Heart Transplant Rejection: From Histological Diagnosis to Precision Medicine

Heart transplantation remains the treatment of choice for patients with end-stage heart failure who are unresponsive to medical therapy or ventricular assist devices. Despite significant advances in surgical techniques and immunosuppressive protocols, heart transplant rejection (HTR) remains a major cause of morbidity and mortality among recipients. This narrative review summarizes current knowledge on HTR, with particular emphasis on immunopathogenic mechanisms, diagnostic approaches, histological classification, and therapeutic strategies, including the most recent non-invasive monitoring techniques. A narrative review of recent literature was conducted, including key publications and the updated International Society for Heart and Lung Transplantation (ISHLT) guidelines on rejection mechanisms, histological grading systems, and therapeutic strategies. HTR occurs via hyperacute, acute cellular, antibody-mediated, and chronic mechanisms, each characterized by complex immunological interactions between donor and recipient. Endomyocardial biopsy (EMB) remains the diagnostic gold standard, while innovations such as gene expression profiling, donor-derived cell-free DNA (dd-cfDNA), and donor-specific antibody (DSA) testing are redefining rejection monitoring. Modern immunosuppressive therapies, particularly tacrolimus-based regimens and B-cell-targeted agents, have reduced the incidence of rejection and improved graft survival. Ongoing refinement of diagnostic techniques and personalized immunosuppressive strategies is essential to enhance post-transplant outcomes. A multidisciplinary approach remains crucial for optimal management of HTR.