Br HeartJ_ 1995;73:422-427

Comparison of five cardiac markers in thedetection of reperfusion after thrombolysis inacute myocardial infarction

F Lavin, M Kane, A Forde, F Gannon, K Daly

AbstractObjective-To investigate and comparethe clinical usefulness of serial measure-ments of five cardiac marker proteins,namely creatine kinase (CK), CK-MBmass, myoglobin, troponin T, andmyosin light chain 1, in the early detec-tion of reperfusion after thrombolytictreatment.Method-Serial blood samples weretaken from 26 patients presenting withacute myocardial infarction. Concen-trations of the five markers were assayedin each sample. Thrombolytic treatmentwas given to the patients who weredivided into those who reperfused (n =17, group A) and those who failed toreperfuse (n = 9, group B) on the basis ofclinical signs and angiography within24 h.Results-The release profiles of CK, CK-MB mass, myoglobin, and troponin T forpatients in group A differed from those ofpatients in group B. No difference wasobserved in the release profile of myosinlight chain 1 between the two groups. Thetime to peak concentration of CK, CK-MB mass, myoglobin, and troponin Toccurred significantly earlier in patientsof group A than in those of group B, withmyoglobin peaking earlier than the othermarkers. An index, defined as the ratio ofthe concentration of each marker imme-diately before and 2 h after the start ofthrombolytic treatment, was calculatedfor each marker in groups A and B. The2 h myoglobin and troponin T indiceswere significantly different betweengroups A and B. The diagnostic efficiencyof the myoglobin index, however, wasbest at 85%.Conclusions-These studies suggest thatmyoglobin has greater potential than theother markers examined in the detectionof reperfusion after thrombolytic treat-ment.

(Br Heartj_ 1995;73:422-427)

Keywords: cardiac marker proteins; reperfusion;thrombolysis

The most important recent development inthe treatment of patients with acute myocar-dial infarction is the ability to reperfuse theischaemic heart muscle in the early hours afterthe onset of coronary occlusion. Intravenous

thrombolytic treatment has now become thestandard therapeutic approach for patientswith acute myocardial infarction. 1-3 Thereduction in short- and long-term mortalitycaused by thrombolytic treatment has beendemonstrated in several large clinical trials.6The greatest therapeutic effect is seen duringthe early phase of acute myocardial infarctionwith improved left ventricular function occur-ring predominantly when reperfusion is estab-lished within 6 h.7-9

Despite early administration of throm-bolytic agents recanalisation of the infarctrelated artery is not always achieved. Varyingcoronary patency rates of 60-70% have beenreported.'0 The management of patients withpatent infarct related arteries after throm-bolytic treatment remains controversial. Theliterature is divided as to whether immediatecoronary angioplasty has an advantage overdelayed elective angioplasty in patients withpatent but critically stenosed coronary arteriesafter thrombolytic treatment."l 12 Conversely,patients with a persistently occluded infarctrelated artery may benefit from invasive inter-ventions.'3 14 The aforementioned reasonsindicate the importance of being able to deter-mine whether or not successful reperfusionhas occurred after thrombolysis.To date, reliable determination of reperfu-

sion status is only possible by coronaryangiography. This technique is frequentlyeither impractical or unavailable in an emer-gency setting. Standard non-invasive criteria,such as rapid relief of chest pain, rapid nor-malisation of ST segment elevation, andoccurrence of reperfusion arrhythmia, havebeen accepted as non-invasive signs of reper-fusion, but they are not sufficiently sensitiveor specific criteria for an accurate evaluationof the reperfusion status. Predictability ofreperfusion proved to be clearly insufficient inseveral trials using these criteria.'5 16A single non-invasive marker to evaluate

reperfusion would be of significant clinicalbenefit. Various studies have assessed differ-ent cardiac marker proteins as indicators ofreperfusion and the value of myoglobin'7 andcreatine kinase (CK)'8 has been demonstratedin this setting. One study suggested that anearly increase in myoglobin, 2 h after adminis-tration of thrombolytic treatment is indicativeof reperfusion.17 Until recently, however,assays of myoglobin were very time consum-ing and therefore of limited value in the acuteclinical setting. Early peaking of CK has beendemonstrated in successful reperfusion butoccurs too late to be of value in the selection

CardiologyDepartment,University CollegeHospital, Galway,IrelandF LavinK DalyNational DiagnosticCentre, BioresearchIreland, UniversityCollege, Galway,IrelandM KaneA FordeEuropean MolecularBiology Organisation,Heidelberg, GermanyF GannonCorrespondence to:Dr Kieran Daly, CardiologyDepartment, UniversityCollege Hospital, Galway,Ireland.Accepted for publication21 December 1994

