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Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

Gongxin Wang, Chieh-Ju Lu, Andrew W. Trafford, Xiaohui Tian, Hannali M Flores, Piotr Maj, Kevin Zhang, Yanhong Niu, Luxi Wang, Yimei Du, Xinying Ji, Yanfang Xu, Lin Wu, Dan Li, Neil Herring, David Paterson, Christopher L.-H. Huang, Henggui Zhang, Ming Lei, Guoliang Hao
doi: https://doi.org/10.1101/2020.05.21.108605
Gongxin Wang
1Henan SCOPE Research Institute of Electrophysiology Co. Ltd., China
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Chieh-Ju Lu
1Henan SCOPE Research Institute of Electrophysiology Co. Ltd., China
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Andrew W. Trafford
2Unit of Cardiac Physiology, Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, UK
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Xiaohui Tian
3Department of Pharmacy, Huaihe Hospital and College of Medicine, Henan University, China
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Hannali M Flores
4Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, UK
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Piotr Maj
5Department of Pharmacology, University of Oxford, Oxford, UK
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Kevin Zhang
6School of Medicine, Imperial College of London, UK
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Yanhong Niu
7Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
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Luxi Wang
1Henan SCOPE Research Institute of Electrophysiology Co. Ltd., China
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Yimei Du
8Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Xinying Ji
3Department of Pharmacy, Huaihe Hospital and College of Medicine, Henan University, China
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Yanfang Xu
9Department of Pharmacology, Hebei Medical University, China
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Lin Wu
10Department of Cardiology, Peking University First Hospital, Beijing, China
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Dan Li
11Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
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Neil Herring
11Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
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David Paterson
11Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
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Christopher L.-H. Huang
12Physiological Laboratory and Department of Biochemistry, University of Cambridge, UK
14Key Laboratory of Medical Electrophysiology of the Ministry of Education and Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Henggui Zhang
4Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, UK
12Physiological Laboratory and Department of Biochemistry, University of Cambridge, UK
14Key Laboratory of Medical Electrophysiology of the Ministry of Education and Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Ming Lei
5Department of Pharmacology, University of Oxford, Oxford, UK
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  • For correspondence: guoliang.hao@epscopelab.com ming.lei@pharm.ox.ac.uk
Guoliang Hao
1Henan SCOPE Research Institute of Electrophysiology Co. Ltd., China
11Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
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  • For correspondence: guoliang.hao@epscopelab.com ming.lei@pharm.ox.ac.uk
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ABSTRACT

Aims We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data.

Methods We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay (CiPA) Schema IC50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling.

Results HCQ blocked IKr and IK1 with IC50s (10±0.6 and 34±5.0 μM) within clinical therapeutic ranges, INa and ICaL at higher IC50s, leaving Ito and IKs unaffected. AZM produced minor inhibition of INa, ICaL, IKs, and IKr,, sparing IK1 and Ito. HCQ+AZM combined inhibited IKr and IK1 with IC50s of 7.7±0.8 μM and 30.4±3.0 μM, sparing INa, ICaL and Ito. Molecular modelling confirmed potential HCQ binding to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged PR, QRS and QT intervals, and caused prolonged, more heterogeneous, action potential durations and intracellular Ca2+ transients. These effects were accentuated with combined HCQ+AZM treatment, which then elicited electrical alternans, re-entrant circuits and wave break. Modelling studies attributed these to integrated HCQ and AZM actions reducing IKr and IK1, thence altering cell Ca2+ homeostasis.

Conclusions Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs with resulting effects on cellular Ca2+ signalling, and action potential propagation and duration. These findings provide an electrophysiological basis for recent FDA cardiac safety guidelines cautioning against combining HCQ/AZM when treating Covid-19.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • CLHH, HZ, ML and GLH are joint senior authors

  • A version ready for JCI

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 28, 2020.
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Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19
Gongxin Wang, Chieh-Ju Lu, Andrew W. Trafford, Xiaohui Tian, Hannali M Flores, Piotr Maj, Kevin Zhang, Yanhong Niu, Luxi Wang, Yimei Du, Xinying Ji, Yanfang Xu, Lin Wu, Dan Li, Neil Herring, David Paterson, Christopher L.-H. Huang, Henggui Zhang, Ming Lei, Guoliang Hao
bioRxiv 2020.05.21.108605; doi: https://doi.org/10.1101/2020.05.21.108605
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Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19
Gongxin Wang, Chieh-Ju Lu, Andrew W. Trafford, Xiaohui Tian, Hannali M Flores, Piotr Maj, Kevin Zhang, Yanhong Niu, Luxi Wang, Yimei Du, Xinying Ji, Yanfang Xu, Lin Wu, Dan Li, Neil Herring, David Paterson, Christopher L.-H. Huang, Henggui Zhang, Ming Lei, Guoliang Hao
bioRxiv 2020.05.21.108605; doi: https://doi.org/10.1101/2020.05.21.108605

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