Abstract：
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.
BACKGROUND: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.
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.
BACKGROUND: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062.
摘要：
背景：依鲁替尼可以增加慢性淋巴细胞白血病（CLL）患者房颤（AF）的风险。然而,依鲁替尼诱发房颤的确切机制仍未完全阐明.
方法：我们调查了依鲁替尼治疗的新发房颤CLL患者的比例。进行光学作图以揭示依鲁替尼对HL-1细胞的致心律失常作用。荧光染色和蛋白质印迹用于比较依鲁替尼治疗组和对照组中的连接蛋白43和40表达。为了识别自噬表型，我们使用westernblot检测自噬相关蛋白，透射电镜对图片自噬体，并转染mCherry-GFP-LC3病毒以标记自噬体和溶酶体。给予羟氯喹作为自噬抑制剂以挽救依鲁替尼诱导的Cx43和Cx40降解。
结果：约2.67%的患者在依鲁替尼给药后出现房性心律失常。与对照相比,用依鲁替尼处理的HL-1细胞表现出降低的传导速度和更高的折返样心律失常发生率。在用依鲁替尼处理的HL-1细胞中，Cx43和Cx40表达减少，自噬标志物增加。抑制自噬上调Cx43和Cx40。
结论：依鲁替尼通过促进自噬对PI3K-AKT-mTOR信号通路的脱靶效应导致间隙连接蛋白降解和房性心律失常。
背景：ChiCTR2100046062，https://clin。larvol.com/trial-detail/ChiCTR2100046062.
方法：我们调查了依鲁替尼治疗的新发房颤CLL患者的比例。进行光学作图以揭示依鲁替尼对HL-1细胞的致心律失常作用。荧光染色和蛋白质印迹用于比较依鲁替尼治疗组和对照组中的连接蛋白43和40表达。为了识别自噬表型，我们使用westernblot检测自噬相关蛋白，透射电镜对图片自噬体，并转染mCherry-GFP-LC3病毒以标记自噬体和溶酶体。给予羟氯喹作为自噬抑制剂以挽救依鲁替尼诱导的Cx43和Cx40降解。
结果：约2.67%的患者在依鲁替尼给药后出现房性心律失常。与对照相比,用依鲁替尼处理的HL-1细胞表现出降低的传导速度和更高的折返样心律失常发生率。在用依鲁替尼处理的HL-1细胞中，Cx43和Cx40表达减少，自噬标志物增加。抑制自噬上调Cx43和Cx40。
结论：依鲁替尼通过促进自噬对PI3K-AKT-mTOR信号通路的脱靶效应导致间隙连接蛋白降解和房性心律失常。
背景：ChiCTR2100046062，https://clin。larvol.com/trial-detail/ChiCTR2100046062.
