Clinical Use of a New High-Sensitivity Cardiac Troponin I ...
Brief Communication Elevated Donor Cardiac...
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2618 Brief Communication Elevated Donor Cardiac Troponin I A Marker of Acute Graft Failure in Infant Heart Recipients James W. Grant, MD; Charles E. Canter, MD; Thomas L. Spray; Yvonne Landt; Jeffrey E. Saffitz, MD, PhD; Jack H. Ladenson, PhD; Allan S. Jaffe, MD One of the major causes of mortality in infant transplant recipients is early graft failure,' which accounts for a substantial percentage of the early 25% mortality associated with infant cardiac transplantation." 2 Previous studies have associated only a limited number of donor characteristics with the development of early graft failure or death in transplant recipients.3,4 The present study was designed to deter- mine if evidence of donor cardiac damage detected by elevated blood levels of cardiac troponin I (cTnI), a sensitive and highly specific marker of cardiac damage, before harvest is related to posttransplantation graft survival. Because elevations of cTnl persist in blood for many days after cardiac injury, diagnosis with this marker requires less precise timing of blood sample acquisition.5-7 Methods Patient Selection The study group was composed of 19 donors whose hearts were used in 18 recipients less than 1 year of age from April 1991 through March 1994. During that time, a total of 27 transplantations were performed in infants less than 1 year of age at St Louis Children's Hospital. The selection of the 19 study patients was determined solely by the availability of donor serum collected at the time of organ harvest. None of the eight donor hearts excluded due to the absence of donor serum before transplantation manifested evidence of graft failure. Information about the donors was obtained by review of the records provided by the UNOS information sheets. Donor cardiac function was evaluated by transthoracic echocardio- grams performed at the referring hospital and was classified as 1, an above-normal shortening fraction (SF) or ejection frac- tion (EF) (SF >0.44 or EF >0.80; 2, a normal shortening fraction or ejection fraction (SF <0.44 and >0.28 or EF <0.79 and >0.58); and 3, a below-normal shortening fraction or ejection fraction (SF <0.28 or EF <0.58). Recipient informa- tion was obtained from the hospital records of each patient. Echocardiographic determinations were performed 8 hours to 1 week after transplant as part of posttransplant clinical evaluation using either a Hewlett-Packard model 77510A or a Toshiba model SSH-140A imaging system and a 5.5-MHz transducer. Shortening fractions in recipients were determined Received August 2, 1994; revision accepted September 23, 1994. From the Department of Pediatrics (J.W.G., C.E.C.), the De- partment of Surgery (T.L.S.), the Departments of Medicine and Pathology (J.H.L., Y.L., JE.S.), and the Department of Medicine (A.S.J.), Washington University School of Medicine, St Louis, Mo. Correspondence to Allan S. Jaffe, MD, Cardiovascular Division, Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. t 1994 American Heart Association, Inc. and analyzed in the same manner as the donor echocardio- grams. The diagnosis of primary graft failure was made clinically, based on the presence of cardiogenic shock or intractable congestive heart failure in the absence of cellular or humoral rejection on endomyocardial biopsy. All clinical decisions regarding donor acceptability or graft failure and function were made without knowledge of the cTnI determinations. cTnI and CK-MB Determinations Serum was stored at -70°C, thawed, and assayed in batches. The concentration of cTnI was determined using a two-site immunoassay in a preliminary research application that uses two cTnI-specific monoclonal antibodies that recognize inde- pendent epitopes.5,6 In most normal adults, cTnI is undetect- able. The upper level of the reference range is 3.1 ng/mL, based on nonparametric analysis of hospitalized adults without overt cardiac disease. The lower limit of detection is 1.5 ng/mL.56 CK-MB was determined as previously described using a commercially available immunoassay (Stratus CK-MB, Baxter-Dade).6 The upper boundary of the reference range is 6.7 ng/mL. The lower limit of detection is 2.2 ng/mL. Abnor- mal values of cTnI and CK-MB were designated without knowledge of patient identity, clinical status, or other labora- tory determinations. Statistical Analysis Comparisons were performed using Fisher's exact test and rank correlation coefficients with RS1 statistical software. Statistical significance was assigned to P values <.05. Results Donor serum cTnI levels are presented in descending order of magnitude in Table 1 and the clinical character- istics of the donors in Table 2. Values ranges from a high of 70.5 ng/mL to undetectable. There were 8 donors with cTnI values >3.1 ng/mL; 5 of these 8 donor hearts were diagnosed as having graft failure. The 4 infants who were the recipients of these 5 hearts died (1 patient received 2 of the hearts that failed; No. 1, Table 1). These deaths accounted for the only mortality in the first 12 months after cardiac transplantation. Four of the donor hearts with graft failure had levels of cTnI in the donor of .10 ng/mL. The association of an elevated cTnI value and graft failure was statistically significant (P<.005). Patient 7, the only patient with cardiac graft failure and a level of <10 mg/mL but >3 ng/mL, was weaned successfully from cardiopulmonary bypass but experienced an ex- tended cardiopulmonary arrest upon transfer to the intensive care unit. Pathological examination of this heart after retransplantation revealed diffuse myocardial necrosis and dystrophic calcification. In the remaining hearts examined histologically, there was also evidence of by guest on May 2, 2018 http://circ.ahajournals.org/ Downloaded from
Transcript of Brief Communication Elevated Donor Cardiac...
