Moscow Institute of Physics and Technology (National Research University), Dolgoprudny, Moscow Region, 141701, Russian Federation.
M.F. Vladimirsky Moscow Regional Clinical Research Institute, Moscow, 129110, Russian Federation.
Sci Rep. 2021 Jan 27;11(1):2336. doi: 10.1038/s41598-020-79085-5.
Cyclophosphamide (CP) is an anticancer drug, an alkylating agent. Cardiotoxicity of CP is associated with one of its metabolites, acrolein, and clinical cardiotoxicity manifestations are described for cases of taking CP in high doses. Nevertheless, modern arrhythmogenicity prediction assays in vitro include evaluation of beat rhythm and rate as well as suppression of cardiac late markers after acute exposure to CP, but not its metabolites. The mechanism of CP side effects when taken at low doses (i.e., < 100 mg/kg), especially at the cellular level, remains unclear. In this study conduction properties and cytoskeleton structure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from a healthy donor under CP were evaluated. Arrhythmogenicity testing including characterization of 3 values: conduction velocity, maximum capture rate (MCR) measurements and number of occasions of re-entry on a standard linear obstacle was conducted and revealed MCR decrease of 25% ± 7% under CP. Also, conductivity area reduced by 34 ± 15%. No effect of CP on voltage-gated ion channels was found. Conduction changes (MCR and conductivity area decrease) are caused by exposure time-dependent alpha-actinin disruption detected both in hiPSC-CMs and neonatal ventricular cardiomyocytes in vitro. Deviation from the external stimulus frequency and appearance of non-conductive areas in cardiac tissue under CP is potentially arrhythmogenic and could develop arrhythmic effects in vivo.
环磷酰胺 (CP) 是一种抗癌药物，属于烷化剂。CP 的心脏毒性与其中一种代谢物丙烯醛有关，临床心脏毒性表现见于大剂量 CP 治疗的病例。然而，现代体外致心律失常性预测检测包括评估节拍节奏和速率，以及急性暴露于 CP 后对心脏晚期标志物的抑制作用，但不包括其代谢物。在低剂量（即 < 100mg/kg）下服用 CP 时的副作用机制，特别是在细胞水平上，仍不清楚。在这项研究中，评估了来自健康供体的人诱导多能干细胞衍生心肌细胞（hiPSC-CMs）在 CP 下的传导特性和细胞骨架结构。进行了致心律失常性测试，包括 3 个值的特征：传导速度、最大捕获率 (MCR) 测量和在标准线性障碍物上折返次数，并发现 CP 下 MCR 降低 25%±7%。此外，电导率面积减少了 34%±15%。CP 对电压门控离子通道没有影响。CP 暴露时间依赖性肌动蛋白破坏导致的传导变化（MCR 和电导率面积降低）在 hiPSC-CMs 和体外新生心室心肌细胞中均有发现。CP 下的心脏组织偏离外部刺激频率和出现非传导区域可能有致心律失常作用，并可能在体内产生心律失常作用。
