Journal of Pediatric Cardiology and Cardiac Surgery

Online ISSN: 2433-1783 Print ISSN: 2433-2720
Japanese Society of Pediatric Cardiology and Cardiac Surgery
Japanese Society of Pediatric Cardiology and Cardiac Surgery Academy Center, 358-5 Yamabuki-cho, Shinju-ku, Tokyo 162-0801, Japan
Journal of Pediatric Cardiology and Cardiac Surgery 2(1): 1-19 (2018)
doi:10.24509/jpccs.180101

ReviewReview

Pediatric Heart Transplant in the United States: Current Status, Outcomes, and Ongoing Challenges

1Pediatric Cardiology, Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children ◇ Wilmington, DE, USA

2Pediatric Cardiology, Nemours Children’s Hospital ◇ Orlando, FL, USA

3Cardiothoracic Surgery, Nemours Cardiac Center, Nemours/Alfred I. duPont Hospital for Children ◇ Wilmington, DE, USA

発行日:2018年3月31日Published: March 31, 2018
HTMLPDFEPUB3

Heart transplant remains an important treatment option for end-stage heart failure in children who have failed maximum medical management. Although the outcome of heart transplant has significantly improved due to advances in perioperative management and immunosuppression, commonly, it is not a permanent solution. We still encounter multiple problems in managing these patients before and after transplant, not only with hemodynamic derangement, but also with functional deterioration of multiple organ systems. Shortage of donor hearts in association with wait-list mortality remains a major ongoing problem, especially for infants. Importantly, transplant for patients with congenital heart disease has unique challenges, including complexity of surgical reconstruction, coagulation abnormalities, allosensitization, and specific problems related to single ventricular palliation. Even after successful transplant, chronic complications emerge as inevitable challenges, including rejection, infection, allograft vasculopathy, lymphoproliferative disorders, and renal dysfunction. Here, we review the current status of pediatric heart transplant in the United States and discuss ongoing major problems frequently encountered with this special life-saving treatment modality. Underlying mechanisms of these complications are reviewed in conjunction with potential management strategies.

Key words: wait-list mortality; immunosuppression; rejection; cardiac allograft vasculopathy (CAV); post-transplant lymphoproliferative disorders (PTLD)

Introduction

Heart transplant has been established as a treatment option for intractable end-stage heart failure in infants, children, and adolescents due to primary myocardial disease and/or complex congenital heart disease (CHD). Survival following heart transplant has significantly improved over the last few decades thanks to improved perioperative management and advances in immunosuppression.1) However, there are still several unsolved problems commonly encountered before and after pediatric heart transplant.2–4) Wait-list mortality is still a serious problem, especially for small infants, primarily due to persistent donor shortage in association with increasing demands.5) Allosensitization is a common challenge in patients with CHD who underwent previous heart surgery, which compromises the optimum control of immunosuppression.6, 7) Rejection and infection are inevitable complications in both acute and chronic phases after transplant.8) Other chronic complications including allograft vasculopathy,9, 10) lympho-proliferative disorders,11, 12) renal dysfunction,13) and graft loss/retransplantation14, 15) are known encounters following heart transplant. Non-adherence to post-transplant management is not infrequently seen in adolescent recipients.16, 17) The longer the patients survive after heart transplant, the more frequently and inevitably we encounter these complications. It is, thus, reasonable to accept heart transplant not as an ultimate solution for the cure of medically refractory organ failure but as a best-available palliation in the current era to improve survival and quality of life for the patients with end-stage heart disease. However, better understanding of underlying mechanisms of pathological consequences is strongly warranted to help improve outcomes for heart transplant.

The aims of this review article are three-fold. First, we present the current status of pediatric heart transplant in the United States in conjunction with the donor allocation system for pediatric heart transplant. Donor shortage is a primary reason for wait-list mortality, but there may be some room for improvement. Second, we address variable challenges and complications encountered in both acute and chronic phases following pediatric heart transplant, especially for those with end-stage CHD. Heart transplant for CHD encompasses unique challenges for success. Lastly, we discuss the underlying pathogenesis of these complications, due mostly to long-term immunosuppression. New science is emerging in the field of pediatric heart transplant to better understand the biological mechanisms of transplant-related complications to help preserve graft survival and improve quality of life for transplant recipients.18, 19)

Current Status and Indications of Pediatric Heart Transplant in the United States

A recent study by Dipchand et al. reported that between 500 and 600 pediatric heart transplants are performed annually in the United States, which is estimated to represent approximately 66% of worldwide cases20) (from International Society for Heart and Lung Transplantation or ISHLT Registry: Fig. 1). Outcomes significantly improved from 1982 to 2011, demonstrating the median survival of 19.7 years for infants, 16.8 years for children from 1 to 5 years, 12.5 years for children from 6 to 10 years, and 12.4 years for children from 11 to 17 years of age at the time of heart transplant.20) For a more recent time period, from 2005 to 2009, the overall survival rates of 91%, 87%, and 83% at 1, 3, and 5 years after transplant, respectively, were reported by Pediatric Heart Transplant Study (PHTS) Registry.21)

Journal of Pediatric Cardiology and Cardiac Surgery 2(1): 1-19 (2018)

Fig. 1 Recipient age distribution by year of transplant

International Society of Heart and Lung Transplantation (ISHLT). From Dipchand et al. J Heart Lung Transplant 2014.20) The annual number of heart transplant has been only modestly increased since 1991.

Heart transplant should be considered for any patients with medically refractory advanced heart failure. However, in the United States, universal guidelines for pediatric heart transplant have not been adopted, and each transplant program is mandated to develop center-specific criteria.22) A scientific statement published in 2007 by the American Heart Association proposed the indications for heart transplant in pediatric heart disease.23) In this statement, indications were suggested based upon the severity of clinical status graded into 4 different stages (A to D) (Table 1). 24)Class D heart failure is defined as symptomatic heart failure at rest requiring continuous inotrope support, mechanical ventilation, or mechanical device support, which has Class I indication for heart transplant.22) Transplant was also recommended in children with Class C heart failure (present or past history of symptomatic heart failure) who are at risk for sudden death or have pulmonary hypertension.22) However, defining symptomatic heart failure in CHD patients is challenging, as they often accommodate their lifestyle to lower levels of activity gradually, making symptoms more difficult to elicit.22)

Table 1 Proposed heart failure staging for infants and children (International Society for Heart and Lung Transplantation 2004)24)
StageInterpretation
APatients with increased risk of developing HF, but who have normal cardiac function and no evidence of cardiac chamber volume overload. Examples: previous exposure to cardiotoxic agents, family history of heritable cardiomyopathy, univentricular heart, congenitally corrected transposition of the great arteries.
BPatients with abnormal cardiac morphology or cardiac function, with symptoms of HF, past or present. Examples: aortic insufficiency with LV enlargement, history of anthracycline with decreased LV systolic function.
CPatients with underlying structural or functional heart disease, and past or current symptoms of HF.
DPatients with end-stage HF requiring continuous infusion of inotropic agents, mechanical circulatory support, cardiac transplantation or hospice care.
HF: heart failure, LV: left ventricle

Indications for pediatric heart transplant include CHD, cardiomyopathies (dilated, hypertrophic, and restrictive), and retransplant for graft failure.23) Common considerations for heart transplant in CHD are listed in Table 2.25, 26) Single ventricular lesions are most common (36%), followed by systemic right ventricle (20%).25) Congenital heart disease remains the most common indication for heart transplant in infants (55%) but has decreased over time, whereas cardiomyopathy increased from 35% in the period of 2000 to 2005 to 41% in the most recent era.20) This may be, in part, reflecting the recent decline in the number of primary heart transplant for the hypoplastic left heart syndrome (HLHS) patients and the significant improvement in interstage survival by a staged surgical palliation when compared with the combined wait-list mortality and early post-transplant mortality for HLHS infants.27, 28) There are certain challenges specific to patients with CHD, including increased allosenstization due to prior cardiac operations,7) technical challenges due to cardiac positional anomalies and previous vascular reconstructions, more prolonged intraoperative preparation, and known comorbidities secondary to single ventricular palliation (discussed later).26, 29) Survival following failed single ventricular palliation carries the highest mortality in infants with 1-year survival of 70%,28) compared with 90% to 94% for dilated cardiomyopathy (DCM).30–32)

Table 2 Indications for heart transplant in patients with congenital heart disease23, 25, 26)
1. SV Physiology36%
a. Failed SV palliation
b. Failed Fontan
c. Unrepaired HLHS
2. Systemic RV
a. d-TGA after atrial switch operation (Mustard/Senning)12%
b. l-TGA (congenitally corrected TGA)8%
3. PA/IVS with RVDCC
4. RVOT lesions (TOF)10%
5. LVOT lesions8%
6. Neonatal Ebstein anomaly with severe cardiomegaly, severe TR, poor RV function, or sluggish antegrade flow into main PA.
7. Complex heterotaxy syndrome (with TAPVR and/or severe AVVR)
8. Others (ASD/VSD/CCAVC)27%*
The percentages are from 488 patients with CHD who underwent heart transplant.25) *Also includes 3, 6, and 7. SV: single ventricle, HLHS: hypoplastic left heart syndrome, RV: right ventricle, TGA: transposition of the great arteries, PA/IVS: pulmonary atresia with intact ventricular septum, RVDCC: right ventricle-dependent coronary circulation, RVOT: right ventricular outflow tract, TOF: tetralogy of Fallot, LVOT: left ventricular outflow tract, TR: tricuspid regurgitation, PA: pulmonary artery, TAPVR: total anomalous pulmonary venous return, AVVR: atrioventricular valve regurgitation, ASD: atrial septal defect, VSD: ventricular septal defect, and CCAVC: complete common atrioventricular canal.

