Primary graft dysfunction after heart transplantation: Impaired metabolic recovery as an emerging mechanism

Primary graft dysfunction (PGD), the most extensively studied phenotype within the evolving spectrum of early graft dysfunction (EGD), remains the leading cause of early mortality after heart transplantation and continues to limit broader utilization of marginal donor organs. Despite advances in donor preservation strategies and perioperative management, the mechanisms underlying PGD remain incompletely understood. Traditionally, PGD has been conceptualized as a manifestation of ischemia-reperfusion injury (IRI) leading to early graft contractile failure. Accumulating evidence suggests that impaired metabolic recovery may represent one important mechanistic layer of multifactorial PGD, characterized by incomplete restoration of mitochondrial energetics and substrate utilization after IRI. Advances in metabolomics have enabled comprehensive profiling of circulating and perfusate metabolites, providing new insights into myocardial energy metabolism during transplantation and identifying candidate biomarkers of PGD. Notably, recent studies suggest that plasma metabolomic signatures may help identify recipients at increased risk of severe PGD, while metabolomic profiling during ex situ organ perfusion reveals the dynamic changes in myocardial fuel utilization that correlate with markers of graft injury. In parallel, machine perfusion technologies provide a unique platform for dynamic metabolic assessment of donor organs before implantation. Metabolic characterization of PGD may improve donor assessment, preservation strategies, and post-transplant monitoring, although clinical implementation will require prospective validation, standardized workflows, and clinically actionable thresholds. In this review, we summarize emerging evidence linking mitochondrial dysfunction and impaired metabolic recovery to PGD and propose a conceptual framework, informed by transplant metabolomic studies, to support graft assessment, preservation, perfusion, and transplantation.