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 (ΔAUC +0.005; cNRI 10.2%), ARIC (ΔAUC +0.006; cNRI 11.7%), and C2HEST (ΔAUC +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.

Translational Perspective

Atrial fibrillation often arises outside conventional clinical and genetic risk tiers. Hepatic fibro-inflammation leaves a circulating metabolomic signature tracking distinct electrical and structural cardiac remodelling pathways, defining a lean, normolipidemic “Fibro-Inflammatory” phenotype carrying high residual AF risk that legacy scores systematically under-classify. A metabolomic risk score unmasked polygenic vulnerability and improved reclassification beyond CHARGE-AF, ARIC, and C2HEST. These findings position liver-derived metabolic dysregulation as a potentially modifiable axis for AF stratification—complementing clinical and genetic information and nominating candidate targets (atherogenic lipoproteins, systemic inflammation, ketogenic stress) for early prevention.