Dilated cardiomyopathy is the most common form of cardiomyopathy in children (83% of 1320 patients with cardiomyopathy had DCM listed for heart transplant from 1993 to 2006).33) Seventy-four percent of listed DCM patients ultimately underwent heart transplant, with a 10-year survival rate of 72%.34) Hypertrophic cardiomyopathy (HCM) is an infrequent etiology to be listed for pediatric heart transplant (6% of cardiomyopathies) for which critically ill infants have the highest wait-list mortality (33% within the first year after listing).35) Restrictive cardiomyopathy (RCM) comprises 11% of pediatric cardiomyopathies listed for heart transplant.36) Children with RCM have a generally low wait-list death rate and reasonable overall survival compared with DCM, but this is due, in part, to early listing before they clinically deteriorate, 36) and a much higher proportion of patients with RCM undergo transplant in comparison with other forms of cardiomyopathy.37)

Mechanism of Donor Organ Allocation: The United Network of Organ Sharing (UNOS) System

The allocation of a donor organ to a heart transplant recipient truly provides the gift life to a person with end-stage heart failure. Unfortunately, for many individuals on the transplant list, there is a world-wide shortage of organs. Today in the United States, there are >100,000 patients waiting for organ transplant daily (https://unos.org). Therefore, adherence to the listing and matching processes must be stringently followed to ensure maximal utilization of this precious resource. The United Network of Organ Sharing (UNOS) is a non-profit organization that administers the Organ Procurement and Transplant Network (OPTN) in the United States. UNOS is responsible for managing the national wait-list and matching process, maintaining databases of all organ transplants in the nation, developing policies, monitoring adherence to policies, educating transplant professionals and the public on the benefits of organ donation, and assisting the patient and family during an organ transplant. The matching process considers multiple factors including: age, ability of the patient to recover, ABO status, distance, height and weight, life-support status, and time on the waiting list (https://optn.transplant.hrsa.gov).

In 2016, UNOS updated the pediatric heart transplant allocation policy to ensure maximal utilization of organs (see Table 3). This allows centers to list patients for heart transplant based on the severity of the clinical disease state and risk of death. Once accepted onto a wait list for heart transplant, patients are registered in one centralized national computer that is run by the UNOS Organ Center and links all centers in the United States together. An Organ Procurement Organization (OPO) is a non-profit organization that provides organ recovery services in a geographic region in the United States (https://organdonor.gov/awareness/organizations/local-opo.html). They have coordinators who will conduct a medical and social history to determine suitability of the organ, work with the family and medical staff to discuss the option of organ donation, and manage the informed consent process. Once consent for donation is received, they will manage the clinical care of the donor, enter all donor information into the UNOS computer system, and once a match is made, they will coordinate the timing of the recovery of the organs with the surgical teams and provide follow-up information to the donor family and medical staff on the outcome of the donations. As donor organs are identified, the procuring organization will run a match of potential recipients based on blood type, tissue type, size of the organ, medical urgency of the patient, time on the waiting list, and distance between donor and recipient. The ethnicity, sex, religion, and financial status are not considered as part of the computer matching system. A procurement coordinator then contacts the transplant center for the top-ranked patient, and if the patient is accepted, will coordinate all transportation and surgical timing for harvesting the donor organ. If the organ is declined by the top-ranked patient’s center due to a donor or recipient issue, then the organ would be offered to the next candidate on the match list. Once an organ is accepted, the receiving center will inform the patient and family and coordinate operating room times based on the arrival of the donor heart. Donor hearts are usually best transplanted within less than six hours of ischemic time (https://optn.transplant.hrsa.gov).

Table 3 Pediatric Heart Transplant Listing
Status 1A: A candidate is <18 years old at the time of registration and meets one of the following five criteria below and must be recertified every 14 days:1. Requires continuous mechanical ventilation and is admitted to the hospital that registered the candidate.
2. Requires assistance of an intra-aortic balloon pump and is admitted to the hospital that registered the candidate
3. Has ductal dependent pulmonary or systemic circulation, with ductal patency maintained by stent or prostaglandin infusion, and is admitted to the transplant hospital that registered the candidate.
4. Has a hemodynamically significant congenital heart disease diagnosis, requires infusion of multiple intravenous inotropes or a high dose of a single intravenous inotrope, and is admitted to the transplant hospital that registered the candidate.
Qualifying Pediatric Status 1A Congenital Heart Disease Diagnoses
• Double Outlet Right Ventricle
• Atrial isomerism / Heterotaxy
• Atrioventricular Septal Defect
• Congenitally Corrected Transposition (L-TGA)
• Ebstein’s Anomaly
• Hypoplastic center Heart Syndrome
• Other center Heart Valvar/Structural Hypoplasia
• Pulmonary Atresia with Intact Ventricular Septum
• Single Ventricle
• Tetralogy of Fallot
• Transposition of the Great Arteries
• Truncus Arteriosus
• Ventricular Septal Defect(s)
• Other (Specify)
Qualifying Pediatric Status 1A Inotropes and Dosages
Requires infusion of a single high dose inotrope:
• Dobutamine greater than or equal to 7.5 µg/kg/min
• Milrinone greater than or equal to 0.50 µg/kg/min
• Dopamine greater than or equal to 7.5 µg/kg/min
• Epinephrine greater than or equal to 0.02 µg/kg/min
***If the candidate is supported by multiple inotropes, the dosage requirements do not apply.
5. Requires assistance of a mechanical circulatory support device
Status 1B: <18 years old and meets one of the following two criteria below and does not require recertification unless the candidates medical status changes:1. Requires infusion of one or more inotropic agents but does not qualify for pediatric status 1A.
2. Is <1 year old at the time of the candidates initial registration and has a diagnosis of hypertrophic or restrictive cardiomyopathy.
Status 2: <18 year old at the time of registration and not meet the criteria for pediatric status 1A or 1B but is suitable for transplant. No recertification required.
Inactive status: A candidate is temporarily unsuitable for transplant, the candidate will not receive any heart offers during this time.
(https://optn.transplant.hrsa.gov/news/pediatric-heart-allocation-policy-and-system-changes/)

Although a national system helps maximize the allocation of donor organs, there is still a significant shortage of heart donors. In 2015, there were 644 candidates listed for heart transplant and 460 heart transplants performed in children ages 0–18 years.38) As a temporalizing measure, ventricular assist devices (VADs) have been used as a bridge to transplant in pediatrics, but size limitations and considerable morbidity remain a challenge. Blume et al. recently reviewed 364 patients ages<19 years with VADs, and 80% received left ventricular assist devices, 15% biventricular assist devices, and 2% total artificial hearts, with almost 50% of this cohort surviving to transplant within 6 months but having overall mortality of 19% on device therapy.39) The wait-list mortality is highest for infants <1 year old and in children with CHD who have undergone prior surgical palliation, especially failed Fontan-palliation.26) Consideration should also be given to teenagers with end-stage heart failure who are approaching their 18th birthday since their wait times will be longer after they become 18 years of age. Peng et al. demonstrated that those listed after their 18th birthday waited approximately 8.5 months longer compared with those listed before their 18th birthday due to the competition from adult recipients after age 18 years.40)

Wait-list mortality is a serious problem for infants and children awaiting heart transplant, with the incidence ranging from 13% to 29%5, 41–43); the highest is in children with end-stage CHD.43) This is considered primarily due to absolute donor shortage in relation to the demand and more stringent acceptance criteria of the donor hearts for the patients with CHD because of multiple comorbidities.41, 44) However, questions have also been raised by Almond et al. that the current allocation system may not be structured optimally to reduce transplant mortality, by which an available heart is offered first to the child who has accumulated more status 1A time rather than a child who is likely to die without transplant.42) To reduce the wait-list mortality, certain endeavors have been trialed. The number of ABO incompatible transplants has been significantly increased in recent years with reasonable outcome, especially for infants with higher immune tolerance than older children.45, 46) Donor hearts with diminished ventricular function have been used for pediatric transplant with comparable post-transplant survival when compared with those with normal systolic function.47, 48) Acceptance of a marginal donor heart should be considered in comparison with expected high wait-list mortality.49, 50) On the current allograft allocation system, only 50% of donor hearts were actually used for transplant, and the others were discarded.48) This is, in part, due to poorly standardized current criteria for acceptance of donor hearts.51) A standardized donor scoring system should accurately reflect the likelihood of organ acceptance and predict long-term survival.52) The increased utilization of these unused marginal donor hearts may ameliorate the donor shortage problem and could reduce wait-list deaths.

Immediate Postoperative Management after Heart Transplant

Pediatric heart transplant presents with unique challenges as approximately 40% of heart transplants are performed for the children with advanced heart failure in complex CHD with or without previous surgery.29, 53) In addition to a high wait-list mortality rate in infants awaiting heart transplant,43) early post-transplant mortality is high in infants with CHD, especially those with HLHS.28) Chrisant et al. reported that post-transplant survival of 175 HLHS infants was 72% at 5 years, with 76% of deaths occurring within 3 months.27) However, among the conditional survivors after 1 month of transplant for HLHS, the survival was 92% and 85% at 1 and 5 years, respectively, which is comparable to that for cardiomyopathies,27) suggesting the presence of critical determinants of long term-survival during the early postoperative period.

