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. 2026 Feb 16;12:100515. doi: 10.1016/j.jhlto.2026.100515

Long-term pediatric heart transplantation

Dimpna C Albert-Brotons 1,⁎, Mohammad AlHaddad 1, Mansour Alyami 1, Yasser Alali 1, Jehad Buraiki 1
PMCID: PMC12969388  PMID: 41809977

Abstract

Pediatric heart transplantation remains the definitive therapy for selected children with end-stage heart failure. Short-term outcomes over the last decades have shown excellent survival; however, long-term outcomes remain a challenge. Cardiac allograft vasculopathy is the leading cause of late graft failure and mortality beyond the first year post-transplant. Chronic rejection, renal dysfunction related to lifelong immunosuppression, and post-transplant lymphoproliferative disorders are major contributors to late morbidity. Adolescents face an increased risk of graft loss, largely driven by nonadherence, which is most frequent during the transition to adult care. Growth, neurodevelopment, and quality of life are generally favorable, especially in children who undergo transplantation at younger ages. Re-transplantation is an option when graft dysfunction, but it is associated with inferior outcomes compared with primary transplant.

This article explores detailed chronic post-transplant complications, including rejection, cardiac allograft vasculopathy (CAV), graft failure, infection, renal dysfunction, and malignancy, which influence long-term results. We highlight that a multidisciplinary approach with a special focus on the transition from pediatric to adult care, individualized immunosuppression, adherence support, cardiac rehabilitation, and early detection of graft vasculopathy is essential to further optimize long-term outcomes.

Keywords: Pediatric heart transplant, Rejection, Outcomes, Cardiac allograft vasculopathy, Surveillance

Background

Pediatric heart transplantation (PHTx) has become a successful therapy for selected children with end-stage heart failure, with significantly improved survival rates in the last few decades.While over 85%-90% of children survive their first year post-transplant based on international registries,1, 2 the management of long-term complications and graft loss over time remains a major challenge,3 mainly due to chronic allograft injury and immunosuppression-related morbidity. Recent technologies and medical advancements have progressively enhanced long-term outcomes; however, further development is needed to achieve better quality of life and survival rates in recipients.3

This article reviews the long-term outcomes in children after heart transplantation, with a particular focus on the immunobiology, surveillance, and advanced management of rejection and other complications that appear years post-transplantation. This review aims to explore the current evidence and real-world practices that have improved long-term follow-up in specialized PHTx programs worldwide. Long-term success requires a multidisciplinary approach to preserve graft function and the patient’s quality of life.

Epidemiological landscape and long-term survival

The evolution of PHTx has transformed it from an experimental procedure to a standard of care, with several hundred procedures performed annually worldwide. Indications are stratified by age: congenital heart disease (CHD) dominates in infants, whereas cardiomyopathy is the primary indication in older children and adolescents.4 The International Thoracic Organ Transplant Registry (ISHLT) reports a median survival of 20+ years for infants (<1 year), ∼17 years for children (1-10 years), and ∼13-15 years for adolescents (11-17 years)4 (Figure 1). There was no significant difference in survival between infants who received hearts from ABO-incompatible donors and those who received hearts from compatible donors.3, 4

Figure 1.

Figure 1

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Kaplan-Meier survival curve out to 25 years after pediatric heart transplantation stratified by age at the time of transplantation (used with permission from the Registry of the International Society of Heart and Lung Transplantation. J Heart Lung Transplant 2019:39:1015-1068).

Risk factors for graft loss after 3 years post-transplant, reported by Hayes et al2 from the Pediatric Heart Transplant Society database, were malignancy, rejection, cardiac allograft vasculopathy (CAV), age, CHD, female sex, and black race. Patients with CHD, particularly those with heterotaxy syndrome, have lower overall post-transplant survival rates.5 Surgical complexity and worse recipient status in patients with heterotaxy contribute to increased early mortality, and the mechanisms of inferior late survival deserve further attention.5 Excellent post-transplant outcomes have been achieved in patients with Fontan circulation failure in recent years using a comprehensive approach, including mechanical support and combined heart-liver transplantation, although early mortality remains higher than that in children with cardiomyopathy.6 Careful candidate selection and tailored surgical strategies for complex CHD are key to achieving acceptable mid- and long-term outcomes in this population.5

Extracorporeal membrane oxygenation as a bridge to transplant was initially used to stabilize patients on the waiting list, but it was associated with higher perioperative and long-term mortality, especially in children with CHD, even after adjusting for other risk factors. These findings have led to a preferential shift toward durable ventricular assist devices (VAD). Long-term VAD support generally has a similar long-term post-transplant survival rate to that of non-mechanical support cohorts.3, 7 Some authors have described a higher risk of sensitization before transplantation, with more rejection episodes occurring after transplantation.7

