Plasma Metabolomic Signatures of Mitochondrial Energetic Disruption in Severe Primary Graft Dysfunction After Heart Transplantation

OBJECTIVES: Heart transplant primary graft dysfunction, defined as severe ventricular dysfunction within 24 hours after allograft reperfusion, is the leading cause of early mortality following heart transplantation. This study used plasma metabolomics to identify metabolic signatures associated with severe primary graft dysfunction. METHODS: This single-centre study collected blood samples from 60 adult heart transplant recipients 12 and 24 hours following graft reperfusion. Patients were categorized according to the International Society for Heart and Lung Transplantation guidelines. Samples underwent metabolomics analysis via liquid chromatography-mass spectrometry. Linear models for microarray data were used to identify the metabolic effects of primary graft dysfunction, time, and their interaction, with pathway enrichment analysis and focused analysis of identified metabolites to interpret biological patterns. RESULTS: Among the 60 patients included in this study, 8 developed severe primary graft dysfunction. Severe primary graft dysfunction was associated with coordinated metabolic alterations central to cellular energetics, including altered amino acid and nitrogen handling, broad acylcarnitine accumulation, and selective perturbations of tricarboxylic acid cycle intermediates. Temporal analyses identified divergent metabolite trajectories between groups, with succinate demonstrating the most pronounced divergence over time, reflecting failure to normalize central energy metabolism in severe primary graft dysfunction. Redox-related metabolites demonstrated patterns consistent with activation of antioxidant buffering. CONCLUSIONS: Severe primary graft dysfunction is characterized by a failure to restore cellular energy metabolism, reflected by coordinated upstream substrate accumulation and a distinct temporal pattern of succinate elevation. As an established metabolic signature of ischaemia-reperfusion injury, the succinate trajectory provides a biologically plausible link between impaired energetic recovery and downstream oxidative stress. Although exploratory, these findings support a coherent metabolic framework distinguishing recovery from persistent energetic stress in severe primary graft dysfunction.