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

Aims: Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because I3-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with I3-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI).Methods: The impact of treatment with commonly used I3-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 factorsResults: The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with I3-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 I3-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that I3-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 I3-blockers.Conclusion: Together, our findings demonstrate that I3-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.