ISSN 0036-5513 print/ISSN 1502-7686 online 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/00365511003716990Scandinavian Journal of Clinical & Laboratory Investigation, 2010; 70: 244251Correspondence:SrenHjortsh j,MD,PhD,DepartmentofCardiology,CardiovascularResearchCentre,AalborgHospital,AarhusUniversityHospital, 16-18 Hobrovej, DK-9000 Denmark. Tel: 45 9932 2178. E-mail: sph@dadlnet.dk (Received 11 November 2009; accepted 16 February 2010) ORIGINAL ARTICLE Determinants of the release pattern of ischaemia-modied albumin in acute ST-elevation myocardial infarction treated with primary PCI SRENHJORTSHJ 1 ,CLAUSDETHLEFSEN 2 ,SREN RISOMKRISTENSEN 3 & JANRAVKILDE 1 1 Department of Cardiology,2 Department of Statistics, and3 Department of Clinical Biochemistry, Cardiovascular Research Centre, Aalborg Hospital, Aarhus University Hospital, Denmark Abstract Background. Ischaemia-modied albumin (IMA) is proposed as a marker of cardiac ischaemia. Release kinetics of IMA have not been investigated during ongoing acute coronary syndrome. We evaluated IMA kinetics in patients with ongoing ST-segmentelevationMI(STEMI)andrevascularizationbyprimarypercutaneouscoronaryintervention(pPCI)asa model.Methods. Twenty-ve patients with STEMI undergoing successful pPCI (Age: median 65 y, range 41 79 y; symp-toms duration: median 4 h, range 1 7 h). Fourteen blood samples were collected (11 during the rst 24 h following pPCI) andanalyzedforIMA,cardiactroponin T,CKMBmass,myoglobin,andheart-typefattyacidbindingprotein.Results. FollowingpPCI,meanIMAincreasedto16%abovebaseline,normalizingwithinlessthan3h.AtthetimeofpPCI, patients with TIMI 0 ow in the infarct artery had low levels of IMA and only exhibited a rise in IMA levels after pPCI, whereas patients with TIMI 1 3 ow had high IMA levels on arrival with a subsequent decrease (p 0.036). There was nostatisticallysignicantassociationbetweenIMAandothervariables,e.g.ECG,symptomsduration,sex,age,blood pressure, and number of vessels affected. Relative concentrations of IMA were low compared with other cardiac biomark-ers.Conclusions. Our results indicate that IMA release may depend on reperfusion-induced events rather than ischaemia per se. Further, we nd a narrow diagnostic time window and a low sensitivity of the IMA assay. Improved understanding of the release mechanisms of IMA is needed before clinical application of the test. Key Words:Acute coronary syndrome, cardiac biomarkers ,cardiology ,ischaemia,ischaemia-modied albumin,myocardial infarction, troponins Introduction Biomarkersofmyocardialnecrosisarepivotalin diagnosingacutecoronarysyndromes(ACS)with cardiactroponinsIand T(cTnIandcTnT)being thepreferredmarkers.Ischaemia-modiedalbumin (IMA) has been proposed as a marker of ischaemia and represents a new approach for the detection and diagnosisofACS[1,2].IMAismeasuredbythe Albumin Cobalt Binding Test (ACB Test), which is therstcommerciallyavailableassayofischaemia approved by the United States Federal Drug Admin-istration. The ACB Test relies on the observation by Bar-Oretal.thathumanserumalbumin(HSA) exhibitsareducedinvitrobindingtoexogenous cobaltinserumfromischaemicindividuals[1,2]. Technicalaspectsoftheassayhavebeendescribed previously [3,4]. ThediagnosticperformanceofIMAhasbeen investigatedinclinicaltrialsinvolvingchestpain patients[2,5 10].Ahighnegativepredictivevalue (NPV)foundinsomestudieshaveledtospecula-tionsthatIMAmaybeausefulrule-outmarkerin theemergencyroom[6,7,11].Inordertodescribe release and modifying mechanisms for IMA, Bar-Or et al. used percutaneous coronary intervention (PCI) in patients with stable angina as a model of transient ischaemia[12].LevelsofIMAshowedarelative increasefollowingPCIbutreturnedtobaseline within6h.LaterstudieshaveshownIMAtobe elevated after PCI and to correlate with the duration of balloon ination as well as the extent of collateral circulation [13,14]. Despiterecentinvestigations,theformationand clearanceofIMAareonlypartlyunderstood[3]. Release of ischaemia-modied albumin in MI 245There has, thus, been uncertainty whether IMA rep-resented only ischaemia or also other manifestations ofdisease,e.g.diffuseactivitybyReactiveOxygen Species (ROS) [15,16]. IMA has also been