Interact CardioVasc Thorac Surg 2005;4:434-439. doi:10.1510/icvts.2004.103978
© 2005 European Association of Cardio-Thoracic Surgery
Institutional report - Transplantation |
Prevalence of graft vessel disease after paediatric heart transplantation: a single centre study of 54 patients
Nicola Erika Hiemanna,*,
Ernst Wellnhoferb,
Rudolf Meyera,
Hashim Abdul-Khaliqc,
Michael Dandela,
Onnen Grauhana,
Manfred Hummela and
Roland Hetzera
a Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
b Department of Cardiology, Deutsches Herzzentrum Berlin, 13353 Berlin, Germany
c Department for Congenital Heart Defects and Paediatric Cardiology, Deutsches Herzzentrum Berlin, 13353 Berlin, Germany
Received 5 December 2004;
received in revised form 12 May 2005;
accepted 18 May 2005
 Presented at the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12-15, 2004.
*Corresponding author. Tel.: +49 30 4593 1715; fax: +49 30 4593 2202.
E-mail address: hiemann{at}dhzb.de (N.E. Hiemann).
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Abstract
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The study tested the prevalence of graft vessel disease (GVD) in 54 paediatric heart transplant (HTx) patients (32 male, age 0–17 years) who underwent coronary angiographic investigations (N=117). These were evaluated according to the Stanford classification and additional criteria (peripheral obliterations, diameter fluctuations, pathologic tapering) were applied for risk assessment (no GVD/minimal lesions, GVD without Stanford lesions, accelerated GVD). In H&E stainings from right ventricular endomyocardial biopsies (EMB=169) diagnosis of acute cellular rejection (ACR, ISHLT) and microvasculopathy were performed. Mild rejection was found in 43% (N=44) and severe rejection in 7% (N=7) of EMB early (1st year) and mild rejection in 31% (N=32) and severe in 8% (N=9) late (>3 years) after HTx. Microvasculopathy was present in 22% of EMB. Risk assessment of coronary angiographies showed no GVD/minimal disease in 25% (N=29), GVD without Stanford lesions in 12% (N=14) and different grades of accelerated GVD in 74% (N=74) of studies. All patients dying due to cardiac related causes of death (N=6, 3–12 years after HTx) had evidence of GVD. The data show GVD to be an important cause of late cardiac related deaths in this population.
Key Words: Children; Diagnosis; Coronary angiography; Endomyocardial biopsy; Heart transplantation; Vasculopathy
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1. Introduction
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Graft vessel disease (GVD) is one of the predominant complications after adult and paediatric heart transplantation (HTx) and one of the most important predictors of patient mortality at >5 years after HTx [1,2].
Since focal stenoses are not mandatory for its definition, Gao published the so-called Stanford classification of morphologic and distributional features of epicardial GVD in coronary angiographies [3]. Controversial discussion is held about the sensitivity of coronary angiography [4,5]. In children, serial coronary angiography has been suggested to identify those at risk for subsequent events related to GVD [6]. Intravascular ultrasound has been shown to be a reliable tool [5], but its use in children is limited due to their small anatomy. Therefore, diagnosis of GVD still seems to lack a cost-effective, fast and reliable tool. This study tested the prevalence of epicardial and microvascular GVD in children by proposing additional angiographic criteria to the Stanford classification [3], including a risk stratification system applied in the context of diagnosis of microvasculopathy in right ventricular endomyocardial biopsies (EMB), which may complement present diagnostic tools and also be useful in paediatric patients.
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2. Materials and methods
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This retrospective study considered 54 HTx patients (32 male, age 1–17 years), out of 124 paediatric patients transplanted between April 1986 and June 1999 at the Deutsches Herzzentrum Berlin, who underwent at least one coronary angiographic investigation (CA) and who survived more than 30 days. All patients without invasive diagnostic procedures (N=70, exitus=33) were excluded from further investigation. Because of the small number of heart lung transplanted patients (N=6) only HTx children were submitted to further statistical analysis.
