferredtoarecontemporaryassaysandnothscTnassays. Manygroupshavecalledforstandardizationofassaysandprospectivecriteriafortheiranalyticcharacterization [1,2326].Thejoint2012EuropeanSocietyofCardiology/AmericanCollegeofCardiologyFoundation/American HeartAssociation/WorldHealthFederationdefinitionofmyocardialinfarctionendorsestheuseoftroponinasthe markerofchoiceoverallandforeachsubcategoryofAMI.Italsostatesthatlaboratoriesshouldutilizeacutoff valueofthe99thpercentileofanormalreferencepopulationtodefinethepresenceofcardiacinjury.Ideallythis valueshouldbemeasurablewithacoefficientofvariation(CV)of10percentorless[23].However,theguidelines donotsuggestraisingthevalueabovethe99thpercentilevalueifthismetricisnotmetandlevelsofimprecision between10and20percentdonotmakeanassayunusable[27].SincecTnTandcTnIlevelsareundetectablein

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mostnormalsubjects,the99thpercentileisverylow(eg,0.01to0.5mcg/L).However,mostassaysareimprecise atthislowlevel[16].Thislimitationdiminishesthesensitivityoftheassaystodetectchangeswithserialsamples butdoesnotsignificantlyincreasetherateofanalyticalfalsepositiveresults[28].Severalcontemporary(sensitive) assaysarenowclosetooratthatlevelofprecisionatthe99thpercentilevalue.Mostcontemporary(sensitive) assaysarestillnotcapableofmeasuringcTninmostnormalsubjectsandthusdeterminingatrue99percentvalue [29]. Sinceallassaysareunique,onecannotextrapolateavaluefromoneassaytoanother.Itisimportantforclinicians tobefamiliarwiththe99thpercentilevalueandthelevelof10percentCVfortheassayusedintheirclinical practiceandtobeawarethatthesereferencelimitsdonotapplytoresultsfromotherclinicalprovidersunlessthey areusingthesameassay.Manyexpertsareurgingthatwholenumbersbereportedtoavoidconfusionsinceas assaysbecomemoresensitive,thenumberofzerosincreasesandthepossibilityofanerrorwithonebeingleftout orbeingmisinterpretedissubstantial. NormalrangeYoung,healthyindividualswithoutpathologicmyocardialcellstressordamageareexpectedto havelittleornomeasurabletroponinintheirbloodwithanyassayandwithmostassayspresentlyinusethisisthe case.Astroponinassaysbecomemoresensitive,however,itappearsthathealthyindividualsdohavetinybut detectablelevelsoftroponin.Thus,definingthenormalrangeismadedifficultbyourincompleteunderstandingof whatanormaltroponinreallyis. Withcontemporaryassays,individualswithincreasedvaluesabovethe99thpercentileURLareatincreased cardiovascularrisk.Somevaluesevenslightlybelowthe99thpercentilevalueseemtosuggestrisk,but contemporaryassaysarenotcapableofdefiningthesevaluesverywellduetomarkedimprecision.(See 'Elevationsinthegeneralpopulation'below.) Thisissuehasbeenaddressedinstudiesthathavecomparedyoungertoolderindividualswithvaluesinthe normalrangethemeanforthetwogroupsdiffered[30].Todetermineifthiswasanormalfindingrelatedtoageor relatedtoacomorbidity,theyexaminedacohortofolderpatientsduringlongtermfollowup.Patientswithvalues betweenthevaluesoftheyoungerandoldergrouphadanincreasedfrequencyofadverseevents.Mortalitywas increasedby50percentinthosewithoutahistoryofcardiovasculardiseaseandbymorethantwofoldinthosewith suchahistory.Theimportanceofvaluesinthisrangehasbeenconfirmedintwoacutestudies,oneinchestpain patientsandoneinEDpatients[31,32]. Ithasalsobeenshownthathavingadetectableleveloftroponindefinesagroupofstablepatientslikelytohave eithersignificantcoronaryarterydiseaseorelevatedfillingpressures[33]. ElevationsinthegeneralpopulationAreportof3557participantsinthepopulationbasedDallasHeartStudy evaluatedtheprevalenceofcTnTelevationsinthegeneralpopulationusingcontemporary(sensitive)assays[34]. Values0.01ng/mL(mcg/L),whichwasthelowerlimitofdetection,wereseenin0.7percent.Fourmajorpredictors ofdetectablecTnTwerediabetesmellitus,leftventricularhypertrophy,chronickidneydisease,andheartfailure. Thesevaluesareofprognosticimportance.Inastudyof957healthyelderlypatientsinwhich4percentwerefound tohaveelevateddetectablelevelofcTnT(0.01ng/mL),therewasanapproximatetwofoldincreasein cardiovascularmortalityinthisgroup,confirmingtheimportanceoftheseelevationsclinically[35].Inastudyof 989individualswithputativelystableCAD[36],6.2percenthadelevationsofcTnTabovethe99thpercentilevalue. Ofthesepatients,58.6percenthadacardiovasculareventduringfollowup,comparedto22.5percentinthegroup withoutelevations.However,thisprognosticrelationshipwasnotfoundtobeindependentwhenechoparameters andanatriureticpeptidewereaddedtothemodel. DiagnosisofprimaryMIThediagnosisofanacutemyocardialinfarction(AMI)hastraditionallyrelieduponthe

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Troponins and creatine kinase as biomarkers of cardiac injury

combinationofchestpain,electrocardiographic(ECG)manifestations,andelevationsinserumorplasma biomarkersofcardiacinjury,orpathologicfindings.(See"Criteriaforthediagnosisofacutemyocardialinfarction", sectionon'Definitions'.) ChestsymptomsarefrequentlyatypicalorabsentandECGabnormalitiesmaybenonspecificorabsent.Asa result,thediagnosisofanAMIhasincreasinglydependeduponevaluationoftheriseand/orfallofblood biomarkers.TroponinsarepreferredtoCKMBduetotheirgreaterspecificityandsensitivity[23,37,38].(See'Why troponinispreferred'below.) ThecriteriausedtodefineMIdiffersomewhatdependingontheparticularclinicalcircumstanceofthepatient: thosesuspectedofanAMIbasedontheirpresentationthoseundergoingrevascularizationwitheithercoronary arterybypassgraftsurgeryorpercutaneousinterventionorthosewhohavesustainedsuddenunexpectedcardiac death. SeveralpointsareimportantfortheunderstandingofhowtousethesecriteriatodiagnoseanAMIindifferent clinicalsettings: The99thpercentileofthenormalrangeofvaluesshouldbethecutoffvalueforbothtroponinandCKMB. Withcontemporaryassays,thesevaluesarestillfarfromthenormalrange. Ariseand/orfallshouldbeobserved.Theabilitytodefinehowmuchofachangeissignificantrequiresa fixedperiodoftime(usuallysixhours)andinformationconcerningthevariabilityofthemeasurements.In general,measurementsareconsideredtobedifferentifthevaluesaremorethanthreestandarddeviations ofthevariabilityaroundthem.Webelievethatlaboratoriesshouldreportwhensignificantchangeshave occurredoverafixedtimeperiodsincetheappropriatemetricswillvarydependingontheassaybeingused. Someassaysseemtoperformreasonablywitha20percentchange[39],somewitha30percentchange [40],andsomewiththeneedforevengreaterchange. ThesecriteriawillidentifymorepatientswithAMIthanpreviouscriteriaastroponinassayscontinuetobecome moresensitive.Consistentuseofthesamecriteriaisurgedtoimprovetheconsistencyofdiagnosis. CardiactroponinconcentrationsusuallybegintorisetwotothreehoursaftertheonsetofAMI.Bytwotothree hoursafterpresentation,upto80percentofpatientswithAMIwillhavetroponinelevations[39]."Rapidlyappearing markers,"suchasmyoglobinandCKisoforms,appeartoprovidelittleadditionalinformationwhenusedtogether withasensitiveassayfortroponin[41].Recentcocaineuse,whichcanelevateCKMB,doesnotincreasecTnI unlessmyocardialdamageispresent[42]. Unfortunately,therehasbeenconsiderablereluctancetousethe99thpercentileURLvalueclinicallybecauseof elevationsthatwerechallengingforclinicianstoexplain.Recentstudieshaveagainconfirmedtheearlydiagnostic andtherapeuticvalueofusingthe99thpercentileURLforcTn.Intwodiagnosticstudies[43,44]thatcomparedthe resultsofnewer,moresensitiveassays(usingthe99thpercentilevalue)tothoseoflessorequallysensitive assaysbeingusedinthecommunityforwhichcutoffvalueshigherthanthe99percentvaluewerebeingused. Thestrategyofusingthesecontemporaryassaysattherecommendedcutoffvaluedetectedmanymorepatients earlierthanifoneusedthesameassayswithhighercutoffvaluesorlesssensitiveassays.Inthesestudies,more than90percentofpatientshadelevatedvaluesintheirfirstsample.Thisfindingreflectsinpartthefactthatmany patientswithnonSTelevationMI(NSTEMI)presentlateaftertheonsetofpain,butthefindingsweresimilarin thosewhoseputativeonsetwasearly(withinthreeorfourhours).Someoftheadditionalreasonsforsuchahigh initialpercentagearediscussedbelow.Sincemostoftheassaysusedinthesestudiesarealreadyinuse,the majorfindingofthesereportswastoreaffirmtheneedtousethe99thpercentilevalueforrapiddiagnosisandto