Mortality follows a bimodal pattern: an early peak (first year) from graft failure, rejection, and infection, followed by a constant late attrition phase driven primarily by CAV, CKD, and malignancy.2

Although the survival rates of PHTx continue to improve, patients remain vulnerable to severe and chronic complications post-surgery. The long-term complications and risks factors for mortality in children undergoing heart transplant could be reviewed in figures and tables from the ISHLT Registry’s online slide set available at https://ishltregistries.org/registries/slides.asp (summarized in Figure 2). Retransplantation is a feasible therapeutic option for selected patients with irreversible graft failure; however, outcomes are generally inferior to those of primary transplantation, emphasizing the importance of careful candidate selection and optimal timing.2, 3

Figure 2.

Figure 2

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Relative incidence of the leading causes of death for the most recent era January 2005 to June 2018, following pediatric heart transplant (used with permission from the Registry of the International Society of Heart and Lung Transplantation. J Heart Lung Transplant 2019:39:1015-1068).

Remarkable survival in the last decades depends on a complex, lifelong management paradigm in which the prevention, detection, and treatment of allograft rejection are the central pillars of post-transplant care. The first cornerstone of better post-transplant outcomes is patient and family education. Effective education on medication adherence,8, 9 lifestyle modifications,10 and regular follow-ups empower families to actively participate in care, reduce complications, and improve long-term survival.3, 11

The central challenge: Allograft rejection

Rejection is an immunological response of the recipient's immune system to the donor’s heart. Its management is the cornerstone of post-transplant care and is categorized into 2 often overlapping, pathophysiological entities12:

Acute cellular rejection

Acute cellular rejection (ACR) is a T-lymphocyte-mediated process directed against donor major histocompatibility complex antigens.

Pathophysiology: Recipient CD4+ T-helper cells recognize donor major histocompatibility complex antigens via direct (donor antigen-presenting cells) or indirect (recipient antigen-presenting cells) pathways. This triggers clonal expansion of CD8+ cytotoxic T-cells, which infiltrate the myocardium, causing myocyte injury and necrosis. The histological hallmark of this condition is a lymphocytic infiltrate associated with myocyte damage.12

Clinical Presentation: Patients may be asymptomatic (detected on surveillance biopsy) or present with nonspecific symptoms such as fatigue, low-grade fever, irritability, or anorexia. Signs include tachyarrhythmia, new-onset mitral regurgitation, hypotension, and heart failure. In infants, the presentation can be subtle, with only feeding intolerance or lethargy being reported.2

Diagnosis: Endomyocardial biopsy (EMB) is the gold standard for diagnosis. The ISHLT grading system (2005, revised 2013) was used.13

* 0R (no rejection): No lymphocytic infiltrate.

* 1R, Mild (formerly Grade 1A, 1B, 2): Focal or diffuse interstitial infiltrates without myocyte injury.

* 2R, Moderate (formerly Grade 3A): Multifocal aggressive infiltrates with associated myocyte damage.

* 3R, Severe (formerly Grade 3B, 4): Diffuse, aggressive infiltrate with multifocal myocyte damage ± edema, hemorrhage, and vasculitis.

Treatment: For asymptomatic, low-grade (1R) rejection, augmentation of oral immunosuppression may suffice. For clinically significant rejection (≥2R), first-line therapy is pulsed intravenous methylprednisolone (e.g., 10-20 mg/kg/day for 3-5 days). Severe or hemodynamically compromising rejection requires more potent T-cell depletion therapy with polyclonal anti-thymocyte globulin or the monoclonal anti-CD3 antibody muromonab-CD3 (OKT3, now rarely used).13

Antibody-mediated rejection

Antibody-mediated rejection (AMR), or humoral rejection, is an antibody-driven process that is increasingly recognized as a major contributor to late graft dysfunction and CAV.14, 15

Pathophysiology: Preformed or de novo donor-specific antibodies (DSAs), primarily against donor HLA class I or II molecules, bind to the vascular endothelium of the allograft. These triggers complement activation (membrane attack complex formation, C4d deposition) and Fc-receptor-mediated recruitment of macrophages and natural killer cells, leading to endothelial activation, vascular inflammation, and myocardial dysfunction without a significant lymphocytic infiltrate.16

Clinical Presentation: Can be acute and severe, mimicking ACR with hemodynamic compromise, or indolent and subclinical, presenting only as a gradual decline in ventricular function or as a precursor to CAV.

