Prolonged ursodeoxycholic acid administration reduces acute ischaemia-induced arrhythmias in adult rat hearts

Abstract

Acute myocardial ischaemia and reperfusion (I–R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague–Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

UDCA and INT-777 suppress cardiac fibrosis triggered by IL-11 through involvement of TGR5

“…The repurposing of UDCA is safely prescribed in the treatment of primary biliary cholangitis (Parés et al, 2006) and intrahepatic cholestasis of pregnancy (Ovadia et al, 2021), would be of clinical value as an antifibrotic agent. There is already mounting evidence that TGR5 agonists are beneficial in patients with heart failure (von Haehling et al, 2012), ischaemia-induced arrythmia in rat (Ferraro et al, 2020) and TAC mice (Eblimit et al, 2018). What is unclear is how the non-fibroblast-mediated effects of TGR5 signalling may affect the long-term function of the heart and other organs.…”

“…4F). It is known that UDCA cannot influence contractility in neonatal mouse myocytes despite promoting cAMP release (Ibrahim et al, 2018) although there is clear evidence that UDCA can influence electrophysiological properties of the heart, and reduce ischaemia-induced arrythmias (Ferraro et al, 2020; Miragoli et al, 2011; Schultz et al, 2016; Gorelik et al, 2003). In our recent publication, this was attributed to increased phosphorylation of connexin-43 proteins (Ferraro et al, 2020), which perhaps explains the increased contraction dynamics of slices treated with UDCA.…”

“…1C) may provide new targets which are more suited to a heart-specific treatment of cardiac fibrosis. Promisingly, there were no adverse events reported during two-week administration of UDCA in adult rats (Ferraro et al, 2020) or to patients for 4 weeks (von Haehling et al, 2012). Von Haehling et al showed that administration of UDCA can increase peripheral blood flow (von Haehling et al, 2012), however there was no indication if this was due to improvement of cardiac function or peripheral vasculature.…”

Enzymatic Synthesis of New Acetoacetate–Ursodeoxycholic Acid Hybrids as Potential Therapeutic Agents and Useful Synthetic Scaffolds as Well

“…UDCA is a primary BA in ursidae [ 4 ] and a secondary one in humans, where it is produced in the intestinal lumen by the bacterial-mediated epimerization of the 7α-hydroxyl group of the primary BA chenodeoxycholic acid (CDCA) [ 5 ]. In addition, used for the dissolution of cholesterol gallstones and the treatment of various liver diseases [ 6 ] (it is the only drug approved by the U.S. Food and Drug Administration for the treatment of primary biliary cirrhosis [ 7 ]), UDCA is now under investigation for its efficacy in the treatment of numerous conditions associated with inflammation and apoptosis including neurological [ 8 ] ocular [ 9 ], bowel [ 5 , 10 ], and cardiovascular diseases [ 11 , 12 , 13 ]. In recent years, the anticancer potential of UDCA has been highlighted by several studies evidencing its capability to limit tumor cell growth and to modulate different molecular pathways implicated in tumor cell growth and/or cell death [ 14 ].…”

The potential roles of stress‐induced phosphoprotein 1 and connexin 43 in rats with reperfusion arrhythmia

“…The most common manifestations of reperfusion arrhythmia (RA) are ventricular tachycardia and ventricular fibrillation (VF), which can lead to hemodynamic disorders and even sudden cardiac death 3 . Reperfusion therapy‐related arrhythmia has conferred an independent mortality risk factor 4 . Therefore, how to alleviate susceptibility to RA and protect myocardial functions effectively is always a hot spot in clinical research.…”