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Troponins and creatine kinase as biomarkers of cardiac injury

optimallyidentifypatientswithAMIwhopresentwithchestdiscomfort.Thesestudiesalsoreinforcedthelackof benefitofsocalledearlyrisingmarkers[44]. Itshouldbenotedthatinthesestudiesthepretestprobabilityofdiseaseevenusingthelesssensitivelocal approachwas36to46percentintheseEuropeanstudies,whichismuchhigherthanusual,especiallyin emergencydepartmentsintheUnitedStates.Thiswillmakeallassaysappeartoperformbetter.Inaddition,these studiesusedalesssensitivestandardastheirgoldstandard,againinflatingtheaccuracyoftheirapproach.Had themoreaccurateassaysbeenusedtoprobethepercentageofearlydiagnoses,thenumberwouldhavebeen lower.Finally,forthemostparttheyconsideredanyelevationindicativeofapositivediagnosisratherthanlooking forariseand/orfallinvaluesandwiththeexceptionofoneanalysis,alternativediagnosesfortheelevatedtroponin valueswerenotexplored[45].Theseapproachesenhancethesensitivityoftheapproachandobfuscatewhatcould beanimportantissuewithit:theideathatwithgreatersensitivity,agreaterpercentageofelevationsarelikelyto bechronicandduetoothercardiaccomorbiditiesandnotacuteischemicheartdisease[45]. ThetherapeuticimportanceofusingsensitivethresholdsintheevaluationofpatientswithACSwashighlightedina studyofpatientswithsuspectedacutecoronarysyndrome(ACS).Themanagementandoutcomesof1038 individualsevaluatedwithasensitivetroponinIassayin2008usingahighcutoffvaluewerecomparedto1054 individualsevaluatedwiththesameassayin2009usingthe10percentcoefficientofvariation(CV)cutoff[46]. Managingphysiciansuseddifferingthresholdsforthedetectionofmyocardialnecrosisinthetwogroups:0.20 ng/mLintheformerand0.05ng/mLinthelatter.Eachgroupwasstratifiedintothreesubgroups(<0.05,0.05to 0.19,and0.20ng/mL).Theprimaryoutcomewasthecombinationofrecurrentmyocardialinfarctionanddeathat oneyear.Thefollowingresultswereobtained: Theratesoftheuseofsecondarypreventativeinterventions,suchasstatinsanddualantiplatelettherapyat discharge,inthesubgroupofpatientswithplasmatroponinconcentrationsof0.05to0.19ng/mLimproved significantlycomparingthe2008to2009cohorts,whiletheuseoftheseinterventionsdidnotchange significantlyintheothersubgroups. In2008,theprimaryoutcomeoccurredin39percentofpatientswithplasmatroponinconcentrationsof0.05 to0.19ng/mLcomparedwith7and24percentofthosewithtroponinconcentrationsof<0.05ng/mLor0.20 ng/mL,respectively. In2009,theprimaryoutcomeoccurredsignificantlylessfrequently(21percent)inpatientswithplasma troponinconcentrationsof0.05to0.19ng/mL,whiletherewasnosignificantchangeintheothertwo subgroupsbetweenthetwoyears. Asacknowledgedbytheauthors,theseresultsmighthavebeenstillbetterhadthe99thpercentileURLvaluebeen used[47]. Becauseofthedelayinbiomarkerelevations,reperfusiontherapyinpatientswhohaveasuspectedacuteST elevationMIshouldnotawaittheresultsofcardiacbiomarkers.Thisapproachwasrecommendedbythe2004 ACC/AHAtaskforce,andwasnotchangedinthe2007ACC/AHAfocusedupdate[38,48].(See"Selectinga reperfusionstrategyforacuteSTelevationmyocardialinfarction".) InpatientswithoutdiagnosticSTsegmentelevation,rapidinterventionislesscritical.Serialbiomarkertestingcan beperformedafterfourtosixormorehoursiftheinitialvaluesareindeterminate,theECGremainsnondiagnostic, andclinicalsuspicionremainshigh.(See"Coronaryarteriographyandrevascularizationforunstableanginaornon STelevationacutemyocardialinfarction"and"Initialevaluationandmanagementofsuspectedacutecoronary syndromeintheemergencydepartment".) AmongpatientswhopresentwithchestpainwithoutischemicchangesontheECG,anelevatedtroponinis

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Troponins and creatine kinase as biomarkers of cardiac injury