Transplant for CHD requires special consideration for post-transplant complications, graft survival, and patient mortality, especially in those with single ventricle with previous staged palliation, when compared with transplant for cardiomyopathies. These considerations include prolonged surgical time due to previous cardiac surgery or for anatomical reconstruction and increased risk of allosensitization.54) Prolonged cardiopulmonary bypass (CBP) time and aortic cross-clamp duration are independent predictors of mortality and morbidity after cardiac surgery primarily via increased systemic inflammatory responses, causing multiple organ dysfunction including low cardiac output, prolonged mechanical ventilation, increased pulmonary vascular resistance, excessive bleeding and need for transfusions, acute renal dysfunction, prolonged hospitalization, and in-hospital death.55, 56)

Surgical Procedures for Complex Anatomy

Patients with certain anatomy, including anomalies of the pulmonary or systemic venous return, pulmonary artery distortion, aortic arch anomalies, previous shunts, LeCompte maneuver, and variation of the cardiac position or situs (mesocardia, dextrocardia or situs inversus), usually require significant reconstruction of the venous pathway, aortic arch, and pulmonary arteries. Thus, modification of the donor and recipient procedure is required, and procurement of additional tissue (pulmonary artery, aorta, superior vena cava) with the donor heart provides the best material to facilitate the reconstruction, which may require significant technical expertise and creativity. This added complexity may be regarded as contraindications to heart transplant or may be an incremental risk factor for early mortality. It is now clearly established that there is no anatomical contraindication to heart transplant. With a number of innovative reconstructions, all anatomical abnormalities can be managed using the donor or recipient tissue or both, with excellent outcomes.57, 58)

Bleeding and Vascular Access

Excessive bleeding is a common complication following pediatric heart transplant. The etiology of bleeding complication is often multi-factorial, including prior congenital heart surgery requiring extensive dissection, aggressive anticoagulation strategy, coagulopathy of CPB, and poor preoperative nutritional status.59) Patients who underwent repair or palliation of CHD commonly present with limited vascular access and development of the collateral vessels network. These two conditions can present a formidable challenge in obtaining appropriate lines for infusion of fluids, vasoactive drugs, medications, and future biopsies. In addition, the presence of arterio-venous and/or veno-veno collaterals can be associated with severe blood loss, particularly when extensive dissection is required. In the presence of extensive venous or arterial collateralization, endovascular coiling should be considered prior to transplant.60) This can provide important advantages including decrease in pulmonary venous return during CPB and improvement in cerebral perfusion due to reduced runoff through aorto-pulmonary collaterals. Nevertheless, this strategy may not be feasible in the presence of low systemic oxygen saturation levels pre-transplant. Similarly, closure of residual collaterals should be considered following cardiac transplantation to reduce volume overload on the transplanted heart.

In anticipation for bleeding during sternotomy or difficult dissection, alternative cannulation sites should be considered, including the axillary, femoral, or carotid vessels. Therefore, preoperative knowledge about patency of these vessels is necessary. Acquisition of hemostasis is extremely important during transplant of those individuals who previously had repeated surgery, particularly for those with chronic cyanosis. This cannot be emphasized enough, as in some cases, postoperative hemorrhage has become uncontrollable, leading to death. Pre-emptive measures to mitigate this complication and the appropriate use of targeted blood component therapy guided by timely assessment of clotting activity are extraordinarily valuable.

Allosensitization and Prevention of Acute Graft Failure

Allosensitization, presented as increased panel-reactive antibody (PRA) that measures anti-HLA antibodies, is significantly associated with increased mortality after pediatric heart transplant by eliciting hyperacute rejection and primary organ dysfunction.7, 61) When PRA is higher than 10%, UNOS recommends a prospective crossmatch to lessen the risk of allosensitization. As a result, many patients with elevated PRA may wait longer to receive a negative crossmatch organ, thereby increasing the risk of wait-list mortality.7, 62) Feingold et al. reported their single-center experience that pre-transplant allosensitization was associated with increased incidence of cardiac allograft vasculopathy (CAV), although there was no significant increase in graft or patient survival compared with those in non-sensitized patients.62) On the other hand, an analysis of the UNOS registry database (3,534 patients) demonstrated that PRA >10% was independently associated with worse long-term graft and patient survival after heart transplant.61) A prior sternotomy, possibly a simple marker for a greater exposure to blood products, was associated with increased risk of allosensitization.7) Homograft materials used in prior reparative or palliative surgery are also thought to elicit an immune response in association with an increase in PRA.63, 64) Sensitized post-transplant pediatric patients are considered at high risk for poor outcome.

There is neither a universally accepted therapeutic strategy for achieving desensitization, nor standard methods for measuring the efficacy of the techniques used to achieve densitization preoperatively.6) Consensus statements in 2009 for sensitized patients awaiting transplant suggested the combined use of plasmapheresis, intravenous immunoglobulin (IVIG), and anti-B cell agents (rituximab) to mitigate the development of hyperacute rejection.65) Pollock-BarZib and colleagues reported 1-year survival of 71% for allosensitized patients using aggressive immunosuppression with thymoglobulin induction; tacrolimus; mycophenolate mofetil; and steroids in combination with daily plasmapheresis, IVIG, and rituximab,66) compared with 50% survival reported by Jacobs et al. for sensitized patients.67) Nevertheless, it seems that significant episodes of rejection and development of coronary allograft vasculopathy (CAV) are quite prevalent following initial success with transplant of sensitized recipient, which has led to selective use of desensitization strategies in different centers. To improve outcome following pediatric heart transplant, further research is imperative to establish an optimum immunosuppression regimen to mitigate the effect of allosensitization for patients with end-stage CHD awaiting heart transplant.

Single Ventricle

Single ventricle management requires a surgical staged palliation, in which the initial palliation carries higher mortality, following an intermediate stage and culminating with the Fontan procedure, which currently has minimal operative risk.54) Due to the scarcity of donors and the fragile circulatory physiology among patients with circulations in parallel connected at the arterial level, wait times for a donor heart are long, and wait-list mortality is considerable. During the wait for an organ, it is highly desirable to transition early to a superior cavo-pulmonary connection, with its inherent physiologic advantages and increased circulatory stability.68) In the case of HLHS, heart transplant is associated with excellent outcomes. However, a reduced donor pool has relegated the use of this management strategy only to patients with HLHS and conditions associated with poor outcomes, namely, significant tricuspid regurgitation and decreased ventricular function.27) In these cases, the use of a hybrid palliation as a bridge to transplant has gained increased application, due to the effective palliation achieved with a less-invasive intervention and mitigation of the possibility of sensitization associated with increased use of blood products and homograft for arch reconstruction during the Norwood procedure.54)

Special Consideration for Failed Fontan

Although initial success with single-ventricle palliation achieving the Fontan circulation is high, the Fontan circulation may fail due to primary ventricular dysfunction, usually associated with a normal pulmonary vascular resistance. Additionally, patients may exhibit a failing Fontan physiology with preserved ventricular function but elevation of pulmonary vascular resistance, leading to high pressure in the Fontan pathway, recurrent pleural effusions, chronic protein-losing enteropathy (PLE), ascites, and/or plastic bronchitis.69, 70) Patients are referred for transplantation either due to pump failure or failed Fontan physiology with preserved ventricular function. These two conditions result in different outcomes. While patients with pump failure usually recover promptly and regain their functional capacity, patients with preserved ventricular function have a more protracted course and risk due to a number of associated issues: namely, malnutrition, sensitization, and chronic cyanosis.71) In the recent retrospective European study of 61 patients of failed Fontan who underwent heart transplant (mean age 15.0±9.7 years) from 1991 to 2011, indications were intractable arrhythmia (28%), complex obstruction of Fontan circuit (16%), PLE (23%), impaired ventricular function (31%), and a combination of the above (15%).72)

The outcomes of heart transplant for failed Fontan have been associated with substantial risk and mortality of 24% to 35% until recently,73, 74) with much improved survival in selected centers with significant expertise in the management of this complex patient population.75) Early referral for transplantation, avoidance of long ischemic times, oversizing of the donor, appropriate myocardial protection, meticulous surgical technique for reentry, and reconstruction and acquisition of hemostasis play key roles in a successful outcome.70) More recently and due to the progressive nature of the liver fibrosis and dysfunction associated with a failed Fontan circulation, heart and liver transplantation has been undertaken with good results in a highly specialized center.76)

Management and Long-Term Complications after Heart Transplant in Children

Optimum immunosuppression is essential for long-term graft survival after heart transplant. Most post-transplant complications are caused by under- or over-immunosuppression. Whereas under-immunosuppression is responsible for rejection, over-immunosuppression results in other problems including infection, CAV, post-transplant lymphoproliferative disorders (PTLD), and renal dysfunction.77) Below, we will discuss general guidelines for immunosuppression therapy and these post-transplant complications.

Overall Strategy of Immunosuppression Therapy

The ISHLT guidelines for the care of heart transplant recipients is a complete overview of the evidence-based approach to immunosuppression.78) There are a few common principles utilized in the immunosuppressive regimens administered at most pediatric centers (http://www.uptodate.com/contents/induction-and-maintenance-of-immunosuppressive-therapy-in-cardiac-transplantation), including;

  1. The highest risk of rejection is early after transplant (within the first 3 to 6 months), for which the most intense immunosuppression should be given (induction) and weaned slowly over the first year.
  2. All immunosuppressive agents have certain side effects; it may be most prudent to use multiple agents at lower doses to avoid possible drug toxicities.
  3. Avoid over-immunosuppression, as this may be associated with infections and various forms of malignancy.

