Integrated Molecular Profiling of Preclinical and Clinical Cardiac Xenotransplants

Heart failure remains a leading cause of death worldwide, and the persistent shortage of donor hearts limits allogeneic cardiac transplantation. Advances in porcine genome editing, immunosuppression, and virological testing have brought cardiac xenotransplantation - the implantation of genetically engineered porcine hearts into humans - to clinical stage. The two recent first-in-human cardiac xenotransplants initially demonstrated adequate function but ended in xenograft failure [1,2], underscoring the need for mechanistic insights linked to patient outcomes. Here, we integrate single-nucleus RNA sequencing and serial blood proteomics data to map how genetically engineered porcine hearts respond or remodel after transplantation in preclinical non-human primate models, and compare these signatures against myocardial biopsies from both human xenografts. Under optimized experimental conditions, preclinical xenografts can achieve coordinated immune and metabolic balance with preserved function. In contrast, xenografts undergoing immune rejection, virus-driven endothelial cell activation, and/or metabolic stress reveal distinct tissue injury patterns. Across species, our preclinical model displays hallmarks of human xenografts, including near-complete immune cell replacement and conserved cardiomyocyte stress signatures, linking early clinical experience to established experimental models. Serial blood proteome profiling further distinguishes rejection from viral injury and identifies candidate biomarkers for non-biopsy, non-invasive xenograft monitoring. This study represents the first integrated cellular and molecular comparison of preclinical and clinical cardiac xenotransplantation, revealing conserved immune, endothelial, and metabolic programs. Together, these described signatures provide a framework for understanding and predicting xenograft behavior, and guide the translation towards clinical application.