CA (N=117, range 1–5, 19 patients (35%) with only one investigation) carried out between the 1st and the 9th year after HTx were evaluated in cross-section according to the Stanford classification [3]. As additional criteria, the presence of peripheral obliterations (yes/no), diameter fluctuations (irregularities of blood vessel walls, yes/no), pathologic tapering (yes/no) and calcifications were evaluated (Fig. 1). Risk assessment of CA was based on patho-morphologic findings and graded as no evidence of GVD/minimal disease, GVD without Stanford lesions and accelerated GVD (Table 1) [7]. Invasive diagnostic procedures were performed according to standard clinical practice. Biplane angiograms (12.5 frames/s) of coronary arteries were acquired digitally or on cinefilm with standard biplane angiographic X-ray equipment (INTEGRISTM / LARC system, Philips®) using a non-ionic contrast agent. CA were stored on CD in DICOM format and on 35 mm cinefilm.
At the Deutsches Herzzentrum Berlin, routine rejection surveillance is done by non-invasive monitoring of the intramyocardial electrocardiogram [8]. Because of the retrospective design of the study, the pool of right ventricular endomyocardial biopsies (EMB) was harvested due to different indications, i.e. suspected acute cellular rejection (ACR) or during routine right and left heart catheterisation with random biopsy. As a result, different numbers of EMB within different time periods after HTx were available for each patient. For this reason, similar time intervals after HTx were fixed and the mean rank of different rejection episodes per patient for each interval was calculated and submitted to further investigation. The biopsy samples (size 1–1.5 mm, N=305) were fixed in 4% buffered Lillie formol, dehydrated and embedded in paraffin. Preparation of tissue sections was done by cooling and cutting the samples into slices (depth 3 µm) and then drying them on glass slides. The tissue sections were deparaffinated with xylol and rehydrated with alcohol (100%, 90%, 70% and distilled water), then stained with hemalaun (3 min) and differentiated with HCl alcohol. Finally eosin (2% in alcohol, 30 s) was applied. Light microscopic diagnosis (magnification x200) of ACR was performed according to the working formulation of the International Society for Heart and Lung Transplantation [9] and microvasculopathy was diagnosed by grading endothelial cell swelling and vessel wall thickening with regard to evidence of luminal obstruction [10].
Immunosuppression was maintained with 2–4 mg/kg cyclosporine (trough level 250 ng/ml, enzyme immune assay), 0.1–0.5 mg/kg prednisolone and 1–5 mg/kg azathioprine (dependent on the white blood cell count). At the time period in which the study patients were transplanted (1986–1999), this regimen was standard practice at our institution and was maintained if well tolerated by the patient. In cases of ACR, 500 mg methyl prednisone(3–5 days) or ATG or OKT 3 (ongoing moderate or severe rejection) was administered intravenously.
All data were analyzed using descriptive statistics. Correlations were analyzed using Spearman's rank correlation. Nominal and ordinal scaled parameters were compared using the chi-square test and metric parameters were compared by means of the Mann–Whitney test. A P value <0.05 was considered to be significant.
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3. Results
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Within the 1st year after HTx no ACR was found in 50% (N=52), mild rejection (ISHLT 1A-2) in 43% (N=44) and severe rejection (ISHLT  3A) in 7% (N=7) of EMB. Between the 2nd and 3rd year in 39% (N=20) there was mild and in 14% (N=10) of EMB there was evidence of severe ACR. Beyond the 3rd year no rejection was found in 57% (N=60) of EMB, mild rejection in 31% (N=32) and severe rejection in 8% (N=9). ACR episodes were found predominantly within the 1st year after transplant, but there was also evidence of late severe ACR episodes beyond the 3rd year after HTx (Table 2).
