Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium

Background Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%–9% of patients during treatment, but the underlying mechanisms remain unclear. Objective The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms. Methods In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca2+ handling and action potentials in atrial myocytes were evaluated. Results Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca2+ handling disorders in atrial myocytes, such as reduced Ca2+ transient amplitude, enhanced spontaneous Ca2+ release, and reduced sarcoplasmic Ca2+ capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17. Conclusion The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca2+ handling disorders in the atrium. Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%–9% of patients during treatment, but the underlying mechanisms remain unclear. The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms. In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-β-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca2+ handling and action potentials in atrial myocytes were evaluated. Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca2+ handling disorders in atrial myocytes, such as reduced Ca2+ transient amplitude, enhanced spontaneous Ca2+ release, and reduced sarcoplasmic Ca2+ capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17. The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca2+ handling disorders in the atrium.