Rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction

JACC V m. Na r April tttl:Ima-1!

1009

Rapid Diagniosis of Coronary Reperfusion by Measurement of Myoglobin Level Every 15 min in Acute Myocardial Infarction MASAAKI MIYATA . MD, SATOSHI ABE. MD . SHINICHI ARIMA . MD, KUNIHIRO NOMOTO, ML! MASAMITSU RAWATAKI, MD .- MAKOTO UENO! TSUMINORI YAMASHITA, MD, SHUICHI HAMASAK1, Ml]. HITOSID TODA, MD,t MINORU TAHARA, MD4 YOSHIHIKO ATSUCHI, -Nat,) SHOICHIRO NAKAD . MD, HIROMI SU TANAKA, MD Kagaskinra, Japan Ohkegra. The pimp... d ads .tedy cam m came whether cure-7 repmhada ma he dlspomd rapidly cad accurately by a mrmaremssds Rasbpm cud. When hdravene a lbeomhdp;ls Is used file =to atreconfid hatrdim, k is fatpartaut so deksmhe curvasay repimi eapld ad trurbwadvely m that further trahsem cm be idddd, Meaesh. We demmlad sayayloifu, nut* blow . (CK) ad Mullis UK-. OB (twwdba (CK-MW hotmyme by i 03 lei wli riledwavyeAwwcn acute myaanW b0rda mill hail 90111 111101191`1110 h6rn edey-awe .i .g.p T . 11(yeghKewawamedhyarbiBaeldehtet .J .t1..,wnRh hen m m e dine of 10 abt. We mm e.d aryaghibr, CK ..d CK M0 every IS raft Y d5 psalm n wills and II pathet without

repatdm. The eadlnnn d th. idnrn+dfM very can mnfmmd every 5 to 0 aft by mammary agloppby . Runltr,Thenledhuru eInailatiloble .CK,edCKMBat 15, 30, 45 end 60 min alder bmaal and roperlbdm wss dguilltmdy high' .I the rgerfned than to use neereperfwed gap. In ate repvhed pap de roe dh aeaae in myop obit waenp if au Iybighertkm lie e .erapemdtee rite oflmrme In CK ad CK-MB at IS, 30 and 49 min after eperf ram . When reperhnis • was ewdoaled a ibe Osdsofa eutoelevel (wyglobb a 2.0, CK a IJA . CK401 a 131, the predictive accursey of wyvglrbin than that d CK (68%) and CK-MB (95%) (73%) mmat dgddaatIy 15 mY alterMgher ropefmleo . Caaimina. Carmseysepukdlncmben%Wly aadaawetdy detected by memmeeal of the phmet myigiebio every IS i . (/ Am Call Cardd 7991;33:1od9-151

Thromholytic therapy is beneficial for treatment of acute myocardial infarction (1-61 . When tbrotnbolytic .gems are inhwvetmusly ate in patients with acute myocar did itdlrctioa without emerget coronary anp ouphy, it Is import" to diapone rapidly .' eeLy and mninvasively whether or not canary repatmim has occurred so that further therapy ®n be initiated . Bioeheial markers that mm be detected and measured quickly would be helpful in the aauinvmive amassment of coronary reperfueion . Current methods for cvdustinO the rea .Bs of repenfusion they spy utilize the washout phenomenon aecompmyhig reperNsla of rmeh biochmeied ®rken as creation kisare (CK), cratioe kiase . M8 fraction (CR-MB) isaencyme, myoglobin and CK-MM and CK MB Worms (7-20). Myodobim is released from the infaraord . necrotic myocardium into the blood earlier than CK and CK-MB during the acute stage of

myocardial infarction (21,22) . Therefore, myoglobm may be the best biochemical marker for the rapid detection of repetfusion anus those cutremly being reported . Because coronary angiogaphy was not frequently per Permed in most province studies that observed the charities in biochemical markcn alter the start of thumbolysis, the time paints of repeibsion after theombdlylis were not accurately detected, and the washout phenomenon .her thnmbolydv might not be reflected precisely. Therefore, we performed cmonmy engiagephy every 5 to 0 min to detect the time point repetftsian and measured every IS minofafter reperfniaw to definethethemyoglobia washoutlevel phenomenon using the newly developed toebidimetic latex agglutination method with an essay time markedly shorter than that for radioimmunswsay (23-25) . The purpose of this study was to examine whether coronary repmfusion can be diagnosed quickly and accurately by measurement of plasma myoglobin every 15 min.