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Brief Communication
Elevated Donor Cardiac Troponin I
A Marker of Acute Graft Failure in Infant Heart Recipients
James W. Grant, MD; Charles E. Canter, MD; Thomas L. Spray; Yvonne Landt;Jeffrey E. Saffitz, MD, PhD; Jack H. Ladenson, PhD; Allan S. Jaffe, MD
One of the major causes of mortality in infanttransplant recipients is early graft failure,'which accounts for a substantial percentage of
the early 25% mortality associated with infant cardiactransplantation." 2 Previous studies have associated onlya limited number of donor characteristics with thedevelopment of early graft failure or death in transplantrecipients.3,4 The present study was designed to deter-mine if evidence of donor cardiac damage detected byelevated blood levels of cardiac troponin I (cTnI), asensitive and highly specific marker of cardiac damage,before harvest is related to posttransplantation graftsurvival. Because elevations of cTnl persist in blood formany days after cardiac injury, diagnosis with thismarker requires less precise timing of blood sampleacquisition.5-7
MethodsPatient SelectionThe study group was composed of 19 donors whose hearts
were used in 18 recipients less than 1 year of age from April1991 through March 1994. During that time, a total of 27transplantations were performed in infants less than 1 year ofage at St Louis Children's Hospital. The selection of the 19study patients was determined solely by the availability ofdonor serum collected at the time of organ harvest. None ofthe eight donor hearts excluded due to the absence of donorserum before transplantation manifested evidence of graftfailure.
Information about the donors was obtained by review of therecords provided by the UNOS information sheets. Donorcardiac function was evaluated by transthoracic echocardio-grams performed at the referring hospital and was classified as1, an above-normal shortening fraction (SF) or ejection frac-tion (EF) (SF >0.44 or EF >0.80; 2, a normal shorteningfraction or ejection fraction (SF <0.44 and >0.28 or EF <0.79and >0.58); and 3, a below-normal shortening fraction orejection fraction (SF <0.28 or EF <0.58). Recipient informa-tion was obtained from the hospital records of each patient.Echocardiographic determinations were performed 8 hours to1 week after transplant as part of posttransplant clinicalevaluation using either a Hewlett-Packard model 77510A or aToshiba model SSH-140A imaging system and a 5.5-MHztransducer. Shortening fractions in recipients were determined
Received August 2, 1994; revision accepted September 23, 1994.From the Department of Pediatrics (J.W.G., C.E.C.), the De-
partment of Surgery (T.L.S.), the Departments of Medicine andPathology (J.H.L., Y.L., JE.S.), and the Department of Medicine(A.S.J.), Washington University School of Medicine, St Louis, Mo.Correspondence to Allan S. Jaffe, MD, Cardiovascular Division,
Box 8086, Washington University School of Medicine, 660 SEuclid Ave, St Louis, MO 63110.t 1994 American Heart Association, Inc.
and analyzed in the same manner as the donor echocardio-grams. The diagnosis of primary graft failure was madeclinically, based on the presence of cardiogenic shock orintractable congestive heart failure in the absence of cellularor humoral rejection on endomyocardial biopsy. All clinicaldecisions regarding donor acceptability or graft failure andfunction were made without knowledge of the cTnIdeterminations.
cTnI and CK-MB DeterminationsSerum was stored at -70°C, thawed, and assayed in batches.