The results of the CA investigations are shown in Table 3. Evidence of diameter fluctuations was found in 86% of investigations and showed no time dependent dynamic. Pathologic tapering and peripheral obliterations were present in 77% and 54%, respectively, of studies done, with an increase of prevalence during post-transplant time. Evidence of focal stenoses was found only beyond the 7th year after HTx in <10% of CA. One third of investigations revealed evidence of type B1 lesions, with stable prevalence during the follow-up. Twenty to thirty percent of studies showed type B2 lesions without a time dependent pattern. In contrast to type B1 lesions, found predominantly in the left anterior descending artery, type B2 lesions were more frequently found in the right coronary artery, but neither finding was statistically relevant.
The results of risk assessment of CA are given in Table 4. Twenty-five percent of CA studied were graded as showing minimal or no disease. GVD without Stanford lesions was present in 12% and evidence of different grades of accelerated GVD (with Stanford lesions) was found in 63% of investigations. Except in one patient, severe progressed GVD was present only beyond the 7th year after HTx. CA findings were stable in 33% (N=18), progressed in 26% (N=14) and even regressed in 6% (N=3) of patients. According to their CA findings, patients were divided into a ‘high risk’ (N=23, 43%) and a ‘low risk’ group (N=31, 57%). The demographic data of these patients were similar and CA findings were independent of these data (Table 5). The number of CA per patient in the ‘low risk’ group was 2.2±1.2 and in the ‘high risk’ group 2.4±1.6 (P not significant). In patients graded as low risk CA findings remained stable in 12 and in patients graded as high risk they remained stable in six patients. Regression (N=3) was only evident in the low risk group. Progression was found in five patients graded as low risk and in nine patients graded as high risk (P=0.040). Of the patients with only one coronary angiography, eleven were grouped as low risk and eight as high risk.
Long-term survivors (5 years) showed macrovascular alterations in more than 2/3 of cases. The five-year survival rate was 92% and the 10-year survival rate 85%. One patient underwent re-HTx due to GVD 11 years after first transplant. In total, 10 patients died: two due to rejection (4, 12 years after HTx), three due to infections (3, 6, 8 years after HTx), one due to progressive graft failure (11 years after HTx), another due to acute myocardial infarction (3 years after HTx), two due to sudden cardiac death/arrhythmias (6, 10 years after HTx) and one due to an unknown cause (6 years after HTx). Of those who died (N=10), 20% had no evidence of GVD/minimal disease, 10% showed GVD without Stanford lesions and 70% had accelerated GVD. All patients dying due to cardiac related causes of death (N=6) had evidence of GVD (P=0.045). Here, two patients died due to ACR, another two patients died because of sudden cardiac death/arrhythmias and two further patients died due to progressive graft failure and acute myocardial infarction. The survival rates of the patients in relation to their risk assessment are given in Fig. 2. The survival of the patients in the low risk group was not different as compared to the high risk group.
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Fig. 2. Survival analysis of cardiac deaths according to coronary angiographic risk assessment (P=not significant).
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No correlations were found between time point or severity of ACR history and the evidence of GVD. The number of EMB per patient in the low risk group was 6.1±8.7 and in the high risk group 4.2±4.2 (P not significant). Evidence of severe endothelial cell swelling was present predominantly within the first two months after HTx and accounted for 5% (N=9) of EMB investigated. Vessel wall thickening with luminal obstruction was found constitutively in 2% of EMB per time interval and in total in 22% (N=37) of EMB investigated (Table 6). Of the patients graded angiographically as low risk 23% and of those graded as high risk 48% (N=6) showed signs of microvasculopathy (P=0.065). Humoral rejection accounted for about 10% of EMB and was predominantly present within the first year after HTx.
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4. Discussion
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Graft vessel disease (GVD) after cardiac transplantation has been described as common and as starting as early in children as in adults [1,2].