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Comparison offive cardiac markers in the detection of reperfusion after thrombolysis in acute myocardial infarction

of patients for further invasive treatment.In recent years, a wide range of rapid assays

for cardiac marker proteins have been devel-oped. The aim of this study was to comparedirectly the release kinetics of five cardiacmarkers for which rapid assays are available:CK, CK-MB mass, myoglobin, troponin T,and myosin light chain 1 throughout thecourse of acute myocardial infarction and todetermine which could provide the earliestand most reliable indication of reperfusionpost-thrombolytic treatment.

Patients and methodsPATIENTSThe study group comprised twenty sixpatients (21 men and five women) admittedto our hospital with acute myocardial infarc-tion and who were eligible for thrombolysis.All patients gave informed consent to the pro-tocol which was approved by the hospitalethics committee. Patients were divided intotwo groups: those who reperfused afterthrombolytic treatment (group A) and thosewho failed to reperfuse (group B).Thrombolytic treatment was given to anypatient presenting within 12 h of the onset ofsymptoms with clinical and electrocardio-graphic evidence of acute myocardial infarc-tion-that is, presenting with typical anginalchest pain for at least 30 min but not greaterthan 24 h and with ST segment elevation onelectrocardiogram (ECG) of greater than orequal to 0 1 mV in two limb leads or 0-2 mV intwo pericardial leads, and who did not have acontraindication to thrombolysis.The thrombolytic agent used was streptoki-

nase in 16 patients, tissue plasminogen activa-tor in five, and combined streptokinase andtissue plasminogen activator in five. The stan-dard doses of streptokinase 1-5 million U andtissue plasminogen activator 100 mg weregiven to all patients with acute myocardialinfarction. The outcome was assumed to beindependent of the type of thrombolytic agentused for the purposes of this study.

ECG RECORDINGSECGs were performed before and 2 h afterthe start of thrombolytic treatment. The leadshowing the greatest ST segment elevationwas used for the initial and subsequent mea-surements. The isoelectric line was defined asthe level of the preceding PR segment and theST segment was measured at the J point. Themean change in ST elevation at 2 h after thestart of thrombolytic treatment was expressedas a percentage reduction from the initialvalue (fractional change).

CLINICAL ASSESSMENT OF INFARCTREPERFIJSIONReperfusion was assessed by standard non-invasive criteria. The first of these was rapidST segment normalisation defined as frac-tional change greater than or equal to 50% at 2h. A previous study suggested that a fractionalchange of 50% was useful for determiningcoronary patency.'9 The second criterion was

Table 1 Patient data

Group A Group B

Sexratio (M:F) 13:4 8:1Mean (range) age (years) 61 (41-72) 61 (42-76)Infarct site

Inferior 9 2Anterior 7 5Posterior 1 2

Mean (range) time tothrombolysis (h) 3 (O-4)h 5-5 (1-10)h

Mean (range) percentageST change 80 (50-100)% 4 (-25)%

Arrythmia 16 3

the occurrence of reperfusion arrhythmia.Accelerated idioventricular rhythm and ven-tricular tachycardia were considered signifi-cant reperfusion arrhythmia. On the basis ofthese criteria, 17 of 26 patients who receivedthrombolytic treatment showed evidence ofreperfusion (group A). The remaining ninepatients were defined as group B.

Classification into groups A and B was sub-sequently confirmed by angiography between12 and 24 h, whereby 16 of the 17 patients ingroup A were shown clearly to have patentinfarct related arteries. Early angiographycould not be carried out on the remainingpatient, but this patient showed almost com-plete normalisation of the ST segment andsignificant arrhythmia, which were consideredadequate for inclusion in group A. The angio-graphic findings were assessed according tothe thrombolysis in myocardial infarction(TIMI) criteria. TIMI grades II or III weredefined as successful reperfusion.Angiography also confirmed the lack of reper-fusion in the nine patients of group B. Table 1gives the clinical details of the two groups.

BLOOD SAMPLINGBlood samples were taken on admission andhourly up to 8 h after the first onset of symp-toms. A maximum of four samples was takenin the first 8 h. Samples were then taken at 8hourly intervals up to 40 h after the onset ofsymptoms and a further two samples weretaken over the next 48 h. Samples were col-lected without angicoagulant and thenallowed to clot at room temperature for 15min. The serum was stored at - 70'C inaliquots after centrifugation until assayed.