The concentration of cTnI was determined using a two-siteimmunoassay in a preliminary research application that usestwo cTnI-specific monoclonal antibodies that recognize inde-pendent epitopes.5,6 In most normal adults, cTnI is undetect-able. The upper level of the reference range is 3.1 ng/mL,based on nonparametric analysis of hospitalized adults withoutovert cardiac disease. The lower limit of detection is 1.5ng/mL.56 CK-MB was determined as previously describedusing a commercially available immunoassay (Stratus CK-MB,Baxter-Dade).6 The upper boundary of the reference range is6.7 ng/mL. The lower limit of detection is 2.2 ng/mL. Abnor-mal values of cTnI and CK-MB were designated withoutknowledge of patient identity, clinical status, or other labora-tory determinations.
Statistical AnalysisComparisons were performed using Fisher's exact test and
rank correlation coefficients with RS1 statistical software.Statistical significance was assigned to P values <.05.
ResultsDonor serum cTnI levels are presented in descending
order of magnitude in Table 1 and the clinical character-istics of the donors in Table 2. Values ranges from a highof 70.5 ng/mL to undetectable. There were 8 donors withcTnI values >3.1 ng/mL; 5 of these 8 donor hearts werediagnosed as having graft failure. The 4 infants who werethe recipients of these 5 hearts died (1 patient received 2of the hearts that failed; No. 1, Table 1). These deathsaccounted for the only mortality in the first 12 monthsafter cardiac transplantation. Four of the donor heartswith graft failure had levels of cTnI in the donor of .10ng/mL. The association of an elevated cTnI value andgraft failure was statistically significant (P<.005). Patient7, the only patient with cardiac graft failure and a level of<10 mg/mL but >3 ng/mL, was weaned successfullyfrom cardiopulmonary bypass but experienced an ex-tended cardiopulmonary arrest upon transfer to theintensive care unit. Pathological examination of thisheart after retransplantation revealed diffuse myocardialnecrosis and dystrophic calcification. In the remaininghearts examined histologically, there was also evidence of
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Grant et al Elevated Donor Cardiac Troponin 1 2619
TABLE 1. Cause of Cardiac Arrest and Relation ofOutcome to cTnI and MB-CK Values in Donors
Patient cTnl, MB-CK, Diagnosed Cause OutcomeNo. ng/mL ng/mL of Brain Death of Graft
Sudden infant death1 71.5 Not done syndrome Failed
Sudden infant death2 19.9 Not done syndrome Failed
Sudden infant death3 16.8 11.3 syndrome Failed
Ventriculoperitoneal4 15.6 22.0 shunt failure Failed
Sudden infant death5 15.0 6.3 syndrome Survived
Sudden infant death6 3.7 4.2 syndrome Survived
7 3.5 2.9 Closed head trauma Failed
8 3.2 12.4 Meningitis Survived
9 3.1 13.8 Closed head trauma Survived
10 2.5 4.7 Closed head trauma Survived
Cerebrovascular11 2.5 Not done accident Survived
12 2.5 4.9 Closed head trauma Survived
13 2.3 8.7 Drowning Survived
14 2.0 Not done Closed head trauma Survived
15 1.9 Not done Closed head trauma Survived
16 1.7 7.7 Seizures Survived17 1.6 Not done Meningitis Survived
Foreign body18 1.6 2.4 aspiration Survived19 0 Not done Birth asphyxia Survived
cTnI indicates cardiac troponin 1. The line under patient 8separates patients who received hearts from donors with ele-vated cTnl values (above the line) from those who receivedhearts from donors with normal values (below the line).
extensive subendocardial myocytolysis and myocardialcoagulative necrosis (Figure). No evidence of humoral orcellular rejection or coronary arteriopathy was present inany of the hearts. The donor heart from patient 1 was notexamined histologically. However, this patient could notbe successfully weaned from cardiopulmonary bypassbecause of hypotension and poor cardiac function. Norecipient of a heart from a donor with a cTnI level <3.1ng/mL exhibited graft failure, required retransplanta-tion, or died.
Clinical variables that were weakly correlated withthe donor cTnI level were the estimate of the cardio-pulmonary arrest time (P<.04, Table 3) and the timebetween cardiopulmonary arrest and organ harvest(P<.05, Table 3). None of the other donor characteris-tics, including the CK-MB value of the donor beforetransplantation, echocardiographic function, age, orcreatinine were significantly correlated with the cTnlvalues. Posttransplant echocardiographic heart functionalso did not correlate with the pretransplant donor cTnIlevel (r=.27); patients with and without elevated cTnllevels had abnormal echocardiographic function (Table2). The diagnosis of sudden infant death syndrome
Low-power micrograph of the left ventricle of the allograft takenfrom a 9-week-old infant approximately 1 month after transplan-tation for hypoplastic left heart syndrome. This allograft showedwidespread areas of coagulative myocardial necrosis appearingas pale staining regions. The anterior left ventricular free wall (A)and anterolateral papillary muscle (PM) are most severely af-fected, but other endocardial structures (arrow) are also in-volved. There was no evidence of lymphocytic infiltrate or otherfeatures of cellular or humoral rejection. Original magnification,x7.5.
