Key result
Combined hydroxychloroquine and azithromycin treatment exerts pro-arrhythmic ventricular events by synergistically inhibiting IKr and IKs, altering cellular Ca2+ signaling and action potentials.
Why the study?
Experimental cardiac safety data were limited regarding the potential pro-arrhythmic mechanisms of hydroxychloroquine alone or combined with azithromycin in COVID-19 management.
Does hydroxychloroquine alone or combined with azithromycin cause pro-arrhythmic ventricular events in experimental cardiac models?
Does hydroxychloroquine alone or combined with azithromycin cause pro-arrhythmic ventricular events in experimental cardiac models?
Combined hydroxychloroquine and azithromycin synergistically inhibit potassium channels and alter calcium signaling, providing an electrophysiological basis for their pro-arrhythmic effects and supporting FDA warnings against their combined use.
Answers are grounded in this paper and cite their sources.
Supports ECG monitoring with hydroxychloroquine-azithromycin in COVID-19; extends mechanistic evidence of IKr/IK1 inhibition to pro-arrhythmia.
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.
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Wang et al. (2020) studied Covid-19. Hydroxychloroquine (HCQ) alone or combined with azithromycin (AZM) was evaluated on Electrophysiological effects including IKr and IK1 inhibition. Combined hydroxychloroquine and azithromycin treatment exerts pro-arrhythmic ventricular events by synergistically inhibiting IKr and IKs, altering cellular Ca2+ signaling and action potentials.
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