Induction is the state of providing intense immunosuppression directly after heart transplant to prevent acute rejection when the immune system is most activated. Induction is usually achieved by administration of anti-thymocyte globulin (ATG)79) or interleukin-2 receptor (IL-2R) antagonists (Basiliximab).80) Utilization of either form of induction helps lessen the need for corticosteroids and calineurin inhibitors (CNI) in the immediate post-operative period. Calcineurin inhibitors are then usually started at 48–72 hours postoperatively when the renal function and urine output are stabilized after surgery. Following transplant, patients usually have a three-drug regimen consisting of a) CNI: tacrolimus or cyclosporine, b) antimetabolite agents: mycophenolate mofetil (MMF) or azathioprine, and c) corticosteroids. Alternatively, mammalian target of rapamycin (mTOR) inhibitors (sirolimus or everolimus) may also be utilized. Immunosuppression in the maintenance phase is focused on providing the lowest dosage of medications to avoid side effects. Most patients are followed on dual therapy with CNI and antimetabolite (tacrolimus/MMF) or CNI and mTOR inhibitors (tacrolimus/sirolimus or everolimus). Corticosteroids are avoided if possible to prevent early-onset diabetes, bone loss, and growth retardation.81, 82) In fact, Auerbach et al. reported no graft survival advantage to using maintenance steroid in pediatric heart transplant recipients.83) Lowering CNI exposure may also help to prevent long-term renal dysfunction, for which mTOR inhibitor (sirolimus) plays a positive role.84, 85) Current trends of immunosuppression therapy in pediatric heart transplant were reviewed elsewhere.86)

Rejection

Following heart transplant, recipients have a life-long threat of rejection, which limits long-term graft survival and endangers patient survival. A recent report demonstrated that 16% of children experienced rejection during the first year post-transplant after discharge (2008 to 2013), a decrease from 27% in the previous era (2004 to 2008).20) Rejection can occur at any time after transplant but may be grouped into three categories: hyperacute, acute, and chronic rejections.78) Hyperacute rejection occurs instantly, within minutes to hours following donor heart reperfusion. Although hyperacute rejection can be severe and even fatal, the incidence has become extremely rare due to the routine use of prospective and virtual cross-match tests.78) Acute rejection starts within the first few weeks post transplant as the immune system gets stimulated directly or indirectly by HLA or non-HLA antigens of the donor heart via acute cellular rejection (ACR) and antibody-mediated rejection (AMR), referring to a response that primarily involves the cell-medicated and humoral arm of the immune system, respectively.87, 88) The recent ISHLT report revealed that the use of induction therapy continues to trend upwards and that most pediatric heart transplant recipients (71%) receive induction therapy of 47% ATG and 25% IL2-R antagonist,89) which is likely responsible for the decline in incidence of rejection.90) However, increased use of induction therapy did not directly influence long-term mortality.90) Chronic rejection typically occurs several years post-transplant and predominantly manifests as CAV leading to graft failure, need for re-transplantation, and/or death. The incidence of late rejection has significantly declined in the recent era, but its effect on mortality and development of CAV has not changed.91) Nonadherence or noncompliance is a known risk factor that is associated with late rejection, especially in adolescents.16, 17, 92)

As clinical manifestation of graft rejection is nonspecific, variable, and unreliable, endomyocardial biopsy (EMB) remains the gold standard for the diagnosis of rejection in cardiac transplant recipients,87) but alternative methods, serum biomarkers and noninvasive image studies, for rejection surveillance have been investigated to overcome the labor-intensiveness, invasiveness, and cost of EMB.93–95) Classical cardiac biomarkers, troponin and brain natriuretic peptide (BNP), have been studied to assess the degree of myocardial damage secondary to graft rejection. The recent study by Patel et al. demonstrated high sensitivity (94%) and high negative predictive value (99%) of cardiac troponin I (cTnI) in detecting acute rejection proven by EMB in 98 adult heart transplant recipients.96) On the other hand, the reliability of BNP for rejection surveillance has not been proven.94, 97) Other novel investigative serum biomarkers have been proposed as tools for rejection surveillance. Quantification genotyping of circulating donor-specific cell-free DNA, a marker for cellular injury caused by rejection, has been proposed as a sensitive, noninvasive method to detect rejection.98, 99) A group of French researchers recently demonstrated differential expression of microRNAs (miRNAs), miR-10a, miR-155, miR-31, and miR-92, both in tissue and serum, that indicates allograft rejection with high accuracy.100)

Noninvasive imaging studies have been investigated for possible diagnostic tools for identifying acute rejection and early graft failure.93, 101) Main features of early graft failure are LV or biventricular dysfunction with hypotension, low cardiac output, and high filling pressure, which can be detected by conventional echocardiogram, but most cases of acute rejection are diagnosed by surveillance EMB even if the patient is asymptomatic with normal LV systolic function.101) Flanagan et al. reported an increase of LV myocardial performance index (MPI) in 40 children with acute cellular rejection compared with 40 control patients without rejection after heart transplant.102) Tissue Doppler imaging (TDI) was assessed in 122 pediatric heart transplant recipients in which significant decline in biventricular TDI velocities were noted during rejection from the baseline. With frequent routine assessment, they proposed an absence of TDI velocities changes from the baseline as a reliable marker for freedom from rejection.103) Global longitudinal peak systolic strain (GLS) obtained by speckle-tracking echocardiography has been suggested as a suitable parameter to detect subclinical allograft dysfunction.101) However, others argued that there were no differences in speckle-tracking measures between transplant patients with rejection and those without.104) At this point, there is no single echocardiographic parameter to sufficiently replace EMB in identifying graft rejection. Butler et al. recently reported the effectiveness of cardiac magnetic resonance imaging (CMRI) as a possible screening method for rejection by demonstrating high sensitivity (93%) and high negative predictive value (98%) in predicting biopsy-positive heart transplant rejection with quantifying myocardial edema (T2 relaxation time) and right ventricular volume index.105) Further investigations are required for establishing noninvasive imaging studies to reliably diagnose acute graft rejection in both symptomatic and asymptomatic patients.

Infections

A timeline of infections after solid organ transplant is generally outlined into 3 phases: within 1 month, at 1 to 6 months, and after more than 6 months.106) More than 90% of infections occurring in the first month are nosocomial bacterial and candida infections of the surgical wound, lungs, urinary tract, or vascular access device. From 1 to 6 months after transplant, the immunomodulating viruses, particularly cytomegalovirus (CMV) and Epstein-Barr virus (EBV), begin to exert clinically significant effects in combination with sustained immunosuppression. Six months after transplant, more than 80% of patients are in stable condition with minimal long-term immunosuppression therapy with good allograft function. Approximately 10% of patients have chronic or progressive infection with hepatitis type B (HBV), hepatitis type C (HVC), CMV, EBV, or papilloma virus.106)

According to a PTHS study database of 2113 transplanted children, infection was a second-most frequent cause of death among 390 post-transplant deaths (rejection 18%, infection 12%, early graft failure 10%, sudden cardiac death 9%, and CAV-related 8%).21) Infection is the most common cause of unexpected hospitalization, particularly during the first transplant year.107) Intensive immunosuppression to prevent acute and chronic graft rejection inevitably causes increased susceptibility to various infections. George et al. demonstrated that adolescents are much more at risk of death from rejection, whereas elderly recipients are at high risk of infectious death, suggesting the inverse relationship between risk of rejection and that of infection among transplant recipients.8) Infant recipients were more vulnerable to more severe form of infections and more chronic/recurrent illness when compared with older children108). In 4458 pediatric heart transplant recipients, 81% developed some type of infection that required hospitalization or intravenous therapy, in which bacterial infection were the most commonly identified pathogens (43%), followed by virus (31%), and fungi (6%).109) Unlike in adults, the most common site of bacterial infections was the bloodstream (25%) in children, followed by pulmonary (21%), gastrointestinal tract (9%), and urinary tract (9%) with overall mortality of 34% during the observation period.109) Risk factors for infectious mortality in pediatric heart transplant recipients include diagnosis of congenital heart disease, pre-transplant ECMO, cardiac reoperation before discharge, pre-transplant infection requiring antibiotics, and pre-transplant creatinine elevation.110) Young children who underwent heart transplant at age less than 2 years are particularly vulnerable to invasive pulmonary infection, pneumonia, and bronchiestasia due to Streptococcus pneumoniae because of failure to produce effective antibodies against capsular polysaccharide.111, 112) Pneumococcal vaccination is highly recommended for transplant patients.

Cytomagalovirus infection is especially significant, as it not only causes direct infections but also modulates the host immune system to induce acute and chronic rejections including CAV.113) In a prospective study of 378 adults after heart transplant in a single center, nearly half of CMV infections occurred within the first 2 months after transplant, and the use of everolimus significantly lowered the rate of CMV infection; no difference was observed between cyclosporine A and tacrolimus-treated patients.114) Chronic infection by EBV elevated risk of PTLD (discussed later).

Invasive fungal infection (IFI) occurs frequently within the first 3 months after heart transplant, largely reflecting early nosocomial Candida and Aspergillus infections via the surgical site.115) Patients requiring additional induction immunosuppression or delayed chest closure are at increased risk of invasive fungal infection. Systematic surveillance of these infections and timely initiation of pre-emptive treatment in addition to prophylactic treatment are imperative to prevent infectious complications. In children, IFI occurs approximately 7% of total post-transplant infection, associated with 49% mortality rate within 6 months after transplant.116) Candida and Aspergillus species made up the majority of fungal infections (66% and 16%, respectively). Risk and mortality are highest in the first 6 months post-transplant especially in those with previous cardiac surgery and those requiring mechanical supports including ECMO, VAD, and mechanical ventilation.116)

Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy is a major cause of late heart graft failure, retransplant, and death that occurs in approximately 25% to 34% of pediatric patients within 10 years of transplant.89, 117, 118) The incidence of CAV is higher in adults, in which more than 50% of graft recipients develop clinically significant CAV within 10 years after transplant.119) Diffuse stenoses due to concentric intimal expansion and inadequate compensatory outward remodeling in both epicardial and intramyocardial arteries result in tissue malperfusion, ischemic injury, and graft loss.9) Morphological manifestations of CAV are diverse vascular narrowing, consisting of intimal fibromuscular hyperplasia, atherosclerosis, and inflammation (vasculitis) in the advantitia with relative preservation of the muscular media.120, 121) Clinical symptoms of myocardial ischemia caused by CAV are either atypical or variable due to absent or partial reinervation of the donor hearts. Price et al. reported their institutional experience of 66 post-transplant children in which 27 (41%) developed CAV over the 16-year period. Of 22 patients with the symptom complex of abdominal, chest, and/or arm pain, 18 (82%) were found to have CAV.122) Sudden death or resuscitated sudden death occurred in 15 (68%) of 22 patients with the symptom complex.122) Despite clinically silent progression and lack of symptoms, early detection of CAV is essential to minimize this life-threatening complication. Although angiography is regarded as a gold standard to make a diagnosis of CAV,123) the confluent nature of vascular narrowing has made its early identification difficult. No ideal modality for surveillance exists at the present time, but some diagnostic modalities have been studied including intravascular ultrasound (IVUS) and dobutamine stress echocardiography (DSE).121, 124) Hemodynamic abnormalities, especially restrictive ventricular physiology and decreased systolic function, were shown to be associated with the development of CAV125–127) and may be helpful in detecting early phase of CAV. Multiple serum markers have been studied for their correlation to the development of CAV, but none of them are specific to CAV.128) Recently, a circulating microRNA, miR-628-5b, was reported as a promising serum biomarker for advanced CAV in adults.129)

