Sympathetic Nerve Activation Drives Cardiac Fibrosis and Arrhythmia in Lean Metabolic Dysfunction‐Associated Steatohepatitis Mice Concurrently Exposed to Ethanol and a High‐Fat/High‐Cholesterol Diet

Background Lean metabolic dysfunction‐associated steatohepatitis (MASH) is increasingly recognised in non‐obese individuals and is associated with cardiovascular complications, including arrhythmias. Although sympathetic activation and inflammation have been implicated in disease progression, their mechanistic roles in cardiac fibrosis and arrhythmogenesis in lean MASH remain unclear. Objective To investigate the contribution of sympathetic nerve activation to myocardial fibrosis and arrhythmia in a lean MASH mouse model. Methods and Results Male C57BL/6J mice were fed a high‐fat/high‐cholesterol diet (STHD‐01) with or without ethanol for 12 weeks. Hepatic and cardiac changes were evaluated by histology, immunohistochemistry, reverse transcription–polymerase chain reaction, and plasma biochemistry. Arrhythmias were recorded by electrocardiogram telemetry. Despite reduced body weight, mice receiving STHD‐01 plus ethanol developed marked hepatic and cardiac inflammation and fibrosis. Sympathetic activation, indicated by tyrosine hydroxylase co‐localization with cluster of differentiation 68‐positive macrophages and with α‐smooth muscle actin–positive fibroblast‐like stromal cells, was associated with increased expression of tumour necrosis factor‐α and transforming growth factor‐β1, respectively. These mice exhibited a significantly higher incidence of lethal arrhythmias. Expression of inflammatory and fibrotic genes showed moderate to strong correlations between the liver and heart. Conclusion Sympathetic nerve–associated activation of macrophages and fibroblast‐like stromal cells is linked to myocardial fibrosis and increased arrhythmia susceptibility in lean MASH. Even modest ethanol intake appears to accelerate disease progression and heighten arrhythmia risk when combined with a high‐fat/high‐cholesterol diet. These findings suggest that targeting sympathetic activation and inflammation may represent a potential therapeutic strategy for cardiovascular prevention in lean MASH.