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Eur J Cardiothorac Surg 2007;32:220-224. doi:10.1016/j.ejcts.2007.03.049
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Outcome after pediatric heart transplantation: two decades of a single center experience

Antonio Gambinoa, Alessia Ceruttib, Giuseppe Feltrina, Giuseppe Toscanoa, Giuseppe Tarantinic, Ornella Milanesib, Annalisa Angelinid, Gino Gerosaa,*

a Department of Cardiovascular Surgery, University of Padova, Padova, Italy
b Department of Pediatrics, University of Padova, Padova, Italy
c Department of Cardiology, University of Padova, Padova, Italy
d Department of Pathology, University of Padova, Padova, Italy

Received 26 June 2006; received in revised form 5 March 2007; accepted 6 March 2007.

* Corresponding author. Address: Istituto di Cardiochirurgia, Azienda Ospedaliera – Università degli Studi di Padova, Dipartimento di Scienze Cardiologiche, Toraciche, Vascolari, Sezione di Cardiochirurgia, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 0498212410; fax: +39 0498211895. (Email: gino.gerosa{at}unipd.it).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Background: Twenty years after the first successful pediatric heart transplantation (HTx), the long-term outcome of this population is still unknown. Current study analyzes our results in pediatric HTx population. Methods and results: Between 1985 and 2005, we performed 604 HTx. Forty-three patients (7%) were less than 18-years old and six patients were less than 1-year old. Mean age at HTx was 9.7 ± 6.3 years (38 days–18 years). Indications were: cardiomyopathy in 33 patients (76%), congenital in 9 (21%), tumor in 1 (3%). Chronic immunosuppression was Cyclosporine A and Azathioprine-based. Overall survival at Kaplan–Meier analysis (CI 95%) was 82.5% at 1-year post-HTx, 73.5% at 5 years, 72.2% at 10 years, 62.1% at 15 years, and 49.3% at 20 years, respectively. We had 14 deaths (32%): 7 within the first year after HTx (early mortality, EM), 7 occurred later (late mortality, LM). Causes of EM were: graft failure (43%), acute rejection (43%) and post transplant lymphoproliferative disease (14%). Causes of LM were: neoplasms (57%), infection (28%), graft vasculopathy (15%). At late follow-up, cardiac function, somatic and psychoaffective development were normal. Fifteen patients (34%) developed neoplasms, nine patients (21%) hypertension, and three patients (8%) developed kidney dysfunction. Neoplasms were found to be an independent predictor of outcome (p = 0.039) (OR = 7). Conclusions: Overall survival in the pediatric population is better than adults’ population (62.1 vs 48% at 15 years after HTx). Neoplasms were the main comorbidities and causes of LM: at multivariate analysis, their incidence was related with hematic Cyclosporine A levels after 10 years from HTx (p = 0.01).

Key Words: Heart transplantation • Pediatric • Immunosuppressive therapy • Neoplasms • CAV • PTLD


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Heart transplantation (HTx) is currently the ‘gold standard’ treatment for patients with end-stage heart failure refractory to medical or conventional surgical therapy. Following the first successful pediatric HTx 20 years ago [1], the worldwide experience has constantly increased showing substantial differences from adult transplantation as far as indications and results. Nevertheless the long-term outcome of this young population still remains unknown [2,3].

The aim of this study is to report our 20-year experience with pediatric HTx patients.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Statistical analysis
 4. Results
 5. Discussion
 References
 
Between November 1985 and January 2005, 604 patients underwent HTx at our Institution, among them 43 (7%) were pediatric patients (less than 18 years of age at the time of HTx).

Twenty-seven were males (62%) and 16 females (38%). Mean age at the time of HTx was 9.7 ± 6.3 years (range 38 days–18 years, median 11 years, interquartile range 2–19 years), mean weight was 29 ± 18 kg (range 2.7–70 kg). There were six patients aged less than 1 year. Mean follow-up time post HTx is 9 ± 4.8 years (range 3 months–19 years).

Indications for HTX (Table 1 ) were: cardiomyopathy in 33 cases (76%), and congenital heart disease in 9 cases (21%).