Understanding of the pathogenesis has been limited in part due to lack of relevant animal models; there are profound differences in how rodents and humans respond to allogenic blood vessels.9, 130) Pathogenesis of CAV consists of complex interactions among multiple factors including infection, ischemia/reperfusioin (I/R) injury, alloantigens, innate immunity, and humoral immunity (Fig. 2), but the main pathological process stems from the consequences of chromic alloimmunity, a finding supported by a study including the involvement of host T cells and B cells, lesions restricted to graft vasculature, lack of over-graft cell lysis, and chronic time course over month to years.131) The chronic alloimmunity involves both (a) innate immune cells, including natural killer (NK) cells and macrophages, and (b) adaptive immune cells including host-derived T cells, B cells, and macrophages.9) Data from animal models and human tissues suggest that CAV is represented by a form of host T cell-mediated delayed type hypersensitivity (DTH) via enhanced production of interferon-γ (IFN-γ), which stimulates proliferation of host smooth muscle cells in the intima.131) Donor-specific antibody (DSA), typically against HLA-DQ molecule expressed by graft endothelial cells, may be responsible for adventitial inflammation and increases a risk of developing CAV.132) Other pathogenetic factors include perioperative ischemia-reperfusion injury with endothelial dysfunction,133–135) conventional risk factors of atherosclerosis,136) CMV infection,137) and genetic predisposition and polymorphism138, 139) (reviewed in Merola et al.,9) Schumacher et al.,10) and Pober et al.131)). Reduced bioavailability of nitric oxide (NO) due to endothelial dysfunction is recognized as contributing to the development of intimal thickening in mice and humans.140, 141)

Journal of Pediatric Cardiology and Cardiac Surgery 2(1): 1-19 (2018)

Fig. 2 Integrated model of CAV pathogenesis

The primary event in the development of CAV is host T cell recognition of alloantigens presented by graft endothelial cells (EC). The activated T cells secretes INF-γ, which acts on the EC to promote further recruitment of T cells and acts upon smooth muscles cells (SMC) to cause proliferation, resulting in intimal expansion and diffuse stenosis characteristic of CAV. Various risk factors include (1) cytomegalovirus (CMV) infection, (2) ischemia/reperfusion (I/R) injury, (3) innate immune signals, such as damage-associated molecular patterns (DAMPs), and (4) donor-specific antibody (DSA). (From Pober et al. Arteroscler Thromb Vasc Biol 2014; 34: 1609–1614).

There is no proven medical intervention to prevent CAV or to reverse established disease; potential prevention of CAV depends primarily on the understanding of underlying molecular and cellular mechanisms.124) Modifications in immunosuppressive therapies have been proposed to reduce the risk of CAV. Newly introduced mammalian targets of rapamycin (mTOR) inhibitors, sirolimus and everolimus, have been shown to attenuate the development of CAV.142) Further basic research in understanding pathogenesis of CAV should be encouraged for better management for this life-threatening condition.

Post-transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorders (PTLD) encompass a broad spectrum of lymphoid disorders that share qualities of both infection and malignant disease, ranging from benign polyclonal hyperplasia to malignant monoclonal neoplasms (lymphoma).143) They are most often B-cell origin and commonly contain EBV.143) Webber and his colleagues reported the data of a multicenter study from the PHTS in which 5% of 1184 primary transplant recipients (6.1±5.7 years old) developed PTLD at 23.9 ±20 months after heart transplant.144) The most common sites were gastrointestinal (39%), lung or airway (25%), and cervical adenopathy (18%). At 3 years after diagnosis, only two-thirds of patients were alive, with about one-fourth of patients dying within the first year after diagnosis.144) Manlhiot et al. reported that 13% of 173 post-transplant children (median 4.1 years) developed PTLD at a median age of 7 years (10 months to 16 years). Freedom of death or disease relapse was 72%, 58%, and 30% at 1, 3, and 5 years after diagnosis, respectively.11)

Because of its rapid progression with high morbidity and mortality after diagnosis, early recognition of PTLD is critical. Prolonged constitutional symptoms, including persistent fever, diaphoresis, and/or weight loss in association with localized symptoms (mainly respiratory and gastrointestinal) should raise alarm for possible PTLD.12, 145) A multidisciplinary approach among the pediatric transplant cardiologist, oncologist, radiologist, and pathologist is warranted to make a prompt and accurate diagnosis of PTLD. Risk stratification with EBV status, i.e., transplant of EBV(+) donors into EBV(−) recipients, elevated EBV load in the peripheral blood, increased dose of ATG, and transplant age have been proposed as important variables to predict PTLD.146, 147) For treatment, reduction of immunosuppression (RI), a 50% to 75% dose reduction, is advised as an initial therapeutic approach, especially for early PTLD. However, RI by itself may lead to potential rejection, as 61% (19 of 31) developed rebound acute cellular rejection during the first 6 months after diagnosis of polymorphic PTLD.144) The use of mTOR inhibitors and antimetabolites (azathioprine and mycophenolate mofetil) allows concomitant reduction of CNI, but their clinical efficacy in suppressing PTLD needs to be further investigated.148) Low-dose cytotoxic chemotherapy may be introduced in combination with rituximab and anti-B cell antibody with reasonable outcome.149)

Renal Dysfunction

Renal dysfunction or acute kidney injury (AKI) is a common complication before and after heart transplant; 73% of heart transplant recipients develop AKI postoperatively.150) Renal dysfunction is frequently seen in advanced heart failure, whereas myocardial dysfunction is induced by worsening renal failure, suggesting bidirectional pathological interaction between heart and kidney to deteriorate circulatory homeostasis (cardio-renal syndrome).151, 152) Post-transplant renal dysfunction comprises 1) pre-transplant baseline renal dysfunction associated with advanced heart failure,153) 2) AKI following cardiac surgery (especially, ischemia-reperfusion injury and low cardiac output),154) and 3) AKI and chronic kidney disease (CKD) due to nephrotoxic medications, especially CNI (cyclosporine and tacrolimus).155) On the contrary, Gupta et al. reported the some improvement of renal function in the acute phase (up to 20 days) after transplant in the majority of patients regardless of age and the underlying cardiac diagnosis, suggesting a certain positive effect of heart transplant in mitigating worsening of renal function.156) In a small institutional study, Chinnock et al. reported that the immunotherapy with sirolimus with reduced CNI improved renal function without increasing risk of rejection.84)

The relationship between AKI and CKD was studied by Hollander et al., who demonstrated that non-recovery from AKI was likely due to more advanced renal injury during an acute phase and was associated with the development of CKD within the first year.155) Post-transplant recipients with chronic renal insufficiency (CRI), defined as serum creatinine >2.5 mg/dL, were seen in 4% of patients at 5 years and nearly 12% of patients at 10 years, and were shown to have 9-fold increased risk of death when compared with patients without (CRI).157) Patients with late renal dysfunction demonstrated continued decline in renal function, and decreased estimated glomerular filtration rate (eGFR) at one year post-transplant was shown to predict late onset of renal dysfunction.13) Careful surveillance of these clinical markers is essential to identify early stage of CKD.

Conclusions

Pediatric heart transplant has been standardized as an established treatment option for medically refractory advanced heart failure with excellent outcome presented as 83% overall survival after 5 years of transplant.21) However, there are certain major unsolved problems that mitigate optimum outcome. First, wait-list mortality is still a serious problem, especially for infants, primarily due to supply-demand mismatch of donor hearts. ABO-incompatible transplant45) and the use of suboptimal donor hearts47, 48) have been trialed with reassuring outcomes. Second, transplant for CHD, the most common indication for heart transplant in children, has specific challenges, including complex anatomical reconstruction, longer bypass time and subsequent coagulopathy, allosensitization, increased pulmonary vascular resistance, and single ventricle physiology.54) Patients with failed Fontan, in particular, have the poorest post-transplant prognosis. Further research efforts are encouraged to understand the complex pathobiology of the Fontan circulation and other organ involvements.70) Lastly, long-term immunosuppression inevitably induces chronic instability of the host immune system including infections, CAV, and PTLD, whereas insufficient immunosuppression can cause rejection, which all could be responsible for morbidity and mortality. In addition, the host immune system in children is much different from that in adults. Endeavors in solid organ transplant medicine would provide us with an ideal medium where basic science meets clinical science to create an innovation.158) This complex, yet exciting, new arena in the field of pediatric cardiology merits further enthusiastic and multidisciplinary scientific efforts for an improved future for children with end-stage heart failure.

謝辞Acknowledgments

The authors thank Dr. Samuel Gidding for his critical reading of the manuscript.

Conflict of Interest

None.