FSee tievwmaty Porn Depnnwu d Iram curnr Netior . 'Mimes pxda d MK .dlem. OMneda ma Depa c dn~, rah. .td, tgy.dse 1b®noal .NdkiNmiaal . Ca n .W nwat.l. :x.aa,ka City Declare Anaitien Hospital end §Tmyokai Chat . Hwp.W. .Adam$, ) PAL : Dr. Him aw Tmb .1,15-1 aalm .a.o m. gVelkioacud,Jap n, slaw by ew Aemk . Calkae d Ceed* .

Methods Study patients . The study group comprised 98 consecutive patients with acute myocardial infarction who were 0715-1097194Wae



1010

JADG Yd. 23. No. S April 199kIUes-1r

MIYATA ET AL RAPID NONINVASIVE DIAGNOSIS OF REPERFIJSRIN

admitted within 6 h after the onset

chest pain. We

were ire patients with renal failure . The purpose of the study was explained to the patients and their family members, and informed consent was obtained before the Stan of the study . Acute myocardial infarction was diagnosed in patients meeting the following criteria : 1) chest pain that persisted for at least 30 min ; 2) ST segment elevation a0 .1 mV that was recorded on at least 2 of the 12 ECG beds ; 3) chest pain that did not subside or ECG changes the did not Improve in

initial pretreatment coronary angiogtam and waded an a duec-point scale (tlMi collateral grades) as follows : I = absent; 2 = mtmmal ; 3 - well developed (27). Blood was drawn from a sheath maintained in the femoral artery every 15 min for W min after the start cf treatment in all patients. In addition, blood was drawn every aS min for 90 min after reperfitsisn in the repedusod grasp . The blood specimen was placed Into a test tube containing ethylenediaminetetraacetic acid daoditen salt and centritged at 3,000 rpm for 5 We. The plasma was collected and assayed immediately . Myoglohto was determined by the newly developed turbidimeiric latex a8glutinadnn method (Dank Seiken) (23-25). CK by an enzymatic method (Boehrioger Mannheim) and CK-MB by an immunoinhibltlon method (Baehringer Mannheim) using an automatic chemical analyxa' (Hitachi 7050) . The time required to determine the myoglobin, CK and CK-MB levels was approxhaetely 10 rain for each test . The upper limit of normal values for myoglobin (Mb) is SO nyml; that for CK is 197 Miter, oral that for CK-MB is 25 11l/liter . The rate of increase (Mb,l

response to the sublingual administration of nitroglycerin or

Mbp, CK,ICK5, CK-MB,ICK-MB.) was obtained by dividing

intravenous injection of Isosorbide ditjtiate ; 4) left ventric ular wall motion that was decreased on the echocardlogram at sites consistent with BOG findings . Praised . Before the start oftreatment, total occlusion of the infarct-related coronary artery was confirmed by coronary angiography using the Judkins technique . Tissue-type plasminogen activator (40 mg) was drip infused intravenously for 60 We in 22 patients and pro-usokinare in I patient. Five ndnute injections of 240,000 U of urokioase into the coronary artery were repeated until repeifusion occurred or until a total dose of 960,000 U was Injected In two patients. Direct percutaneous tmasmminal coronary angioplasty was performed in 32 patients . Six patients were treated conservatively . All patients received a bolus InieoLion of 5,000 U of heparin and a continuous Injection of nitroglycerin or inoembide dinitrate and lidocaine . Coronary angiogmphy was performed every S to 8 min after the start of therapy, as well as when events indicative

the levels at 15, 30.45 and 60 min (Mb„ CK„ CK-MB,) by

of

txchuied 20 patients with a patent infarct-related coronary artery at the time of initial angiagraphy with roucclusion that was confirmed within 90 min after roperfusion (4 patients)

