Integrated Cardiac and Circulating N-glycan Signatures Reflect Atrial Remodeling in Patients with Atrial Fibrillation

Background Atrial adverse remodeling drives the maintenance and progression of atrial fibrillation (AF) through electrical and structural myocardial changes, often accompanied by inflammation. Circulating N-glycans are emerging as biomarkers in inflammatory diseases, yet their role in AF remains undefined. Methods We profiled the serum N-glycome of 138 patients with AF, non-AF arrhythmias, or sinus rhythm (SR) controls from peripheral venous (PV) and coronary sinus (CS) samples using hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry. Glycan traits associated with AF were identified via logistic regression adjusted for clinical risk factors. Multivariate glycan scores were derived from PV and CS datasets using LASSO regression. In a subset (N=37), plasma proteome profiling was performed with the Olink Reveal panel. Results Sixty-two glycan peaks were detected; 27 in PV and 8 in CS serum differed significantly between AF and controls. PV and CS glycan scores accurately classified AF, with the PV score correlating with 11 plasma proteins linked to structural remodeling and thrombo-inflammatory processes. The most abundant glycan, A2G2S2 (peak 30), was associated with higher odds of AF after adjusting for confounders (OR 2.22 [95% CI: 1.40–3.75], P = 0.001). CS A2G2S2 correlated with C-reactive protein (R = 0.432, P = 0.0275) and was elevated in patients with left atrial enlargement (P = 0.0354), but unchanged in those with impaired left ventricular ejection fraction or hypertrophy. Conclusion Integrated profiling of peripheral and cardiac serum identifies novel N-glycosylation signatures in AF. Specific cardiac and circulating N-glycan signatures, including A2G2S2, are associated with AF and reflect inflammation-driven atrial remodeling, highlighting potential mechanistic pathways and biomarker applications.