Troponins and Creatine Kinase As Biomarkers of Cardiac Injury

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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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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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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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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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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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CardiactroponinIconcentrationandmortalityinunstable angina
Mortalityrateat42daysaccordingtothelevelofcardiactroponinI measuredatbaselinein1404patientswithunstableanginaornonQ wavemyocardialinfarction.Therewasaprogressiveincreaseinrisk withhighertroponinlevels.

DatafromAntmanEM,TanasijevicMJ,ThompsonB,etal.NEnglJMed1996 335:1342.
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PlasmatroponinTandmortalityinacutemyocardial ischemia
Mortalityratesat30daysrelatedtotheplasmalevelofcardiac troponinTmeasuredatbaselinein801patientspresentingwith symptomsandECGchangesofacuteischemia.Thereisaprogressive increaseinmortalitywithhighertroponinlevels.

DatafromOhmanEM,ArmstrongPW,ChristensonRH,etal.NEnglJMed1996 335:1333.
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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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Troponins and Creatine Kinase As Biomarkers of Cardiac Injury

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02/05/13

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

Mortalityrateat42daysaccordingtothelevelofcardiactroponinI measuredatbaselinein1404patientswithunstableanginaornonQ wavemyocardialinfarction.Therewasaprogressiveincreaseinrisk withhighertroponinlevels.

Troponins and creatine kinase as biomarkers of cardiac injury

Mortalityratesat30daysrelatedtotheplasmalevelofcardiac troponinTmeasuredatbaselinein801patientspresentingwith symptomsandECGchangesofacuteischemia.Thereisaprogressive increaseinmortalitywithhighertroponinlevels.

Troponins and creatine kinase as biomarkers of cardiac injury

Troponins and creatine kinase as biomarkers of cardiac injury

KaplanMeierestimatesofsurvivalshowthatapositiveserum troponin,obtainedanytimeduringthefirst24hoursafter admissionforanacutecoronarysyndrome,predictsahigher mortalityat30daysandoneyear.

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