BackgroundIbrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear.Methods and ResultsThe effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na⁺ current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na⁺ current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K⁺ current, while acalabrutinib had no effects on SAN myocyte action potential firing.ConclusionsIbrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.

中文翻译：

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依鲁替尼和 Acalabrutinib 对小鼠心房和窦房结电生理和心律失常的不同影响

背景Ibrutinib 和acalabrutinib 是用于治疗B 细胞淋巴增生性疾病的Bruton 酪氨酸激酶抑制剂。依鲁替尼与新发心房颤动有关。依鲁替尼治疗后还报告了窦性心动过缓和窦性停搏的病例。相反，acalabrutinib 致心律失常的可能性较小。这些不同影响的基础尚不清楚。方法和结果在麻醉小鼠中使用心内电生理学、在离体心房制剂中使用高分辨率光学标测以及在离体心房和窦房结 (SAN) 中研究 ibrutinib 和 acalabrutinib 对心房电生理学的影响使用膜片钳的肌细胞。acalabrutinib 的急性给药不影响小鼠体内心房颤动易感性或心房电生理学的其他测量。光学映射表明依鲁替尼剂量依赖性地损害心房和 SAN 传导并减慢搏动率。Acalabrutinib 对心房和 SAN 传导或跳动率没有影响。在孤立的心房肌细胞中，依鲁替尼降低动作电位上冲速度和 Na⁺电流。相比之下，acalabrutinib 对心房肌细胞上行速度或 Na ⁺电流没有影响。两种药物都增加了动作电位持续时间，但与依鲁替尼相比，acalabrutinib 的这些影响较小，并且通过不同的机制发生。在 SAN 肌细胞中，依鲁替尼通过抑制延迟的整流器 K ⁺电流损害自发动作电位放电，而阿卡布替尼对 SAN 肌细胞动作电位放电没有影响。使用依鲁替尼增加心房颤动易感性和 SAN 功能障碍，但不使用阿卡拉布替尼。