ANALYTICAL METHODSActivity ofCK was determined using an auto-mated CK NAC-activated CK UTV test kit(Human GmbH, Taunusstein, Germany) ona Technicon RA 1000 analyser. CK-MB masswas measured by the IMx CK-MB mass assay(Abbott GmbH Diagnostica, Wiesbaden,Germany) on the Abbott IMx analyser. Thisis a two step automated microparticle enzymeimmunoassay which uses two different anti-bodies specific for the M and the B subunitsof CK-MB. Myoglobin was determined by animmunoturbidimetric method (TurbiquantMyoglobin; Behringwerke AG, Marburg,Germany) using the Behring Turbitimeranalyser. Cardiac troponin T was determinedby the enzyme linked immunosorbent assay ofBoehringer Mannheim, Germany on their

423

Lavin, Kane, Forde, Gannon, Daly

Serum concentrationprofiles of (A) creatinekinase (CK),(B) CK-MB mass,(C) myoglobin (Mb), and(D) troponin T (TnT) inpatients who reperfused(group A), and those whodid not (group B). Medianvalues are plotted. AMI,acute myocardialinfarction.

-|- Group A-*- Group B

-o- Group A- - Group B

24 36 48Time after AMI (h)

Enzymun-test system ES300 batch analyser.The concentration of cardiac myosin lightchain 1 was also measured by a fully auto-mated assay for the IMx immunoassay sys-tem.20 Appropriate control samples wereanalysed for quality control of each assaysystem.

STATISTICAL ANALYSISVariables are given as mean (SE) but in allfurther analysis non-parametric (distribution-free) statistics were used. Differences betweengroups were analysed by the Kruskal-Wallistest and the Mann-Whitney U test. TheFriedman rank test was used to compare vari-ables within each group. Significance wastaken at the 5% level. Sensitivity, specificity,efficiency, and positive and negative predic-tive values were calculated to describe the per-formance of CK, CK-MB mass, myoglobin,troponin T, and myosin light chain 1 index inthe detection of successful reperfusion.

ResultsCLINICAL DATAReliable and accurate determination of reper-fusion can be difficult with standard non-inva-sive clinical criteria. The predictive accuracyof these standard markers when used in com-bination is high only when they are concor-dant.2' Biochemical markers offer an objectivealternative to these criteria. The aim of thisstudy was to identify the most appropriatebiochemical marker which could be used topredict accurately and rapidly the reperfusionstatus of the patient after thrombolytic treat-ment and so allow further interventive actionto be taken if appropriate.The mean (range) percentage change in ST

segment normalisation in patients who reper-fused after thrombolytic treatment (group A)was 80 (50-100)%, while in those who failedto reperfuse (group B) the mean (range) per-centage change was only 4 (0-25)% (table 1).There was considerable variation in arrhyth-mia that occurred early after myocardialinfarction. Sixteen of the 17 patients in groupA had significant reperfusion arrhythmia.Eight patients had prolonged episodes of slowventricular tachycardia and eight had acceler-ated idioventricular rhythm. The remainingpatient showed very rapid near normalisationof all ST segments, which was considered suf-ficiently diagnostic for inclusion in group A.Angiography confirmed that this classificationwas correct. Thfee of the nine patients ingroup B had short runs of non-sustained ven-tricular tachycardia (six to 10 beats maxi-mum) and these arrhythmia were notconsidered significant.

EFFECT OF EARLY REPERFUSION ON RELEASEPROFILES OF CARDIAC MARKER PROTEINSThe serum concentrations of the five markers,namely CK, CK-MB mass, myoglobin, tro-ponin T, and myosin light chain 1, weretraced for approximately 3 days after the onsetof symptoms in each group. The figure showsthe resulting profiles. The profiles of all

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424

Comparison offive cardiac markers in the detection of reperfusion after thrombolysis in acute myocardial infarction

Table 2 Peak concentration, time from first onset ofsymptoms to peak value, and 2h indices of cardiac marker proteins

Creatine CK-MB Myosin lightkinase mass Myoglobin Troponin T chain 1

Peakconcentration*Group A 2334 (335) 218 (22) 1400 (345) 10-0 (0 9) 6-8 (0 9)Group B 1776 (271) 222 (36) 735 (280) 10-2 (1-3) 9-0 (3-8)