and who developed cardiogenic shock

(I

patients) and

underwent direct countershoek (4 patients) . The remaining 63 patients with acute myocardial infarction (47 men . 16 women, 32 to flS years old, mean [*SE) age 63.7 s 1.6 years) were studied who had total occlusion of the infarct-elated ,:Oroaary artery that corresponded to electrocardiographie

iECGQ) changes confirmed by coronary angiogaphy . There

of repetlosion, such as new arthythmlas, changes in ST segment elevation or reduction in chest pain, occurred . The

the initial levels (Mba, CKe, CK-MB0). To use one cutoff level to evaluate reperfxuion, the rates

of increase in the biochemical matters at 15. 30, 45 and 60 min after treatment were summed for the reperfused and nonreper6sed groups. The level that olibred the Maximal predictive accuracy was taken as the cutoff level for the detection of reperfimabn. Statistical aneyste . Results arc expressed as mean value * SE . Differences In clinical characteristics between the mepedhsed and nonreperflused groups were analyzed with the Student r test, chi-square test sad the Fisher enact test. The rates of increase between the two smW were compared by the Drum multiple comparison test . The rates of increase among myaglobin, CK and CK-MB were cow pared by the Tokey multiple comparison teat. The sensitivity. specificity and predictive accuracy among myogkbim. C K and CK-MB were compared by the Fresher exact test and the Dunn multiple comparison test . Difierences at p < 0.05 . were regarded as significant

time of reperfllaioa was recorded as the time that reperf tsloo of the infarct-related coronary artery was confirmed by coronary anglogrephy. Patients with Thrombolyse in Myoardial Infarction Trial Mad) perfusion grade 2 or 3 flow (26) achieved by thrombolyais and coronary angioplasty, or both, were assigned to the repetfosed group (45 patlems), and those with Only TIMI reperfision grade 0 or I flow (12 patients) or those treated conservatively (6 patients)

were assigned to the nomepeitLaed group (orb patients). By coronary angiagraphy, potency of the infarct-related artery was confirmed for 90 min after repeKUsion in the reperfaaed group, whereas an occlusion was confirmed for 90 min after

the Stan of treatment in the nonreperfuaed group, including those patients treated with conservative therapy . Collateral vessels to the infarct-related artery were evaluated from the

Reaulta Comical closraslerWe. Table I shows the age. gender

and time from onset of acute myoca die iimction to Stmt of treatment ; myoglobin. CK and CK-MB levels at the Stan of treatment ; the Inftirct-rclated coronary artery; TIM! collateral flow grades; and treatment in the reper[wed (43 padams) and nonrepe used (18 patients) groups . There were no significant differences in clinical characteristics between the two groups. The 63 patients were assigned four TIMI perfusion grades after treatment (grade 0, 16 patients ; grade 1, 2 patients; grade 2, 9 patients ; grade 3, 36 patients) . In 18 patients with successful thrombolysis, reperfusion was observed at 21 *



IACC Vol . 23. N0 . 5 April 1YM:I (Ipr-15

NIYATA ET AL. RAPID NONINVASIVE DIAGNOSIS OF REPERFUSION

Table I . Clinical Cloaacterislics of the Study Groups Nnnreperfased

Group

Group

Are IYr) binder(M11)

It= IronmtelIdAMI In toMMent Ihl Levels at lrenrcnt Mning(nlll CK

MAW

IIU7iler) Infarct-mhted artery LAD CK-Mi

I.C .

RCA TIMI cahlcrd flow trade

63 0 2 32113

66 0 3 1515

715

4 .5 t 113

46 t 0 .3

AS

934tI70

N5

((S n 40

463 - 113

S5

48 r. 7

(6 = 13

N5

ul

NS lo

III

4

6

U.9 02.9t5

7.201 .4

3.5=0.5 4.8x0.1

NI

14.0n3Ae

8.401 .4

5.9

15

1.1 _ 0.1

1.1 _ 0.1

1 .1 0 0 .1

30

13-_0.1

1 .2_0.1

12--0.1

u

14 G.Ii

1300.1

1 .200.1

1 .600.1

1 .400.1

1 .300.1

kl

p Slit

< Was vcrw, -line Innam (CK) ,p < 0,01 'VMS -14a, ka-' . )merino ICK-61BI . Ip < 9.91 verso, CK. Ip < 0-05 0015 CK-MB. presented one ran value ± SE. Mb - mynglobin .

