{Reference Type}: Journal Article
{Title}: Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway.
{Author}: Qin H;Zheng B;Lin Z;Ji Y;Wang C;Zhu H;Cui C;Wang Z;Chen M;
{Journal}: Front Biosci (Landmark Ed)
{Volume}: 29
{Issue}: 5
{Year}: 2024 May 22
{Factor}: 3.115
{DOI}: 10.31083/j.fbl2905201
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy.<BR><B>BACKGROUND: </B>ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.