Peak time (h)Group A 18-9** (2 4) 14-6** (1-1) 5-1*** (0 4) 17-0** (1-0) 50 4 (6-3)Group B 23-4 (2-4) 20-1 (2-1) 10-4 (1-5) 29-8 (8-4) 48-3 (4 7)

2 h indexGroup A 3.0 (0 6) 19-3 (13-9) 9-8** (4 1) 9-8 ** (6 8) 24-0 (20 4)Group B 1-3 (0 3) 2-5 (0-9) 2-0 (0 3) 1-0 (0-3) 2-0 (0 9)

Values are mean (SE). * Peak concentration units are U/i for creatine kinase, and ,ug/l for CK-MB mass, myoglobin, troponin T,and myosin light chain 1. ** Significantly different from values in group B (Mann-Whitney U test). *** Significantly differentfrom values in group B (Mann-Whitney U test) and significantly different from the other values in group A (Friedman test). CK-MB, creatine kinase-MB.

markers, except myosin light chain 1, inpatients of group A are shifted to the left ofthe corresponding profiles of patients in groupB, indicating that reperfusion was associatedwith an earlier, more rapid increase in theconcentration of four of the markers. Themyosin light chain 1 profiles of the two groups

were similar, indicating that release of myosinlight chain 1 after acute myocardial infarctionis independent of reperfusion.

EFFECT OF EARLY REPERFUSION ON PEAKVALUES AND TIMES TO PEAKTable 2 gives the peak concentrations andtimes from the onset of symptoms to peak val-ues of CK, CK-MB mass, myoglobin, tro-ponin T, and myosin light chain 1. There was

wide variation in the peak concentrations ofall markers among each group. The peak con-

centrations therefore were not significantlydifferent from each other and were of no pre-dictive value. The times at which the concen-

trations of four of the markers, namely CK,CK-MB mass, myoglobin, and troponin T,peaked were significantly earlier in patients ofgroup A than in those of group B. Theseresults emphasise the earlier release of thesemarkers when reperfusion is established. Peaklevels of myoglobin in patients of group Aoccur significantly earlier than the othermarkers (P < 0 01).

PREDICTION OF INFARCT REPERFUSION BY USE

OF AN INDEX CALCULATED FOR EACH MARKER

An index, defined as the ratio of the concen-

tration of each marker immediately beforeand 2 h after the start of thrombolytic treat-ment was calculated for each marker ingroups A and B. The indices calculated at 2 h(table 2) for myoglobin and troponin T were

statistically different in patients of group A, inwhom early reperfusion occurred, compared

with those of patients in group B who did notreperfuse. These two markers, therefore, havepotential as indicators of reperfusion statuswithin 2 h of administration of thrombolytictreatment. The difference between the 2 hindices for CK and CK-MB was slightly shortof significance. The mean 2 h index of myosinlight chain 1 in patients of group A was muchgreater than in those of group B but there waswide variation in the results. This was becauseof the low or undetectable levels of thismarker at the stage when thrombolytic treat-ment was administered.The diagnostic performance of tl h

index of all markers to detect reperfusi( As

assessed (table 3). The discriminator , uewas taken as the mean plus twice the standarddeviation of the indices for group B. Thespecificity and positive predictive value of allindices were excellent with this cut-off point.The sensitivity and diagnostic efficiency of themyoglobin index, however, was much betterthan the other indices.

DiscussionThrombolysis is now standard treatment forpatients with acute myocardial infarction andis widely used even in centres lacking cardiaccatheterisation facilities. There is conse-

quently an increasing need for a reliable,rapid, non-invasive marker of reperfusion topermit identification of those patients whomight benefit from further interventional pro-cedures such as rescue coronary angiography.Clinical and electrocardiographic indices ofreperfusion, either alone or in combination,are not sufficiently reliable to predict reperfu-sion with a high degree of accuracy.'5 16 It iswell established that the pattern of several car-

diac markers is altered in the blood whenreperfusion occurs. We decided therefore to

Table 3 Comparison of 2 h indices of creatinine kinase, CK-MB mass, myoglobin, troponin T, and myosin light chain 1

Creatine CK-MB Myosin lightkinase mass Myoglobin Troponin T chain 1

Diagnostic sensitivity (%) 33 40 80 57 33Diagnostic specificity (%) 100 100 100 100 100Positive predictive value (%) 100 100 100 100 100Negative predictive value (%) 33 36 63 45 33Diagnostic efficiency (%) 50 55 85 68 50

CK-MB, creatine kinase-MB.

