Redox Phenotyping of the Donor Heart: A New Paradigm for Precision Heart Transplantation

Heart transplantation remains the definitive treatment for selected patients with advanced heart failure, yet current donor heart assessment relies predominantly on clinical, functional, and biochemical variables that incompletely reflect the biological resilience of the graft. Increasing evidence indicates that oxidative stress represents a central mechanism linking donor characteristics, brain death, ischemia-reperfusion injury, endothelial dysfunction, mitochondrial impairment, inflammation, and regulated cell death. These interconnected processes collectively determine graft susceptibility to preservation injury and post-transplant dysfunction. This review introduces redox phenotyping as a novel conceptual framework for donor heart evaluation, integrating oxidative injury, antioxidant defenses, mitochondrial competence, endothelial integrity, metabolic adaptation, and redox-sensitive molecular signaling into a multidimensional assessment of graft biology. We summarize the mechanisms underlying donor heart oxidative remodeling throughout life, the molecular basis of ischemia-reperfusion injury, and emerging biomarkers, including metabolomics, lipidomics, extracellular vesicles, cell-free nucleic acids, and mitochondrial biomarkers. We further discuss how ex vivo machine perfusion enables real-time biological assessment and targeted therapeutic intervention, transforming organ preservation into a platform for dynamic redox characterization. Finally, we explore the integration of multi-omic profiling with artificial intelligence to enable individualized donor assessment and biological optimization.