vmucs

1-PA Pr6UK

27 I 17 m

1

. .-Ii Can

-

6

Vakes prewnlml am neon value 0 SE or member of Patients. Atli amae nynanlhl infumtium ; F fenwle; M = mule: Sib = myogk bin; ('K creatiee kkme; CK-MR - -Wine ki0 •ase . MB 11-tan nsneymn; LAI) = left anterior Jncemfint , .am artery : I.Ca = left cimumfes -nary artery: RCA , ntht crMaaay ancry : 14CA = percula erw, tmnJuminal awnary anghplosty: UK = umkime. I-PA Ii-type plaamiwpen a ewer .

2 min after the start of thrombolysis . The degree of reperfusian was TIMI geode 2 in 9 patients and TIMI grade 3 in 9 patients . In 27 patients with successful coronary angieplusly, reetnaliration X5091 • of the diameter of the coronary artery was obtained . There were no significant differences between the time from the onset of acute myocardial infarction to repcrfusiun in the repcrfuaal group (4 .9 ± 0 .3 h) and the time from the

Figure 1. WINS showing the time course curves of the one of increme in myugksbin (Mb) tieR parIt crestine blouse (CK) (mMdk pall and crraline kinase. MB fraction ICK-MB) trtt1ht pad) from the nlan of treatment m 60 min. The runes of itenmse in myogksbin. CK and CK-MB in the reperllued group (sail drills) were sigrliflmmty higher than these in the nampai' ed group lapm Min) at 15. 30, 4.4 unit 60 min after treatment . ap < 0 .01 versus the nonreperfoed pap . values shown are Mom value x SE .

2.0a03

4)

9

29

CK-SIB

Noommillowd Group

8

1

CK

4.1nl .4~ 2 .500.3 3.45 .1=I .0

15

6 16

Mb Reused Group

NS 23

2

UK

Time after T:eymenl (meat

NS

6Y6 .Ill

I

Tmaline d PIt'A

Fraction

P Valo,

In = 181

45)

Raic, of Increase ip Myoelobin, Creahae Mum and Gcatien . Kin B After Treatment Table 2.

Reperfuacl In -

101 1

onset of acute myocardial infarction to treatment in the nonreperfused group. There were also no significant differences between myoglobin. CK and CK-MB levels at reperfusion in the reperfused group (myogtobin 760 # III ngiml, CK 375 = 49 lUlliter, CK-MB 49 ± 7 lU/liter) and those at the start of Ircetme0t in the nonreperfused group . Comparison of the rates of increase In myoglobin, CK and CK•M B between the repatriated and nomeperfusrd groups after treatment. The rates of increase its myoglobin, CK and CK-MB in the reperfused group were significantly higher than those in the nonrepetfused group at 15, 30, 45 laid 60 min after the start or treatment (lag . 1). The rates of increase among myoglobin, CK and CK-MB were compared at 15 . 30 .45 and 60 min after the start of treatment (Table 2) . In the rpcrfused group, the rates of increase in myoglobin were significantly higher than those in CK at 15, 30 and 45 min after treatment and those in CK-MB at 15, 30 .45 and 60 min after Treatment. In the nonreperfused group, there were no significant

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JACC V.I. 23 . No . 5 Apil 1904,1009-15

MIVATA ET AL. RAPID NONINVASIVE DIAGNOSIS OF REPERFUSION

Table 3. Sensitivity . Specificity and Predictive Accuracy in Detection of Coronary Keuerfesivn After Start of Treatment Tone after Semidvby 5pecifidly Predidire Accuracy Treaaner (Min) Mb CK CK-MB Mb CK CK.MB Mb CK Is 719' 40% 44% 10) 104 100% 79%' 57% O2431 (18/451 1201451 118,181 11/IR1 (I9I10) (54/%3) 50/6.3) 30 82% 625/ 76% ISF7 100^) 78% 87% 73% (37,45) (28451 (34451 1181161 (181181 (14/15) (55•U 146431 45 9606 90% 845£ 91% 9.., 79)7 959) 94% 172/45) (361451 130/45) 117'181 (17181 414)15) (6a'63) (53/63) 60 100% 8757 91% 470/ 99% 67% 87% 145/45) (391451 141.451 (36'14) 116:161 (11,15) (61163) 0631 'p < 0.01 versus crealine kinese (CM, Parenthesis ( in a nunber of pmann. 01her abdrev,aoeen as in Table 1.

bin at 15 min after reperfusion were significantly higher than that °f CK-ME.

