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Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19
  • +17
  • Gongxin Wang,
  • Chieh-Ju Lu,
  • Andrew Trafford,
  • Xiaohui Tian,
  • Hannali Flores,
  • Piotr Maj,
  • Kevin Zhang,
  • Yanhong Niu,
  • Luxi Wamg,
  • yimei Du,
  • Xinying Ji,
  • Yanfang Xu,
  • Lin Wu,
  • Dan Li,
  • Herring Neil,
  • David Paterson ,
  • Christopher Huang,
  • Henggui Zhang,
  • Ming Lei,
  • Guoliang Hao
Gongxin Wang
Henan SCOPE Research Institute of Electrophysiology Co. Ltd.
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Chieh-Ju Lu
Henan SCOPE Research Institute of Electrophysiology Co. Ltd.
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Andrew Trafford
Manchester University
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Xiaohui Tian
Huaihe Hospital, Henan University
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Hannali Flores
The University of Manchester
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Piotr Maj
University of Oxford
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Kevin Zhang
Imperial College London
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Yanhong Niu
Fuwai Central China Cardiovascular Hospital
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Luxi Wamg
Henan SCOPE Research Institute of Electrophysiology Co. Ltd.
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yimei Du
Union Hospital
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Xinying Ji
Henan University
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Yanfang Xu
Hebei Medical University
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Lin Wu
Peking University First Hospital
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Dan Li
Uinversity of Oxford
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Herring Neil
University of Oxford
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David Paterson
Uinversity of Oxford
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Christopher Huang
University of Cambridge
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Henggui Zhang
The University of Manchester
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Ming Lei
Uinversity of Oxford
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Guoliang Hao
Henan SCOPE Research Institute of Electrophysiology Co. Ltd.
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Abstract

Background and Purpose: 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. Experimental Approach: We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay 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. Key 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. Conclusion and implications: 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.