Key result
Hydroxychloroquine inhibited IKr and IK1 channels and reduced action potential conduction velocities, which were accentuated and led to torsadogenic-like episodes when combined with azithromycin.
Why the study?
Hydroxychloroquine, used alone or with azithromycin in Covid-19, raised cardiac arrhythmogenic concerns.
HCQ alone and in combination with AZM exerts significant electrophysiological effects, including IKr and IK1 inhibition and action potential prolongation, providing a mechanistic basis for its proarrhythmic potential.
May underlie reported HCQ arrhythmogenicity; hypothesis-generating for in vivo confirmation.
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.
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Wang et al. (2021) studied this question. Hydroxychloroquine (HCQ) alone or with azithromycin (HCQ+AZM) was evaluated on Electrophysiological effects (IKr and IK1 inhibition, AP conduction velocities, APDs). Hydroxychloroquine inhibited IKr and IK1 channels and reduced action potential conduction velocities, which were accentuated and led to torsadogenic-like episodes when combined with azithromycin.
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