1. Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis
- Author
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Desai, Moreshwar S, Eblimit, Zeena, Thevananther, Sundararajah, Kosters, Astrid, Moore, David D, Penny, Daniel J, and Karpen, Saul J
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Digestive Diseases ,Cardiovascular ,Heart Disease ,Chronic Liver Disease and Cirrhosis ,Liver Disease ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,ATP Binding Cassette Transporter ,Subfamily B ,Member 11 ,ATP-Binding Cassette Transporters ,Adrenergic beta-Agonists ,Animals ,Biomarkers ,Cardiomyopathies ,Cholestasis ,Cholic Acid ,Disease Models ,Animal ,Drug Resistance ,Liver ,Liver Cirrhosis ,Biliary ,Male ,Mice ,Inbred C57BL ,Mice ,Knockout ,Pyridines ,Recovery of Function ,Signal Transduction ,Time Factors ,Ventricular Function ,Left ,bile acid-myocardial interaction ,cardiac adaptation ,cholanaemia ,hepatic - cardiopathy ,liver injury ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
BackgroundTriggers 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.AimsWe 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.Methods6-8 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 analysed for key components of function and cell signalling. Cardiac physiological and molecular parameters were similarly analysed in Abcb11(-/-) mice (n = 5/grp) fed 0.5% cholic acid supplemented diet for 1 week.ResultsMice 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 physiological and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11(-/-) mice.ConclusionsCardiomyopathy resolves with resolution of liver injury, is associated with cholanaemia, and can be induced by BA feeding.
- Published
- 2015