associatedwithsignificantincreasesintheincidenceofbothcoronaryarterydiseaseinthesubsetofpatientswho underwentangiography(90versus23percentintheabsenceoftroponinelevations)andadversecardiacevents overthenextyear(33versus13percent)[49].Thisstudyusedacutoffhigherthanthe99thpercentile.Itislikely thatthedifferenceswouldhavebeengreaterhadtherecommendedcutoffbeenused.However,itshouldalsobe appreciatedthatanycardiacinjurycaninduceelevationsoftroponin.Itisalsoclearthatwiththeuseofreasonable assaysforcTn,abortedAMI(thosewithoutanyelevationsinbiomarkers)nolongerexist.However,thesmallerthe amountofdamage,thebettertheprognosis[50]. TherearemultiplepotentialproximalcausesofMI.Thesearediscussedseparately.(See"Criteriaforthediagnosis ofacutemyocardialinfarction",sectionon'AcuteMI'.) ItisnowclearfromseveralseriesthatpatientswithAMIneednotalwayshavefixedcoronaryarterydisease.This assumptionhasbeenresponsibleforconcernsthatcTnvaluesarefalselypositive.Upto30percentofpatients withunstablecoronaryarterydiseasemaynothaveaculpritlesionbutoftenrespondtoacetylcholinewith recapitulationoftheirchestdiscomfort[51].Thesepatientshaveanexcellentlongtermprognosis[52].Includedin thisgroupmostlikelyarethepatientsreportedinseveralserieswhohaveelevatedcTnvalues,normalcoronary arteriesbutmagneticresonanceimagingevidenceofAMIwithdelayedsubendocardialhyperenhancement.Of interest,mostofthesepatientsarewomen[5355].Thesepatientswouldbedesignatedastype2AMIsbythe globaltaskforcedefinitionofAMI[23].(See"Criteriaforthediagnosisofacutemyocardialinfarction"and"Criteria forthediagnosisofacutemyocardialinfarction",sectionon'AcuteMI'.) Inaddition,patientswithfixedcoronaryarterydiseaseandsupplydemandabnormalities,suchaspostoperative patients,fitintothiscategory[56].Itisthoughtthatthesepatientsincludemostlysocalledtype2AMIssuchas thoseidentifiedaboveandthusarelessinneedofaggressiveinterventionthanothers.Unfortunately,these distinctionsareimpossibletomakebasedonthecTndataandthusmustbemadeclinically. LatediagnosisandreinfarctionElevationsincTnTandcTnIafteranAMIpersistforupto10days,thus permittinglatediagnosis[57,58]. Troponinscanalsobeusedfordetectingreinfarction.Thiswasillustratedinaseriesofninepatientsinwhomre elevationsincTnIwerepromptandpermittedthediagnosisofreinfarction[59].Asaresult,CKMBisnolonger requiredeventhoughitreturnstobaselinelevelsearlier. Accordingtothe2012JointEuropeanSocietyofCardiology/AmericanCollegeofCardiologyFoundation/American HeartAssociation/WorldHealthFederationTaskForcefortheUniversaldefinitionofMyocardialInfarction, reinfarctionisusedforanacuteMithatoccurswithin28daysofanincidentorrecurrentMI.Ifreinfarctionis suspected,animmediatemeasurementofcardiactroponinshouldbemade[60].Asecondsampleisobtained threetosixhourslaterandrecurrentinfarctionispresentifthereisa20percentincreaseinthesecondsample. DifferentialdiagnosisThediagnosismostapttomimicAMIbothintermsofclinicalpresentationandcTn resultsisacutemyocarditis.BothsyndromescanpresentwithSTsegmentelevationandsubstantialelevationsin cTn[61].Inaseriesof60patientswhopresentedwithpossibleAMIbuthadnormalcoronaryarteries,30hadMRI featuresofacutemyocarditis[62].Thus,thisshouldbeaconsiderationinpatientswhopresentinthismannerand havenormalcoronaryarteries.OnepossibleindicationforCMRwouldbetodeterminethesourceofmyocardial damageinapatientwithelevatedtroponinlevelsbutwithoutobstructivecoronarydiseaseatinvasivecoronary angiography.(See"Clinicalutilityofcardiovascularmagneticresonanceimaging".) Apicalballooningshouldalsobeconsidered,butingeneral,elevationsofcTnaremoremodestinthiscondition. (See"Stressinduced(takotsubo)cardiomyopathy",sectionon'Clinicalpresentation'.) BothcTnIandcTnTprovideimprovedspecificitycomparedtotheothermarkerproteinsforthedetectionof myocardialinjury,butelevationsdonotnecessarilyimplythatthecauseisischemicheartdisease.Troponin

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elevationsoccurinavarietyofclinicalconditions,includingdisordersthatareinthedifferentialdiagnosisofacute infarctionsuchasamoderatetoseverepulmonaryembolismwithacuterightheartoverload,heartfailure,and myocarditis.Thetroponinelevationsaremoreoftenmodestinthesedisordersand,amongpatientswithpulmonary embolism,usuallyresolvewithin40hoursincontrasttothemoreprolongedelevationwithacutemyocardialinjury [4].Theseissuesarediscussedindetailseparately.(See"Elevatedcardiactroponinconcentrationintheabsence ofanacutecoronarysyndrome"and"Diagnosisofacutepulmonaryembolism",sectionon'Troponin'and"Clinical manifestationsanddiagnosisofmyocarditisinadults".) Troponinelevationsarealsoindicativeofmyocardialinjuryinpatientswhoarecriticallyillandareassociatedwith anadverseprognosis[63].(See"Elevatedcardiactroponinconcentrationintheabsenceofanacutecoronary syndrome",sectionon'Criticalillness'.) Troponinreleasecanbeinducedbytrauma,asoccursduringcardiopulmonaryresuscitation,electrical cardioversion,orimplantablecardioverterdefibrillator(ICD)firings.Inonestudyof38patientsundergoingelective cardioversionusingamediancumulativeenergyof300J,forexample,threepatientshadminimalelevationsof cTnI(0.8to1.5mcg/L)suggestiveofsubtlemyocardialinjury[64].Substantialtroponinelevationssuggestthe presenceofmyocardialinjuryfromcausesunrelatedtodirectcurrentcardioversion.(See"Basicprinciplesand techniqueofcardioversionanddefibrillation"and"Generalprinciplesoftheimplantablecardioverterdefibrillator".) InfarctsizeManycliniciansusepeakvaluesofbiomarkerstoprovidearoughestimateofinfarctsize.Recent datausingbothscintigraphy[65,66]andMRI[67]suggestthatpeakcTnTvaluesorthe72to96hourvalues correlatewithinfarctsizedeterminedfromimagingapproaches.Theslopeoftherelationshipisdifferentifoneuses the24hour,48hour,orpeakvalueversusthe72to96hourvalue[68]and,aswithCKMB,thecorrelationisless robustwithNSTEMIthanwithSTEMI.Inaddition,theslopeoftherelationshipisdifferentwithandwithout reperfusion.Nonetheless,correlationrangesaregood(from0.8to0.93)inthesestudiesandarebetterthanthe correlationsreportedforCKMB.SimilardataareavailableforcTnIaswell[69]. PrognosisafterMITheprognosticvalueofelevatedtroponinshasbeendemonstratedinpatientswithST segmentelevationMI(STEMI)andnonSTelevationMI(NSTEMI).BothcTnIandcTnTappeartobeequivalentfor thispurposeandanydetectableelevationatthetimeofpresentationisofsignificance(figure1)[7072].The optimalcutoffvalueisthe99thpercentile[73]. STelevationMITherangeoffindingsinacuteSTEMIisillustratedbythefollowingobservations: TheGUSTOIIItrialevaluated12,666patientswithanSTEMIwhoreceivedfibrinolytictherapy[74].An elevatedcTnTatthetimeofpresentationwasanindependentpredictorofmortalityat30daysina multivariateregressionanalysis(15.7versus6.2percentforanegativecTnT).Thisislikelyatleastinpart becausepatientswithelevatedvaluespresentlater. TheadmissiontroponinconcentrationhasprognosticvalueinpatientswithanSTEMIwhoundergoearly PCI.Thiswasillustratedinareportof140patientsundergoingPCIusuallywithstenting.Thosewith admissioncTnT0.1mcg/Lweremorelikelytohavepersistentlyreducedbloodflowintheinfarctrelated artery(TIMIflowgradelessthan3)aftertheprocedure(25versus8percentfornegativecTnT),ahigher incidenceofnoreflow,andahighermortalityatboth30daysandninemonths(12.5versus4and14versus 4percent,respectively)[75].Thisislikelyatleastinpartbecausepatientswithelevatedvaluespresent later. Apooledanalysisof21studiesinvolving18,982patientswithanacutecoronarysyndromefoundthatan elevatedserumcTnIorcTnTwasassociatedwithanincreasedriskofcardiacdeathorreinfarctionat30 days(oddsratio3.44,95%CI2.944.03)[76].Elevatedtroponinsonadmissionwerealsopredictiveoflong termoutcome(fivemonthstothreeyears)inthosewithaSTEMI(OR3.11).