引用文献References

1) Singh TP, Edwards LB, Kirk R, et al: Era effect on post-transplant survival adjusted for baseline risk factors in pediatric heart transplant recipients. J Heart Lung Transplant 2009; 28: 1285–1291

2) Jeffries H, Bird G, Law Y, et al: Complications related to the transplantation of thoracic organs: Consensus definitions from the Multi-Societal Database Committee for Pediatric and Congenital Heart Disease. Cardiol Young 2008; 18 Suppl 2: 265–270

3) Kindel SJ, Everitt MD: A contemporary review of paediatric heart transplantation and mechanical circulatory support. Cardiol Young 2016; 26: 851–859

4) Zangwill S: Five decades of pediatric heart transplantation: Challenges overcome, challenges remaining. Curr Opin Cardiol 2017; 32: 69–77

5) Mah D, Singh TP, Thiagarajan RR, et al: Incidence and risk factors for mortality in infants awaiting heart transplantation in the USA. J Heart Lung Transplant 2009; 28: 1292–1298

6) Castleberry C, Ryan TD, Chin C: Transplantation in the highly sensitized pediatric patient. Circulation 2014; 129: 2313–2319

7) Mahle WT, Tresler MA, Edens RE, et al: Pediatric Heart Transplant Study Group: Allosensitization and outcomes in pediatric heart transplantation. J Heart Lung Transplant 2011; 30: 1221–1227

8) George JF, Taylor DO, Blume ED, et al: Minimizing infection and rejection death: Clues acquired from 19 years of multi-institutional cardiac transplantation data. J Heart Lung Transplant 2011; 30: 151–157

9) Merola J, Jane-Wit DD, Pober JS: Recent advances in allograft vasculopathy. Curr Opin Organ Transplant 2017; 22: 1–7

10) Schumacher KR, Gajarski RJ, Urschel S: Pediatric coronary allograft vasculopathy—A review of pathogenesis and risk factors. Congenit Heart Dis 2012; 7: 312–323

11) Manlhiot C, Pollock-Barziv SM, Holmes C, et al: Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients. J Heart Lung Transplant 2010; 29: 648–657

12) Haynes SE, Saini S, Schowengerdt KO: Post-transplant lymphoproliferative disease and other malignancies after pediatric cardiac transplantation: An evolving landscape. Curr Opin Organ Transplant 2015; 20: 562–569

13) Feingold B, Zheng J, Law YM, et al: Pediatric Heart Transplant Study Investigators: Risk factors for late renal dysfunction after pediatric heart transplantation: A multi-institutional study. Pediatr Transplant 2011; 15: 699–705

14) Conway J, Manlhiot C, Kirk R, et al: Mortality and morbidity after retransplantation after primary heart transplant in childhood: An analysis from the registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2014; 33: 241–251

15) Mahle WT: Cardiac retransplantation in children. Pediatr Transplant 2008; 12: 274–280

16) Oliva M, Singh TP, Gauvreau K, et al: Impact of medication non-adherence on survival after pediatric heart transplantation in the U.S.A. J Heart Lung Transplant 2013; 32: 881–888

17) Savla J, Lin KY, Lefkowitz DS, et al: Adolescent age and heart transplantation outcomes in myocarditis or congenital heart disease. J Heart Lung Transplant 2014; 33: 943–949

18) Daly KP: Emerging science in paediatric heart transplantation: Donor allocation, biomarkers, and the quest for evidence-based medicine. Cardiol Young 2015; 25 Suppl 2: 117–123

19) Dodd DA: Pediatric heart failure and transplantation: Where are we in 2013? Curr Opin Pediatr 2013; 25: 553–560

20) Dipchand AI, Edwards LB, Kucheryavaya AY, et al: International Society of Heart and Lung Transplantation: The registry of the International Society for Heart and Lung Transplantation: Seventeenth official pediatric heart transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014; 33: 985–995

21) Dipchand AI, Kirk R, Mahle WT, et al: Ten yr of pediatric heart transplantation: A report from the Pediatric Heart Transplant Study. Pediatr Transplant 2013; 17: 99–111

22) Hsu DT, Lamour JM: Changing indications for pediatric heart transplantation: Complex congenital heart disease. Circulation 2015; 131: 91–99

23) Canter CE, Shaddy RE, Bernstein D, et al: American Heart Association Council on Cardiovascular Disease in the Young; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Cardiovascular Nursing; American Heart Association Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group: Indications for heart transplantation in pediatric heart disease: A scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 115: 658–676

24) Rosenthal D, Chrisant MR, Edens E, et al: International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. J Heart Lung Transplant 2004; 23: 1313–1333

25) Lamour JM, Kanter KR, Naftel DC, et al: Cardiac Transplant Registry Database; Pediatric Heart Transplant Study: The effect of age, diagnosis, and previous surgery in children and adults undergoing heart transplantation for congenital heart disease. J Am Coll Cardiol 2009; 54: 160–165

26) Kirklin JK: Current challenges in pediatric heart transplantation for congenital heart disease. Curr Opin Organ Transplant 2015; 20: 577–583

27) Chrisant MR, Naftel DC, Drummond-Webb J, et al: Pediatric Heart Transplant Study Group: Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: A multicenter study. J Heart Lung Transplant 2005; 24: 576–582

28) Everitt MD, Boyle GJ, Schechtman KB, et al: Pediatric Heart Transplant Study Investigators: Early survival after heart transplant in young infants is lowest after failed single-ventricle palliation: A multi-institutional study. J Heart Lung Transplant 2012; 31: 509–516

29) Shi WY, Saxena P, Yong MS, et al: Increasing complexity of heart transplantation in patients with congenital heart disease. Semin Thorac Cardiovasc Surg 2016; 28: 487–497

30) Pietra BA, Kantor PF, Bartlett HL, et al: Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy. Circulation 2012; 126: 1079–1086

31) Singh TP, Almond CS, Piercey G, et al: Current outcomes in US children with cardiomyopathy listed for heart transplantation. Circ Heart Fail 2012; 5: 594–601

32) Tsirka AE, Trinkaus K, Chen SC, et al: Improved outcomes of pediatric dilated cardiomyopathy with utilization of heart transplantation. J Am Coll Cardiol 2004; 44: 391–397

33) Dipchand AI, Naftel DC, Feingold B, et al: Pediatric Heart Transplant Study Investigators: Outcomes of children with cardiomyopathy listed for transplant: A multi-institutional study. J Heart Lung Transplant 2009; 28: 1312–1321

34) Kirk R, Naftel D, Hoffman TM, et al: Pediatric Heart Transplant Study Investigators: Outcome of pediatric patients with dilated cardiomyopathy listed for transplant: A multi-institutional study. J Heart Lung Transplant 2009; 28: 1322–1328

35) Gajarski R, Naftel DC, Pahl E, et al: Pediatric Heart Transplant Study Investigators: Outcomes of pediatric patients with hypertrophic cardiomyopathy listed for transplant. J Heart Lung Transplant 2009; 28: 1329–1334

36) Zangwill SD, Naftel D, L’Ecuyer T, et al: Pediatric Heart Transplant Study Investigators: Outcomes of children with restrictive cardiomyopathy listed for heart transplant: A multi-institutional study. J Heart Lung Transplant 2009; 28: 1335–1340

37) Webber SA, Lipshultz SE, Sleeper LA, et al: Pediatric Cardiomyopathy Registry Investigators: Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: A report from the Pediatric Cardiomyopathy Registry. Circulation 2012; 126: 1237–1244

38) Colvin-Adams M, Smith JM, Heubner BM, et al: OPTN/SRTR 2013 Annual Data Report: Heart. Am J Transplant 2015; 15 Suppl 2: 1–28

39) Blume ED, VanderPluym C, Lorts A, et al: Second annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report: Pre-implant characteristics and outcomes. J Heart Lung Transplant 2017

40) Peng DM, Qu Q, McDonald N, et al: Impact of the 18th birthday on waitlist outcomes among young adults listed for heart transplant: A regression discontinuity analysis. J Heart Lung Transplant 2017; 36: 1185–1191

41) Jeewa A, Manlhiot C, Kantor PF, et al: Risk factors for mortality or delisting of patients from the pediatric heart transplant waiting list. J Thorac Cardiovasc Surg 2014; 147: 462–468

42) Almond CSD, Thiagarajan RR, Piercey GE, et al: Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009; 119: 717–727

43) Mital S, Addonizio LJ, Lamour JM, et al: Outcome of children with end-stage congenital heart disease waiting for cardiac transplantation. J Heart Lung Transplant 2003; 22: 147–153

44) Feingold B, Park SY, Comer DM, et al: Outcomes after listing with a requirement for a prospective crossmatch in pediatric heart transplantation. J Heart Lung Transplant 2013; 32: 56–62

45) Almond CS, Gauvreau K, Thiagarajan RR, et al: Impact of ABO-incompatible listing on wait-list outcomes among infants listed for heart transplantation in the United States: A propensity analysis. Circulation 2010; 121: 1926–1933

46) Urschel S, Larsen IM, Kirk R, et al: ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits. J Heart Lung Transplant 2013; 32: 285–292

47) Rossano JW, Lin KY, Paridon SM, et al: Pediatric heart transplantation from donors with depressed ventricular function: An analysis of the United Network of Organ Sharing Database. Circ Heart Fail 2013; 6: 1223–1229

48) Easterwood R, Singh RK, McFeely ED, et al: Pediatric cardiac transplantation using hearts previously refused for quality: A single center experience. Am J Transplant 2013; 13: 1484–1490

49) Singh TP, Almond CS, Piercey G, et al: Risk stratification and transplant benefit in children listed for heart transplant in the United States. Circ Heart Fail 2013; 6: 800–808

50) Feingold B, Webber SA, Bryce CL, et al: Comparison of listing strategies for allosensitized heart transplant candidates requiring transplant at high urgency: A decision model analysis. Am J Transplant 2015; 15: 427–435

51) Khush KK, Menza R, Nguyen J, et al: Donor predictors of allograft use and recipient outcomes after heart transplantation. Circ Heart Fail 2013; 6: 300–309

52) Smits JM, De Pauw M, de Vries E, et al: Donor scoring system for heart transplantation and the impact on patient survival. J Heart Lung Transplant 2012; 31: 387–397

53) Dipchand AI, Rossano JW, Edwards LB, et al: International Society for Heart and Lung Transplantation: The Registry of the International Society for Heart and Lung Transplantation: Eighteenth official pediatric heart transplantation report—2015; focus theme: Early graft failure. J Heart Lung Transplant 2015; 34: 1233–1243

54) Kirklin JK, Carlo WF, Pearce FB: Current expectations for cardiac transplantation in patients with congenital heart disease. World J Pediatr Congenit Heart Surg 2016; 7: 685–695

55) Salis S, Mazzanti VV, Merli G, et al: Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth 2008; 22: 814–822

