Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rainer, P.
The effects of Cholestasis on the Heart
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 80
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- Autor*innen der Med Uni Graz:
- Rainer Peter
- Betreuer*innen:
- Pieske Burkert Mathias
- Trauner Michael
- von Lewinski Dirk
- Altmetrics:
- 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, 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 atrial fibrillation and ECG parameters analyzed. Additionally, we conducted electrophysiological studies in murine myocytes and assessed expression of bile acid transporters and receptors in human hearts. Taurocholic acid concentration-dependently induced arrhythmias in atrial trabeculae (14/28 at 300µM TCA, p<0.01) while ursodeoxycholic acid did not. Patients with atrial fibrillation had significantly decreased serum levels of ursodeoxycholic acid conjugates and increased levels of non-ursodeoxycholic bile acids. In isolated myocytes, taurocholic acid depolarized the resting membrane potential, enhanced Na+/Ca2+ exchanger (NCX) tail current density, and induced afterdepolarizations. Inhibition of NCX prevented arrhythmias in atrial trabeculae. Conclusion: High taurocholic acid concentrations induce arrhythmia in adult human atria while ursodeoxycholic acid does not. Atrial fibrillation 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.