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Bile acids induce arrhythmias in human atrial myocardium—implications for altered serum bile acid composition in patients with atrial fibrillation
  1. Peter P Rainer1,2,
  2. Uwe Primessnig1,
  3. Sandra Harenkamp1,
  4. Bernhard Doleschal1,3,
  5. Markus Wallner1,
  6. Guenter Fauler4,
  7. Tatjana Stojakovic4,
  8. Rolf Wachter5,
  9. Ameli Yates6,
  10. Klaus Groschner3,
  11. Michael Trauner7,
  12. Burkert M Pieske1,
  13. Dirk von Lewinski1
  1. 1Division of Cardiology, Medical University of Graz, Graz, Austria
  2. 2Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  3. 3Institute for Biophysics, Medical University of Graz, and Institute of Pharmacology and Toxicology, Karl-Franzens University, Graz, Austria
  4. 4Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
  5. 5Department of Cardiology and Pneumology, Georg-August-University, Göttingen, Germany
  6. 6Division of Cardiac Surgery, Medical University of Graz, Graz, Austria
  7. 7Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Dr Peter P Rainer, Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; peter.rainer{at}medunigraz.at

Abstract

Objective High bile acid serum concentrations have been implicated in cardiac disease, particularly in arrhythmias. Most data originate from in vitro studies and animal models. We tested the hypotheses that (1) high bile acid concentrations are arrhythmogenic in adult human myocardium, (2) serum bile acid concentrations and composition are altered in patients with atrial fibrillation (AF) and (3) the therapeutically used ursodeoxycholic acid has different effects than other potentially toxic bile acids.

Methods and Results Multicellular human atrial preparations (‘trabeculae’) were exposed to primary bile acids and the incidence of arrhythmic events was assessed. Bile acid concentrations were measured in serum samples from 250 patients and their association with AF and ECG parameters analysed. Additionally, we conducted electrophysiological studies in murine myocytes.

Taurocholic acid (TCA) concentration-dependently induced arrhythmias in atrial trabeculae (14/28 at 300 µM TCA, p<0.01) while ursodeoxycholic acid did not. Patients with AF had significantly decreased serum levels of ursodeoxycholic acid conjugates and increased levels of non-ursodeoxycholic bile acids. In isolated myocytes, TCA depolarised the resting membrane potential, enhanced Na+/Ca2+ exchanger (NCX) tail current density and induced afterdepolarisations. Inhibition of NCX prevented arrhythmias in atrial trabeculae.

Conclusions High TCA concentrations induce arrhythmias in adult human atria while ursodeoxycholic acid does not. AF is associated with higher serum levels of non-ursodeoxycholic bile acid conjugates and low levels of ursodeoxycholic acid conjugates. These data suggest that higher levels of toxic (arrhythmogenic) and low levels of protective bile acids create a milieu with a decreased arrhythmic threshold and thus may facilitate arrhythmic events.

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