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NonSTelevationMIAnelevationintroponinisassociatedwithanadverseearlyandlongtermprognosisin menandwomenwithanonSTelevationacutecoronarysyndrome(NSTEMI)[71,7685]: InametaanalysisofsevenclinicaltrialsandnineteencohortstudiesofpatientswithNSTEMI,5360 patientshadacTnTmeasurementand6603hadacTnImeasurement[71].Themortalityratewashigherfor patientswitheitheranelevatedcTnT(6.0versus1.5percentat28weeks)oranelevatedcTnI(5.5versus 1.7percentat10weeks). Similarfindingswerenotedinasecondmetaanalysisof21studies:3579patientswithNSTEMIhad30day followup,and2227hadlongtermfollowup(fivemonthstothreeyears)[76].PatientswithanelevatedcTnT orcTnIhadasignificantlyhighercardiacmortalityrateinboththeshortterm(5.9versus1.3percent)and longterm(10.1versus4.0percent). Anumberoffactorsmaycontributetotheincreaseinmortality.InthenoninvasivearmintheFRISCIItrial,any elevationincTnTwasassociatedwithanincreasedlikelihoodofseverethreevesseldisease,anunstableplaque withthrombusanddownstreammicroembolization,impairmentofcoronaryflow,andreinfarction[82].Amore pronouncedtroponinelevationwasassociatedwithagreaterlikelihoodofpersistentocclusionoftheculpritvessel andareducedleftventricularejectionfraction. Probablybecauseofthehigherrisk,patientswithanACSandelevatedtroponinsbenefitmorefromanearly invasivetherapythanthosewhodonothaveelevatedtroponins[8688]andfromtheuseofGPIIb/IIIainhibitors [72]andlowmolecularweightheparin[77],perhapsbecausetroponinelevationsareassociatedwithcomplex lesioncharacteristicsandthrombusformation[82,89].(See"Trialsofconservativeversusearlyinvasivetherapyin unstableanginaandnonSTelevationmyocardialinfarction",sectionon'Gradationofrisk'and"Antiplateletagents inacutenonSTelevationacutecoronarysyndromes",sectionon'Serumtroponins'.) DegreeoftroponinelevationThedegreeofelevationofcTnIorcTnTalsohassignificantprognosticvalue [7880,84,90,91].Thiseffecthasbeenillustratedinanumberofmajortrials: IntheGUSTOIVACStrial,over7000patientswhodidnotundergoearlyrevascularizationwerestratifiedby quartilesofcTnT(0.01,0.01to0.12,0.12to0.47,and>0.47)andbyquartilesofCRP[90].The30day mortalityrateincreasedfrom1.1to7.4percentfromthefirsttofourthquartilesofcTnT.Therewasalsoa significantincreaseinthe30dayrateofMIfromthefirsttosecondquartilesofcTnT(2.5versus6.7 percent),butnofurtherincreasebetweentheupperthreequartiles.CRPandtroponinThadindependentand complementaryprognosticsignificancethemortalityrateat30daysrangedfrom0.3to9.1percentfor patientsinthelowesttohighestquartileofbothmarkers. AsimilarcorrelationofthedegreeoftroponinelevationwithmortalitywasseenintheTIMIIIIBtrial(figure 2),theGUSTOIIatrial(figure3),andtheFRISCstudy(figure4)[7880,84].Thecorrelationwithinhospital andlongtermmortalityhasalsobeennotedinpatientstreatedwithanearlyinvasivestrategy[92]. Optimaluseforprognosisrequiresmorethananinitialsample.TheGUSTOIIatrialobtainedbaseline,peak,and late(8and16hour)cTnTmeasurementsin734patientswithanacutecoronarysyndrome.Mortalityat30days was10percentinthosewithanelevatedcTnT(>0.1mcg/L)atbaseline,5percentwithalateelevationofcTnT, and0percentinpatientswhoneverdevelopedapositivetest[93].Afteradjustmentforbaselinecharacteristics, anyelevatedcTnTvaluepredicted30dayandoneyearmortality,andthe8and16hourvaluesaddedstrengthto thebaselinevalue(figure5). Patientswithmarkedtroponinelevations(eg,highesttertile)havepresentedlater,havevisiblethrombuson angiographyandalowerrateofTIMI3flow,depressedleftventricularfunction,andabnormalQwavesontheECG comparedtothoseinthesecondtertile[82,94].ThesepatientsarelesslikelytohaverecurrentMIatoneyearthan

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thoseinthelowertertiles,perhapsbecausetheyweremorelikelytohavetotalcoronaryocclusionandcompleted infarctions. HighsensitivityassaysThereareseveralhighsensitivity(hs)assaysthathavebeenorarebeingdeveloped [95103].Aproposedoptimalcriterionforcallinganassayhsisthenumberofnormalsubjectsitiscapableof detecting[104].Mostcontemporary(sensitive,butnothighsensitive)assaysdetectveryfewnormalsubjects, whereassomeofthesehsassaysdetectnearly100percentdependingonthepopulation[95102].Partofthe probleminthisareaisthatcompaniesdostudiesunderidealcircumstances.Forexample,thehscTnTassaywas reportedtodetectroughly80percentofnormalsubjects[99].However,inastudyofbasedonapopulation includingabnormalswhereonemightanticipatefewerundetectablevalues[105],only25percentofthepopulation haddetectablevalues.Thislikelyreflectsdifferencesinpopulations,theageofthesamples,andthespecific equipmentusedfortheanalysis[106]. AnalyticalconsiderationsOnlythehscTnTassayhasbeenreleasedforuseandithasnotyetbeen approvedforuseintheUS.Itsanalyticalcharacteristicsincludea99thpercentilevalueof13.5ng/L(0.0135ug/L) anda10percentCVvalueof13.0ng/L[99].Thus,avalueabove14ng/L(0.014ug/L)isconsideredabnormal.In atleasttwostudies,however,theperformanceofthisassayhasnotbeensuperiortoconventionalassaysusedat the99thpercentileURL[43,107]. Itshouldbenotedthathsassaysarepotentiallyfarmorepronethansensitiveassaystoanalyticalproblems becausesmalldifferencescanbeofsuchimportance.Forexample,evenmilddegreesofhemolysisreduce hscTnTvalues[108]anddifferencesinthetypeofsample(heparincomparedtoserumorEDTA)canalsomakea difference[29].Inaddition,withthehscTnTassay,itshouldbenotedthatthepotentialforelevationsdueto skeletalmusclediseasewillbegreaterwiththishsassaythanwiththepresentgenerationassay[15].Finally,with twoofthehsassays[99,109]butnotathird[98],menandwomenhavedifferent99thpercentilevalues ClinicalconsiderationsNewerassaysareasmuchas10timesmoresensitivethanmostsocalled sensitiveassaysandtheyhavepartiallyclarifiedsomeoftheissuesraisedregardingnormalrange(see'Normal range'above).Withtheseassays,mostindividuals,eventhosewithoutapparentmyocardialdisease(normals), havedetectablevaluesforcTn[95,96,99].Theetiologyoftheseminoramountsofproteinisunclearandthisisan areaunderactiveinvestigation[8,110]. Usingthesehighlysensitiveassays,valuesthatareelevatedabovethe99thpercentileURLdefineahighrisk groupregardlessofthetypeofunderlyingcardiovasculardisease.Evenwithinthenormalrangeofthesehighly sensitiveassays,itappearsthatthehigherthevalue,thegreatertherisk[100,105,111113].Thissuggeststhat eachindividualhashis/herownnormalbaselineandthatelevationsabovethatbaselineoccurascardiacdisease ensuesandthusdefinesincreasedrisk. Thesenewerassayshavetremendouspotentialforclinicalmedicine.Forinstance,theyarelikelytoincreasethe rapidityandaccuracyofdiagnosisofacutecoronarysyndromes[96,97,101,102,114]ortoidentifypatientsathigh riskofeventswithcardiovasculardisease[111]. Thepotentialbenefitfromtheuseofhighlysensitiveassayswasevaluatedinastudyof413patientswho presentedtoemergencydepartmentsinGermanywithsymptomssuggestiveofanacutecoronarysyndromeand wereultimatelydiagnosedwithacutemyocardialinfarctionusingtherecommendeduniversaldefinition(evidenceof myocardialnecrosisinaclinicalsettingconsistentwithmyocardialischemiaandclinicalmanifestationsof ischemia,includingsymptoms,characteristicchangesintheelectrocardiogram,orimagingevidenceofischemiaor infarction)[114].(See"Criteriaforthediagnosisofacutemyocardialinfarction",sectionon'AcuteMI'.) Inthisstudy,thediagnosisofmyocardialnecrosiswasestablishedbyatleastonetroponinmeasurementabove the10percentimprecisioncutoffofthehospitalspecifictroponinassay,togetherwithanincreasingand/or