In this study, evidence of GVD was independent of demographic data (Table 6). However, these results must be rated carefully because of the retrospective design of the study. Even in prospective trials so-called risk factors are a matter of controversial discussion. This applies also to the role of acute cellular rejection (ACR) in the development of GVD in HTx patients [1,6]. In this study, there was no association between frequency and severity of ACR and the development of GVD but it is noteworthy that about half of the EMB were harvested due to clinically suspected acute cellular rejection, so that ACR may be ‘over-represented’ in the specimen pool. In published data, ACR with severe haemodynamic compromise has been described in 11% of paediatric patients by Pahl and colleagues [11], and mild ACR has been found in 20% of a cohort analysis based on the ISHLT registry [12]. Published data show treated rejections within the first year after transplant to occur in 40% of patients [13] and to be slightly more frequent in paediatric than in adult HTx patients [14].
Although intravascular ultrasound has been shown to be a highly sensitive diagnostic tool for GVD in adults [5], routine availability in post-transplant management of children is limited due to the small anatomy of patients [5,15]. Therefore coronary angiography remains the standard diagnostic procedure for routine clinical practice. The so-called Stanford classification published in 1988 [3] was proposed as a standardized evaluation system for epicardial GVD in coronary angiographies. However, it is not used constitutively. The sensitivity of coronary angiography for the diagnosis of GVD is controversial [4,5], and this may be due to some extent to variable evaluation systems. Therefore, we hypothesized that the sensitivity of coronary angiography may be increased by adding additional criteria to the Stanford classification, including a risk stratification model for coronary angiographic findings.
In this study, patho-morphologic findings of epicardial coronary arteries were frequent after paediatric HTx and were present in 50–85% of investigations. Evidence of pathologic tapering and peripheral obliterations rose during the post-transplant time. Less than 10% of coronary angiographic investigations were affected by focal stenoses, which occurred only in the later post-transplant time. One third of investigations revealed evidence of Stanford type B lesions. Usually, this high prevalence of GVD is found in intravascular ultrasonic investigations or in autopsy studies, even in paediatric patients with long-term follow up [1,15]. In contrast, published data concerning angiographically identifiable coronary alterations in HTx children suggest much lower incidences of 7% [15]. Here the data of the registry of the ISHLT show a prevalence of GVD in adult HTx survivors of 8%, 33% and 43% at one, five and seven years [14], and in HTx children of 3%, 11% and 14%, respectively [13].
According to the risk assessment model proposed here, 25% of coronary angiograms studied were graded as showing minimal or no disease and about 60% showed evidence of different grades of accelerated GVD (with Stanford lesions). Progression of lesions was present in almost one third of the studied patients and significantly more pronounced in the ‘high risk’ patients. This suggests prognostic impact of the risk stratification proposed here. The fact that survival was not different in the low risk group may be due to the small number of deaths in this population. All patients dying due to cardiac related causes of death (N=6) had evidence of GVD. The leading causes of death in these cases were arrhythmias, progressive graft failure and acute myocardial infarction. Sudden and unexpected deaths in paediatric patients with GVD have also been described by others [15]. In contrast to the findings in the study presented here, where overall survival in patients with GVD was 71% (24/34), Pahl and colleagues described only nine of 58 (15%) patients with GVD surviving [15].
The five-year survival rate in this study was 92% and the 10-year survival rate was 85%. These data show excellent survival in this study population, but it should be remembered that only patients with coronary angiographies were included in the study who survived more than 30 days.
In this study, there was a positive, but not-significant, association between the development of macrovasculopathy and microvasculopathy. This phenomenon is the subject of controversial discussion with regard to adult HTx patients [2,3], whereas no data have been published concerning this topic in paediatric patients.
In conclusion, the development of macrovascular GVD after paediatric HTx is as frequent as in adult cardiac transplant patients. Lethal course of GVD in this study accounted for 1% of deaths 1–5 years and 6% >5 years after HTx and was less frequent than in adult patients (5% at one year, 15% at 1–3 years, 18% at 3–5 years and 16% at >5 years [14]). The additional criteria to the Stanford classification and the risk stratification system proposed complement present diagnostic tools and are also useful in paediatric patients.
