When the liver is in poor condition, so is the heart - cardiac remodelling in MASH mouse models

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) confers a risk for cardiovascular diseases in patients. Animal models may help exploring the mechanisms linking liver and heart diseases. Hence, we explored the cardiac phenotype in MASH mouse models. MethodsWe evaluated pathological alterations in liver and heart in foz/foz mice fed a high fat diet for 24 or 60 weeks and in C57BL/6J mice fed a high fat, high fructose diet for 60 weeks. Angiotensin ll (Angll) was used as an additional cardiovascular stressor. ResultsFoz/foz mice with fibrosing MASH developed cardiac hypertrophy with adverse cardiac remodelling not seen in WT similarly fed the high fat diet. Angll caused hypertension and upregulated the expression of genes contributing to pathological cardiac hypertrophy (Nppa, Myh7) more severely so in foz/foz mice than in controls. After 60 weeks of HFD, while liver disease had progressed to burn-out non steatotic MASH with hepatocellular carcinoma in 50% of the animals, the cardiomyopathy did not. In an independent model (C57BL/6J mice fed a high fat, high fructose diet), moderate fibrosing MASH is associated with cardiac fibrosis and dysregulation of genes involved in pathological remodelling (Collal, Col3al, Vim, Myh6, Slc2al). ConclusionAnimals with MASH present consistent adverse structural changes in the heart with no patent alteration of cardiac function even when stressed with exogenous Angll. Liver disease, and not overfeeding or aging alone, is associated with this cardiac phenotype. Our findings confirm foz/foz mice as suitable for studying links between MASH and heart structural changes ahead of heart failure.