Heart transplantation has transformed survival in end-stage heart failure but remains constrained by donor scarcity, lifelong immunosuppression, and late graft-related morbidity. Over the next 5 decades, converging advances in immune tolerance, xenotransplantation, bioengineered organs, and fully implantable artificial hearts are likely to reshape the therapeutic landscape of cardiac replacement. Early signals of these transitions are already visible in tolerance-induction trials, first-in-human cardiac xenograft implantation, cardiac tissue engineering, and next-generation mechanical circulatory support platforms. By 2076, donor-dependent transplantation may persist but will no longer represent the singular standard of care. Instead, clinicians and patients will navigate a diversified ecosystem of biologic and synthetic heart-replacement strategies tailored to individual risk profiles, cultural context, and health-system resources. As improved early survival the dominant metric of success will shift toward long-term functional independence and freedom from therapy-related disease. The future of transplantation will therefore be defined less by technical feasibility than by its ability to evolve alongside engineered alternatives while remaining equitable and globally accessible.
Malik Wellington received his first heart transplant at age 17 years for idiopathic dilated cardiomyopathy. In the setting of chronic immunosuppression, he was diagnosed with testicular cancer, requiring orchiectomy, and renal cell carcinoma, requiring left open partial nephrectomy. Twenty-four years later, he received his second heart transplant for cardiac allograft vasculopathy as well as a simultaneous kidney transplantation at NewYork Presbyterian-Columbia Medical Center. While waiting for his second heart and kidney transplant in the hospital, he graduated from his Master of Business Administration program at Long Island University. Now almost 4 years after his second transplant, he currently works as an analyst for a gas & electric utility company and he hopes to go back to school for engineering. In his spare time, he enjoys salsa dancing and writing short stories.
BACKGROUND:Donation after circulatory death (DCD) heart transplantation has expanded rapidly in the United States, but whether outcomes have evolved during national dissemination remains uncertain. Given the increasing complexity of candidates with advanced heart failure, understanding the stability of outcomes during expansion is clinically important. We evaluated temporal changes by comparing early adoption with later expansion. METHODS:Adult DCD heart transplant recipients in the United Network for Organ Sharing registry (January 2019 to June 2024) were stratified into an early era (2019-2021) and a late era (2022-2024). The primary endpoint was 1-year graft failure. Secondary endpoints included 1-year all-cause mortality, renal-replacement therapy before discharge, and length of stay. A secondary exploratory analysis assessed overall survival up to 2 years. Inverse probability of treatment weighting was applied to adjust for baseline differences. Prespecified subgroup analyses were performed in high-risk recipients, including those with impaired functional status, pulmonary hypertension, and preoperative mechanical circulatory support. RESULTS:Among 1489 recipients (303 early, 1186 late), DCD use increased substantially over time and expanded across a greater number of transplant centers. Unadjusted and inverse probability of treatment weighting-adjusted analyses showed no significant differences between eras in length of stay, renal-replacement therapy, 1-year mortality, retransplantation, or graft failure. Exploratory analyses of overall survival up to 2 years showed no significant difference between groups. Outcomes were consistent across high-risk subgroups. CONCLUSIONS:Early outcomes after DCD heart transplantation remained stable during rapid national expansion despite broader recipient risk profiles, supporting the scalability of this strategy without evidence of outcome deterioration.
BACKGROUND:Sex differences after cardiac transplantation are well described; whether similar sex differences exist after simultaneous heart-kidney transplantation (SHKT) remains unknown. METHODS AND RESULTS:Adults (≥18 years) undergoing first-time SHKT between January 1, 1999, and September 30, 2024, were identified in the United Network for Organ Sharing registry. Rates of SHKT by sex were examined across allocation-policy eras. Post-transplant survival was compared by sex using multivariable Cox regression. Among 3068 recipients (19.7% women), women were more likely to have nonischemic cardiomyopathy and a higher pulmonary vascular resistance and less likely to have durable left ventricular assist device support at the time of transplant. Unadjusted survival did not differ by sex at 1 or 5 years (log-rank P = .236 and P = .593, respectively). After multivariable adjustment, as sex violated proportional hazards, a piecewise constant Cox model showed a numerically higher perioperative than postperioperative sex hazard, neither significant in the full cohort (adjusted hazard ratio [aHR] 1.38 [P = .061] and aHR 1.19 [P = .473]). The perioperative disparity was significant in the prespecified 90-day landmark analysis (days 0-90, aHR 1.58, 95% confidence interval 1.12-2.22 [P = .009]; days 91-365, aHR 0.91 [P = .729]) and in the contemporary allocation era (aHR 1.78, 95% confidence interval 1.19-2.65, P = .005). No sex differences were observed at 5 years and no significant sex interactions were identified across 10 prespecified effect modifiers (all P > .005). CONCLUSIONS:Women demonstrated an early post-transplant mortality signal concentrated within the first 90 days after SHKT, without excess long-term risk. These findings underscore the need for earlier referral and perioperative optimization of high-risk women to improve equity in SHKT outcomes.