reported toreectconditionsotherthancardiacischaemia [17 23]. Determinants of IMA elevations in cardiac ischaemia,andespeciallyitsreleasekinetics,have only been scarcely described and never in the context of ongoing ACS. Theaimofourstudywastoevaluatethedeter-minantsofIMAkineticsinfull-scalemyocardial infarction(MI).Wethereforeinvestigatedpatients with ST-segment elevation MI (STEMI) undergoing primary percutaneous intervention (pPCI), having a modelofsevereischaemiawithangiographically proven reperfusion Materials and methods Patient specimens Twenty-ve patients with STEMI undergoing pPCI wereincluded(male:femaleratio2.1:1;medianage 65 y, range 41 79 y). All patients had symptom dura-tion below 7 h (median 4 h, range 1 7 h). Blood sampling Patientshad14bloodsamplesdrawn(beforeand afterangiography,immediatelyafterpPCI,and15, 30, 45, 60, 90, 120 min as well as 6, 24, 48, 72, and 96 h after pPCI). Samples were drawn from a large arm vein into serum tubes without any anticoagulant andwerecentrifugedat4000gfor10min.Serum was stored at 80 C before analysis. Frozen samples weremixedafterthawingandre-centrifugedbefore analysis. Samples didnot undergo repeat freeze-thaw cycles.Inordertoevaluatesensitivityoftheassays, relativeconcentrationswerecalculatedasmeasured concentrationdividedby99thpercentilegiventhe lowest concentration with CV 10%. For IMA, rel-ativeconcentrationswerecalculatedasmeasured concentrations divided by 95th percentile. Cardiac biomarkers Ischaemia-modied albumin (IMA) was determined fromserumwithAlbuminCobaltBinding(ACB) Test (InvernessMedicalInnovationsInc.Stirling, UK). The principle of the assay is described elsewhere [3,4]. AnalyseswereperformedonaCobasMIRA Plusinstrument(RocheDiagnostics,Mannheim, Germany). Thewithin-seriescoefcientofvariation (CV) was 4.4% and the between-day imprecision was 6%. Previously, a reference interval was obtained from 258 healthy blood donors and analysed on a Hitachi 911instrument(RocheDiagnostics,Mannheim, Germany)[24]. TheassayexhibitedaCV 10%at boththeupper95thand99thpercentile(88.2and 111.8U/mL,respectively). The95thpercentilehas been used in other studies [6,10], and 88.2 U/mL was thereforedenedasupperlimitofnormal(ULN). Blood samples were handled and analyses performed according to the manufacturer s protocols. Cardiac Troponin T (cTnT), creatine kinase MB mass (CKMBmass), and myoglobin was determined from serum at 37 C on Elecsys 2010 (Roche Diag-nostics, Germany). For cTnT (4th generation assay), the lowest concentration exhibiting imprecision coef-cientofvariation(CV) 10%was0.03 g/L [25,26]. Upper reference value for CKMBmass was 4.0 (females) and 7.0 g/L (males), respectively [27], andformyoglobin51 g/L(females)and72 g/L (males), respectively [28]. Heart type fatty acid binding protein (H-FABP) was analysed from dipotassium ethylenediamine tet-raacetic acid (K-EDTA) plasma using enzyme linked immunosorbentassaytechnique(HyCultBiotech-nology,Uden,TheNetherlands);upperreference value is 6.0 g/L with CV 10% [28]. Electrocardiogram (ECG), invasive procedures, and assessment of reperfusion Patients were diagnosed by a 12 lead ECG showing ST-segment elevation of 0.2 mV in at least two con-tinuousleadsandreferredforemergencycoronary angiography(CAG).ECG-12wasperformedinall patients prior to admission, either in the ambulance ortheemergencyroom.Patientswerepre-treated with aspirin 300 mg, clopidogrel 300 mg, and unfrac-tionatedheparin10,000IU.Allcoronaryarteries were visualized by CAG before any decision on revas-cularization.Allincludedpatientshadsuccessful pPCIaccordingtoguidelines[29].Allhadstent implantationoftheculpritlesion.Meanballoon inationtimeduringpPCIwas15s(range10 25 sec).FollowingpPCI,patientswithSTEMIwere treated with a bolus of glycoprotein IIb/IIIa receptor-blocker (ReoPro (abciximab)) and infusion for 12 h. Flow in the coronary arteries was assessed using the TIMI scale (Thrombolysis in Myocardial Infarction) beforeandafterrevascularization[30].Allpatients had TIMI3owinallvesselsfollowingpPCIand were thus considered successfully reperfused. Ethics The study was approved by the ethical committee of NorthJutlandand ViborgCounties,Denmark.All participants gave informed consent. Statistics