Mandeep R Mehra, Milica Vukićević, Felix Schoenrath
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 By 2076, donor-dependent transplantation may persist but will no longer represent the singular standard of care.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.