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decreasingpatternofatleast20percentwithinsixhoursafteradmission.Thediagnosticperformanceoftwo protocolspecifiedtroponinassays(differentfromthehospitalspecificassays)wasevaluated.Thesetwoassays weremeasuredonadmissionandafterthreeandsixhours.OneoftheseassayswasanovelhsTnI(levelof detection=3.4pg/mL99thpercentileURL=24pg/mLdiagnosticthresholdforMI=30pg/mL).Theotherisa standardavailableassayfromAbbott(thelevelofdetection=10pg/mL99thpercentileURL=280pg/mL diagnosticthresholdforMI=300pg/mL).Thefollowingfindingswerenoted: Theareaunderthereceiveroperatingcharacteristic(ROC)curveswashighforbothtestsonadmission (0.96and0.92,respectively).TheROCcurvesweresimilarexceptatthelowerconcentrationsoftroponinI, whichweredetectableonlywiththehighlysensitiveassay.Thisdifferencewasmostapparentwhenthe onsetofchestpainwaslessthantwohours. Atadmission,hsTnIhadasensitivityof82.3percentandanegativepredictivevalueof94.7percent(for rulingoutMI).ComparablevaluesforcTnIwere79.4and94.0percent. Atthreehours,thesensitivitywas98.2andthenegativepredictivevaluewas99.4percentforbothassays. Combiningthe99thpercentilecutoffatadmissionwiththeserialchangeintroponinconcentrationwithin threehours,thepositivepredictivevalue(forrulinginMI)forhsTnIincreasedfrom75.1to95.8andforcTnI from80.9to96.1percent. OptimalspecificityforthediagnosisofAMIwasachievedusingapercentagechangeof250percentbutat thecostofasubstantialreductioninsensitivity.A50percentchangeoptimizedthediagnosisofAMIinlate presentersatasimilarcost. ThesedataindicatethathsassayswillfacilitatethediagnosisofpresentlydefinedAMIs,butimportantissues remainunresolved,including: Thegoldstandardappliedinthisandotherstudiesisbasedonolder,lesssensitiveassays.Performance characteristicscomparinghsassaysareunknownandwilllikelyinfluencetheoptimaldeltachangevalue. Thehsassayusedinthestudyandothershavesexbaseddifferencesinthe99thpercentile.Itremains uncertainwhethersexspecificcutpointsneedtobeestablishedforhsassays. Optimalthresholdsforchangevaluesarenotyetdefined: a)Thereisacleartradeoffbetweensensitivityandspecificitythatcliniciansmustrecognize. b)Therearedifferencesamongthehsassaysstudiedandthisprecludesestablishingconsistentcriteria forusewithallassays. Furthermore,theymaybeofvalueinpatientswithstabledisease[101,112]andeventuallyformorechronic screening[29],includingduringstresstesting[6,7]andinpatientswithheartfailure[100].Forexample,inastudy of3546ofparticipantsintheDallasheartstudywhowereevaluatedusingahighlysensitiveassayhscTnTassay, thelowerlimitofdetectionwas0.005ng/mLandthe99thpercentilevalueintheseapparentlyhealthyindividuals was0.014ng/mL.Troponinwasdetectablein25.0percent,and2.0percenthadelevationsabovethe99th percentile[105].Amongthosewithelevationsabovethe99thpercentile,thevastmajorityhaddetectable cardiovascularcomorbidities. However,theuseofmoresensitiveassaysmayleadtosituationsinwhichthecauseoftheelevationsisnot

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apparent[99,102].Althoughtheseelevationsarelikelytoberelatedtocardiovascularabnormalities[101],itis unclearatpresenthowcliniciansshouldrespondtosuchelevationsotherthantoexcludeanacuteprocesswith theuseofserialmeasurementstoseeifachangingpatternispresent[29,102,115].Inaddition,subsettingpatients beforereceivingtheresultsoftestinginaBayesianmannermayhelpimprovetheabilitytomanagethesepatients ratherthanallowingthelabtesttooverrideclinicaljudgment[102]. TheprognosticimplicationsofelevationsofcTnhavebeenevaluatedinmultiplestudiesofwhichthefollowing threearerepresentative: Inthe2010reportof3546individuals(discussedabove)whowereevaluatedwithahighlysensitiveassay, elevationofcTnTwassignificantlyassociatedwithallcausemortalityinthehighestcTnTcategory (adjustedhazardratio2.8,95%CI1.45.2)[105].Inaddition,thereweredifferencesinthenormalvalues foundinmenandwomenandasopposedto0.7percentofthepopulationhavinganelevatedvalue. Inastudyofadultsaged65yearsorolderwithoutpriorheartfailure(HF),highsensitivitycTnTwas measuredatbaseline(n=4221)andtwotothreeyearfollowup(n=2918)[113].cTnTwasdetectable (3.00pg/mL)in66percentatbaseline.Duringamedianfollowupofnearly12years,therewasa significantlyincreasedriskofHFandcardiovasculardeathinthosewithdetectablelevelsatbaseline, comparedtothosewithout.AmongindividualswithinitiallydetectablecTnT,asubsequentincreaseofmore than50percentwasassociatedwithagreaterriskforHFandcardiovasculardeath. Theseobservationsdemonstratethattroponinelevationscanbeduetostructuralheartdiseaseintheabsenceof anyacuteprocessandthushaveprognosticvalue.Asassaysbecomemoresensitiveasdiscussedabove,this percentagewilllikelyincreaseandtheneedtoobservearisingpatterntodistinguishacutefromchronicelevations willbecomemoreimportant[116]. ThereisstillconsiderablecontroversyabouthowtousetheseassaystodetectacuteeventssuchasAMI.In manypatientswithAMI,largechangesincTnoccurovertimeandthediagnosisiseasy[117].However,especially withhscTnassays,thenumberofmoresubtlecaseswillincrease.Thesechallengesrevolvearoundacoupleof issues: The99thpercentileURLisdifferentfordifferentgroups.Insomeassays,thiscanbegenderrelatedandin someitisrelatedtounderlyingcomorbiditiessuchasage[118]ordiabetes[119].Thus,whereassome cliniciansinthepasthaveusedanabnormalvalueinmanysituationsassynonymouswithacutedisease, suchastrategywillmisclassifyevenmorepatientswithhscTnassays. Becauseofthelargenumberofminorelevationsassociatedwithchronicdisease,whetherdetectedor undetected,theabilitytodefinearisingorfallingpatternhasbecomeevenmoreimportant.However,the optimalcriterionforameaningfulchangehasnotyetbeendefined.Severalapproacheshavebeen advocated,eachofwhichincreasesspecificityatthecostofreducingsensitivity.Becausemoststudiesare predicatedontheuseofoldercTnassaysasthegoldstandard,casesofMIdetectableonlywithhsassays arenotincluded[43,107],whereaspatientswhohaveCADareoftenincludedashavingAMIifabaseline elevationofhscTnisfoundevenifariseisnotfound.Therefore,eventheapproachesproposedtodate maynotbeoptimal: Biologicalvariation:Thisapproachisbasedonconjointbiologicalandanalyticvariabilitythatcanonly bederivedinnormalsubjects.Thismetricdefinestheextenttowhichvariationalonecanexplaina givenriseand/orfallofvalues.Thekeymetricisthereferencechangevalue(RCV).TheRCVhas varied,dependingupontheassay,from42to86percent[106,120,121]andisuniquenotonlytoeach individualassaybutevenwiththesamereagents,todifferingpiecesofequipment[106].Someexperts