Categorical variables were compared between groups withtheChi-squaretest.Continuousdatawere 246 S. Hjortshj et al. analysedbythettestandpresentedasmeansand 95% CI of the mean (95% CI). The level of signi-cancechosenwas0.05.Unlessotherwisespecied, dataaregivenasmean 2standarddeviations(2 SD). Student s paired t test was used in comparison of time to maximum between serum markers. When comparingreleasekineticsfordifferentpatient groups, a mixed linear effect model was applied. Cor-relationsweretestedusingSpearman scorrelation test. Thestatisticalanalyseswereperformedusing STATA statisticalsoftwarepackage(StataCorp, Texas, USA). Results Baseline characteristics of enrolled patients are shown inTableI.Themajorityofpatients(88%)were asymptomaticwithrespecttoCADpriortothe indexMI.IndividualcurvesofIMAinallpatients followingpPCIthroughtherst6hareshownin Figure 1. ThepeakvaluewasaboveULNin23patients (92%). Therewassubstantialvariationbetweenthe patients. Thirteenpatients(52%)hadcTnTabove ULN on admission. There was a non-signicant rela-tionship between cTnT on admission and symptoms duration (r 2 0.57, p 0.67). Figure2,panelAshowsmean 2SDofIMA fromangiographyandpPCIthroughoutthesam-plingperiod,whilepanelBfocusesontherst6h followingrevascularization.Onadmission,mean IMAwas94 12.6U/mL. Thirteenpatients(52%) hadIMAaboveULN(88.2U/mL)onadmission. MeanIMAlevelsincreasedsharplywithapeak IMAoccurringbetween1545minafterpPCIin almostallpatients.Themeanpeaklevelwas 106.4 9.6 U/mL (range: 72125) reached 40 min afterpPCI,whichis16%aboveULN. Themean increase in IMA levels was 15.1 11.4 U/mL equiv-alenttoamean relativechangeinIMAon12.9%. PeakIMAwasindependentofage,sex,previous hypertensionandhypercholesterolaemia,anddia-betesmellitus.Nineteenpatients(76%)hadST segment elevations 0.2 mV in the ECG, whereas sixpatients(24%)hadSTsegmentelevationsin regression ( 0.2 mV) on arrival. There was no sig-nicant association between duration of symptoms and peak IMA ( p 0.82). Nor was there any asso-ciation between the presence of ST segment eleva-tions in the ECG on arrival and higher IMA levels ( p 0.81). After the peak mean IMA subsequently decreased at a very steep rate and levels were nearly normalized after 2.5 h (p 0.001 compared with peak values). After 7 h, mean IMA was normalized remaining con-stantforthedurationofthestudyformostofthe patients, although a few patients had an unexplained smaller, prolonged secondary increase. Some patients (n 10) already exhibited elevated levelsofIMAonarrival,whereasothers( n 15) exhibited a later rise in levels of IMA (p 0.036). Table I. Baseline characteristics of patients with STEMI (N 25).STEMI patients (N 25) Clinical characteristics Age, median; range, years 58; 41 93Sex, male/female, n17/8Weight, median; range (kg) 79; 55 119Systolic/diastolic blood pressure on arrival, median; range (mm Hg) 120; 105 180/80; 60 109Prior known coronary artery disease, n (%) 3 (12)Hypertension, n (%) 11 (44%)Diabetes, n (%) 2 (8)Duration from onset of symptoms to pPCI, median; range (hours) 4; 1 7 Medication prior to hospitalization Beta-blockers, n (%) 7 (28)Calcium antagonists, n (%) 5 (20)ACE-inhibitors/A-II receptor blockers, n (%) 5 (20)Statins, n (%) 3 (12) Biochemical variables on arrival Creatinine, median; range ( mol/L) 97.5; 67 139Albumin, median; range (g/L) 36; 25 50 Other variables Infarct related artery, n (%)Left anterior descendent artery 6 (24)Left circumex artery 9 (36)Right coronary artery 10 (40)No. of vessels affected, n (%)1-vessel/2-vessels/3-vessels 13 (52)/5 (20)/7 (28)TIMI ow on arrival, n (%)TIMI 0/1/2/3 15 (60)/3 (12)/5 (20)/2 (8)ECG on arrivalST elevations 0.2 mV/ 0.2 mV 19 (76)/6 (24) Release of ischaemia-modied albumin in MI 247Neitherdurationofsymptomsnorthepresenceof ST-elevationsonarrivalorabsoluteST-elevations (measuredinmV)wasassociatedwiththis phenomenon(p 0.84,0.71,andp0.57, respectively). Theowinthecoronaryarterywasgraded accordingtothe TIMIscale.Patientswithnoow (TIMI 0) had lower levels of IMA on arrival as com-pared to patients with the TIMI 1 3 ow (p 0.042) (Figure 3). There was no statistical signicant asso-ciationbetweenthecourseofIMAandothervari-ables, e.g. sex, age, blood pressure, number of