Diagnosis: Requires a multifaceted approach, as per the ISHLT guidelines. Diagnosis is based on a combination of16, 17:

  • 1.

    Clinical Allograft Dysfunction: Unexplained reduction in ejection fraction.

  • 2.

    Histologic Findings (pAMR grading): Capillary endothelial changes (swelling, detachment), intravascular macrophage accumulation, and/or neutrophilic margination. Myocyte necrosis is typically absent unless it is severe.

  • 3.

    Immunopathological Evidence: Positive immunofluorescence or immunohistochemistry for the complement split product C4d in the myocardial capillaries. CD68 staining highlighted the presence of intravascular macrophages.

  • 4.

    Serological Evidence: Presence of circulating DSAs detected using solid-phase assays (e.g., Luminex).

Grading is pAMR 0 (negative), 1 (subclinical, histologic/immunologic findings only), 2 (clinically significant), or 3 (severe).16

Treatment: AMR is more resistant to conventional anti-cellular therapy and requires a multimodal approach aimed at removing circulating antibodies, inhibiting antibody production, and blocking the complement system. First-line strategies typically include Plasmapheresis or Immunoadsorption (to remove circulating DSAs); Intravenous Immunoglobulin (IVIG)(modulates immune response, neutralizes antibodies) and Rituximab (anti-CD20) (depletes B-cells, reducing antibody production).17, 18

For refractory or severe cases, second-line agents include18: Bortezomib (a proteasome inhibitor that targets plasma cells, the source of antibodies)19; Eculizumab/Ravulizumab (Monoclonal antibodies that inhibit terminal complement-C5, preventing membrane attack complex formation); Daratumumab (anti-CD38) (an emerging therapy targeting plasma cells, showing promise in severe, refractory AMR).20

Noninvasive surveillance and emerging diagnostics

While EMB remains the cornerstone of diagnosis,14, 21 noninvasive tools are evolving to reduce the frequency of biopsies and provide complementary data.

  • −

    Gene Expression Profiling (e.g., AlloMap) measures the expression of a set of peripheral blood mononuclear cell genes associated with rejection. A low score has a high negative predictive value for moderate/severe ACR, potentially avoiding biopsies in stable, low-risk patients,22, 23 however its utility in AMR is limited. Ongoing efforts are being made to validate these markers as clinical prediction tools.18

  • •

    Donor-Derived Cell-Free DNA (dd-cfDNA): Measures the fraction of cell-free DNA in the recipient's blood that originates from the donor organ. Elevated levels (>0.2%-0.5%) are a sensitive, although not specific, marker of allograft injury from rejection (both ACR and AMR) or infection. It serves as a "liquid biopsy" to trigger further investigation.24, 25

Chronic rejection and long-term graft injury

Chronic rejection is the central mechanism underlying late graft failure after PHTx. It is characterized by sustained immune-mediated injury involving both cellular and humoral pathways, leading to progressive vascular and myocardial injuries.21, 24, 25, 26, 27, 28 CAV and chronic graft dysfunction should be understood as interrelated phenotypes within the spectrum of chronic graft injury.

Cardiac allograft vasculopathy: The epitome of chronic injury

CAV is a progressive form of diffuse coronary artery disease that affects transplanted hearts and is the leading cause of late post-transplant mortality in heart transplant recipients. CAV affects approximately 10%-15% of PHTx recipients within 5 years post-transplant, with the incidence increasing over time. By 10 years post-transplant, the prevalence of CAV rises to 30%-50%.29, 30

Pathophysiology: A final common pathway for injuries While chronic alloimmune damage (from both subclinical ACR and AMR) is the primary instigator, non-immune factors (CMV infection, hypertension, dyslipidemia, and ischemia-reperfusion injury)25, 26 critically accelerate the process.30 It is characterized by diffuse concentric intimal hyperplasia affecting the epicardial and intramural vessels of the coronary arteries.

