Chronic Dietary Stress Is Associated with Early Cardiac Dysfunction and Progressive MASH Accompanied by Systemic Inflammation and Fibrosis

Introduction: Animal models of cardiac dysfunction and heart failure play important roles in preclinical study and drug discovery. Cardiovascular disease and metabolic dysfunction-associated steatohepatitis (MASH) are closely associated metabolic disorders that frequently coexist in individuals with obesity and metabolic syndrome. However, the mechanisms linking diet-induced metabolic stress to cardiac dysfunction and hepatic pathology remain understudied. Method: In this study, six-week-old C57Bl/6J male mice were fed standard normal chow or a Gubra Amylin NASH (GAN) diet for six months to investigate the concurrent cardiac and hepatic manifestations. Results: Our results indicated that GAN diet-fed mice developed early cardiac dysfunction characterized by reduced ejection fraction (EF) and impaired diastolic function, as indicated by increased E/A and E/E′ ratios. These cardiac changes were accompanied by worsening hepatic pathology, including elevated total cholesterol (TC) and liver injury markers such as ALT, AST and ALP. By 6 months, mice developed pronounced fibrotic remodeling and inflammation in both the heart and liver, as confirmed by histopathological and gene expression analyses. Metabolic assessments further demonstrated a decreased respiratory exchange ratio (RER) in GAN diet-fed mice, particularly during the dark cycle, suggesting enhanced lipid utilization and decreased metabolic flexibility. In addition, reduced oxygen consumption, carbon dioxide production, and locomotor activity suggested impaired energy expenditure and reduced physical activity levels. Conclusion: Collectively, our findings demonstrate that chronic GAN diet feeding induces early cardiac dysfunction accompanied by progressive MASH-like hepatic pathology, with inflammation and fibrotic remodeling developing in both the heart and liver. These findings establish GAN diet feeding as a useful model for investigating the concurrent cardiac and hepatic consequences of chronic metabolic stress.