Abstract：
BACKGROUND: Ibrutinib, a Bruton\'s tyrosine kinase inhibitor used in cancer therapy, exerts ventricular proarrhythmic effects; however, the underlying mechanisms remain unclear. Excitation-contraction coupling (E-C) disorders are pivotal for the genesis of ventricular arrhythmias (VAs), which arise mainly from the right ventricular outflow tract (RVOT). In this study, we aimed to comprehensively investigate whether ibrutinib regulates the electromechanical activities of the RVOT, leading to enhanced arrhythmogenesis, and explore the underlying mechanisms.
METHODS: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes.
RESULTS: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 μM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes.
CONCLUSIONS: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.
METHODS: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes.
RESULTS: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 μM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes.
CONCLUSIONS: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.
摘要：
背景：伊布替尼，用于癌症治疗的布鲁顿酪氨酸激酶抑制剂，发挥室性心律失常作用；然而，潜在机制尚不清楚.兴奋-收缩耦合（E-C）障碍对于室性心律失常（VA）的发生至关重要，主要来自右心室流出道（RVOT）。在这项研究中,我们旨在全面调查ibrutinib是否调节RVOT的机电活动，导致心律失常发生，并探索潜在的机制。
方法：我们利用常规微电极在用依鲁替尼（10、50和100nM）治疗前后同步记录兔RVOT组织制剂中的电和机械反应，并研究其在编程电刺激期间的电相互作用和心律失常发生。荧光比技术用于测量分离的RVOT肌细胞中的细胞内钙浓度。
结果：依鲁替尼（10-100nM）缩短了动作电位持续时间。100nM的Ibrutinib显着增加了起搏引起的室性心动过速（VT）（从0％到62.5％，n=8,p=0.025)。起搏引起的VT与非VT发作之间的比较表明，VT发作与非VT发作相比，收缩力增加更大（402.1±41.4％vs.232.4±29.2%，p=0.003)。雷诺嗪（10μM，晚期钠电流阻滞剂）预防了依鲁替尼诱导的VA的发生。伊布替尼（100nM）增加了晚期钠电流，减少细胞内钙瞬变，增强RVOT心肌细胞的钙渗漏。
结论：Ibrutinib由于机电反应失调而增加了RVOT中VAs的风险，可以通过雷诺嗪或阿帕明减毒。
方法：我们利用常规微电极在用依鲁替尼（10、50和100nM）治疗前后同步记录兔RVOT组织制剂中的电和机械反应，并研究其在编程电刺激期间的电相互作用和心律失常发生。荧光比技术用于测量分离的RVOT肌细胞中的细胞内钙浓度。
结果：依鲁替尼（10-100nM）缩短了动作电位持续时间。100nM的Ibrutinib显着增加了起搏引起的室性心动过速（VT）（从0％到62.5％，n=8,p=0.025)。起搏引起的VT与非VT发作之间的比较表明，VT发作与非VT发作相比，收缩力增加更大（402.1±41.4％vs.232.4±29.2%，p=0.003)。雷诺嗪（10μM，晚期钠电流阻滞剂）预防了依鲁替尼诱导的VA的发生。伊布替尼（100nM）增加了晚期钠电流，减少细胞内钙瞬变，增强RVOT心肌细胞的钙渗漏。
结论：Ibrutinib由于机电反应失调而增加了RVOT中VAs的风险，可以通过雷诺嗪或阿帕明减毒。
