Abstract Tu037: Unraveling the Cellular Mechanisms of Cardiogenic Liver Disease

Abstract

Background: Right heart failure (RHF) is associated with chronically elevated central venous pressures which can lead to hepatic dysfunction, fibrosis, and ultimately cirrhosis. Despite the prognostic importance of liver disease in RHF little is understood about the cellular and molecular changes that define cardiogenic liver disease. Filling this knowledge gap has the potential to lead to better diagnostic and therapeutic approaches for patients with heart failure and liver dysfunction. Aims: 1) To evaluate the key clinical and pathologic features of cardiogenic liver disease in humans 2) To explore shifts in the cellular landscape in the congested liver using human samples and a mouse model congestive hepatopathy. Methods: We identified 34 patients with heart failure who underwent liver biopsy due to concern for cardiogenic liver disease. These biopsy samples were stained for numerous cellular markers (macrophage subsets, activated stellate cells, endothelial cells, biliary cells) and compared to normal controls. Clinical data was also collected for the included patients. To model cardiogenic liver disease in a mouse we performed partial IVC ligation (pIVCL) to induce liver congestion and then assessed the liver response using flow cytometry, tissue imaging and mRNA analysis. Results: Liver biopsies from patients with cardiogenic liver disease demonstrated increased liver fibrosis, macrophage aggregates, and biliary metaplasia. The severity of biliary metaplasia was closely associated with the extent of liver congestion. Using multi-marker staining the metaplastic cells were found to be of hepatocyte origin. Interestingly, the liver niche containing metaplastic biliary cells was also enriched for recruited macrophages and activated stellate cells. Similar pathologic features were observed in the mouse model of liver congestion. Conclusions: In this study we identified biliary metaplasia and macrophage recruitment as key pathologic features of cardiogenic liver disease. Ongoing investigation of the interplay between macrophages and metaplastic biliary in humans and animal models of congestive hepatopathy may lead to the discovery of novel disease mechanisms and biomarkers for liver dysfunction in heart failure.