Li Shuang, Yue Liang, Xie Yulong, Zhang Henggui
Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom.
Front Physiol. 2024 Aug 13;15:1436727. doi: 10.3389/fphys.2024.1436727. eCollection 2024.
Remdesivir (RDV) is the first drug approved by the FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety of viruses, including Arenaviridae and Coronaviridae viral families. However, it has been reported that its clinical treatment leads to the symptoms of sick sinus syndrome such as sinus bradycardia, conduction block, and sinus arrest, but the electrophysiological mechanism of its specific cardiac adverse events is still unclear. We report complementary, experimental, studies of its electrophysiological effects. In wireless cardiac telemetry experiments and electrocardiographic studies in cardiac preparations, RDV significantly caused sinus bradycardia, sinus atrial block, and prolongation of the QT interval in guinea pigs. Dose-dependent effects of RDV on the electrical activities of sinoatrial node (SA node) preparations of guinea pigs were characterised by multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced sinoatrial conduction time (SACT), increased AP durations (APDs), and decreased the pacemaking rate of the SA node. Patch-clamp experiments showed that RDV significantly inhibited the I current of HCN4 channels, resulting in a significant decrease in the spontaneous firing rate of SA node cells, which may underlie the development of sick sinus node syndrome. In addition, RDV significantly inhibits I currents in hERG channels, leading to prolongation of the QT interval and playing a role in bradycardia. Therefore, these findings provide insights into the understanding the bradycardia effect of RDV, which may be used as basic theoretical guidance for the intervention of its adverse events, and prompt safety investigations of RDV's cardiac safety in the future.
瑞德西韦（RDV）是美国食品药品监督管理局（FDA）批准的第一种用于临床治疗新冠肺炎住院患者的药物，因为它已被证明对多种病毒具有良好的抗病毒活性，包括沙粒病毒科和冠状病毒科病毒家族。然而，有报道称其临床治疗会导致病态窦房结综合征的症状，如窦性心动过缓、传导阻滞和窦性停搏，但其特定心脏不良事件的电生理机制仍不清楚。我们报告了对其电生理效应的补充性实验研究。在无线心脏遥测实验以及心脏制剂的心电图研究中，RDV在豚鼠中显著引起窦性心动过缓、窦房传导阻滞和QT间期延长。通过多电极光学RH237电压标测对RDV对豚鼠窦房结（SA结）制剂电活动的剂量依赖性效应进行了表征。这些结果显示窦房传导时间（SACT）可逆性缩短、动作电位时程（APD）延长以及SA结起搏速率降低。膜片钳实验表明，RDV显著抑制HCN4通道的I电流，导致SA结细胞的自发放电率显著降低，这可能是病态窦房结综合征发生的基础。此外，RDV显著抑制hERG通道中的I电流，导致QT间期延长并在心动过缓中起作用。因此，这些发现为理解RDV的心动过缓效应提供了见解，这可能为干预其不良事件提供基础理论指导，并促使未来对RDV的心脏安全性进行安全性研究。
