Lipid-associated macrophages infiltration is associated with cardiac remodeling in a NASH

Non-alcoholic steatohepatitis (NASH) refers to a fatty liver with lobular inflammation that can progress to liver fibrosis. Although a statistical association between NASH and cardiovascular disease has been demonstrated in epidemiological studies, the nature of the links between liver disease and cardiac remodeling remains to be established. We hypothesize that alterations in circulating and tissue-resident immune cells contribute to inappropriate cardiac remodeling during the development of NASH. We explore a cohort of patients candidates for cardiac surgery (POMI-AF – NCT03376165) comparing liver status and myocardial immune profile. We characterized the structural remodeling and contractile dysfunction using transthoracic echocardiogram (TTE) and histology in a diet-induced mouse model of NASH. Leukocyte infiltration in the mice heart is explored using flow cytometry and single cell RNA sequencing (scRNAseq) analysis. The specific role of the liver is studied using hepatocyte-PPARα KO mice under NASH-diet. In human myocardium, patients with high risk of NASH with fibrosis had an increased number of M2-like macrophages compared to control patients. In our NASH-diet mice, we showed left ventricular hypertrophy, dilated left ventricle and an impaired diastolic function. We also found more ventricular fibrosis and increased cardiomyocyte area. Using scRNAseq, we identified an increased expression of the pro-fibrotic marker Galectin-3 by pro-inflammatory macrophages, and finally we identified an enriched “lipid-associated Ly6C- TREML4+ myeloid cells” cluster within the heart of NASH mice. This subpopulation was also enriched in the blood of hepatocyte-PPARα KO mice after 24 weeks of NASH diet. Using a translational approach, we here describe an association between NASH and altered cardiac macrophages. Although fibrosis can be partially explained by the expression of Galectin-3 by macrophages, the potential involvement of lipid-associated myeloid cells in cardiac hypertrophy remains to be established. As macrophages are implicated in several cardiac remodeling etiologies, our new results could explain the adverse remodeling observed in NASH.