56) Al-Sarraf N, Thalib L, Hughes A, et al: Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. Int J Surg 2011; 9: 104–109

57) Hasan A, Au J, Hamilton JR, et al: Orthotopic heart transplantation for congenital heart disease. Technical considerations. Eur J Cardiothorac Surg 1993; 7: 65–70

58) Vouhe PR, Tamisier D, Le Bidois J, et al: Pediatric cardiac transplantation for congenital heart defects: Surgical considerations and results. Ann Thorac Surg 1993; 56: 1239–1247

59) Raffini L, Witmer C: Pediatric transplantation: Managing bleeding. J Thromb Haemost 2015; 13 Suppl 1: S362–S369

60) Krishnan US, Lamour JM, Hsu DT, et al: Management of aortopulmonary collaterals in children following cardiac transplantation for complex congenital heart disease. J Heart Lung Transplant 2004; 23: 564–569

61) Rossano JW, Morales DL, Zafar F, et al: Impact of antibodies against human leukocyte antigens on long-term outcome in pediatric heart transplant patients: An analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg 2010; 140: 694–699, 699.e1–699.e2

62) Feingold B, Bowman P, Zeevi A, et al: Survival in allosensitized children after listing for cardiac transplantation. J Heart Lung Transplant 2007; 26: 565–571

63) Meyer SR, Campbell PM, Rutledge JM, et al: Use of an allograft patch in repair of hypoplastic left heart syndrome may complicate future transplantation. Eur J Cardiothorac Surg 2005; 27: 554–560

64) Hooper DK, Hawkins JA, Fuller TC, et al: Panel-reactive antibodies late after allograft implantation in children. Ann Thorac Surg 2005; 79: 641–644, discussion, 645

65) Kobashigawa J, Mehra M, West L, et al: Consensus Conference Participants: Report from a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant 2009; 28: 213–225

66) Pollock-BarZiv SM, den Hollander N, Ngan BY, et al: Pediatric heart transplantation in human leukocyte antigen sensitized patients: Evolving management and assessment of intermediate-term outcomes in a high-risk population. Circulation 2007; 116 Suppl: I172–I178

67) Jacobs JP, Quintessenza JA, Boucek RJ, et al: Pediatric cardiac transplantation in children with high panel reactive antibody. Ann Thorac Surg 2004; 78: 1703–1709

68) Jacobs ML, Rychik J, Rome JJ, et al: Early reduction of the volume work of the single ventricle: The hemi-Fontan operation. Ann Thorac Surg 1996; 62: 456–461, discussion, 461–462

69) Khairy P, Fernandes SM, Mayer JE Jr., et al: Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008; 117: 85–92

70) Bernstein D, Naftel D, Chin C, et al: Pediatric Heart Transplant Study: Outcome of listing for cardiac transplantation for failed Fontan: A multi-institutional study. Circulation 2006; 114: 273–280

71) Griffiths ER, Kaza AK, Wyler von Ballmoos MC, et al: Evaluating failing Fontans for heart transplantation: Predictors of death. Ann Thorac Surg 2009; 88: 558–563, discussion, 563–564

72) Michielon G, van Melle JP, Wolff D, et al: Favourable mid-term outcome after heart transplantation for late Fontan failure. Eur J Cardiothorac Surg 2015; 47: 665–671

73) Voeller RK, Epstein DJ, Guthrie TJ, et al: Trends in the indications and survival in pediatric heart transplants: A 24-year single-center experience in 307 patients. Ann Thorac Surg 2012; 94: 807–815, discussion, 815–816

74) Davies RR, Sorabella RA, Yang J, et al: Outcomes after transplantation for “failed” Fontan: A single-institution experience. J Thorac Cardiovasc Surg 2012; 143: 1183–1192.e4

75) Simpson KE, Pruitt E, Kirklin JK, et al: Fontan patient survival after pediatric heart transplantation has improved in the current era. Ann Thorac Surg 2017; 103: 1315–1320

76) D’Souza BA, Fuller S, Gleason LP, et al: Single-center outcomes of combined heart and liver transplantation in the failing Fontan. Clin Transplant 2017; 31: 31

77) Soderlund C, Radegran G: Immunosuppressive therapies after heart transplantation—The balance between under- and over-immunosuppression. Transplant Rev (Orlando) 2015; 29: 181–189

78) Costanzo MR, Dipchand A, Starling R, et al:International Society of Heart and Lung Transplantation Guidelines: The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29: 914–956

79) Di Filippo S, Boissonnat P, Sassolas F, et al: Rabbit antithymocyte globulin as induction immunotherapy in pediatric heart transplantation. Transplantation 2003; 75: 354–358

80) Grundy N, Simmonds J, Dawkins H, et al: Pre-implantation basiliximab reduces incidence of early acute rejection in pediatric heart transplantation. J Heart Lung Transplant 2009; 28: 1279–1284

81) Singh TP, Faber C, Blume ED, et al: Safety and early outcomes using a corticosteroid-avoidance immunosuppression protocol in pediatric heart transplant recipients. J Heart Lung Transplant 2010; 29: 517–522

82) Marshall CD, Richmond ME, Singh RK, et al: A comparison of traditional versus contemporary immunosuppressive regimens in pediatric heart recipients. J Pediatr 2013; 163: 132–136

83) Auerbach SR, Gralla J, Campbell DN, et al: Steroid avoidance in pediatric heart transplantation results in excellent graft survival. Transplantation 2014; 97: 474–480

84) Chinnock TJ, Shankel T, Deming D, et al: Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients. Pediatr Transplant 2011; 15: 746–749

85) Balfour IC, Srun SW, Wood EG, et al: Early renal benefit of rapamycin combined with reduced calcineurin inhibitor dose in pediatric heart transplantation patients. J Heart Lung Transplant 2006; 25: 518–522

86) Irving CA, Webber SA: Immunosuppression therapy for pediatric heart transplantation. Curr Treat Options Cardiovasc Med 2010; 12: 489–502

87) Tan CD, Baldwin WM 3rd, Rodriguez ER: Update on cardiac transplantation pathology. Arch Pathol Lab Med 2007; 131: 1169–1191

88) Gates KV, Pereira NL, Griffiths LG: Cardiac non-human leukocyte antigen identification: Techniques and troubles. Front Immunol 2017; 8: 1332

89) Dipchand AI, Kirk R, Edwards LB, et al: International Society for Heart and Lung Transplantation: The registry of the International Society for Heart and Lung Transplantation: Sixteenth official pediatric heart transplantation report—2013; focus theme: Age. J Heart Lung Transplant 2013; 32: 979–988

90) Castleberry C, Pruitt E, Ameduri R, et al: Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi-institutional study. J Heart Lung Transplant 2017

91) Ameduri RK, Zheng J, Schechtman KB, et al: Has late rejection decreased in pediatric heart transplantation in the current era? A multi-institutional study. J Heart Lung Transplant 2012; 31: 980–986

92) Ringewald JM, Gidding SS, Crawford SE, et al: Nonadherence is associated with late rejection in pediatric heart transplant recipients. J Pediatr 2001; 139: 75–78

93) Kindel SJ, Hsu HH, Hussain T, et al: Multimodality noninvasive imaging in the monitoring of pediatric heart transplantation. J Am Soc Echocardiogr 2017; 30: 859–870

94) Kennel PJ, Schulze PC: Novel biomarker approaches for managing patients with cardiac transplantation. Curr Heart Fail Rep 2015; 12: 328–332

95) Crespo-Leiro MG, Barge-Caballero G, Couto-Mallon D: Noninvasive monitoring of acute and chronic rejection in heart transplantation. Curr Opin Cardiol 2017; 32: 308–315

96) Patel PC, Hill DA, Ayers CR, et al: High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant. Circ Heart Fail 2014; 7: 463–469

97) Arnau-Vives MA, Almenar L, Hervas I, et al: Predictive value of brain natriuretic peptide in the diagnosis of heart transplant rejection. J Heart Lung Transplant 2004; 23: 850–856

98) De Vlaminck I, Valantine HA, Snyder TM, et al: Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med 2014; 6: 241ra77

99) Hidestrand M, Tomita-Mitchell A, Hidestrand PM, et al: Highly sensitive noninvasive cardiac transplant rejection monitoring using targeted quantification of donor-specific cell-free deoxyribonucleic acid. J Am Coll Cardiol 2014; 63: 1224–1226

100) Duong Van Huyen JP, Tible M, Gay A, et al: MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J 2014; 35: 3194–3202

101) Badano LP, Miglioranza MH, Edvardsen T, et al: Document reviewers: European Association of Cardiovascular Imaging/Cardiovascular Imaging Department of the Brazilian Society of Cardiology recommendations for the use of cardiac imaging to assess and follow patients after heart transplantation. Eur Heart J Cardiovasc Imaging 2015; 16: 919–948

102) Flanagan R, Cain N, Tatum GH, et al: Left ventricular myocardial performance index change for detection of acute cellular rejection in pediatric heart transplantation. Pediatr Transplant 2013; 17: 782–786

103) Lunze FI, Colan SD, Gauvreau K, et al: Tissue Doppler imaging for rejection surveillance in pediatric heart transplant recipients. J Heart Lung Transplant 2013; 32: 1027–1033

104) Ambardekar AV, Alluri N, Patel AC, et al: Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation. J Am Soc Echocardiogr 2015; 28: 478–485

105) Butler CR, Savu A, Bakal JA, et al: Correlation of cardiovascular magnetic resonance imaging findings and endomyocardial biopsy results in patients undergoing screening for heart transplant rejection. J Heart Lung Transplant 2015; 34: 643–650

106) Fishman JA, Rubin RH: Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751

107) Hollander SA, McElhinney DB, Almond CS, et al: Rehospitalization after pediatric heart transplantation: Incidence, indications, and outcomes. Pediatr Transplant 2017; 21: 21

108) Kulikowska A, Boslaugh SE, Huddleston CB, et al: Infectious, malignant, and autoimmune complications in pediatric heart transplant recipients. J Pediatr 2008; 152: 671–677

