ESC Congress 2026 Abstract · Oct 26, 2026
Integrated molecular profiling of preclinical and clinical cardiac xenotransplants
By Hadizadeh N, Becker F, Bender M et al.
Background: Due to the shortage of human donor hearts, porcine cardiac xenotransplantation (xHTx) has emerged as a promising strategy for patients with end-stage heart failure. However, early graft dysfunction and rejection continue to limit clinical success. Purpose: We present the first integrated cross-species framework combining preclinical (porcine-to-baboon) and clinical (porcine-to-human) xHTx at single-nucleus resolution. By linking transcriptional remodeling signatures with blood-based proteomics, we aim to provide a translational roadmap toward sustained xenograft adaptation and improved patient outcomes. Methods: We transplanted 19 genetically engineered porcine hearts into baboons under standardized immunosuppression and stratified them based on main clinical outcomes. Upon study endpoints, left ventricular free walls were retrieved for single-nucleus RNA sequencing in addition to serial blood plasma proteomic profiling. For the clinical cohort, single-nucleus RNA sequencing was performed on cardiac biopsies from two end-stage heart failure patients who received genetically modified porcine hearts. A dual-genome mapping approach and advanced computational workflows were utilized to explore the cellular and transcriptional alterations in xHTx failure and success. Results: Both xHTx cohorts displayed time-dependent donor-recipient immune chimerism. Rejection xenografts revealed significant immune activation modules including inflammatory macrophage polarization and enrichment of key cytokines (CXCL13, CCL2, IL6) and interferon-stimulated genes (MX1/2, IFIT1/2/3). Our analysis further revealed non-immunological components in graft failure, including time-dependent hypoxia (HIF1A, VEGFA) associated with a maladaptive metabolic shift from fatty acid oxidation toward anaerobic glycolysis (PKM, PFKL, ENO1) within cardiomyocytes. This glycolysis was uncoupled from glucose oxidation, reflected by the downregulation of mitochondrial pyruvate entry (MPC2) and PDK-mediated inhibition of the pyruvate dehydrogenase complex (PDH). The resulting accumulation of proton and lactate byproducts is implicated in promoting acidic microenvironments that impair calcium handling, previously observed in heart failure. These findings were confirmed at transcriptomic and proteomic levels, showing reduced contractility (SMTN) and impaired calcium signaling (CAMK2D, RYR2). This is consistent with the heart failure with preserved ejection fraction (HFpEF) phenotype observed in the rejection samples. Conclusions: By integrating preclinical and clinical cardiac xenotransplantation at single-nucleus resolution, we identify conserved immune activation programs and hypoxia-driven metabolic remodeling associated with xHTx rejection. These findings provide mechanistic insights between experimental models and early clinical experience, highlighting both immunological and cardiometabolic processes as contributors to xenograft dysfunction.Graphical Abstract