vessels affected, and infarct related artery. LevelsofcTnT,CKMBmass,myoglobin,and H-FABP increased markedly following STEMI and revascularization consistent with signicant myocar-dialnecrosis(p 0.0001forallmarkers).Mean relative concentrations of these markers are shown in Figure 4. IMA relative concentrations remained low comparedtoothermarkers(p 0.001forcTnT, CKMBmass,myoglobin,andH-FABP),indicating a low sensitivity of the ACB assay. Peak levels of IMA werenotcorrelatedtopeaklevelsofnecrosis markers. Discussion IMA following revascularization Thisistherststudytodescribedeterminantsof IMA release and clearance during ongoing ACS. We usedSTEMIpatientsundergoingpPCIasamodel of severe cardiac ischaemia and found an increase in meanlevelsto16%aboveULN. Themeanrelative increasefromadmissionwas12.9%.Previously, Bar-Oretal.found10%relativeincreaseinIMA levels in patients with stable angina undergoing PCI withprolongedballooninations[12].Ourstudy population had ongoing MI, and it may be question-abletocomparethepresentstudywithprevious studiesinpatientswithstableangina.Inourstudy, levelsofIMAincreasedabruptlyfollowingpPCI, peaked after 40 min, and returned to almost normal levelswithinlessthan2 3h,whereasBar-Oretal. describednormalizationover6 8hours.However, Bar-Oretal.tookonlyfourbloodsamplesagainst our10samplesfrombaselineto6hfollowingPCI and it may well be that we are simply able to describe the kinetics more precisely. Notably, only 13 patients (52%)hadIMAaboveULNonadmissioninthe setting of severe myocardial ischaemia. This observa-tionsuggeststhatintheclinicalsetting,onehasto rely on at least two samples before ruling out a patient with an IMA value below ULN. IMA and coronary ow Some patients showed signs of normalization of ow intheinfarctarteryonadmission,possiblydueto pre-treatment with antithrombotic drugs and inher-entspontaneousbrinolysis.Itisthuspossibleto divide patients into those who were partly reperfused on arrival and those who were not. Patients who had TIMI 1 3 ow in the infarct artery had signicantly lowerandfallingIMAlevelsthatseemedtohave peaked before arrival (Figure 3). On the other hand, an initial rise and peak of IMA was seen in patients whohadtheirinfarctarteryopenedonlyduring Figure1.IndividualcurvesofIMAinpatientswithSTEMI ( N 25)throughtherst6hfollowingpPCI.Bloodsampling continued up to 96 hours after pPCI, but IMA remained constant during this time. Figure 2. Mean IMA levels with 2 SD in patients with STEMI ( N 25) undergoing angiography and primary pPCI. Panel A: Mean IMA in entire sampling period (96 h). Panel B: First 6 h following pPCI. 248 S. Hjortshj et al.pPCI,thusbeingexposedtotheimmediateeffects of reperfusion. IMA thus seems to reect the response to reperfusion at a time, where ischaemia supposedly should be relieved. This poses the question whether IMA is solely an ischaemia marker or may also be a markerofdiffusereperfusion-inducedeventsby reactive oxygen species (ROS). ROS activity has also been proposed as the cause of IMA elevation follow-ingDCcardioversionandablation[19,20].Others, however, have found IMA levels directly correlating to the extent of ischaemia [13,14,31]. In this study, we did not have access to measures of ROS activity, e.g. isoprostanes, but future studies may address this particular issue. ThereleasepatternofIMAresemblesthatof myoglobin, and it may also be that we are observing thesamephenomenonasinastudybyJurlander etal.wherepatientswithSTEMIreceivingthrom-bolytic therapy were investigated with CAG and clas-sied as reperfused or non-reperfused [32], i.e. that opening the artery releases IMA entrapped distal to the coronary occlusion of blood with very high IMA levels although the total volume of trapped blood in the microvascular bed of the heart is likely to be very small relatively to the systemic intravascular volume. Inthatstudy[32]thetimetopeakformyoglobin wassignicantlyshorterinthereperfusiongroup comparedwiththenon-reperfusiongroup,i.e.a short time to peak is a marker of reperfusion. How-ever, Haastrup et al. investigated non-invasive meth-odsforassessmentofreperfusionandfoundthat biochemical markers were very dependent of infarct sizeandthusnotveryusefulintheassessmentof