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  		Table 1 Indications for heart transplantation in our patients
 
One patient (3%) had a primary cardiac fibroma with fetal diagnosis and underwent HTx at 38 days of age. All patients affected by congenital heart disease (Table 2 ). Associated diseases are shown in Table 3 .


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  		Table 2 Description of congenital HTX recipients
 

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  		Table 3 Description of Associated Diseases in congenital patients
 
Orthotopic heart transplantation was performed in 40 cases (93%): in 23 cases (57%) a standard technique was adopted while in 17 (43%) cases a bicaval technique was preferred. In the remaining three patients (7%), with pulmonary arteriolar resistance greater than 6 UW/m2, we performed heterotopic HTx: in two cases as left ventricular-bypass, in one case as biventricular bypass.

Combined heart and kidney transplantation from the same donor were performed in two female recipients, 3- and 15-years old, respectively, affected by severe renal failure due to congenital kidney disease. Forty-three donors were used (24 male, 19 female), mean age was 13.8 ± 12 years, and mean weight was 41 ± 25 kg. Due to poor donors’ availability, in an urgent HTx, a donor–recipient weight mismatch of 300% (12 kg donor–4 kg recipient) was successfully accepted.

The causes of donor's death were: head trauma (55%), intracranial bleeding (26%), multiple trauma (13%), cerebellar tumor (3%), anoxia (3%).

Mean cold ischemia time was 188 ± 66 min (range 58–320 min). Among the 43 donors, 6 (14%) were ‘marginal donors’ because they presented one or more of the following conditions [4]:

• Left ventricular ejection fraction (LVEF) <45% and/or left ventricular hypertrophy and/or valvular disease at transthoracic echocardiographic examination.
• A cumulative dosage of inotropic drugs infusion greater than 15 mcg/kg/min.

Standard post-HTx regimen of immunosuppression included Cyclosporine A, (4–40 mg/kg/day) and Azathioprine (0.5–3 mg/kg/day). Steroids were used only in selected cases.

In the first year after HTx, Cyclosporine A levels were kept between 150 and 300 ng/ml. Since the second year, Cyclosporine A levels were kept between 80 and 180 ng/ml. Azathioprine doses were adjusted on white blood cell count (total WBC ranging from 5000 to 6000). We used chronic steroids only in patients with episodes of refractory rejection. In order to reduce side effects of immunosuppressive therapy, this standard protocol was tailored on each patient: at 1-year follow-up 23% of patients were already in single therapy (CyA), and 19% still under steroid therapy; after 5 years 43% were in single therapy (CyA), and only 9% still used steroids. After 10 years half population was treated with monotherapy (CyA), and no patient had chronic steroid therapy. Induction therapy was adopted in 10 patients (26%): OKT3 in 2 patients, Thymoglobulin in 4 patients and Lymphoglobulin in 4 patients. Acute rejection episodes were treated by intravenous steroids (10 mg/kg i.v. for 3 days).

Diagnosis of acute rejection episodes was based on both clinical (non-specific malaise, fever with gallop rhythm) and non-invasive instrumental methods (ECG, ECHO). Endomyocardial biopsies were reserved to unclear cases [5]: the youngest patient who underwent biopsy weighed 4 kg. Vasculopathy was detected by means of bi- or tri-annual coronarography.

For statistical purposes, graft function was assessed evaluating left ventricular ejection fraction (LVEF) by means of ECHO at 3 months and 1, 5, 10, 15 years post Htx.

Kidney function was monitored on a regular basis: data on Creatinine serum level at 1 and 3 months and at 1, 5, 10, 15, 20 years, respectively, were recorded as well as data on liver function (AST (U/l), ALT (U/l), and total bilirubin (µmol/l).

Somatic growth was evaluated by plotting weight and height of each patient at follow-up visit on Tanner-Whitehouse tables. All measurements ranging between two standard deviations from the average (between the 3rd and 97th percentile) were considered as normal.


