Bile acids induce arrhythmias: old metabolite, new tricks

Bile acids (BAs) have traditionally been viewed as mere ‘detergent’ molecules responsible for absorption of dietary fats and lipid-soluble vitamins. However, over the past decade, research in the field of bile acid biology has provided evidence which redefine BAs as potent circulating signalling molecules with the ability to regulate cell biology, metabolism and function of various extrahepatic organs,¹ with potential effects on the heart. BAs are secreted in the duodenum and then reabsorbed efficiently from the ileum back to the liver via mesenteric and portal veins. This tightly regulated enterohepatic circulation is disrupted in diseases of the liver such as obstructive jaundice, intrahepatic cholestasis of pregnancy, chronic viral hepatitis and cirrhosis, which leads to spillage of these metabolites into the systemic circulation at pathologically high concentrations (>100–200 μmol/L), resulting in organ dysfunction.^{2, 3}

It has long been known that high levels of bile acids are toxic to the heart. The cardiotoxicity of bile acids was documented as early as 1863, by Röhrig, who showed that filtered ox bile when injected into the jugular veins of rabbits caused bradycardia, while repeated doses caused cardiac arrest, a phenomenon he described as ‘cardiac paralysis’. At the same time, Landois showed that bile induced bradycardia persisted despite denervation of the heart and proposed a direct cardiodepressant effect of bile on the heart.⁴ Wakim et al⁵ in 1939 followed these observations by demonstrating that whole bile as well as sodium taurocholate salt produced hypotension, bradycardia and rhythm disturbance in dogs in the absence as well as the presence of cardiac autonomic nerves. Joubert in 1978 showed that infusion of cholic acid (primary unconjugated bile acid in humans) induced dose-dependent bradycardia in a rodent heart.^{6, 7} In the late 1980s, Binah et al⁸ were the first to report that taurocholic acid (TCA; conjugated primary bile acid) reduced slow inward Na⁺ and Ca²⁺ current while increasing the outward K⁺ current, thus reducing the duration of action potential in the ventricular myocytes. TCA has been associated with fetal arrhythmias, fetal stress and intrauterine deaths in intrahepatic cholestasis of pregnancy, and its arrhythmogenic properties have been extensively studied in rodent models by Gorelik and Williamson over the past decade.^9–11 However, whether TCA and other bile acids induce electrocardiographic abnormalities in adult hearts was unknown, and was the main focus of the current study.

Rainer et al describe a series of elegant experiments to support their hypothesis that hydrophobic conjugated bile acid at high concentrations induce arrhythmias in humans. Using isolated human atrial trabeculae, the authors demonstrate that TCA has a dose-dependent increase in arrhythmic extra contractions, without affecting key functional parameters of the heart such as contractile force, diastolic tension and relaxation. They further show that hydrophilic bile acid ursodeoxycholic acid (UDCA) and its taurine conjugate do not induce arrhythmias even at high concentrations.¹² 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.

An additional observation of this study is the fact that serum levels of UDCA are lower, while serum levels of non-UDCA bile acids are higher in patients with arrhythmias. This suggests that bile acid ‘composition’ is equally important as bile acid ‘concentration’ in the pathogenesis of rhythm disturbance. This subtle but important clinical finding adds to the growing body of literature supporting the therapeutic efficacy of UDCA. UDCA has traditionally been used as a hepatoprotective agent in human cholestatic liver diseases.²² Recent rodent and human studies suggest that UDCA may have a cardioprotective role. It has been shown to protect rat neonatal cardiomyocytes from arrhythmogenic effects of TCA.²³ In a rat model of ischaemia-reperfusion injury, UDCA reduces cell death and apoptosis by Protein Kinase B (AKT)-mediated pathways.²⁴ A report published in 2012 in the Journal of American College of Cardiology shows that apart from being well tolerated, UDCA improves peripheral blood flow and is associated with improved liver function in patients with congestive heart failure (New York Heart Association (NYHA) Class II/III).²⁵ The Rainer study now adds a new facet to the biological importance, safety and therapeutic profile of UDCA.

The question that still remains unanswered is how these extracellular bile acids affect intracellular myocardial cell biology. It is possible that hydrophobic bile acids such as TCA, by virtue of their ‘detergent’-like properties alter the composition and structure of the cardiomyocyte cell membrane causing a direct damage to the cardiac ion channels, thus affecting Ca²⁺ signalling as this¹² and other studies imply.^26–28 It is also possible that the bile acids exert intracellular effect on pathways that regulate Ca²⁺ homoeostasis and signalling through membrane receptors such as muscarinic receptors²⁹ or the newly discovered bile acid receptor TGR5 which is present in rodent, rabbit and human hearts.^{1, 13, 30}

In summary, the observations made here help advance our understanding and knowledge of favourable as well as unfavourable effects of bile acids on the heart. These findings provide a springboard for conducting further in-depth studies looking into mechanisms of the bile acid-myocardial interaction, which will hopefully lead to rational therapeutic interventions which are seriously lacking in the field of cardiomyopathy and heart failure.