reperfusion status [33]. Another less possible explanation for the observed phenomenoncouldbedislodgementofthrombus materialfromthesiteofocclusionandsubsequent blockageofthemicrovasculaturewithresulting ischaemia.However,ischaemiashouldbeexpected to be at its maximum before opening the artery, and is therefore unlikely to see yet another increase as a result of thrombus material in parts of the microvas-cular bed. IMA and ECG Regression of ST elevations are used when assessing theefcacyofrevascularizationtherapy[34],and onemaythereforehaveexpectedanassociation between the presence of ST elevations and IMA on admission. Themajorityofpatients(76%)hadST elevations 0.2 mV in the ECG on arrival, but this was not associated with an elevated arrival IMA. Nei-ther was there any relationship between absolute ST elevations and IMA. In this case, it was not possible to link different release patterns of IMA to the ECG, possibly due to the size of the study. To explain this, one may again draw on experiences from the throm-bolyticerashowingapossibleconnectionbetween therapidreleaseofamarkerandregressionof ST-changes. Thus,Jurlanderetal.foundaninverse relationship between a rapid peak of myoglobin and Figure 3. IMA with 2 SD in STEMI patients grouped according to TIMI ow in the infarct artery on arrival. Panel A: TIMI 0 ow. Panel B: TIMI 1, 2, and 3 ow. Patients with TIMI 0 ow exhibit lower IMA values on arrival and later peak values (p 0.042). Figure 4. Release of biomarkers of myocardial necrosis, i.e. cTnT and myoglobin. Data are shown as mean relative concentrations. Pleasenotethatthescaleonthelefty-axisisofmuchsmaller magnitude. Necrosis markers exhibit signicant release following pPCI,consistentwith full-scalemyocardialinfarction.Relative concentrations of IMA are plotted against the left y-axis remaining at a low amplitude compared with necrosis markers. Release of ischaemia-modied albumin in MI 249ahighrateofST-segmentresolutionintheECG using continuous ST-segment monitoring and a val-idatedassessmentofmyocardialsalvage[35].Itis possible that in patients who were partly reperfused beforeadmission,IMApeakedearlywithconcomi-tant ST-segment regression. IMA and symptoms duration ST-elevations in the ECG and an occluded epicardial artery denitely represent afull-scale MI as can also beseenfromtheelevatednecrosismarkers(Figure 3). As IMA levels in stable patients undergoing PCI dependonthemagnitudeanddurationofmyocar-dialischaemia(balloonination)[14],onecould expect that IMA levels were higher in those patients withthelongestsymptomsduration.However,we found no relationship between IMA on arrival, peak IMA, and symptoms duration. Neither was there any statistical signicant relationship between cTnT and symptomsduration.Further,thereseemstobea niteupperlevelforIMAformation,whereonlya certain proportion of circulating albumin can be con-verted into IMA regardless of the magnitude or dura-tionofischaemia,cf.thesmallrelativechangesof IMAcomparedtothenecrosismarkers. Thiswar-rants further investigation. IMA compared with other biomarkers ItisreadilyseenfromFigure3thatothernecrosis markers are signicantly above discriminatory limits. The shape of the IMA curve shape is similar to that ofmyoglobinandtoalesserextentH-FABP (cf.Figure2),butthelattermarkersdecreasedto normal levels at a slower rate. IMA has been found tohaveahigh negativepredictivevalueinpatients presenting with symptoms of ACS [6,11]. However, the very sharp rise and decline in IMA levels follow-ing severe ischaemia means that the negative predic-tivevaluedecreasesifthepatientpresentsinthe emergency room just a few hours beyond the ischae-mic event where IMA may have returned to normal levels. On the other hand, the release characteristics withrapidnormalizationcouldindicatearolefor IMA as a marker of re-infarction. There are, however, no available clinical data to support this. A role as a marker of re-infarction would also be on the expense ofaverynarrowdiagnostictimewindowmeaning thatthetestcanbeappliedonlyinthosepatients withveryshortsymptomsduration. Thus,itisnot clear to what extent IMA offers any advantages over cardiac necrosis markers in a clinical setting. IMA and specicity Fromacardiologist