   3. Statistical analysis
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistical analysis
4. Results
 5. Discussion
 References
 
Data are expressed as mean values ± SD for continuous variables, as frequency with percentage for categorical variables. Differences between means of continuous variables were tested by unpaired Student t-test as appropriated. Frequencies were compared using chi-square or Fisher exact test analysis when the expected value of cell was <5.

Cumulative survival curves were constructed according to the Kaplan–Meier methods. The contribution of variables to death rate was evaluated by univariate and multivariate logistic regression analysis.

The following variables: cold ischemic time, causes of donors’ death, use of marginal donors, immunosuppressive regimen, CyA doses (calculated as C0 trough levels), incidence of acute rejection and CAV (detected with serial bi- or tri-annual coronary angiography), comorbidities (infections, neoplasms, hypertension, diabetes mellitus) were included.

Backward elimination was used to eliminate potential predictors, maintaining into the model variables with p value ≤ 0.1. The univariate and multivariate odds ratio (OR) and their corresponding 95% confidence intervals (CIs) were calculated. A p-value < 0.05 was considered significant. Data were analyzed with SPSS for Windows, release 10 (SPSS Inc, Chicago, Illinois).


   4. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistical analysis
 4. Results
5. Discussion
 References
 
The overall mortality was 32% (14 patients): 11 were males and 3 females, with age ranging from 1 to 31 years. There were seven deaths (50%) within the first-year of follow-up (early mortality). The main causes of early deaths were: acute rejection in three patients (43%), graft failure in three patients (43%) and post transplant lymphoproliferative disease (PTLD) in one patient (14%). There were seven deaths (50%) after the first year post-HTx (late mortality). In our experience late mortality accounts for less than 1% per year of follow-up.

The causes of late deaths were: neoplasms in four patients (57%), infections in two patients (28%), severe graft vasculopathy in one patient (15%).

Actuarial survival by Kaplan–Meier (CI 95%) analysis was 82.5% at 1-year post HTx, 73.5% at 5 years, 72.2% at 10, 62.1% at 15 years, 49.3% at 20 years. (Fig. 1 ).


Figure 1
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  		Fig. 1. Overall survival (Kaplan–Meier analysis).

 
Graft function analysis showed a mild increase of LVEF in the first five years post-HTx and then a slight reduction that became more evident after the 10th year: mean LVEF was 69.6% at 3 months post HTx, 69.5 at 1 year, 72% at 5 years, 69.6% at 10, and 63% at 15 years, respectively.

Mean incidence of acute rejection at 1-year follow-up was 0.4 episodes/patient.

All infections requiring treatment were analyzed: infection rate was 0.6 episodes per patient. There were two late deaths due to myocarditis: one was caused by CMV and one by Toxoplasma Gondii.

Fifteen patients (34%) developed one or more neoplasms, among them five died, respectively 8 months, 3, 8, 13, 16 years post HTx (three patients for lymphoproliferative disorders, one patient for leukaemia, one patient for CNS neoplasm). Among the other 10 patients, a 13-year old child developed a non-Hodgkin liver lymphoma that fully healed at 15-year follow-up after 12 cycles of chemotherapy. A 12-year old girl required surgery because of bleeding due to a uterine fibroma. Three female patients transplanted at the age of 6, 12, and 18 years, suffered for a breast adenoma after 7, 6, 4 years post HTx, respectively. After surgical exeresis they are still followed-up with serial soft-tissue echograms. A 3-year old baby had an EBV related PTLD 2 years after HTX, treated to resolution with reduction of immunosuppressive and antiviral therapy.

Another patient had three different tumors: in situ epidermoid carcinoma of the lips 4 years after HTx, a lips papilloma 1 one year later and an EBV related PTLD 2 years after. The neoplasms were treated by surgical exeresis of the lips tumor and immunosuppressive therapy reduction. At 6-year follow up the patient is still alive.

Two patients, transplanted at 2 and 8 months of age developed an EBV related PTLD 3 months and 15 years after HTx, respectively. Both patients did not respond to immunosuppression reduction and required chemotherapy and antibodies against CD20+ receptor. A patient transplanted at the age of 14 years developed a vulvar papilloma 15 years after HTx that was surgically treated. Graft vasculopathy occurred in four patients (9%) 1, 6, 9, 13 years after HTx, respectively.

