Electrophysiological and Proarrhythmic Effects of Hydroxychloroquine Challenge in Guinea-Pig Hearts

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

Research output: Contribution to journalArticlepeer-review


Hydroxychloroquine (HCQ), clinically established in antimalarial and autoimmune therapy, recently raised cardiac arrhythmogenic concerns when used alone or with azithromycin (HCQ+AZM) in Covid-19. We report complementary, experimental, studies of its electrophysiological effects. In patch clamped HEK293 cells expressing human cardiac ion channels, HCQ inhibited IKr and IK1 at a therapeutic concentrations (IC50s: 10 ± 0.6 and 34 ± 5.0 μM). INa and ICaL showed higher IC50s; Ito and IKs were unaffected. AZM slightly inhibited INa, ICaL, IKs, and IKr, sparing IK1 and Ito. (HCQ+AZM) inhibited IKr and IK1 (IC50s: 7.7 ± 0.8 and 30.4 ± 3.0 μM), sparing INa, ICaL, and Ito. Molecular induced-fit docking modeling confirmed potential HCQ-hERG but weak AZM-hERG binding. Effects of μM-HCQ were studied in isolated perfused guinea-pig hearts by multielectrode, optical RH237 voltage, and Rhod-2 mapping. These revealed reversibly reduced left atrial and ventricular action potential (AP) conduction velocities increasing their heterogeneities, increased AP durations (APDs), and increased durations and dispersions of intracellular [Ca2+] transients, respectively. Hearts also became bradycardic with increased electrocardiographic PR and QRS durations. The (HCQ+AZM) combination accentuated these effects. Contrastingly, (HCQ+AZM) and not HCQ alone disrupted AP propagation, inducing alternans and torsadogenic-like episodes on voltage mapping during forced pacing. O'Hara-Rudy modeling showed that the observed IKr and IK1 effects explained the APD alterations and the consequently prolonged Ca2+ transients. The latter might then downregulate INa, reducing AP conduction velocity through recently reported INa downregulation by cytosolic [Ca2+] in a novel scheme for drug action. The findings may thus prompt future investigations of HCQ's cardiac safety under particular, chronic and acute, clinical situations.

Original languageEnglish
Pages (from-to)1639-1653
Number of pages15
JournalACS Pharmacology & Translational Science
Issue number5
Early online date30 Aug 2021
Publication statusPublished - 8 Oct 2021


  • Covid-19
  • azithromycin
  • cardiac electrophysiology CiPA
  • hydroxychloroquine
  • ion channels


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