Surveillance and Management: Surveillance relies on annual angiography ± intravascular ultrasound (IVUS)31, 32 or optical coherence tomography (OCT).33, 34 IVUS and OCT are intracoronary imaging techniques. Both are performed during coronary angiography using dedicated intracoronary catheters. IVUS uses high-frequency ultrasound to obtain cross-sectional images of coronary arteries. OCT uses near-infrared light to generate detailed cross-sectional images of the coronary artery walls. These modalities allow for earlier detection of intimal thickening and microstructural changes than angiography alone, supporting timely risk stratification and therapeutic adjustments. OCT has demonstrated a higher CAV detection rate of CAV compared to coronary angiography.34

Management is preventive: optimal immunosuppression to minimize rejection, strict control of cardiovascular risk factors, and the use of mTOR inhibitors (sirolimus/everolimus) for their antiproliferative effects in established CAV.35

Chronic rejection-related graft dysfunction

Chronic rejection-related graft dysfunction reflects progressive myocardial injury and fibrosis driven by sustained low-grade alloimmune activation, endothelial inflammation, and interstitial remodeling. This phenotype may coexist with CAV but can also occur in patients with minimal epicardial coronary disease. Chronic rejection leads to progressive myocardial injury and fibrosis, resulting in diastolic and systolic graft dysfunction. This phenotype may occur independently of overt coronary disease and often precedes the development of heart failure.21

The clinical presentation is often insidious and may include reduced exercise tolerance, fatigue, poor growth, and arrhythmias. Echocardiography remains the first-line diagnostic tool, and global longitudinal strain by speckle-tracking echocardiography can identify subclinical dysfunction before a decline in ejection fraction.36 Buddhe et al37 published speckle-tracking echocardiography imaging correlate better with gold standard pulmonay capillary wedge pressure measurement than traditional echocardiographic parameters (study of a total of 50 recipients undergoing routine cardiac catheterization post heart transplant). Pediatric patients with coronary artery disease had a significantly higher mitral early diastolic velocity-to-strain rate ratio during early left ventricular filling than those without the disease. It is important to highlight that abnormalities in longitudinal left ventricular systolic function may be more common than previously thought in PHTx recipients without acute graft rejection.37

Cardiac magnetic resonance imaging may support the assessment of myocardial fibrosis38 and help characterize graft dysfunction. No curative treatment exists for patients with progressive graft dysfunction requiring re-transplantation during follow-up.27, 29

Other long-term complications

Infections

Infections remain a major cause of morbidity and mortality in the pre- and post-transplant processes, with a higher incidence of death in the first year and a significant reduction in the long term, although they remain among the top 5 causes of death.28 The risk of long-term infection depends on the level of immunosuppression and is higher during rejection episodes. Long-term prophylactic strategies include cytomegalovirus-directed antiviral prophylaxis in high-risk recipients, Pneumocystis jirovecii prophylaxis, and vaccination according to transplant-specific schedules. CMV prophylaxis during rejection episodes may be required, especially if thymoglobulin and/or steroid boluses are administered to the patients.39

Children bridged to transplantation with VADs or extracorporeal membrane oxygenation represent a higher-risk population because of prolonged hospitalization, indwelling devices, and prior infectious exposure.7

Post-transplant lymphoproliferative disorder

Post-Transplant Lymphoproliferative Disorder (PTLD) is a type of lymphoma that occurs due to chronic immunosuppression, often linked to Epstein–Barr virus (EBV). Risk factors include EBV-seronegative recipients receiving EBV+ donor hearts and patients receiving high-dose immunosuppression.40, 41 Monitoring EBV viral load is crucial for the early detection of PTLDs, particularly in EBV-seronegative recipients. Preemptive PTLD prevention strategies combine serial quantitative EBV DNA monitoring in peripheral blood with reduced immunosuppression, which may lower the risk of PTLD. As transplant patient survival improves, late and EBV-negative PTLD will represent an increasing proportion of cases in the adult population.41

Symptoms often begin with lymphadenopathy, unexplained fever, weight loss, and gastrointestinal issues such as abdominal pain or GI bleeding.

Diagnosis is performed by monitoring the EBV PCR viral load and through tissue examination. EBV can be detected in significant amounts in tissues and is considered the gold standard for diagnosis.42

The antiviral drugs acyclovir and ganciclovir inhibit EBV lytic replication but have no effect on latent infection. PTLD management strategies include immunosuppression modulation, rituximab therapy, and chemotherapy for advanced-stage diseases, in collaboration with pediatric oncology teams.40

Renal dysfunction and hypertension

Combined kidney and heart transplantation should be considered in PHTx candidates with kidney failure requiring dialysis or eGFR ≤35 ml/min/1.73 m2 and remains uncommon in children.43 Overall survival was not significantly different between the adult cohorts.44

