Key result
Combined hydroxychloroquine and azithromycin synergistically inhibited IKr (IC50 7.7 µM) and IK1 channels, prolonging action potential duration and provoking ventricular arrhythmias in ex vivo hearts.
Why the study?
Experimental cardiac safety data were limited regarding the mechanisms of potential pro-arrhythmic effects of hydroxychloroquine alone or combined with azithromycin in COVID-19 management.
Does hydroxychloroquine alone or combined with azithromycin cause pro-arrhythmic electrophysiological changes in preclinical cardiac models?
Does hydroxychloroquine alone or combined with azithromycin cause pro-arrhythmic electrophysiological changes in preclinical cardiac models?
Effect estimate: IC50 7.7 µM
Combined HCQ and AZM treatment synergistically inhibits IKr and IK1, altering cellular Ca2+ signaling and action potential propagation, providing an electrophysiological basis for their pro-arrhythmic risk.
Hypothesis-generating for pro-arrhythmic risk of HCQ ± AZM; leaves open clinical translation in COVID-19.
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 IC 50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca 2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling. Results HCQ blocked I Kr and I K1 with IC 50 s (10±0.6 and 34±5.0 μM) within clinical therapeutic ranges, I Na and I CaL at higher IC 50 s, leaving I to and I Ks unaffected. AZM produced minor inhibition of I Na , I CaL , I Ks , and I Kr ,, sparing I K1 and I to . HCQ+AZM combined inhibited I Kr and I K1 with IC 50 s of 7.7±0.8 μM and 30.4±3.0 μM, sparing I Na , I CaL and I to . 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 Ca 2+ 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 I Kr and I K1 , thence altering cell Ca 2+ homeostasis. Conclusions Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting I Kr , I Ks with resulting effects on cellular Ca 2+ 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.
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Wang et al. (2020) studied COVID-19 (Cardiac safety/arrhythmogenesis). Hydroxychloroquine combined with azithromycin vs. Control (baseline/vehicle) or HCQ alone was evaluated on Inhibition of IKr (hERG) channel current (IC50 7.7 µM). Combined hydroxychloroquine and azithromycin synergistically inhibited IKr (IC50 7.7 µM) and IK1 channels, prolonging action potential duration and provoking ventricular arrhythmias in ex vivo hearts.
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