Heart transplantation remains the definitive therapy for end-stage heart failure, yet graft survival continues to be limited by acute and chronic rejection and the cumulative toxicity of lifelong immunosuppression. Extracorporeal photopheresis (ECP), an immunomodulatory therapy with established efficacy in graft-versus-host disease and lung transplantation, has been investigated for more than 3 decades as an adjunctive therapy in heart transplantation. While prior reviews have summarized historical outcomes, the role of ECP in contemporary transplant practice remains incompletely defined. This state-of-the-art review examines the immunologic basis, clinical evidence, and evolving applications of ECP in heart transplant recipients, with particular focus on rejection prophylaxis, acute cellular rejection, recurrent rejection, and antibody-mediated processes. We contextualize existing evidence within modern immunosuppressive regimens and emerging noninvasive rejection surveillance tools, including donor-specific antibodies and molecular biomarkers. Beyond its role as salvage therapy, accumulating evidence suggests that ECP may function as an immunosuppression-sparing strategy, particularly in high-risk patients with recurrent rejection, infection vulnerability, or intolerance to intensified immunosuppression. We highlight unresolved knowledge gaps, propose patient selection frameworks, and identify future research directions necessary to define the role of ECP in modern heart transplantation. Overall, ECP appears to be a safe and underutilized adjunct with potential to reduce rejection burden while mitigating the long-term consequences of immunosuppression.
The United States heart allocation system prioritizes transplant candidates using therapy-based categorical urgency tiers that measure treatment decisions rather than biological risk. This miscalibration is associated with observable downstream issues: status exception rates exceeding 40% of adult listings, systematic escalation of temporary mechanical circulatory support in hemodynamically stable candidates, missed opportunities for myocardial recovery, and structural inequities in access. This review argues that meaningful reform requires a sequenced agenda: developing validated continuous urgency scores grounded in objective biological variables for both adult and pediatric candidates, reforming the exception process through standardized prospectively applied criteria, and building a new allocation policy using accurate inputs.
In recent years, the field of donor heart preservation has rapidly expanded to incorporate several new technologies aimed at increasing the available donor pool. Traditional ice cold storage, although effective, allows for limited preservation time and also subjects the organ to cold-induced injury. Controlled hypothermia systems improve temperature stability and reduce cold injury, while normothermic ex vivo perfusion platforms enable continuous metabolic support while also incorporating functional assessment, allowing for the utilization of extended-criteria and donation after circulatory death donors. Hypothermic oxygenated perfusion represents a hybrid approach combining the benefit of hypothermia with continuous oxygen delivery, allowing for enhanced preservation and extended preservation times. Emerging techniques such as rapid recovery and intermediate-temperature (10°C) storage further aim to enhance myocardial protection while offering to reduce costs and logistical complexities. Altogether, these technologies represent various strategies that have the potential to expand donor utilization, improve graft preservation, and increase access to heart transplantation.