Discussion A.:. .ldtages of our Study. We analyzed the changes in myoglobin, CK and CK-MB after the start of reperfusion therapy. In addition, to observe the washout phenomenon after repes'fllsion precisely, we performed coronary angiog vaphy every 5 tog min to detect the time point of reperfusion and to confirm the perfusion state of the infarct-related coronary artery Std measured the myoglobin level every 15 min after reperfusion. As a result myoglobin showed a rapid increase after rcperfusion . Because total occlusion of the infarct-related coronary artery bas not been demonstrated in pretreatment coronary angiography in most published reports, some cases of sport . taneoua repettthsion may have been included. Therefore . we performed coronary angiography before treatment in all patients to exclude spontaneous reperfusion. Furthermore, we measured the myoglobin level by the newly developed turbidimetnic latex agglutination method With an assay time of 10 min using an automatic chemical analyzer (23-25). Determination of myoglobin by this system Is clinically useNl for the rapid diagnosis of coronary reperfusim .

Is 24 45

Sensitivity

CK-MB 6409 (15/63) 7609 (45163) 53% (57/6)1 846 IS1'63)

Biochemical detection of coronary rperusion. There are several reports in which the increases Or the rates of increase in CK, CK-MB, myoglobin, CK-MM isoforms and CK-MB isoforms were used as indexes for rapid detection +cor3nary reperfusion (10 .11,13,15 .17-20) . Lewis et a), (10) reported an absolute and relative 1sthour increase in CK and CK-MB activity in patients with successful rpeALsion . Schofer et al. (18) found that the increase in and ratio of CK-MM isofonns had already increased at 30 min after the start of thrombolytic therapy . However, they reported that because of significant overlap, no cutoff values for patients with patent versus occludei vessels could be determined from their data (I8) . Puleo and Perryman (19) reported that the plasma CK-MB ise.foml activity ratio reflected coronary artery patency after 1 to 2 h of intravenous thrombolytic therapy . In 1988, Ellis et al. (13) reported that the success of reperfusion therapy could be determined by the rate of increase in plasma myoglobin at I or 2 h after the application of reperfusion therapy when the plasma myoglobin levels were measured every 30 min . In our study, the rates of increase in myoglobin in the rep :rfused group were also significantly higher than those in the nooreperfased group at 15 .30 .45 and 60 min after treatment . Our study showed that the rates of increase in myoglobin were significantly higher than (hose in CK at 15, 30 and 45 min after treatment and

Table 4. Sensitivity. Specificity and Predictive Accuracy in Detection or Coronary Reperfmion after Time Paint of Tim after Then" e(®n)

1013

Keperfusion

Predictive Accuracy

Speciacisy

Mb

CK

CK-MB

Mb

CK

CK-MB

Mb

CK

C&MB

93%'s (44)45) 98%k (4495) 9e%

5654 (2595) 78% (35455) 94% (38951 89% (4045)

6256 045) 91% (41145) 96% (43/45) 99% (44145)

I0/% (18:18) 100% (18/1111 94% (17118) 09% (16118)

loo%

003% (18118) 78% 114119) 78% 114/18) 67% (12118)

95%'t (68167) 90%) (67163) 97% (61163) 95^+. (68/63)

68% (41'33) 84/5 (53163) 87% (53/93) 89% (5693)

73% (46163) 87%

(15/18) 100% (18118) 94% 117/18) 89% (16'18)

(5593)

90% (44)45) (57)67) 89% 60 96% (56163) (44(45) -p< 4/01 van nsermllrc Id.- (CU (p < ((.01 eersas creasine Idnau . MB fraaann(CK'MB). )p < n .0/ vemm CK. Pemntmsis indicate number dpatients. Mb-myodobie .

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