In order to assess the long-term effects of immunosuppression on multiorganic performance we have studied serum creatinine (CRE) in all our patients: CRE was within normal ranges (<60 µmol/l) in 35% of patients, there was a mild kidney dysfunction (61 < CRE < 120 µmol/l) in 22% of the cases, and only 12% of patients had moderate to severe kidney impairment (CRE > 200 µmol/l) (Fig. 2 ).


Figure 2
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  		Fig. 2. Freedom from moderate to severe kidney dysfunction (CRE > 200 µmol/l).

 
None of our patients required hemodialysis. As far as liver function is concerned, a mild increase (within 20% above normal values) in AST, ALT and Serum bilirubin was observed in 70% of cases, whereas in 30% of cases their values were exceeding of 20% the normal range. Nevertheless in all cases INR, serum albumin and total proteins were within normal values.

Nine patients (21%) suffered from hypertension requiring drug therapy. Neoplasms were the only independent predictor of outcome (p = 0.039). Marginal donors showed only a trend for increase in cardiac death (p = 0.08).


   5. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistical analysis
 4. Results
 5. Discussion
References
 
HTx in pediatric age has been proved to be a valid therapy for end-stage cardiomyopathies when no conventional therapeutical alternatives are available. Long-term results are satisfactory in terms of either survival and quality of life [6]. Moreover, in our series, overall survival rate of pediatric patients is better than the adults’ one (62.1 vs 48% at 15 years after HTx). At the moment of HTx, 14 patients (34%) were under the 3rd percentile of weight: HTx led to a complete recovery of somatic growth and cognitive skills in all patients, as observed at last follow-up. According to ISHLT Registry report 2006 [6], the indication to HTx and the severity of illness at the time of heart transplantation are relevant risk factors for early survival: in our experience, congenital diseases were associated with worst early survival (30% early deaths in congenital subgroup vs 12% in the remaining patients) while they did not affect late outcomes (16% late deaths in congenital subgroup vs 18% in the others).

Early mortality accounted for half of all deaths. Main causes of early mortality were represented by acute rejection and graft failure. It is interesting to note that all these patients had well known pre-HTx risk factors [6]: four patients were on mechanical circulatory support and three patients were on high-dosage inotropic support. Our experience confirms that, in this era of donor shortage, the timing of waiting-list entrance appears to be crucial, before worsening of hemodynamic performance occurs [6,7]. Main cause of late mortality in our series was represented by neoplasms, followed by infections and vasculopathy. Interestingly acute rejection had no influence on the causes of late mortality.

Occurrence of neoplasms is a well-recognized complication of solid organ transplantation [6–8]. Prevalence of different types of neoplasms in transplanted patient is 3–20 times higher than a control population [8].

After HTx, non-melanoma skin cancer and PTLD are the types with higher incidence. For skin cancer patients’ age greater than 40 years and immunosuppressive therapy levels are proved risk factors [9].

Our experience with paediatric HTx patients confirms a prevalence of PTLDs (53.3%) on all the other types of neoplasms, and a low skin cancer incidence (13%).

In our multivariate analysis, the correlation between the immunosuppressant therapy, with or without corticosteroids and neoplasms insurgence is not statistically significant (p = 0.15), while p-value becomes statistically significant (p = 0.01) when we correlate the hematic Cyclosporine A levels and neoplasms insurgence after 10 years from transplant (Fig. 3 ).


Figure 3
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  		Fig. 3. Results (multivariate analysis). Incidence of neoplasms is related to average blood levels of CyA at 10 years.

 
In patients in which neoplasm has already been diagnosed there is a trend between hematic Cyclosporine A levels and overall survival (p = 0.05) (Fig. 4 ).


Figure 4
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  		Fig. 4. Results (multivariate analysis). Fatal neoplasms are related to average blood levels of CyA at 10 years.

 
To explain the higher incidence of PTLD in HTx patients when compared to non-immunosuppressed population, an activation of oncogenic viruses (Epstein-Barr virus, HHP8 and HPV) has been hypothesized [10].

