Beta-blocker treatment of patients with atrial fibrillation attenuates spontaneous calcium release-induced electrical activity

• Published in: Biomedicine & pharmacotherapy 2023-02, Vol.158, p.114169-114169, Article 114169
• Main Authors: Jiménez-Sábado, Verónica, Casabella-Ramón, Sergi, Llach, Anna, Gich, Ignasi, Casellas, Sandra, Ciruela, Francisco, Chen, S.R. Wayne, Guerra, José M., Ginel, Antonino, Benítez, Raúl, Cinca, Juan, Tarifa, Carmen, Hove-Madsen, Leif
• Format: Article
• Language: English
• Subjects: Action Potentials; Adrenergic beta-Antagonists - pharmacology; Arrhythmia; Atrial Fibrillation - metabolism; Calcium - metabolism; Calcium currents; Calcium sparks; Cyclic AMP - metabolism; Heart Atria - metabolism; Human atrial myocyte; Humans; Myocytes, Cardiac - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic reticulum; β-blocker treatment
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.114169

Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because β-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with β-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI). The impact of treatment with commonly used β-blockers was analyzed in human atrial myocytes from 371 patients using patch-clamp technique, confocal calcium imaging or immunofluorescent labeling. Data were analyzed using multivariate regression analysis taking into account potentially confounding effects of relevant clinical factors The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with β-blockers did not affect ICa density in any group. By contrast, the ITI frequency was elevated in patients with either paroxysmal or chronic AF that did not receive treatment, and β-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that β-blocker treatment also reduced the calcium spark frequency in patients with AF to levels observed in those without AF. Furthermore, phosphorylation of the ryanodine receptor (RyR2) at Ser-2808 and phospholamban at Ser-16 was significantly lower in patients with AF that received β-blockers. Together, our findings demonstrate that β-blocker treatment may be of therapeutic utility to prevent spontaneous calcium release-induced atrial electrical activity; especially in patients with a history of paroxysmal AF displaying preserved ICa density. [Display omitted] •Multivariate analysis of clinical factors in big human atrial myocyte population.•β-blocker treatment normalizes Ca2+ spark and ITI frequency in patients with AF.•Decreased ICa in patients with chronic AF is not prevented by β-blocker treatment.•Treatment with β-blockers restores Ca2+ homeostasis in paroxysmal AF only.•β-blocker treatment may prevent Ca2+-induced electrical activity in paroxysmal AF.