Hydroxychloroquine induces long QT syndrome by blocking hERG channel

Abstract

Objective: In March 2022, more than 600 million cases of Corona Virus Disease 2019 (COVID-19) and about 6 million deaths have been reported worldwide. Unfortunately, while effective antiviral therapy has not yet been available, chloroquine (CQ)/hydroxychloroquine (HCQ) has been considered an option for the treatment of COVID-19. While many studies have demonstrated the potential of HCQ to decrease viral load and rescue patients' lives, controversial results have also been reported. One concern associated with HCQ in its clinical application to COVID-19 patients is the potential of causing long QT interval (LQT), an electrophysiological substrate for the induction of lethal ventricular tachyarrhythmias. Yet, the mechanisms for this cardiotoxicity of HCQ remained incompletely understood. Materials and methods: Adult New Zealand white rabbits were used for investigating the effects of HCQ on cardiac electrophysiology and expression of ion channel genes. HEK-293T cells with sustained overexpression of human-ether-a-go-go-related gene (hERG) K⁺ channels were used for whole-cell patch-clamp recordings of hERG K⁺ channel current (I_hERG). Quantitative RT-PCR analysis and Western blot analysis were employed to determine the expression of various genes at mRNA and protein levels, respectively. Results: electrocardiogram (ECG) recordings revealed that HCQ prolonged QT and RR intervals and slowed heart rate in rabbits. Whole-cell patch-clamp results showed that HCQ inhibited the tail current of hERG channels and slowed the reactivation process from inactivation state. HCQ suppressed the expression of hERG and hindered the formation of the heat shock protein 90 (Hsp90)/hERG complex. Moreover, the expression levels of connexin 43 (CX43) and Kir2.1, the critical molecular/ionic determinants of cardiac conduction thereby ventricular arrythmias, were decreased by HCQ, while those of Cav1.2, the main Ca²⁺ handling proteins, remained unchanged and SERCA2a was increased. Conclusion: HCQ could induce LQT but did not induce arrhythmias, and whether it is suitable for the treatment of COVID-19 requires more rigorous investigations and validations in the future.

Keywords

COVID-19 / hydroxychloroquine / LQT / hERG / Hsp90

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