sperspective,biomarkersof ischaemia have an important inherent problem from theclinician spointofview,astheyarenotheart specic[16 18,2123].Ifindeedoriginatingfrom the heart, the marker may not reect coronary artery diseasebutpossiblyotherprocesses,e.g.stunning afterelectricalcardioversion[19,20].Inthecaseof IMA,thereareindicationsthatthismarkermay reect ischaemic processes throughout the organism [18,36 40], and thus an elevated IMA may not guide the clinician sufciently. Further, if ROS activity dur-ing reperfusion plays a major role in IMA formation, there may be numerous non-cardiac conditions where IMA may be elevated due to diffuse ROS activity. Limitations The number of included patients is small which does notallowforrobustconclusionsinsomeareas,e.g. regarding inuence of gender on IMA levels. Apreviousreportquestionedtheuseoffrozen IMAsamples[41].However,thestudyinvestigated IMA results from samples frozen at 20C, whereas the present study investigated samples stored at 80C whichcomplieswiththemanufacturer sadjusted recommendations. Ideally, the results from the present study should have been compared with data from individuals who did not obtain reperfusion. However, it is not possible to include patients with STEMI who were not revas-cularized, as this is unethical or would demand a very largescreeningpopulationinordertoobtainarea-sonablestudygroup,asamongSTEMIpatients,it canbeexpectedthatapproximately3%ofpatients have TIMI0or1owfollowingprimaryPCI[42]. At present, no animal model has been validated with the concept of IMA. It is still unknown whether the decreasedcobalt/albuminbindinginischaemiais conned to humans or also present in other species. In this study, we found that the main changes in IMA occur during the rst 2 3 hours. Therefore, the inclusionofpatientswithupto7hofsymptoms duration may be problematic, as some patients may present with already decreased levels of IMA. Future studiesmayfocusexclusivelyonthersthoursto obtain an even more homogenous population. Conclusions WeconcludethatthereleasepatternofIMAin STEMIpatientsundergoingpPCIwassignicantly associated with the degree of ow in the infarct artery on arrival. Patients with no ow in the artery (TIMI 0)hadlowerlevelsonarrivalandaccordinglylater peaksinIMA.Ourndingssuggestthatincreases inIMAbeyondbaselinelevelscouldhaveother causesthanischaemia,i.e.reperfusion-induced events,possiblybyreactiveoxygenspecies(ROS), possibly in addition to indicating successful reperfu-sion.Further,theveryfastclearanceofIMAmay 250 S. Hjortshj et al. Sinha MK, Roy D, Gaze DC, Collinson PO, Kaski JC. Role[9] ofIschemia modied albumin , a new biochemical marker ofmyocardialischaemia,intheearlydiagnosisofacute coronary syndromes. Emerg Med J 2004;21:29 34. Wu AH,MorrisDL,FletcherDR, AppleFS,Christenson[10] RH,PainterPC.AnalysisoftheAlbuminCobaltBinding (ACB) test as an adjunct to cardiac troponin I for the early detection of acute myocardial infarction. Cardiovasc Toxicol 2001;1:147 51. PeacockF,MorrisDL,AnwaruddinS,ChristensonRH,[11] Collinson PO, Goodacre SW, Januzzi JL, Jesse RL, Kaski JC, KontosMC,LefevreG,MutrieD,SinhaMK,Uettwiller-GeigerD,PollackCV.Meta-analysisofischemia-modied albumin to rule out acute coronary syndromes in the emer-gency department. Am Heart J 2006;152:253 62. Bar-OrD, WinklerJV, VanbenthuysenK,HarrisL,LauE,[12] Hetzel FW. Reduced albumin-cobalt binding with transient myocardialischemiaafterelectivepercutaneoustranslumi-nal coronary angioplasty: a preliminary comparison to cre-atinekinase-MB,myoglobin,andtroponinI.AmHeartJ 2001;141:985 91. GarridoIP,RoyD,CalvinoR,Vazquez-RodriguezJM,[13] AldamaG,Cosin-SalesJ,QuilesJ,GazeDC,KaskiJC. Comparison of ischemia-modied albumin levels in patients undergoing percutaneous coronary intervention for unstable angina pectoris with versus without coronary collaterals. Am J Cardiol 2004;93:88 90. Quiles J, Roy D, Gaze D, Garrido IP, Avanzas P, Sinha M,[14] KaskiJC.Relationofischemia-modiedalbumin(IMA) levels following elective angioplasty for stable angina pecto-ris to duration of balloon-induced myocardial ischemia. Am J Cardiol 2003;92:322 4. RoyD,QuilesJ,GazeDC,CollinsonP,KaskiJC,Baxter[15] GF. Role of reactive oxygen species on