The Role of Lipophilic Bile Acids in the Development of Cirrhotic Cardiomyopathy

Abstract

Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to beta-adrenoceptor activation, and excitation-contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to beta-adrenoceptor activation, both of which appeared to result from altered ECC. beta-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed beta-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered beta-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and beta-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

Bile acids and cardiovascular function in cirrhosis

“…Zavecs and Battarbee have shown that acute exposure of cardiac muscle to cholic acid mimics several characteristics of cardiac dysfunction observed in cirrhotic rat models including depressed β‐adrenoceptor‐mediated inotropism and decreased depolarization‐dependent calcium entry. Furthermore, replacing lipophilic BAs with UDCA reduces cardiac impairment . By obtaining similar results in cirrhotic and noncirrhotic portal vein stenosis models, their results suggest that bile acids themselves are significant factors in the genesis of cirrhotic cardiomyopathy.…”

Bile acids induce arrhythmias: old metabolite, new tricks

“…These human experiments, which were faithfully reproduced in isolated adult mouse cardiomyocytes, further strengthen the long-held notion that high levels of circulating bile acids adversely affect myocardial cell biology. More importantly, these studies add clinical relevance to the animal studies which speculated a role for bile acids in the pathophysiology of cardiac dysfunction in cirrhosis,13 14 termed cirrhotic cardiomyopathy,15 16 which has a prevalence of ∼50% according to some studies 17 18. Electrocardiographic abnormalities, more specifically prolonged QT interval is a key derangement of cirrhotic cardiomyopathy and is known to cause sudden death in adults 19 20 and increases mortality risk in children21 with liver failure.…”

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart

“…Elevated serum bile acids have long been speculated to cause cirrhotic cardiomyopathy . In fact, bile was first observed to mediate cardiotoxicity almost a century ago .…”