通过下一代布鲁顿的氨酸激酶抑制剂Acalabrutinib进行心律失常性心室重塑
Yanan Zhao1, Praloy Chakraborty1, Julianna Tomassetti1
1Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2M1, Canada.
International journal of molecular sciences
|June 19, 2024
概括
易布鲁替尼和阿卡拉布鲁替尼都会增加心室心律不整的风险. 下一代药物阿卡拉布鲁丁尼显示出更高的心律失常规性,表明潜在的前节律效应类似于易布鲁丁尼.
科学领域:
- 心血管药理学心血管药理学
- 心脏电生理学 心脏电生理学
- 瘤学 药物安全 药物安全
背景情况:
- 易布鲁替尼 (IBR) 是第一代布鲁顿的氨酸激酶抑制剂 (BTKi),与心律失常有关.
- 下一代BTKi的acalabrutinib (ABR) 已经显示出较少的心房律乱事件,但其心室律乱 (VA) 风险尚不清楚.
研究的目的:
- 为了研究慢性阿卡拉布鲁丁尼 (ABR) 治疗对心室心律不整的脆弱性和电生理学的影响.
- 为了比较ABR与IBR对心脏功能和心律失常风险的影响.
主要方法:
- 在雄性Sprague-Dawley大鼠中进行心上光学映射,以评估心室电压和Ca2+动态.
- 通过电刺激诱导心室心律失常的ex-vivo透气心脏模型.
- 对体Ca2+和心室组织中的代谢调节蛋白质的蛋白质分析.
主要成果:
- 无论是ABR和IBR治疗都增加了VA的脆弱性,ABR表现出更高的规律性指数 (RI).
- 这两种药物都降低了导电速度 (CV) 和增加了CV分散,同时增加了透气Ca2+泄漏和Ca2+替代物.
- IBR,但不是ABR,缩短了动作潜力持续时间 (APD) 并导致APD变换. 两者都降低了SERCA2a表达和AMPK酸化.
结论:
- 阿卡拉布鲁丁尼 (ABR) 治疗通过诱导Ca2+信号和心脏电生理学中的前节律变化增加了腹腔失常风险,类似于易布鲁丁尼 (IBR).
- ABR和IBR的明显的电生理效应可能解释VA脆弱性和特征的差异.
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