(SIDS) was common among the donors with elevatedcTnI values and was associated with prolonged out-of-hospital arrest times.
DiscussionThese data define a significant relation between the
cTnI concentration in the donor sera before harvest andthe subsequent presence of fatal primary graft failure ininfant cardiac transplant recipients. Five of the 8 heartsfrom donors with elevated values of cTnI developedintractable graft failure leading to death or retransplan-tation. In contrast, all hearts from donors with a cTnIvalue of <3.1 ng/mL were associated with successfultransplantation. The likely explanation for the associa-tion of an elevated value of cTnI in donors and theadverse effects in recipients is that the elevated levels ofcTnI reflect ischemic damage in the donor heart beforeharvest. This hypothesis is supported by the pathologi-cal findings of myocardial necrosis in the absence ofevidence of rejection in the hearts of the patients whodied. In each instance, the pathological findings wereassociated with elevated values of cTnI in the donors. Itis not surprising that elevated cTnI values tended tooccur in patients with out-of-hospital cardiopulmonaryarrest such as in patients with the diagnosis of SIDS;
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2620 Circulation Vol 90, No 6 December 1994
TABLE 2. Characteristics of Donors
Harvest to Arrest toPatient Weight, Arrest Time, Transplant Donor Echo Creatinine, Harvest RecipientNo. Age, d kg min Time, min Score mg/dL Time, min Echo Score1 56 5.6 60 132 1 1.8 46 3
2 51 2.2 45 Not reported 2 Not reported 72 Not reported3 210 7.7 30 205 2 0.3 46 2
4 210 3.0 15 203 2 2.7 48 3
5 30 4.3 15 210 2 3.4 72 3
6 30 4.8 0 180 2 0.4 96 2
7 30 8.0 20 Not reported 1 0.4 48 2
8 600 11.0 0 181 2 0.3 72 19 60 4.5 20 225 Not reported 0.4 72 2
10 90 8.3 0 170 2 Not reported 56 2
11 210 5.0 0 94 1 1.2 120 3
12 105 4.8 5 78 2 0.3 27 2
13 750 10.2 65 230 1 0.8 100 Not reported14 420 8.6 15 202 2 Not reported Not reported 2
15 150 7.0 2 224 2 0.2 42 2
16 60 6.7 5 228 1 1.1 72 3
17 6 2.9 0 240 2 0.4 96 2
18 620 10.1 8 195 2 0.3 144 1
19 6 7.7 0 94 2 0.8 144 3
Patient numbers are the same as in Table 1. The line under patient 8 separates patients with elevated cardiac troponin values (abovethe line) from those with normal values (below the line).
these patients experienced longer cardiac arrest timesbefore resuscitation. CK-MB values were not uniformlyelevated in the donors whose hearts subsequently de-veloped graft failure. This is probably due to the factthat elevations of CK-MB do not persist as long inserum as do elevations of cTnI.5,6 In addition, CK-MBwas elevated in some patients with normal values ofcTnI who did not develop graft failure. These elevationsin CK-MB could have been due to release of CK-MBfrom skeletal muscle, which has been reported to occurwhen skeletal muscle damage is severe.6,8The use of a simple and rapid blood test such as cTnl
may permit less restrictive donor selection criteria by
TABLE 3. Comparison of Donor Characteristics andDonor cTnl Levels
cTnl Level
Donor <3.1 >3.1Characteristics ng/mL ng/mL rAge, d 225+244 152+184 -.16Weight, kg 6.9+2.3 5.8+2.7 -.34Arrest time, min 11±+ 18 23+19 .51*Preservation time, min 180+59 185+29 -.16
Serum creatinine 0.6+0.4 1.3+1.3 .27Time between arrestand harvest, h 87±41 63±+17 -.5*
cTnl indicates cardiac troponin I.* P<.05.