109) Rostad CA, Wehrheim K, Kirklin JK, et al: Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes. J Heart Lung Transplant 2017; 36: 996–1003

110) Vanderlaan RD, Manlhiot C, Edwards LB, et al: Risk factors for specific causes of death following pediatric heart transplant: An analysis of the registry of the International Society of Heart and Lung Transplantation. Pediatr Transplant 2015; 19: 896–905

111) Gennery AR, Cant AJ, Spickett GP, et al: Effect of immunosuppression after cardiac transplantation in early childhood on antibody response to polysaccharide antigen. Lancet 1998; 351: 1778–1781

112) Tran L, Hebert D, Dipchand A, et al: Invasive pneumococcal disease in pediatric organ transplant recipients: A high-risk population. Pediatr Transplant 2005; 9: 183–186

113) Rubin RH: Prevention and treatment of cytomegalovirus disease in heart transplant patients. J Heart Lung Transplant 2000; 19: 731–735

114) Durante-Mangoni E, Andini R, Pinto D, et al: Effect of the immunosuppressive regimen on the incidence of cytomegalovirus infection in 378 heart transplant recipients: A single centre, prospective cohort study. J Clin Virol 2015; 68: 37–42

115) Rabin AS, Givertz MM, Couper GS, et al: Risk factors for invasive fungal disease in heart transplant recipients. J Heart Lung Transplant 2015; 34: 227–232

116) Zaoutis TE, Webber S, Naftel DC, et al: Pediatric Heart Transplant Study Investigators: Invasive fungal infections in pediatric heart transplant recipients: Incidence, risk factors, and outcomes. Pediatr Transplant 2011; 15: 465–469

117) Kobayashi D, Du W, L’Ecuyer TJ: Predictors of cardiac allograft vasculopathy in pediatric heart transplant recipients. Pediatr Transplant 2013; 17: 436–440

118) Kirk R, Edwards LB, Kucheryavaya AY, et al: The Registry of the International Society for Heart and Lung Transplantation: Thirteenth official pediatric heart transplantation report—2010. J Heart Lung Transplant 2010; 29: 1119–1128

119) Lund LH, Edwards LB, Kucheryavaya AY, et al: International Society for Heart and Lung Transplantation: The registry of the International Society for Heart and Lung Transplantation: Thirtieth official adult heart transplant report—2013; focus theme: Age. J Heart Lung Transplant 2013; 32: 951–964

120) Lu WH, Palatnik K, Fishbein GA, et al: Diverse morphologic manifestations of cardiac allograft vasculopathy: A pathologic study of 64 allograft hearts. J Heart Lung Transplant 2011; 30: 1044–1050

121) Jeewa A, Dreyer WJ, Kearney DL, et al: The presentation and diagnosis of coronary allograft vasculopathy in pediatric heart transplant recipients. Congenit Heart Dis 2012; 7: 302–311

122) Price JF, Towbin JA, Dreyer WJ, et al: Symptom complex is associated with transplant coronary artery disease and sudden death/resuscitated sudden death in pediatric heart transplant recipients. J Heart Lung Transplant 2005; 24: 1798–1803

123) Mehra MR, Crespo-Leiro MG, Dipchand A, et al: International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010. J Heart Lung Transplant 2010; 29: 717–727

124) Kindel SJ, Pahl E: Current therapies for cardiac allograft vasculopathy in children. Congenit Heart Dis 2012; 7: 324–335

125) Kindel SJ, Law YM, Chin C, et al: Improved detection of cardiac allograft vasculopathy: A multi-institutional analysis of functional parameters in pediatric heart transplant recipients. J Am Coll Cardiol 2015; 66: 547–557

126) Aiyagari R, Nika M, Gurney JG, et al: Association of pediatric heart transplant coronary vasculopathy with abnormal hemodynamic measures. Congenit Heart Dis 2011; 6: 128–133

127) Law Y, Boyle G, Miller S, et al: Restrictive hemodynamics are present at the time of diagnosis of allograft coronary artery disease in children. Pediatr Transplant 2006; 10: 948–952

128) Seki A, Fishbein MC: Predicting the development of cardiac allograft vasculopathy. Cardiovasc Pathol 2014; 23: 253–260

129) Neumann A, Napp LC, Kleeberger JA, et al: MicroRNA 628-5p as a novel biomarker for cardiac allograft vasculopathy. Transplantation 2017; 101: e26–e33

130) Yacoub-Youssef H, Marcheix B, Calise D, et al: Chronic vascular rejection: Histologic comparison between two murine experimental models. Transplant Proc 2005; 37: 2886–2887

131) Pober JS, Jane-wit D, Qin L, et al: Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy. Arterioscler Thromb Vasc Biol 2014; 34: 1609–1614

132) Ticehurst EH, Molina MR, Frank R, et al: Antibody-mediated rejection in heart transplant patients: Long-term follow up of patients with high levels of donor-directed anti-DQ antibodies. Clin Transpl 2011; 409–414

133) Weis M, Cooke JP: Cardiac allograft vasculopathy and dysregulation of the NO synthase pathway. Arterioscler Thromb Vasc Biol 2003; 23: 567–575

134) Valantine HA: Cardiac allograft vasculopathy: Central role of endothelial injury leading to transplant “atheroma”. Transplantation 2003; 76: 891–899

135) Rahmani M, Cruz RP, Granville DJ, et al: Allograft vasculopathy versus atherosclerosis. Circ Res 2006; 99: 801–815

136) Mahle WT, Vincent RN, Berg AM, et al: Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant 2005; 24: 63–66

137) Koskinen PK, Kallio EA, Tikkanen JM, et al: Cytomegalovirus infection and cardiac allograft vasculopathy. Transpl Infect Dis 1999; 1: 115–126

138) Gallardo ME, Garcia-Pavia P, Chamorro R, et al: Mitochondrial haplogroups associated with end-stage heart failure and coronary allograft vasculopathy in heart transplant patients. Eur Heart J 2012; 33: 346–353

139) Benza RL, Grenett HE, Bourge RC, et al: Gene polymorphisms for plasminogen activator inhibitor-1/tissue plasminogen activator and development of allograft coronary artery disease. Circulation 1998; 98: 2248–2254

140) Tanaka M, Sydow K, Gunawan F, et al: Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation 2005; 112: 1549–1556

141) Potena L, Fearon WF, Sydow K, et al: Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: Modulation by sirolimus. Transplantation 2008; 85: 827–833

142) Eisen HJ, Tuzcu EM, Dorent R, et al: RAD B253 Study Group: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349: 847–858

143) Nalesnik MA: Clinical and pathological features of post-transplant lymphoproliferative disorders (PTLD). Springer Semin Immunopathol 1998; 20: 325–342

144) Webber SA, Naftel DC, Fricker FJ, et al: Pediatric Heart Transplant Study: Lymphoproliferative disorders after paediatric heart transplantation: A multi-institutional study. Lancet 2006; 367: 233–239

145) Lim GY, Newman B, Kurland G, et al: Posttransplantation lymphoproliferative disorder: Manifestations in pediatric thoracic organ recipients. Radiology 2002; 222: 699–708

146) Chinnock R, Webber SA, Dipchand AI, et al: Pediatric Heart Transplant Study: A 16-year multi-institutional study of the role of age and EBV status on PTLD incidence among pediatric heart transplant recipients. Am J Transplant 2012; 12: 3061–3068

147) Schubert S, Abdul-Khaliq H, Lehmkuhl HB, et al: Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients. Pediatr Transplant 2009; 13: 54–62

148) Al-Mansour Z, Nelson BP, Evens AM: Post-transplant lymphoproliferative disease (PTLD): Risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep 2013; 8: 173–183

149) Gupta S, Fricker FJ, Gonzalez-Peralta RP, et al: Post-transplant lymphoproliferative disorder in children: Recent outcomes and response to dual rituximab/low-dose chemotherapy combination. Pediatr Transplant 2010; 14: 896–902

150) MacDonald C, Norris C, Alton GY, et al: Western Canadian Complex Pediatric Therapies Follow-Up Group: Acute kidney injury after heart transplant in young children: Risk factors and outcomes. Pediatr Nephrol 2016; 31: 671–678

151) Ronco C, Haapio M, House AA, et al: Cardiorenal syndrome. J Am Coll Cardiol 2008; 52: 1527–1539

152) Riley A, Gebhard DJ, Akcan-Arikan A: Acute kidney injury in pediatric heart failure. Curr Cardiol Rev 2016; 12: 121–131

153) Price JF, Mott AR, Dickerson HA, et al: Worsening renal function in children hospitalized with decompensated heart failure: Evidence for a pediatric cardiorenal syndrome? Pediatr Crit Care Med 2008; 9: 279–284

154) Toth R, Breuer T, Cserep Z, et al: Acute kidney injury is associated with higher morbidity and resource utilization in pediatric patients undergoing heart surgery. Ann Thorac Surg 2012; 93: 1984–1990

155) Hollander SA, Montez-Rath ME, Axelrod DM, et al: Recovery from acute kidney injury and ckd following heart transplantation in children, adolescents, and young adults: A retrospective cohort study. Am J Kidney Dis 2016; 68: 212–218

156) Gupta P, Rettiganti M, Gossett JM, et al: Longitudinal renal function in pediatric heart transplant recipients: 20-years experience. Pediatr Transplant 2015; 19: 182–187

157) Lee CK, Christensen LL, Magee JC, et al: Pre-transplant risk factors for chronic renal dysfunction after pediatric heart transplantation: A 10-year national cohort study. J Heart Lung Transplant 2007; 26: 458–465

158) Law YM: Pathophysiology and diagnosis of allograft rejection in pediatric heart transplantation. Curr Opin Cardiol 2007; 22: 66–71

This page was created on 2018-03-28T11:00:14.679+09:00
This page was last modified on 2018-04-16T10:46:17.720+09:00


このサイトは(株)国際文献社によって運用されています。