Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term Cholecardia. Fxr; Shp double knockout (DKO) mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, DKO mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of Pgc1α, a key regulator of fatty acid metabolism, and that Pgc1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the DKO mice. Conclusions Overall, we propose that decreased Pgc1α expression contributes to the metabolic dysfunction in Cholecardia, and that reducing serum bile acid concentrations will be beneficial against metabolic and pathological changes in the heart.

Bile acids, specifically TGR5 agonists, induce cytoprotective changes in the heart and improve myocardial response to physiologic, inotropic, and hemodynamic stress in mice. TGR5 plays a critical role in myocardial adaptability, and TGR5 activation may represent a potentially attractive treatment option in heart failure.

Background Triggers and exacerbants of cirrhotic cardiomyopathy (CC) are poorly understood, limiting treatment options in patients with chronic liver diseases. Liver transplantation alone reverses some features of CC, but the physiology behind this effect has never been studied. Aims We aimed to determine whether reversal of liver injury and fibrosis in mouse affects cardiac parameters. The second aim was to determine whether cardiomyopathy can be induced by specifically increasing systemic bile acid (BA) levels. Methods 6–8 week old male C57BL6J mice were fed either chow (n=5) or 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine (DDC) (n=10) for 3 weeks. At the end of 3 weeks, half the mice in the DDC fed group were randomized to chow (the reversed [REV] group). Serial ECHOs and electrocardiographic analysis was conducted weekly for 6 weeks followed by liver tissue and serum studies. Hearts were analyzed for key components of function and cell signaling. Cardiac physiologic and molecular parameters were similarly analyzed in Abcb11−/− mice (n=5/grp) fed 0.5% cholic acid supplemented diet for 1 week. Results Mice in the REV group showed normalization of biochemical markers of liver injury with resolution of electrocardiographic and ECHO aberrations. Catecholamine resistance seen in DDC group resolved in the REV group. Cardiac recovery was accompanied by normalization of cardiac troponin-T2 as well as resolution of cardiac stress response at RNA level. Cardiovascular physiologic and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11−/− mice. Conclusions Cardiomyopathy resolves with resolution of liver injury, is associated with cholanemia, and can be induced by BA feeding.

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Skeletal muscle wasting is a common co‐morbidity in cholestatic liver diseases. We hypothesize that cholestasis and bile acid (BA) excess (cholanemia) directly induces muscle atrophy by decreasing translation and stimulating protein degradation in muscle. Biliary fibrosis and cholestasis was induced in 6–8 week old male C57BL/6J mice by feeding a DDC supplemented diet for 3 weeks and compared with isocaloric chow fed mice (n=3/group). DEXA scan, exercise tolerance, and fasting circulating BA, glucose and insulin were analyzed, and quadricep muscle signaling was determined. Compared to controls, DDC had 1/3 less food intake, lower body weight (17±0.6 vs. 25±0.5g), lean (11.4±0.8 vs. 16.1±0.4g) and fat mass (2.3±0.1 vs. 3±0.2g) and demonstrated early fatigue on the treadmill. DDC had liver injury, cholestasis, cholanemia (BA: 1000±250 vs. 7±1 μmol/L), and lower glucose (60±5 vs. 150±15mg/dl) and insulin levels (0.15±0.01 vs. 0.53±0.01 ng/L) than controls. DDC had lower muscle mass (0.05±0.006 vs. 0.14±0.01g), higher phosphorylation of AKT, 4E‐BP1 and eIF4G, lower AMPK, eIF2α, YAP phosphorylation, and lower LC3‐II and MuRF1 abundance than controls. These findings suggest that cholanemia stimulates translation initiation, and represses autophagy and protein degradation signaling despite physical evidence of muscle atrophy. (Supported by Pediatric Critical Care Internal Funding)