Beyond Tacrolimus: Toward Personalized Immunosuppression in 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.