Our results seem to confirm these data: B-Lymphocyte phenotype is the only form that we have observed in our patients, the majority of them were EBV-linked (75%). We had an early PTLD insurgence (<12 months) in two cases: one of them had induction therapy with OKT-3 and this is in keeping with reports referring a higher PTLD incidence in patients treated with this drug [11]. Anyway, the small number of patients of our cohort treated with induction therapy using different drugs (OKT3 in two cases, Lymphoglobulin in four cases, Thymoglobulin in four cases) does not allow any statistical inference on its association with PTLD.

In our experience higher haematic C0 through levels of Cyclosporine A were related to higher incidence of neoplasms (p = 0.001).

The introduction of new immunosuppressive agents, i.e., Everolimus, in adult patients, plays an important role in preventing acute and chronic rejection with low Cyclosporine A dosage [12]; moreover its antiviral role could lower the incidence of EBV and HHP8 infections, which can be considered responsible of PTLDs activation.

As far as infections are concerned, remarkably, both fatal infections observed in our patients were recurrences of myocarditis. In those two patients HTx was indicated because of dilated cardiomyopathy following biopsy proven myocarditis. After HTx, in one of these patients we detected the same viral genome being responsible of both native heart and donor heart myocarditis.

Overall incidence of graft vasculopathy in our population is lower than that of the International experience (9 vs 11.4% at 5 years), although our data may be limited [6].

As reported in other studies, avoiding the use of steroids in chronic immunosuppression might be responsible for lower vasculopathy occurrence [14,15].

Heterotopic technique was used in patients with high arteriolar pulmonary resistances (RVPo > 6 U/m2) and transpulmonary gradient >15 mmHg: two patients with restrictive and one patients with hypertrophic myocardiopathy. In this subgroup (follow up period 8 ± 1 years), this technique was effective in avoiding right ventricular graft failure, all patients are now alive with a satisfactory quality of life at a follow-up of 8 ± 1 years [16].

Although a large donor recipient weight mismatch has been referred as cause of cerebrovascular incidents [17], none of our patients had the ‘Big Heart Syndrome’.

The normal graft function observed along all the follow-up period was not related to recipients’ age at the time of HTx. The incidence of major complications and comorbidities was lower than in the adult population: hypertension occurred in nine patients (21%) but it is remarkable that six of these patients were transplanted with a heart from an oversized donor (mean donor–recipient weight ratio = 1.6 ± 0.5). Hypertension did not occur in the two combined heart–kidney transplants. There was no new-onset of diabetes mellitus. Incidence of neoplasms still remains a major issue (34%), although their mortality is low (33% of all cases) at long-term follow-up and healing rate is good. It is interesting to highlight that in our series we observed an increase of the rate of neoplasm in association with high haematic C0 through levels of Cyclosporine A over a prolonged period of time. This correlation might suggest the need of lowering CyA levels. In our study we found CyA levels to be higher in the subgroup of patients with higher rejection scores. In adult HTx a late reduction of immunosuppression could be a relatively safe procedure, the same can not be stated for pediatric patients, where recurrence of acute fatal rejections is a well known complication [6]. Thus we suggest a reduction of Cya dosages and the concomitant start-up of other immunosuppressive drugs. The introduction of new immunosuppressant agents [13–19], (i.e., mycophenolate, everolimus), prevents acute and chronic rejection with low Cyclosporine A dosage, and it could play a crucial role in preventing these severe complications in the pediatric population.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistical analysis
 4. Results
 5. Discussion
 References
 