the formation of the novel diagnostic marker ischaemia modied albumin. Heart 2006;92:113 4. Borderie D, Allanore Y, Meune C, Devaux JY, Ekindjian OG,[16] KahanA.Highischemia-modiedalbuminconcentration reectsoxidativestressbutnotmyocardialinvolvementin systemic sclerosis. Clin Chem 2004;50:2190 3. Can M, Demirtas S, Polat O, Yildiz A. Evaluation of effects[17] of ischaemia on the albumin cobalt binding (ACB) assay in patients exposed to trauma. Emerg Med J 2006;23:537 9. Falkensammer J, Stojakovic T, Huber K, Hammerer-Lercher[18] A, Gruber I, Scharnagl H, Fraedrich G, Santner W, Schocke M,Greiner A.Serumlevelsofischemia-modiedalbumin inhealthyvolunteersafterexercise-inducedcalf-muscle ischemia. Clin Chem Lab Med 2007;45:535 40. Roy D, Quiles J, Sinha M, Floros D, Gaze D, Collinson P,[19] Baxter GF, Kaski JC. Effect of radiofrequency catheter abla-tion on the biochemical marker ischemia modied albumin. Am J Cardiol 2004;94:234 6. RoyD,QuilesJ,SinhaM,AldamaG,GazeD,KaskiJC.[20] Effect of direct-current cardioversion on ischemia-modied albumin levels in patients with atrial brillation. Am J Car-diol 2004;93:366 8. AppleFS,QuistHE,OttoAP,MathewsWE,Murakami[21] MM.Releasecharacteristicsofcardiacbiomarkersand ischemia-modiedalbuminasmeasuredbythealbumin cobalt-binding test after a marathon race. Clin Chem 2002;48:1097 100. TroxlerM, ThompsonD,Homer-VanniasinkamS.Ischae- [22] micskeletalmuscleincreasesserumischaemiamodied albumin. Eur J Vasc Endovasc Surg 2006;31:164 9. Abboud H, Labreuche J, Meseguer E, Lavallee PC, Simon[23] O,OlivotJM,MazighiM,DehouxM,BenessianoJ,Steg PG,AmarencoP.Ischemia-modiedalbumininacute stroke. Cerebrovasc Dis 2007;23:216 20. Hjortshoj S, Kristensen SR, Ravkilde J. Diagnostic value of[24] Ischemia Modied Albumin in patients with suspected acute coronary syndrome. Am J Emerg Medicine 2010;28:1706. suggest a role for IMA in the detection of re-infarction, althoughnotsupportedbyavailableclinicaldata. Until questions regarding IMA formation and clear-ancehavebeenresolved,thereseemstobelimited benet of IMA sampling in a clinical context. Acknowledgements Wearegratefultothestaffatthedepartmentsof CardiologyandClinicalChemistry, AalborgHospi-tal,AarhusUniversityHospitalfortheirhelpand support during sampling and analysis of samples. Funding The study was nancially supported by The Danish Heart Foundation and the County of North Jutland ResearchFoundation. Also,wewouldliketothank InvernessMedicalInnovations,Inc.forproviding assays and technical support. Declarationofinterest:Theauthorsreportno conictsofinterest. Theauthorsalonearerespon-sible for the content and writing of the paper. References Bar-OrD,LauE,RaoN,BamposN, WinklerJV,Curtis[1] CG.Reductioninthecobaltbindingcapacityofhuman albumin with myocardial ischemia. Ann Emerg Med 1999;34 (4 Suppl.): S56 (Abstract). Bar-OrD,LauE, WinklerJV.Anovelassayforcobalt- [2] albumin binding and its potential as a marker for myocar-dialischemiaapreliminaryreport.JEmergMed2000;19:311 5. Bar-OrD,RaelLT,Bar-OrR,SloneDS,MainsCW,Rao[3] NK, Curtis CG. The cobalt-albumin binding assay: insights into its mode of action. Clin Chim Acta 2008;387:120 7. Bar-Or D, Curtis G, Rao N, Bampos N, Lau E. Character- [4] ization of the Co(2 ) and Ni(2 ) binding amino-acid resi-dues of the N-terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia. Eur J Biochem 2001;268:42 7. Abadie JM, Blassingame CL, Bankson DD. Albumin cobalt[5] bindingassaytoruleoutacutecoronarysyndrome.Ann Clin Lab Sci 2005;35:66 72. Christenson RH, Duh SH, Sanhai WR, Wu AH, Holtman V,[6] Painter P, Branham E, Apple FS, Murakami M, Morris DL. CharacteristicsofanAlbuminCobaltBindingTestfor assessmentofacutecoronarysyndromepatients:amulti-center study. Clin Chem 2001;47:464 70. Collinson PO, Gaze DC, Bainbridge K, Morris F, Morris B,[7] Price A, Goodacre S. Utility of admission cardiac troponin and IschemiaModiedAlbuminmeasurementsforrapid evaluationandruleoutofsuspectedacutemyocardial infarction in the emergency department. Emerg Med J 2006;23:256 61. RoyD,QuilesJ, AldamaG,SinhaM, AvanzasP, Arroyo- [8] EspligueroR,GazeD,CollinsonP,CarlosKJ.Ischemia Modied Albumin for the assessment of patients present-ingtotheemergencydepartmentwithacutechestpain