Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway

Background: Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients.However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated.Methods: We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF.Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells.Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups.To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes.Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation.Results: About 2.67% of patients developed atrial arrhythmias after ibrutinib administration.HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls.Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib.Inhibiting autophagy upregulated Cx43 and Cx40.Conclusions: The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy.