Liver-to-Atria Inflammatory Axis Driving Arrhythmia

Area of Science:

• Cardiology
• Hepatology
• Immunology
• Molecular Biology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is an emerging risk factor for cardiometabolic diseases, including atrial fibrillation (AF).
• The liver, under metabolic stress, releases inflammatory mediators and hepatokines that may influence atrial remodeling and arrhythmogenesis.

Purpose of the Study:

• To investigate the association between liver fibrosis indicators and AF risk in a human cohort.
• To elucidate the mechanisms by which MASH contributes to atrial remodeling and AF susceptibility in a murine model.
• To identify therapeutic targets for MASH-associated atrial arrhythmogenesis.

Main Methods:

• Analysis of the Atherosclerosis Risk in Communities (ARIC) cohort to correlate FIB-4 index with AF incidence.
• Induction of MASH in mice using a specific diet, followed by electrophysiological studies, echocardiography, and molecular analyses (proteomics, snRNA-seq).
• Investigation of the role of hepatocyte-derived osteopontin (OPN) and inflammatory macrophages in MASH-induced atrial remodeling.

Main Results:

• Higher FIB-4 indices were associated with increased AF incidence in the ARIC cohort.
• MASH mice showed enhanced AF susceptibility, atrial enlargement, and fibrosis, linked to OPN-mediated recruitment of TGFBR1+ inflammatory macrophages.
• These macrophages activated gasdermin D (GSDMD), promoting proarrhythmic atrial remodeling; interventions targeting OPN, CD44, or GSDMD mitigated these effects.

Conclusions:

• Hepatokine osteopontin plays a critical role in MASH-induced atrial remodeling and AF by driving inflammatory macrophage activation and recruitment.
• The OPN-CD44-macrophage-GSDMD axis represents a novel pathway linking liver disease to atrial arrhythmogenesis.
• Targeting osteopontin or GSDMD offers promising therapeutic strategies for preventing AF in patients with MASH.