providing for the screening of potential donor heartsbiochemically. Previous studies of pediatric heart trans-plantation examining donor characteristics such asweight, diagnosis, level of support, and echocardio-graphic assessment of left ventricular function havefailed to predict the success or failure of donor heartsafter transplantation.3,410,12 This finding is not surpris-ing, given the lack of standardization of assessments ofglobal ischemic dysfunction by echocardiography, thepreselection of "normal" echocardiographic evaluationsin donors, the diversity of loading conditions present indonors, and the known autonomic dysfunction associ-ated with brain death. In addition, studies of pediatricheart transplantation have been limited by the numbersof patients present with primary graft failure. Biochem-ical markers have not been measured previously indonors and related to the subsequent course ofrecipients.3,4,9,1041Our promising results in a small cohort of patients
suggest that a larger study to confirm our findings andto define the level of donor cTnI that provides the bestpredictive value is warranted. Because the donorhearts in infants are quite small, the use of an adultreference range may not be optimal, although it washighly predictive in this preliminary study. If it werepossible to identify damaged donor organs, avoidingtheir use might reduce the incidence of acute graftfailure. It also may be that strategies to protectrecipients from cardiac graft failure could be devel-oped based on a risk assessment predicated on theextent of injury of the donor heart as defined by cTnI.
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Grant et al Elevated Donor Cardiac Troponin I 2621
The utility of cTnI values as a marker of donormyocardial damage for older children and adults isunclear but worthy of aggressive investigation.
ConclusionsIt appears that biochemical evaluation of donor heart dam-
age by measurement of cTN1 is likely to predict the responseof the heart after transplantation in recipients less than 1 yearof age.
AcknowledgmentsThis study was supported in part by a grant from Baxter
Diagnostics, Inc. The authors thank Diane Chandler of Mid-America Transplantation for her help in obtaining many of thedonor serum samples, Sharon Morehead for the collection ofsamples and patient data, and Sharon Porter for her technicalassistance.
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JB, Kubo SH, Olivari MT, Kasper EK. Pretransplantation riskfactors for death after heart transplantation: a multiinstitutionalstudy. J Heart Lung Transplant. 1993;12:549-562.
2. Kaye MP. The registry of the International Society for Heart andLung Transplantation: Tenth Official Report-1993. J Heart LungTransplant. 1993;12:541-548.
3. Kawauchi M, Gundry SR, de Begona JA, Razzouk AJ, Bailey LL.Utilization of pediatric donors salvaged by cardiopulmonary resus-citation. J Heart Lung Transplant. 1993;12:185-188.
4. Tweddel JS, Canter CE, Bridges ND, Moorhead S, HuddlestonCB, Spray TL. Predictors of operative mortality and morbidityafter infant heart transplant. Ann Thorac Surg. In press.
5. Bodor GS, Porter S, Landt Y, Ladenson JH. Development ofmonoclonal antibodies for an assay of cardiac troponin-I and pre-liminary results in suspected cases of myocardial infarction. ClinChem. 1992;38:2203-2214.
6. Adams JE III, Bodor GS, Davila-Roman VG, Delmez JA, AppleFS, Ladenson JH, Jaffe AS. Cardiac troponin I: a marker with highspecificity for cardiac injury. Circulation 1993;88:101-106.
7. Adams JE III, Schechtman KB, Landt Y, Ladenson JH, Jaffe AS.Comparable detection of acute myocardial infarction by MB cre-atinine kinase and cardiac troponin I. Clin Chem. 1994;40:1291-1295.
8. Adams JE III, Sicard GA, Allen BT, Gridwell KH, Lenke LG,Davila-Roman VG, Bodor GS, Ladenson JH, Jaffe AS. Diagnosisof perioperative myocardial infarction with measurement ofcardiac troponin I. N Engl J Med. 1994:330:670-674.
9. Boucek MM, Kanakriyeh MS, Mathis CM, Trimm RF III, BaileyLL. Cardiac transplantation in infancy: donors and recipients.J Pediatr. 1990;116:171-176.
10. de Begona JA, Gundry SR, Razzouk AJ, Boucek MM, KawauchiM, Bailey LL. Transplantation of hearts after arrest and resusci-tation. J Thorac Cardiovasc Surg. 1993;106:1196-1201.
11. Kawauchi M, Gundry SR, Beierle F, de Begona JA, Bailey LL.Myosin light chain efflux after heart transplantation in infants andchildren and its correlation with ischemic preservation time.J Thorac Cardiovasc Surg. 1993;106:458-462.
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J W Grant, C E Canter, T L Spray, Y Landt, J E Saffitz, J H Ladenson and A S Jafferecipients.
Elevated donor cardiac troponin I. A marker of acute graft failure in infant heart
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1994 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.90.6.2618
1994;90:2618-2621Circulation.
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