425

Lavin, Kane, Forde, Gannon, Daly

examine and compare the performance of fivecardiac markers to predict reperfusion afterthrombolytic treatment.Our studies confirmed previous observa-

tions that peak times of the four markers,namely CK, CK-MB mass, myoglobin, andtroponin T, were significantly earlier whenreperfusion occurred.2223 We have also con-firmed that the time to peak myosin lightchain 1 activity is not affected by reperfu-sion.4 Several studies have assessed the clinicalusefulness of the time to peak concentra-tion of these markers as indicators ofreperfusion. I * 14 25 For example, Katus et al I I

showed that the time of peak serum concen-tration of myoglobin, CK, and CK-MB activ-ity predicted reperfusion with diagnosticefficiencies of 93, 89, and 88%, respectively.Hohnloser et al,2' found that the time to peakCK activity in combination with two clinicalmarkers, resolution of ST segment elevation,and occurrence of arrhythmia could predictthe occurrence of reperfusion with 100%sensitivity 90% specificity.

Determination of the time to peak concen-tration of any marker, however, involves mea-surement of the concentration of the markerby serial blood sampling until the decline inplasma concentration is observed. Such a pro-cedure does not lend itself to early indication ofthe reperfusion status of the patient. As analternative, the rate of change in the serumconcentration of some markers shortly afteradministration of thrombolytic agent has beenexamined. Ellis et al 17 reported that a myoglo-bin index, defined as the ratio of myoglobinconcentration immediately before and 2 hafter the start of thrombolytic treatment couldgive useful information about coronarypatency. Increases in CK-MB mass of 2-2-fold over baseline within 90 min or increasesin CK-MB activity (mean (SE)) of 48 (36)U/l in the first hour after treatment wereindicative of reperfusion in other studies.2627The ratio of troponin T concentration on day 1to that on day 4 was shown to discriminatebetween patients who reperfused and thosewho failed to reperfuse.2' This would, how-ever, have no practical use in the selection ofpatients for coronary angiography.The present study allows direct comparison

of how the early rate of increase in the con-centration of five cardiac markers can predictreperfusion after thrombolytic treatment.Because all the markers were analysed in thesame patient group, we were able to comparedirectly the diagnostic performance of each ofthese indices in the prediction of reperfusion.The myoglobin index is clearly the best bio-chemical discriminator in this study, with anoverall diagnostic efficiency of 85%. We havealso identified troponin T as a promising bio-chemical marker of reperfusion. The increasein concentration of troponin T occurs toolate, however, to be of clinical benefit. Thediagnostic sensitivity and specificity of themyoglobin index obtained in this study arecomparable to those reported by Ellis et al,17although higher sensitivities have beenreported.28

The ideal non-invasive marker of reperfu-sion must indicate as early as possible whetherreperfusion has occurred to permit maximumbenefit to be derived from further interven-tional procedures. In addition to the presenceof the marker in concentrations related to thereperfusion status of the patient, it is essentialthat rapid assay methods are available for themarker. Otherwise, the benefits of early detec-tion will not be realised.

In this study, myoglobin was measured byan immunoturbidimetric method carried outon a specialised analyser, which can giveresults in less than 10 min29 and is thus ideallysuited to act as an early marker of reperfusion.We chose to measure CK-MB mass in thisstudy because of its reported higher sensitivitythan the traditional activity measurements.'0A sensitive immunometric assay3l was per-formed by the use of automated analyser. Theturnaround time of this assay for one to 24samples is approximately 40 min, which is stillreasonably acceptable. Several alternativeassays for CK-MB mass have been described,many giving results in less time. The troponinT assay used here takes 90 min for results tobe made available. Therefore, troponin T fallsbehind myoglobin and CK-MB as a non-inva-sive marker of reperfusion in terms of clinicalperformance and speed of availability ofresults.

In conclusion, this study has shown thatmyoglobin allows the earliest prediction ofinfarct reperfusion. The diagnostic sensitivityand efficiency of myoglobin were significantlybetter than the other markers tested andtherefore should be the marker of choice forthe prediction of reperfusion.We thank Behringwerke AG Diagnostica for the TurbiquantMyoglobin kits and for loan of the Turbitimer; BoehringerMannheim, Germany for the Troponin T kits, Drs NedBarrett and Paula Comber of the biochemistry department,Regional Hospital, Limerick, Ireland for use of theirEnzymun-test system ES300, and Abbott Diagnostics, Illinois,USA for analysis of CK-MB mass and myosin light chain 1.

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