History and Recent Advances in Heart Transplantation: A Narrative Review

Background: Heart transplantation (HTx) has undergone a transformative evolution since the first successful human procedure in 1967. Initially limited by surgical challenges, graft preservation and rejection, the field has advanced through innovations in immunosuppression, mechanical circulatory support (MCS), and donor organ utilization. Despite these achievements, critical challenges persist, including organ shortages, ischemia-reperfusion injury (IRI), and inequities in allocation. Emerging technologies such as normothermic machine perfusion (NMP), donation after circulatory death (DCD) and xenotransplantation aim to expand the donor pool and improve graft viability. Methods: This review synthesizes historical and contemporary literature on the evolution of HTx, examining milestones in surgical technique, immunosuppressive strategies and graft preservation. Special emphasis is placed on recent innovations, including ABO-incompatible transplantation, machine perfusion systems, DCD protocols, and xenotransplantation. Comparative analyses of donor policies and the role of MCS as bridge or destination therapy are also considered. Results: HTx has progressed from experimental surgery to the gold standard for end-stage heart failure, with survival markedly improved by modern immunosuppression and surgical refinements. However, donor shortage and IRI remain major limitations. Recent advances are reshaping the field: DCD, supported by ex vivo and regional perfusion, is expanding the donor pool with comparable outcomes to traditional donation. Machine perfusion technologies enable prolonged preservation, functional assessment of marginal grafts, and potential reduction of IRI. ABO-incompatible transplantation, particularly in infants, has increased donor availability with outcomes comparable to compatible grafts and is now being explored in adults. Xenotransplantation, enabled by CRISPR/Cas9 gene editing of porcine hearts, has reached early human applications, representing a potential paradigm shift despite unresolved immunological and ethical challenges. Meanwhile, durable ventricular assist devices (LVADs) and short-term MCS (e.g., Impella 5.5, ECMO) continue to evolve, serving as effective bridges to transplant or alternatives for non-eligible patients, with survival outcomes approaching transplantation in select groups. Conclusion: HTx is entering a new era defined by advanced preservation technologies, expanded donor utilization, and the promise of gene-edited xenografts. While outcomes continue to improve, successful integration of these innovations requires addressing ethical, economic, and equity challenges. Ongoing research, clinical trials, and policy reforms will be critical to fully realize their potential and ensure equitable access for patients with advanced heart failure.