药物影响心肌离子通道功能可延迟或促进动作电位复极，分别延长或缩短心电图QT间期，药物延长QT间期引发心律失常的风险已被新药研发行业广泛认知。 然而对药物缩短QT间期的潜在风险迄今了解很少，国际技术指导原则对此亦无说明。我们的前期实验和以往报道均显示该类药物/化合物可引发室性心动过速和室颤，提示可能具较高的心律失常风险性。由于新药研发过程中此类缩短QT间期的活性化合物数目不断增加，因此亟待对其潜在风险加以评价。本项目以缩短QT间期的几种不同K+通道开放剂为工具药，采用离体灌流心脏记录心电图、离体乳头肌记录动作电位以及单细胞膜片钳记录K+电流等电生理技术从不同水平研究心脏不同靶点缩短QT药物的致心律失常风险特征，寻找致心律失常的风险标志物。

Ion channels are responsible for the currents that generate the cardiac action potential. Drug interactions with cardiac ion channels delay or promote the action potential repolarization，leading to a prolonged or shortened QT interval in the surface electrocardiogram (ECG). The prolongation of QT interval has been widely studied in view of its association with the cardiac arrhythmia torsades de pointes (TdP) and QT prolongation is routinely used as a safety biomarker in drug discovery and develpoment. In contrast, relatively little is known about the potential proarrhythmic risk of drug-induced QT shortening and thus the current regulatory guideline does not directly assess the concern. Several reports and our previous study have shown that QT interval-shortening drugs/compounds induce non-TdP-like ventricular tachycardia and ventricular fibrillation. Recent literature indicates that the number of compounds that induced QT shortening in drug discovery and there is a need to better understand the relavance of this change in the ECG. To highlight this potential issue and gain a better understanding of the existing experience of drug-induced QT shortening, this project was designed to address the following questions by using langendorff perfused heart and isolated singel cardiomyocytes: (1) potential proarrhythmia effects of QT-shortening drugs targetting different K+ channels and the risk factors for the occurrence of arrhythmia; (2) mechanisms underlying the proarrhythmia effects; (3) new surrogate markers for prediction of the arrhythmia risk for QT-shortening drugs. The result will be critically important for the clinical and the the commercial risks in drug doscovery and development.

药物影响心肌离子通道功能可延迟或促进动作电位复极，分别延长或缩短心电图QT间期，药物延长QT间期引发心律失常的风险已被新药研发行业广泛认知，然而对药物缩短QT间期的潜在风险及其标志物迄今了解很少，由于新药研发过程中此类缩短QT间期的活性化合物数目不断增加，因此亟待对其潜在风险加以评价。本项目以缩短QT间期的几种不同K+通道开放剂为工具药，采用电生理技术研究缩短QT药物的致心律失常风险特征，寻找致心律失常的风险标志物，揭示心律失常发生的机制。我们的研究发现，在离体灌流心脏不同K+通道开放剂浓度依赖性缩短QT间期，引发非TdP样的VT/VF，豚鼠心脏比兔心脏具有更高的心律失常易感性。ECG参数中JTpeak间期的缩短和JT area的增大是预测QT缩短药物潜在致心律失常风险的标志物。选择性增大早期复极电流，缩短早期复极动作电位时程，缩短有效不应期，可能是此类药物引发兴奋折返产生VT/VF的细胞机制。以上的实验结果为创新药物非临床安全性评价提供了新的参考，同时为解释药物致心律失常机制、临床规避药物风险提供了新的实验依据。