Hepatic Fibro-Inflammation and Atrial Fibrillation: A Dual-Track Metabolic Axis Revealed by a Metabolomic Clock

Aims: Fatty liver disease has been associated with atrial fibrillation (AF), yet the liver-heart axis, the interplay between hepatic fibro-inflammation, systemic metabolism, and genetic susceptibility, remains poorly defined. We aimed to characterize this axis and its association with incident AF. Methods and Results: In this prospective cohort study, liver fibrosis was assessed via four biochemical indices and magnetic resonance imaging (corrected T1 [cT1]). We integrated metabolome-wide causal mediation (249 nuclear magnetic resonance [NMR] features) with Elastic Net modelling, cardiac phenomapping (cardiac magnetic resonance and electrocardiogram), and unsupervised clustering. A metabolomic risk score (MRS) was derived and evaluated for gene-environment interactions with an AF polygenic risk score (PRS) and for incremental prediction beyond CHARGE-AF, ARIC, and C2HEST. Among 403,974 UK Biobank participants (median follow-up 13.18 years), 26,677 developed incident AF. High-risk NAFLD fibrosis score (NFS; HR 1.54, 95% CI 1.43-1.66), Fibrosis-4 index (FIB-4; HR 1.53, 95% CI 1.44-1.62), and liver MRI cT1 (HR 1.41, 95% CI 1.11-1.79) were independently associated with AF. Phenomapping identified a dual-track axis: (1) systemic inflammation and lipotoxicity linked to electrophysiological alterations without chamber dilation, and (2) fatty-acid imbalance associated with structural enlargement. Three metabolomic clusters emerged; a "Fibro-Inflammatory" phenotype exhibited distinct metabolomic derangements, ketogenic stress, and a high residual AF risk independent of traditional comorbidities. The MRS compounded AF risk across all PRS strata and improved prediction beyond CHARGE-AF ({Delta}AUC +0.005; cNRI 10.2%), ARIC ({Delta}AUC +0.006; cNRI 11.7%), and C2HEST ({Delta}AUC +0.042; cNRI 32.2%). Conclusions: Liver fibrosis is a robust predictor of AF. A fibro-inflammatory hepatic-metabolomic signature defines a modifiable axis that potentiates genetic susceptibility and enhances AF risk stratification. Targeting liver-derived metabolic dysfunction may offer a new therapeutic avenue for AF prevention.