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Appendix. Conference discussion
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Dr G. Laufer (Innsbruck, Austria): Are you using any intravascular ultrasound technology nowadays, at least in the larger hearts of the children to have a more sophisticated baseline for the development of lesions in the epicardial coronary arteries?
Dr Hiemann: Yes, we do intravascular ultrasound but only in studies, not routinely. We do routinely first cardiac catheterization within the first 4 to 6 weeks after heart transplantation and then after the first year. And then we decide if next year recatheterization or, if we have time, 2 years, 3 years.
Dr R. Radley-Smith (Harefield, UK): Why do you think your incidence is so high? Is it to do with your immunosuppressive regime? Is it to do with donor age? Do you have any theories as to why it's so high? Because it's higher than the reported incidence in the registry.
Dr Hiemann: I think the main problem with all these data published is that these incidences depend on the time point of study, the diagnostic tool that is used, and the morphological region that is investigated. And I think we have such a high incidence because we added these additional criteria for graft vessel disease.
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Appendix A. ICVTS on-line discussion: Invited Editorial eComment
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Author: Elfriede Pahl (Feinberg Northwestern School of Medecine, Chicago, USA)
eComment: Transplant coronary artery disease (TCAD) is the major limitation to late survival in both pediatric and adult recipients [A1,A2]. Both immune and non-immune risk factors play a role in its pathogenesis [A3,A4], although in children immune factors such as rejection are more likely contributors to etiology [A5].
The report in this journal by Drs. Hiemann and colleagues reviews the angiographic incidence of GVD (graft vessel disease) or TCAD in 54 pediatric recipients transplanted over a thirteen-year period at a single center in Berlin [A6]. As an adjunct to the angiographic study, histologic assessment of coronary pathology was performed when endomyocardial biopsies were taken to rule/out rejection. The study includes only perioperative survivors with invasive evaluation and excludes 70 patients who were transplanted during this time period but followed non-invasively.
The reported incidence of TCAD for this group was quite significant. Pathologic tapering and obliteration were present in 77% and 54% of all angiograms reviewed, respectively. This is a remarkably high incidence of coronary abnormalities on angiography, and yet survival in this cohort was excellent. No other pediatric series has reported such a high incidence of abnormalities. One wonders if some of these coronary abnormalities could have been due to vasospasm. At our center, we have also routinely used intracoronary nitroglycerin after each selective coronary injection, to determine if there was any improvement in coronary caliber, and rule out any component of coronary vasospasm.
Since this cohort represented only  of the patients transplanted, the incidence/prevalence could potentially be quite different. The use of IVUS in this cohort would be very interesting, and may be revealing in future studies of these patients [A7,A8]. The authors do not report how many observers reviewed the angiograms, and what the inter and intra- observer variability was. Additionally, it would be interesting to know whether the angiograms were reviewed by adult or pediatric cardiologists. We have learned that experienced reviewers are much more likely to comment on abnormalities, and that pediatric cardiologists often underestimate mild coronary abnormalities in transplant recipients that are detected when an adult cardiologist reviews the study.
It is not clear why a large percentage of the survivors didn't receive invasive surveillance, although this center uses intramyocardial (IMEG) rejection surveillance for their heart recipients; thus, it is likely that the 70 patients represent a cohort with either early mortality, or the survivors who had low risk based on IMEG parameters and thus didn't undergo biopsy/coronary angiography. Rejection was mild in 44% and severe in 7%, although, again, less than half of subjects underwent biopsies for surveillance. Of interest, the study found 22% ‘microvasculopathy’ on the biopsies; the incidence may have been falsely high if one assumes the patients who didn't have biopsy had less rejection.
