Proteomic Remodeling in Fontan Circulation Associated with Fibrosis and Time-Dependent Immune-Metabolic Alteration

The Fontan circulation is associated with progressive multisystem complications, yet its underlying molecular mechanisms remain incompletely understood. We aimed to characterize systemic proteomic alterations and identify biological pathways associated with Fontan physiology, long-term adaptation, and clinically unfavorable phenotypes. Peripheral vein serum proteomics was performed using mass spectrometry in 48 Fontan patients and matched controls. Differential protein expression and pathway enrichment analyses were applied across the overall cohort and clinically defined subgroups according to Fontan duration and composite clinical risk phenotyping. More than one third of quantified proteins were differentially expressed, demonstrating extensive systemic proteomic remodeling. Extracellular matrix remodeling emerged as the dominant signature, characterized by fibrosis-associated proteins and enrichment of TGF-β-related profibrotic pathways. Prolonged Fontan duration and clinically unfavorable status were not associated with substantially amplified extracellular matrix signatures. Instead, long-term Fontan patients demonstrated increasing immune, complement, and endothelial activation, whereas high-risk patients showed metabolic and redox-related alterations. These findings indicate that extracellular matrix remodeling and profibrotic signaling are dominant features of the Fontan circulation, while increasing Fontan duration and clinical deterioration are associated with immune activation, endothelial stress, and metabolic dysregulation with oxidative stress.