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haveadvocatedthesevaluesbeusedtodefinewhenarisingandfallingpatternispresent[122].To date,therearenopublishedclinicaldatasupportingthisapproach. Percentagechange:Theuseofapercentagecriteriacanbebasedonbiologicalvariationorsomeother derivedmetric.Notably,someofthepercentagesproposedforclinicalusearemuchlowerthan biologicalchange.Inaddition,atlowvaluesalargepercentagechangemaybereasonablebutathigher values,itmaynotbenearlyassuccessful.Inaddition,itislikelyfromthetheoryofbiologicalvariation thatthefurtheravalueisfromtheRCV,themorecasesduetovariabilityalone(truefalsepositives)will beincluded. Absolutechange:ArecentpaperusingthehscTnTassayhassuggestedthattheuseofavalueof7to 9ngoveraonetotwohourperiodoptimizessensitivityfordetectionofacutechangesandthusAMI. Thesedatarequireconfirmationanddependingonthebaselinevalue,willoftenbebelowbiological variation,sowillbydefinitionlikely(dependingonthepercentchange)includesomeindividualswhose changeisduetovariabilityalone. GiventhelimitationstoeachoftheseapproachestoclinicalapplicationofhscTnassays,carefulindividualization ofpatientsbasedonclinicalgroundsismandatory.Italsoshouldbeappreciatedthatsomepatientswhodonot manifestchangecouldbelateafterAMIandthatmayonlybeapparentbyseeingafallinginvaluesovertime. Finally,somepatientswithputativeunstableanginawillhaveelevatedhscTnvaluesthatdonotchangebutare likelyduetostructuralheartdisease.Thisgroupcouldbeconfusingtoclinicians.Finally,itislikelythattherelative percentageofType2AMIswillincreasewithuseofincreasinglysensitivecTnassays.SuchpatientswithType2 (demandrelated)MIarenotlikelytobenefitfromtheaggressiveantithrombotictherapythatpriorstudieshave documentedtobeofbenefitinpatientswithpredominantlyType1(acuteatherothrombotic)nonSTEMI.The clinicalimplicationisthatuntilmoredataareavailable,cliniciansmayneedtoindividualizethecareofthese patients. Basedontheconcernsstatedabove,wewouldsuggestthatadditionaldataareneededbeforeadvocatingthe routineuseofhighsensitivetroponinassays. CREATINEKINASETheenzymecreatininekinase(formerlyreferredtoascreatininephosphokinase)existsas isoenzymes,whicharedimersofMandBchainsandexistinthreecombinations:MM,MB,andBB[123].These isoenzymesresideinthecytosolandfacilitatetheegressofhighenergyphosphatesintoandoutofmitochondria. Theirdiagnosticusehasbecomemarkedlydiminishedovertimebuttheyareincludedherepredominantlyforthose areasoftheworldwherecardiactroponinassaysarenotyetinexclusiveuse. CKbasicsCreatineKinase(CK)isoenzymeactivityisdistributedinmanytissues,includingskeletalmuscle, butthereismoreoftheCKMBfractionintheheart[124].MostmuscleshavemoreCKpergramthanhearttissue [125,126].Thus,skeletalmusclebreakdowncanleadtoabsoluteincreasesinCKMBintheplasma.Inaddition,in responsetoorgandamage,includingvigorousexercise[127],thereisregenerationofskeletalmusclefibersandre expressionofproteinsthatexistedduringontogeny,resultinginincreasedproductionofBchainCKprotein [126,128,129].AlargepercentageoftheCKthatisreleasedisdegradedlocallyorinlymph[130].Reperfusion truncatesthisprocessandincreasestherapidityandmagnitudeofegressofCKintoplasma[131]. TotalCKmeasurementsforthedetectionofcardiacdamageElevationsintotalserumCKlackspecificityfor cardiacdamage,whichimproveswithmeasurementoftheMBfraction.ThenormalrangeofCKalsovaries considerablyatwofoldorgreaterincreaseintheCKconcentrationisrequiredfordiagnosis.Thiscriterioncanbe problematicinolderindividualswho,becauseoftheirlowermusclemass,mayhavelowbaselineserumtotalCK and,duringMI,mayhaveelevatedserumCKMBwithvaluesoftotalCKthatrisebutremainwithinthenormal range[132134].Forthesereasons,totalCKhasnotbeenusedinthediagnosisofmyocardialdamageforyears. CKMBfractionfordiagnosisofAMIWhencardiactroponinisavailable,CKMBshouldnotbeusedforthe diagnosisofacutemyocardialinfarction.Ifitistheonlyassayavailable,itcanbeusedbutisfarlesssensitiveand