The results of this study are quite different when compared to a recent multicenter series published by Pahl and colleagues [A5] which was an analysis of 2049 angiograms performed in 751 pediatric patients from 20 centers. This is the largest pediatric series of TCAD published to date, and found that the incidence of TCAD on angiography was much lower than reported in adults, and far less than report in Hiemann's study. In this study, donor and recipient age were the primary risk factors identified. The youngest recipients had the lowest incidence of TCAD. Older recipients, and older donor age as well as rejection were risk factors for the development of TCAD.
Hiemann and colleagues should be congratulated on their outstanding survival in this transplant group, which well exceeds the international registry report [A1]. Their patients are maintained on triple therapy immunosuppression with cyclosporine, azathiaprine and steroids. Many centers have changed to tacrolimus and/or mycophenolate mofetil for maintenance therapy; it is not mentioned in the methods whether some of the patients are were switched to other immunosuppressive agents after 1999.
One wonders if the low incidence of mortality and TCAD could be improved even further by use of any prophylactic therapies, such as statins, aspirin, vitamins or the use of TOR inhibitors, especially in the higher risk group. It is not stated whether these agents have been introduced in children at this center.
Although angiography for surveillance of TCAD is routine, few centers assess biopsies for presence of ‘microvascular coronary disease’. This is a unique feature of Hiemann's study, and warrants more emphasis, as this intriguing adjunct to the use of the endoymyocardial biopsy may have prognostic implications for future progression of TCAD, and is not routinely commented on at most institutions when patients are subjected to biopsy.
Furthermore, the authors recommendation for ‘risk assessment’ may be very helpful in determining which patients should receive a change in therapy, e.g. with TOR inhibitors or use of statins, and with more frequent invasive analysis. Clearly, ongoing further study is warranted to determine the implications of angiographic coronary disease in children after heart transplantation.
References
A1 Boucek MM, Edwards LB, Keck Bm, Trulock EP, Taylor DO, Mohacsi PJ, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation Sixth Official Pediatric Report 2003. J Heart Lung Transplant 2003;22:636–652.[CrossRef][Medline]
A2 Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Post-transplant coronary artery disease in children: a multicenter national survey. Circulation 1994;90:II-1156–1160.
A3 Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, Reed EF, Fishbein MC. Humoral rejection in cardiac transplantation risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant 2003;22:58–69.[CrossRef][Medline]
A4 Johnson MR. Transplant coronary disease non-immunologic risk factors. J Heart Lung Transplant 1992;11:S124–S132.[Medline]
A5 Pahl E, Naftel DC, Kuhn MA, Shaddy RE, Morrow WR, Canter CE, Kirklin J. The impact and outcome of transplant coronary artery disease in a pediatric population: a 9 year multi-institutional study. J Heart Lung Transplant 2005;24:645–651.[CrossRef][Medline]
A6 doi: 10.1510/icvts.2004.103978Hiemann NE, Wellnhofer E, Meyer R, Abdul-Khaliq H, Hetzer R. Prevalence of graft vessel disease after paediatric heart Transplantation: a single center study of 54 patients. Interact CardioVasc Thorac Surg.[Abstract/Free Full Text]
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Acknowledgements
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We thank C. Knosalla, MD, PhD, and G. Siegel, MD, PhD, for their valuable comments on this manuscript and we are grateful for editorial assistance from A. Gale, ELS. This study was supported by the German Research Foundation (HE 1669/13-1).
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References
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N. E. Hiemann, E. Wellnhofer, R. Meyer, H. Abdul-Khaliq, M. Dandel, O. Grauhan, M. Hummel, and R. Hetzer
Prevalence of graft vessel disease after paediatric heart transplantation: a single centre study of 54 patients
Interactive CardioVascular and Thoracic Surgery,
October 1, 2005;
4(5):
434 - 439.
[Abstract]
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Abstract
1. Introduction