  1. Fricker FJ, Griffith BP, Hardesty RL, Trento A, Gold LM, Schmeltz K, Beerman LB, Fischer DR, Mathews RA, Neches WH. Experience with heart transplantation in children. Pediatrics 1987;79:138-146.[Abstract/Free Full Text]
  2. Webber SA. The current state of, and future prospects for, cardiac transplantation in children. Cardiol Young 2003;13:64-83.[CrossRef][Medline]
  3. Smith RR, Wray J, Khaghani A, Yacoub M. Ten year survival after paediatric heart transplantation: a single centre experience. Eur J Cardiothorac Surg 2005;27(5):790-794.[Abstract/Free Full Text]
  4. Boucek MM, Mathis CM, Kanakriyeh MS, McCormack J, Razzouk A, Gundry SR. Bailey donor shortage: use of the dysfunctional donor heart L. J Heart Lung Transplant 1993;12(6 Pt 2):S186-S190.[Medline]
  5. Balzer DT, Moorhead S, Saffitz JE, Huddleston CB, Spray TL, Canter CE. Utility of surveillance biopsies in infant heart transplant recipients. J Heart Lung Transplant 1994;14:1095-1101.
  6. Bouchek MM, Waltz DA, Leah B, Edwards BE, David O, Taylor DO, Berkley MK, Trulock EP, Marshall I, Hertz MI. Registry for the International Society for Heart and Lung Transplantation: Ninth Official Pediatric Report-2006. J Heart Lung Transplant 2006;25:893-903.[CrossRef][Medline]
  7. Baley LL, Gundry SR, Razzouk AJ, Wang N, Sciolaro CM, Chiavarelli M, the Loma Linda University Pediatric Heart Transplant Group Bless the babies: 115 late survivors of heart transplantation during the first year of life. J Thorac Cardiovasc Surg 1993;105:805-815.[Abstract]
  8. Penn I. De-novo malignancies in pediatric organ transplant recipients. Pediatr Transplant 1998;2:56.[Medline]
  9. Caforio ALP, Belloni Fortina A, Piaserico S, Alaibac MSA, Tona F, Feltrin G, Pompei E, Testolin L, Gambino A, Dalla Volta S, Thiene G, Casarotto D, Peserico A. Skin cancer in heart transplant recipients: frequency and risk factor analysis and relevance of immunosuppressive therapy. Circulation 2000;102(Suppl 2).
  10. Zangwill SD, Hsu DT, Kichuk MR, Garvin JH, Stolar CJ, Haddad Jr. J, Stylianos S, Michler RE, Chadburn A, Knowles DM, Addonizio LJ. Incidence and outcome of primary Epstein-Barr virus infection and lymphoproliferative disease in pediatric heart transplant recipients. J Heart Lung Transplant 1998;17(12):1161-1166.[Medline]
  11. Swinnen LJ, Costanzo Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI. Increased incidence of lymphoproliferative disorders after immunosuppression with the monoclonal antibody OKT-3 in cardiac transplant recipients. N Engl J Med 1990;323:1723-1728.[Abstract]
  12. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P, RAD B253 Study Group Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349(9):847-858.[Abstract/Free Full Text]
  13. Valantine H, Zuckermann A. From clinical trials to clinical practice: an overview of Certican (everolimus) in heart transplantation. J Heart Lung Transplant. 2005;24(4 Suppl):S185–90; discussion S210-1. Review. Erratum in: J Heart Lung Transplant 2005;24(6):787.
  14. Phal E, Hornung T, Parry G, Dark JH. Pediatric cardiac transplant. Results using a steroid-free maintenance regimen. Pediatr Transplant 2003;7:59-63.[Medline]
  15. Phal E, Zales VR, Fricker FJ, Addonizio LJ. Post transplant coronary artery disease in children. A multicenter national survey. Circulation 1994;9011-56-11-60.
  16. Cochrane AD, Adams DH, Radley Smith R, Khaghani A, Yacoub MH. Heterotopic heart transplantation for elevated pulmonary vascular resistance in pediatric patients. J Heart Lung Transplant 1995;14(2):296-301.[Medline]
  17. Reichert B. Size matching in heart transplantation. J Heart Lung Transplant 1992;11:S199-S202.[Medline]
  18. Tramisier D, Vouhe P, Le Bidois J, Mauriat P, Khoury W, Leca F. Donor recipient size matching in pediatric heart transplantation: a word of caution about small grafts. J Heart Lung Transplant 1996;15(2):190-195.[Medline]
  19. Pietra BA, Boucek MM. Immunosuppression for pediatric cardiac transplantation in the modern era. Progress Pediatr Cardiol. 2000;11:115-129.[CrossRef]




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