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specific.AssaysforCKMBcanbeperformedeasilyandrapidly. MostassaysmeasureCKMBmass,whichismoresensitivethanactivityassays.Inaddition,massassaysavoid, forthemostpart,detectionofmacrokinases(CKlinkedtoIgGanddimersofmitochondrialCK)thatcanconfound diagnosiswithactivityassays.Thepresenceofmacrokinasesshouldbeconsidered,asonepossibility,whenCK MBisaveryhighpercentage(>20percent)oftotalCK[9].However,patientswithchronicskeletalmuscledisease oftenhavefalselypositiveCKMBresultswhenpercentagecriteriaareused[129,135137].TheproportionofCK thatisCKMBcanbeashighas50percentwithchronicskeletalmuscleinjury,suchas dermatomyositis/polymyositis,duetoincreasedproductionofBchainCKprotein[126,129,135]. SpecificityandsensitivityCKMBhashighspecificityforcardiactissueandwasthepreferredmarkerof cardiacinjuryformanyyears[9].CKMBtypicallybeginstorisefourtosixhoursaftertheonsetofinfarctionbutis notelevatedinallpatientsuntilabout12hours[138,139]. AnelevatedCKMBisrelativelyspecificformyocardialinjury,particularlyinpatientswithischemicsymptoms whenskeletalmuscledamageisnotpresent.Elevationsreturntobaselinewithin36to48hours,incontrastto elevationsintroponin,whichcanpersistforaslongas10to14days[140].ThismeansthatCKMB,unlike troponins,cannotbeusedforthelatediagnosisofanacuteMIbutcanbeusedtosuggestinfarctextensionif levelsriseagainafterdeclining.(See"Criteriaforthediagnosisofacutemyocardialinfarction".) Genderspecificvaluesareessentialfordiagnosticuse[17].CKMBtypicallybeginstorisefourtosixhoursafter theonsetofinfarctionbutisnotelevatedinallpatientsuntilabout12hours[138,139].ItisnowclearthatcTnrises farmorerapidly[41].Elevationsreturntobaselinewithin36to48hours,incontrasttoelevationsintroponin,which canpersistforaslongas10to14days[140].BecauseCKMBcanbereleasedfromskeletalmuscle,its diagnosticuseisimpairedwhenskeletalmuscleinjuryispresent[42].SomehavesuggestedusingaratioofCK MBtototalCKtoimprovespecificity,butthatapproachmarkedlyreducesthesensitivity. CKMBfractionforprognosisThereisarelationshipbetweeninfarctsize,whichcanbeestimatedbyCKMB andprognosis.Peakvaluesarelessprecise,butifadequatenumbersofsamplesareobtained,theycanprovidea reasonableestimate.ComparisonswithcTnsuggestthatcTnprovidesbetterestimates[6569]. CKandcoronaryreperfusionThetimetopeakCKlevelsandtheslopeofCKMBreleasecanbeusedto assesswhetherreperfusionhasoccurredafterfibrinolysisand,whenusedinconjunctionwithclinicalvariables,can predictwhetherTIMI0or1andTIMI2or3gradeflowispresent[57].However,CKMBcriteriacannotidentifythe presenceofTIMI3flow,whichistheonlylevelofperfusionassociatedwithimprovedsurvivalafterfibrinolysisand thisapproachisnotnecessaryatallwithprimaryPCI. ReinfarctionandlatediagnosisSinceCKlevelsreturntobaseline36to48hoursafterinfarction,resampling canbeusedtodetectreinfarction,andbecausecTndoesnotnormalizethatrapidly,itwasinitiallysuggestedthat CKMBmightbeofvalueinthisarea.ItisnowclearthatcTnincreasesrapidly,albeitfromanabnormalbaselinein patientswithreinfarction.Therefore,theuseofcTnhasbeenrecommendedforallAMIdiagnosis,including reinfarction[23]. WHYTROPONINISPREFERRED DiagnosisBecauseoftheirincreasedsensitivityandspecificitycomparedwithCKMBandothermarkers, troponinsarepreferredforthediagnosisofMI.(See'DiagnosisofprimaryMI'above.) ThebasisfortheconsistentobservationthattroponinismoresensitivethanCKMBrelatestothefactthatmore troponinisfoundintheheartpergramofmyocardiumandthatagreaterpercentagedepletedfromtheheartby cardiacinjuryarrivesintheblood[37]. Withregardtospecificity,troponinelevationsarealmostalwaysspecificforcardiacinjury,exceptfortheinfrequent

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analyticalfalsepositivescausedbyfibrininterferenceand/orcrossreactingantibodies[37].Asmentionedabove, CKMBisnotspecificforcardiacinjury,asasmallamountisfoundinskeletalmuscle.(See'CKbasics'above.) ItisdifficulttodaytofindanysituationinwhichCKMBaddsanythingotherthancosttotheclinicalutilityofcTnif thatmarkerisusedproperly[37]. PrognosisAnumberofwelldonestudieshaveshownthattroponinmeasurementshaveenhancedprognostic valuecomparedtoCKMBmeasurementsinpatientswithanonSTelevationACS[76,141143].Thiswas illustratedinareviewofalmost30,000suchpatientsfromthemulticenterCRUSADEinitiativeintheUnitedStates [141].Thefollowingfindingswerenoted: Theresultswerediscordantin28percentofpatients.Troponinwasmoresensitive,as18percenthad elevatedtroponinbutnormalCKMBvalues.Inaddition,10percenthadfalsepositiveCKMBelevations,as definedbynormaltroponinvalues. Comparedtopatientswhowerenegativeforbothbiomarkers,inhospitalmortalitywasnotincreasedin patientswhoweretroponinnegativeandCKMBpositive(ie,falsepositives3.0versus2.7percent, adjustedoddsratio1.02,95percentCI0.751.38) Comparedtopatientswhowerenegativeforbothbiomarkers,therewasanonsignificanttrendtoward increasedmortalityinpatientswhoweretroponinpositive/CKMBnegative(4.5versus2.7percent,adjusted oddsratio1.15,95percentCI0.861.54)andasignificantincreaseinmortalityinpatientswhowerepositive forbothbiomarkers(5.9versus2.7percent,adjustedoddsratio1.53,95percentCI1.181.98). Thesedifferencesinoutcomescouldnotbeexplainedbydifferencesintherapysincethetwodiscordantgroups weretreatedsimilarlywithantithromboticagentsandpercutaneouscoronaryintervention(PCI).Thus,anisolated CKMBelevationhaslimitedprognosticvalueinpatientswithanonSTelevationACS,whileanisolatedtroponin elevationwasassociatedwithincreasedrisk. Similarfindingshavebeennotedinotherstudies[76,142,143].Inareportofover10,000patientswithanACSfrom themulticenterGRACEregistry,1110(10.4percent)weretroponinpositive/CKMBnegativeand822(7.7percent) weretroponinnegative/CKMBpositive(falsepositives)[143].Inhospitalmortalitywashighestwhenbothtroponin andCKMBwerepositive(7.7percent),intermediateintroponinpositive/CKMBnegativepatients(3.9percent), andlowestinpatientsinwhombothmarkerswerenegativeandthosewhoweretroponinnegative/CKMBpositive (1.7and2.3percent,respectively). BIOMARKERSAFTERREVASCULARIZATION AfterPCITherehasbeenconsiderablecontroversyovertheprognosisofelevatedcardiacbiomarkersafter percutaneouscoronaryintervention(PCI).Thisissueisdiscussedindetailelsewhere.(See"Periprocedural myocardialinfarctionfollowingpercutaneouscoronaryintervention",sectionon'Prognosis'.) AfterCABGPerioperativeMIafterCABGisdefinedasincreasesinbiomarkersgreaterthan10timesthe99th percentileupperreferencelimit(URL)pluseithernewpathologicalQwavesorLBBBonthepostoperativeECG,or angiographicallydocumentednewgraftornativecoronaryocclusion,orimagingevidenceofnewlossofviable myocardium.(See"Criteriaforthediagnosisofacutemyocardialinfarction",sectionon'Afterrevascularization'.) MIinthissettingoccursin4to5percentofpatients.(See"Earlycardiaccomplicationsofcoronaryarterybypass graftsurgery",sectionon'PerioperativeMI'.) ElevationsinCKMBaremuchmorecommonthanQwaves,occurringin62to90percentofpatients[144146]. ThisdissociationfromQwavessuggeststhatmostofthedamagethatoccursduringCABGissubendocardialand thusisaroutinesequelaoftheprocedureratherthanacoronaryarteryproblem[147].OnlymarkedCKMB