but normal or non-diagnostic 12-lead electrocardiograms andnegativecardiactroponin T.IntJCardiol2004;97:297 301. Release of ischaemia-modied albumin in MI 251markersinacutemyocardialinfarction.HeartDrug2001;1:197 206. de Lemos JA, Braunwald E. ST segment resolution as a tool[34] forassessingtheefcacyofreperfusiontherapy.J AmColl Cardiol 2001;38:1283 94. JurlanderB,HolmvangL,GalatiusS, VaughtC,Johanson[35] P,KrucoffMW,GrandeP,ClemmensenP,WagnerGS. Mirror-lake serial relationship of electrocardiographic and biochemical indices for the detection of reperfusion and the predictionofsalvageinpatientswithacutemyocardial infarction. Am Heart J 2003;146:757 63. Abboud H, Labreuche J, Meseguer E, Lavallee PC, Simon[36] O,OlivotJM,MazighiM,DehouxM,BenessianoJ,Steg PG,AmarencoP.Ischemia-modiedalbumininacute stroke. Cerebrovasc Dis 2006;23:216 20. GunduzA, TurediS,MenteseA,Altunayoglu V, TuranI,[37] KarahanSC,TopbasM,AydinM,EraydinI,AkcanB. Ischemia-modiedalbuminlevelsincerebrovascularacci-dents. Am J Emerg Med 2008;26:874 8. GunduzA,TurkmenS,TurediS,MenteseA,YulugE,[38] Ulusoy H, Karahan SC, Topbas M. Time-dependent varia-tionsinischemia-modiedalbuminlevelsinmesenteric ischemia. Acad Emerg Med 2009;16:539 43. RoyD,QuilesJ,SharmaR,SinhaM, AvanzasP,GazeD,[39] KaskiJC.Ischemia-modiedalbuminconcentrationsin patients with peripheral vascular disease and exercise-induced skeletal muscle ischemia. Clin Chem 2004;50:1656 60. TurediS,Gunduz A,Mentese A,KarahanSC, YilmazSE,[40] Eroglu O, Nuhoglu I, Turan I, Topbas M. Value of ischemia-modied albumin in the diagnosis of pulmonary embolism. Am J Emerg Med 2007;25:770 3. BeethamR,MonkC,KeatingL,BengerJR,KendallJ.[41] Effects of storage at 20 degrees C on ischaemia-modied albumin results. Ann Clin Biochem 2006;43:500 2. AndersenHR,NielsenTT,RasmussenK,ThuesenL,[42] Kelbaek H, Thayssen P, Abildgaard U, Pedersen F, Mad-senJK,GrandeP, Villadsen AB,KrusellLR,Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard HK, Mortensen LS. A comparison of coronary angioplasty with brinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733 42. Apple FS, Wu AH, Jaffe AS. European Society of Cardiology[25] andAmericanCollegeofCardiologyguidelinesfor redenitionofmyocardialinfarction:howtouseexisting assays clinically and for clinical trials. Am Heart J 2002;144:981 6. Panteghini M, Pagani F, Yeo KT, Apple FS, Christenson RH,[26] Dati F, Mair J, Ravkilde J, Wu AH. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin Chem 2004;50:327 32. AppleFS,QuistHE,DoylePJ,Otto AP,MurakamiMM.[27] Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society ofCardiology/AmericanCollegeofCardiologyconsensus recommendations. Clin Chem 2003;49:1331 6. Pelsers MM, Chapelle JP, Knapen M, Vermeer C, Muijtjens[28] AM,Hermens WT,GlatzJF.Inuenceofageandsexand day-to-dayandwithin-daybiologicalvariationonplasma concentrations of fatty acid-binding protein and myoglobin in healthy subjects. Clin Chem 1999;45:441 3. SilberS, AlbertssonP, AvilesFF,CamiciPG,Colombo A,[29] Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines for percutaneous coronaryinterventions.TheTaskForceforPercutaneous Coronary Interventions of the European Society of Cardiol-ogy. Eur Heart J 2005;26:804 47. TheThrombolysisinMyocardialInfarction(TIMI)trial.[30] PhaseIndings. TIMIStudyGroup.NEnglJMed1985;312:932 6. Sinha MK, Vazquez JM, Calvino R, Gaze DC, Collinson PO,[31] Kaski JC. Effects of balloon occlusion during percutaneous coronaryinterventiononcirculatingIschemiaModied Albuminandtransmyocardiallactateextraction.Heart 2006;92:1852 3. JurlanderB,ClemmensenP,OhmanEM,ChristensonR,[32] WagnerGS,GrandeP.Serummyoglobinfortheearly non-invasive detection of coronary reperfusion in patients withacutemyocardialinfarction.EurHeartJ1996;17:399 406. Haastrup B, Gill S, Haghfelt T, Horder M, Kristensen SR.[33] Dependencyoninfarctsizelimitstheclinicalapplicability ofnon-invasivereperfusionassessmentbybiochemical Copyright of Scandinavian Journal of Clinical & Laboratory Investigation is the property of Taylor & FrancisLtd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyrightholder's express written permission. However, users may print, download, or email articles for individual use.