Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium
Ibrutinib promotes atrial fibrillation by inducing structural remodeling and calcium dysregulation in the atrium
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依鲁替尼通过诱导心房结构重塑和钙失调促进心房颤动
DOI：
10.1016/j.hrthm.2019.04.008
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发表时间：
2019-09-01
期刊：
影响因子：
5.5
通讯作者：
Ma, Chang-Sheng
中科院分区：
文献类型：
--
作者：
Jiang, Le;Li, Linling;Ma, Chang-Sheng
背景：伊替尼是一种以布鲁顿酪氨酸激酶为靶点的新型抗肿瘤药物，用于治疗慢性淋巴细胞白血病。房颤（Atrial fibrillation，AF）发生率为5%~ 9%，但其机制尚不清楚。目的建立伊鲁替尼（iveratinib）诱导的小鼠AF模型，探讨其预防AF的机制。（25 mg/kg/d）或溶媒（羟丙基-β-环糊精）分别经口给药4周。经食管脉冲刺激诱发房颤，并进行心脏超声心动图检查，以探讨房颤的发生机制。结果与对照组相比，伊曲替尼组房颤发生率高，房颤持续时间长，超声心动图显示左房重量增加，Masson三色染色显示左房心肌纤维化，房颤持续时间长，房颤持续时间长。（4）心房肌细胞内Ca ~（2+）处理障碍，如Ca ~（2+）瞬时振幅降低、自发性Ca ~（2+）释放增强、肌浆Ca ~（2+）容量降低;（6）CaMKII表达增加，RyR 2-Ser 2814和PLN-Thr 17磷酸化水平升高。结论口服伊鲁替尼4周可建立小鼠房颤模型。该模型的致炎机制可能与心房结构重塑和Ca 2+处理障碍有关。
BACKGROUND Ibrutinib is a novel antitumor drug that targets Bruton tyrosine kinase for treatment of chronic lymphocytic leukemia. Atrial fibrillation (AF) occurs in 5%-9% of patients during treatment, but the underlying mechanisms remain unclear.OBJECTIVE The purpose of this study was to develop a mouse model of ibrutinib-induced AF and investigate its proarrhythmic mechanisms.METHODS In C57BI/6 mice in the ibrutinib and control groups, ibrutinib (25 mg/kg/d) or vehicle (hydroxypropy1-beta-cyclodextrin), respectively, was administered orally for 4 weeks. Transesophageal burst stimulation then was used to induced AF. To evaluate the underlying mechanism of AF, cardiac echocardiography was performed. Ca2+ handling and action potentials in atrial myocytes were evaluated.RESULTS Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca2+ handling disorders in atrial myocytes, such as reduced Ca2+ transient amplitude, enhanced spontaneous Ca2+ release, and reduced sarcoplasmic Ca2+ capacity; (5) enhanced delayed after-depolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17.CONCLUSION The present study established a mouse model of AF by oral administration of ibrutinib for 4 weeks. The arrhythmogenic mechanisms underlying this model likely are associated with structural remodeling and Ca2+ handling disorders in the atrium.