Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada; British Columbia Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1A6, Canada.
Stem Cell Reports. 2019 May 14;12(5):996-1006. doi: 10.1016/j.stemcr.2019.03.011. Epub 2019 Apr 25.
Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.
依鲁替尼（IB）是一种口服布鲁顿酪氨酸激酶（BTK）抑制剂，已证明对 B 细胞癌症有效，但与心房颤动（AF）的发生率显著增加有关。我们采用细胞特异性分化方案和光学映射来研究 IB 和其他酪氨酸激酶抑制剂（TKI）对心房和心室人多能干细胞衍生心肌细胞（hPSC-CMs）的电压和钙瞬变的影响。IB 对心房 hPSC-CMs 表现出直接的细胞特异性作用，这可能会导致 AF 易感性。第二代 BTK 抑制剂则没有相同的作用。此外，IB 暴露与许多调节途径的室特异性差异调节有关，包括受体酪氨酸激酶途径，这可能与 AF 的发病机制有关。我们的研究首次证明了 hPSC 衍生的心房和心室心肌细胞的细胞类型特异性毒性，这可靠地再现了临床观察到的心脏毒性。
