获得性长QT综合症（LQTs）增加恶性心律失常发生，是抗肿瘤药物克唑替尼在心血管系统的严重副反应，影响了其应用，但其中机理尚未阐明。我们在临床上发现2名非小细胞肺癌患者在使用克唑替尼后出现显著的QT间期延长并导致停药，进一步对他们进行LQTs的常见单核苷酸多态性（SNP）筛查，提示2名患者在编码钠通道蛋白ɑ亚单位的SCN5A基因发生了R1193Q突变，该SNP是晚钠电流的功能获得性突变。综合文献及前期研究结果，我们提出如下假说：克唑替尼抑制PI3K-AKT通路增大晚钠电流延长QT间期，而R1193Q突变进一步增强晚钠电流使突变患者的疾病表型更为明显。本研究的目的是利用疾病特异性iPSC-CMs模型，探究克唑替尼致LQTs细胞电生理和分子生物机制，以及SCN5A基因多态性在相关表型中所起的作用，为临床个体化精准治疗提供新的思路和方法。

Drug induced long QT syndrome (LQTs) is thought to increase the incidence of malignant arrhythmias. LQTs caused by crizotinib is one of the most severe side effects on cardiovascular system, which limits the application of this kind of drugs in the patients with malignant tumor. In clinical practice, we found 2 patients with non-small cell lung cancer had significant QT interval prolongation after crizotinib use and led to discontinuation of the drug. Furthermore, we performed common single nucleotide polymorphisms (SNP) of LQTs screen on these two patients. The results suggested that both of the patients had a R1193Q mutation, which is a gain-of-function mutation in SCN5A producing late sodium current. Based on the systematic bioinformatic analyses and our previous findings, we propose the following hypothesis: crizotinib changes various late sodium current of cardiomyocytes and prolongs the QT interval through PI3K-AKT pathway, and R1193Q mutation may exacerbate the QT prolongation in mutant patients by enhancing late sodium current. The purpose of this study was to investigate the electrophysiological and molecular biological mechanisms of crizotinib-induced LQT and the role of individual SNPs in related phenotypes using disease-specific iPSC-CMs cell models, based on which the individualized therapeutic strategy would be developed.