Heart transplantation remains the definitive treatment for end-stage heart failure, and contemporary immunosuppressive regimens, typically a calcineurin inhibitor, antiproliferative agent, and corticosteroids applied with minimal preemptive individualization, despite profound heterogeneity in recipient immune biology, pharmacokinetics, comorbidity burden, and alloimmune risk. This review examines the case for personalized immunosuppression in heart transplantation across 4 domains. First, we survey the current landscape of immunosuppression, identify key gaps, and discuss emerging strategies. Second, we review the evolving toolbox of posttransplant immune monitoring and molecular biomarkers, including donor-specific antibodies, gene-expression profiling, donor-derived cell-free DNA, and technologies in development, appraising their clinical evidence, performance characteristics, and limitations. Third, we propose a framework for integrating existing tools into composite risk assessment and for developing new approaches to individualized patient management. Finally, we outline future directions for the field, including preimplantation graft gene editing, AI-assisted donor-recipient matching, and continuous risk assessment. Realizing the potential of personalized immunosuppression in heart transplantation will require not only a broader suite of validated biomarkers and integrative risk scores but also novel pragmatic trial designs and surrogate endpoints to support the development of next-generation therapeutics.
BACKGROUND:Donor heart-allocation policies aim to prioritize patients with the greatest clinical need while ensuring equitable distribution of scarce donor organs. Although most systems adopt a "sickest-first" approach, how urgency is defined varies across countries. We performed a comparative analysis of global donor heart-allocation policies to examine how clinical urgency is defined. METHODS:Countries performing ≥50 heart transplants annually between 2018 and 2024 were identified using the Global Observatory on Donation and Transplantation database. National or international allocation policies were systematically analyzed. Urgency criteria including mechanical circulatory support (MCS) and exception pathways were extracted. A structured rubric was used to evaluate the explicitness and operational clarity of urgency criteria across domains. Hierarchical clustering explored structural similarity between systems. Qualitative thematic analysis was conducted to contextualize quantitative findings. RESULTS:Twenty-nine countries representing 16 allocation frameworks were included. Most systems (93%) used tier-based urgency categorization. Temporary MCS consistently afforded the greatest urgency tier, although criteria and device definitions varied. Durable MCS complications, inotrope dependence, and refractory ventricular arrhythmias were also commonly prioritized. Rubric scoring demonstrated substantial heterogeneity in the explicitness of urgency criteria, particularly regarding exception processes and reassessment policies. Exploratory clustering identified 3 structural typologies of allocation design. Qualitative analysis highlighted variability in reliance on explicit thresholds versus clinician judgement. CONCLUSION:International donor heart-allocation systems share common urgency principles but differ substantially in how these are operationalized. These findings provide a reference for allocation policy design and highlight the trade-offs between standardization and clinical flexibility that may influence future policy development.
BACKGROUND:Heart transplantation (HT) remains the gold-standard therapy for selected patients with advanced heart failure. Increasing recipient complexity and donor organ scarcity have led to the increased use of short-term mechanical circulatory support (ST-MCS) as a bridge to HT. The prognostic impact of ST-MCS on primary graft dysfunction (PGD) and other early outcomes remains limited. METHODS:We analyzed data from the Primary Graft Dysfunction Consortium, a retrospective registry including 3800 adult HTs at 14 centers in the United States, Canada, and Europe between 2010 and 2020. Primary outcomes were severe PGD (according to International Society for Heart and Lung Transplantation criteria) and 1-year mortality. Multivariable logistic regression and Cox models were used, with multiple imputation for missingness. RESULTS:Overall, 669 patients (17.6%) received pre-HT ST-MCS. Among them, 16.9% were supported with extracorporeal membrane oxygenation (ECMO), 60.4% with an intra-aortic balloon pump, 9.1% with a percutaneous left ventricular assist device, 9.1% with surgical ventricular assist devices, and 4.5% with other devices. ST-MCS use increased over time and varied by region, with the intra-aortic balloon pump predominating in the United States and ECMO more frequently used in Canada and Europe. Overall, ST-MCS was not associated with severe PGD after adjustment; however, ECMO was independently associated with greater PGD risk (adjusted odds ratio 3.28, 95% confidence interval 1.90-5.66). One-year mortality was 11.0% and did not differ significantly according to ST-MCS use after multivariable adjustment. CONCLUSIONS:In this large contemporary multinational cohort, pretransplant ST-MCS use has increased, with geographic heterogeneity observed. Although ECMO is associated with a greater risk of severe PGD, ST-MCS does not independently increase 1-year mortality after HT, supporting its use as a bridge in high-risk patients.