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elevations(5to10timestheupperlimitofnormal)areassociatedwithtransmuralinfarction[147]andincreased longtermmortality[145]. ElevatedtroponinmaybeamorespecificandsensitivemarkerthanCKMBofanewMIafterCABG,andmaybe morepredictiveofearlycomplications: Thediagnosticvalueoftroponinelevationswasillustratedinastudyof590patientsinwhomacTnT concentration>3.4mcg/L24hoursafterCABGcorrelatedbestwithaperioperativeMIasdefinedbynewQ wavesontheECGandCKMB>100IU/Lwithin48hoursaftersurgery[148].Thesensitivityandspecificity, andpositiveandnegativepredictivevalueswere90and94percent. Theprognosticvalueoftroponinelevationswasaddressedinareportof224patientsinwhomcTnTandCK MBweremeasuredeveryeighthoursaftercardiacsurgery[146].Inamultivariableanalysis,serumtroponin Tconcentrations1.58mcg/L(whichrepresentedtheupperquintile)werethestrongestpredictorof postoperativedeathorshockimmediatelypostoperativelyorat18to24hours.CKMBdidnothave independentshorttermprognosticimportancewhentroponinTwasmeasured.Longtermdatawerenot provided. Arecentinvestigationof1365patientssupportsthiscontentionforcTnIaswell.Measurementsweretaken 2and24hoursaftersurgery.Aftermultivariatecorrection,cTnIlevelswerepredictiveofboth30dayand oneyearmortalityandtherewasagradationofriskwiththosewiththehighestvaluesmanifestingthe greatestrisk[149]. However,itshouldbeappreciatedthatallelevationsoftroponinafterCABGarenotindicativeofavascularevent. Theprocessofcardiopulmonarybypassitself,issuesrelatedtocardiacpreservation,andmechanicalinjurycanall contribute.RecentCMRIdatasuggestthatuntiltroponin(orCKMB)valuesareveryelevated,mostofthedamage issubendocardialandoftenapical,suggestinganonvascularetiology[147].Evenwhenmarkedelevationsoccur, only67of118patientshaveaprimarygraftocclusion,emphasizingtheneedtoconsidertheetiologyofbiomarker elevationsandnotconsideringallelevationsduetovascularevents[150]. Forinfarctionaftercardiacsurgicalprocedures,afivefoldincreasefrombaselineinbiomarkersisrecommended alongwithancillarycriteriasuchasnewQwaves. BIOMARKERSAFTERNONCARDIACSURGERYTroponinsareidealfordiagnosingperioperativeMIafter noncardiac(mostlyvascular)surgery.ThesamecutofflevelsusedtodiagnoseanacuteMIshouldbeusedto detectperioperativeinjuryinsuchpatients.Thediscussionofthesignificanceofapostoperativetroponinelevation isfoundelsewhere.(See"Perioperativemyocardialinfarctionafternoncardiacsurgery".) USEINRENALFAILUREIssuesrelatingtotheclinicaluseofcardiactroponinsandCKMBinpatientswith renalfailurearepresentedindetailseparately.(See"Serumcardiacenzymesinpatientswithrenalfailure".) SUMMARYThemeasurementofserumbiomarkersisakeycomponentinthediagnosisofirreversible myocardialcelldeath(asoccurswithmyocardialinfarction)orpossiblyreversiblecellinjury.Troponinsandcreatine kinase(CK)MBarethetwobiomarkerswhichhavethegreatestutilityforthispurpose.Theyarealsosuperiorto otherbiomarkersforassessingprognosis.(See"Biomarkersofcardiacinjuryotherthantroponinsandcreatine kinase".) Thefollowingpointssummarizetheproperuseofthesebiomarkersfordiagnosisandprognosisofacute myocardialinfarction: Troponinvalueswithinthenormalrange(usingcurrentmethodologies)likelycomefromamixtureoftruly normalindividualswithdetectablevaluesandsomewithcomorbiditiesreflectedbylowbutdetectable

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values.(See'Normalrange'above.) Troponinelevations(abovethe99thpercentile)canbeduetostructuralheartdiseaseintheabsenceofany acuteprocess.(See'Elevationsinthegeneralpopulation'above.) Thediagnosisofanacutemyocardialinfarctiondependsonobservationofariseand/orfallofblood biomarkers,particularlytroponins,withatleastonevalueabovethe99thpercentile,inadditiontoclinical informationorelectrocardiographicchanges.Themoresensitivetheassay,themoreimportantitisto determineachangeforconfirmation.Thisneedisparticularlyimportantwithhighlysensitiveassays.(See 'Highsensitivityassays'above.) WerecommendusingcardiactroponinsinpreferencetoCKMBfordiagnosticandprognosticpurposesitis unnecessarytoobtainbothvalues.CardiactroponinsIandTareequallyuseful.Wedonotrecommendthe routineuseofhighsensitiveassaysoftroponinatthepresenttime. TheimpactofariseisserumbiomarkersafterPCIisdiscussedelsewhere.(See"Periproceduralmyocardial infarctionfollowingpercutaneouscoronaryintervention",sectionon'Prognosis'.) Forthediagnosisofmyocardialinfarctionaftercoronaryarterybypassgraftsurgery(CABG),a10fold increasefrombaselineinbiomarkersalongwithancillarycriteria,suchasnewQwaves,isneeded. MyocardialinfarctionafterCABGisassociatedwithanincreaseinmortality.(See'Biomarkersafter revascularization'above.) ThereisadelayintheriseofbiomarkersafteranacuteMI.InpatientswhohaveanacuteSTEMI, reperfusiontherapyshouldnotawaittheresultsofcardiacbiomarkers.InpatientswithoutdiagnosticST segmentelevation,serialbiomarkertestingisperformedafterfourormorehoursiftheinitialvaluesare indeterminate,theECGremainsnondiagnostic,andclinicalsuspicionremainshigh.(See'Diagnosisof primaryMI'above.)

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Troponins and creatine kinase as biomarkers of cardiac injury

GRAPHICS
Cardiactroponinsarepredictiveofoutcomein unstableangina

AmongpatientswithclassIIIBunstableangina(primaryacute restanginawithinthepreceding48hours),bothSTsegment depressionandserumtroponinshaveindependentpredictive value.Serumtroponinscandistinguishbetweenpatientsathigh riskforacardiaceventat30daysandthoseatlowrisk(20 percentiftroponinpositiveversuslessthan2percentif troponinnegative).


TnI:troponinITnT:troponinT. DatafromHammCW,BraunwaldE.Circulation2000102:118.

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Troponins and creatine kinase as biomarkers of cardiac injury

CardiactroponinIconcentrationandmortalityinunstable angina

Mortalityrateat42daysaccordingtothelevelofcardiactroponinI measuredatbaselinein1404patientswithunstableanginaornonQ wavemyocardialinfarction.Therewasaprogressiveincreaseinrisk withhighertroponinlevels.


DatafromAntmanEM,TanasijevicMJ,ThompsonB,etal.NEnglJMed1996 335:1342.

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Troponins and creatine kinase as biomarkers of cardiac injury

PlasmatroponinTandmortalityinacutemyocardial ischemia

Mortalityratesat30daysrelatedtotheplasmalevelofcardiac troponinTmeasuredatbaselinein801patientspresentingwith symptomsandECGchangesofacuteischemia.Thereisaprogressive increaseinmortalitywithhighertroponinlevels.


DatafromOhmanEM,ArmstrongPW,ChristensonRH,etal.NEnglJMed1996 335:1333.

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Troponins and creatine kinase as biomarkers of cardiac injury

STsegmentdepressionandtroponinspredictoutcome innonSTelevationACS

IntheFRISCtrialof917patientswithanonSTelevationacute coronarysyndrome(unstableanginaornonSTelevation myocardialinfarction),elevatedserumtroponinT,obtained within24hours,isassociatedwithanincreasedincidenceof deathfromcardiaccausesatameanfollowupof37monthsits effectsareadditivetothepresenceofSTsegmentdepression.


DatafromLindahlB,TossH,SiegbahnA,etal.NEnglJMed2000 343:1139.

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PositiveserumtroponinTpredictslowersurvivalafter myocardialinfarction

KaplanMeierestimatesofsurvivalshowthatapositiveserum troponin,obtainedanytimeduringthefirst24hoursafter admissionforanacutecoronarysyndrome,predictsahigher mortalityat30daysandoneyear.

DatafromNewbyLK,ChristensonRH,OhmanM,etal.fortheGUSTOIIa Investigators,Circulation199898:1853.

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