Chronic kidney disease (CKD) is a major long-term complication of heart transplantation. The risk factors associated with CKD are prolonged use of calcineurin inhibitors (with or without episodes of toxicity), hypertension, dehydration, and the use of nephrotoxic drugs. Renal function at the time of transplantation is not associated with the onset of late renal dysfunction.45 CKD diagnosis requires serum creatinine and eGFR monitoring, along with 24-hour urine protein analysis during follow-up. Management includes a calcineurin inhibitors-sparing strategy using mTOR inhibitors, control of hypertension with angiotensin-converting enzyme inhibitors, and regular nephrology follow-up.45

Growth and developmental issues

Children who undergo heart transplantation often experience growth delay and developmental challenges due to chronic illnesses before transplantation, steroid use, and nutritional deficiencies. They gained significant weight in the first postoperative year, with weight normalization at 2 years.46 Management includes growth hormone therapy for severe growth failure, vitamin D and calcium supplementation, physical therapy, and developmental screening.47

Psychological and psychosocial challenges

Children have a high prevalence of depression and anxiety due to medical trauma after heart transplantation, necessitating mental health interventions to mitigate adverse impacts on health-related outcomes.48

Adolescents are at risk of medication nonadherence, which can lead to rejection of the graft. Cognitive behavioral therapy, family therapy, peer support programs, and transition programs for adult care are useful for minimizing psychological trauma, and the effectiveness of psychosocial interventions should be evaluated in future studies.49

Foundational adjuncts to medical management

Cardiac rehabilitation

Many recipients experience reduced exercise capacity due to pre-transplant deconditioning, chronotropic incompetence, residual comorbidities, and the long-term effects of immunosuppression. Structured and supervised rehabilitation programs can improve functional status, quality of life, and psychosocial well-being and may support adherence during adolescence.50

A structured multidisciplinary cardiac rehabilitation (CR) program is vital for optimizing the long-term outcomes of patients with CAD. It encompasses50:

  • •

    Supervised Exercise Training: Improves peak VO2, endothelial function, muscular strength, and counters corticosteroid-induced myopathy and metabolic syndrome. A pragmatic approach is to prescribe individualized moderate-intensity aerobic exercise (e.g., walking, cycling, and swimming) combined with age-appropriate resistance training.

  • •

    Patient and Family Education: Reinforces medication adherence, nutritional counseling, and self-monitoring skills.

  • •

    Psychosocial Support: Addresses anxiety and depression, improving health-related quality of life. Data in adults strongly support CR's role of CR in improving survival and function; its integration into pediatric care is a critical, evidence-based priority.

Programs should be tailored to graft function, coronary status (including the presence or suspicion of CAV), musculoskeletal limitations, and patient preferences and should include education on safe exertion, hydration, and recognition of warning signs. Whenever available, referral to a multidisciplinary CR team—integrating cardiology, physiotherapy, nursing, psychology, and nutrition—facilitates standardized assessment, goal setting, and monitoring.

Transitional care

Children who undergo heart transplantation currently have longer life expectancies and live into late adolescence and adulthood. This population has the highest risk of non-adherence8, 51 to medical care, including medication compliance and attendance at follow-up appointments, resulting in an increased risk of severe rejection episodes and graft loss.51

Structured programs initiated in early adolescence are essential for educating patients, promoting self-management, and ensuring the continuity of care.

A collaborative multidisciplinary transition program with interventions from nurse practitioners and coordinators, pharmacists, social workers, dietitians, psychologists, and cardiologists favorably influences long-term results in young adults.52

Conclusion

PHTx is a successful therapy for children with end-stage heart failure and a longer life expectancy. Post-transplant complications, such as persistent chronic rejection and graft dysfunction, remain challenging. Optimizing long-term outcomes requires an integrated multidisciplinary approach that combines individualized immunosuppression, systematic rejection, CAV surveillance, infection prevention, renal protection, and early recognition of psychosocial risk factors. The judicious use of emerging biomarkers, advanced imaging modalities, and tailored rehabilitation programs may further enhance graft longevity and the quality of life. Timely diagnosis and individualized management strategies can significantly improve patient outcomes.

Integrating strategies for transitional care and long-term follow-up within specialized transplant centers is essential for improving patient outcomes. The journey of pediatric heart transplant recipients demands multidisciplinary commitment to manage therapy over decades. Continued collaboration across international registries and clinical networks will be critical for refining evidence-based strategies and further improving the long-term outcomes in this growing population.

Disclosures

During the preparation of this work, the author(s) used [ChatGPT/ PaperPal) to improve readability and language. After using these tools, the author(s) reviewed and edited the content as needed and took (s) full responsibility for the content of the publication. No funding resources were used for the elaboration of this manuscript.

Conflicts of Interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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