Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

Abstract

CLHH, HZ, ML and GLH are joint senior authors Article length: 6234 words, including figure legends and references, excluding abstract and acknowledgements 3 ABSTRACT 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 IC50 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 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 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 IKr and IK1, thence altering cell Ca 2+ homeostasis. Conclusions:Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs 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.

A High Fidelity Transmural Anisotropic Ventricular Tissue Model Function to Investigate the Interaction Mechanisms of Drug: An In-Silico Model for Pharmacotherapy

“…To understand the influence of different dosages of HCQ alone and in combination with AZM in the COVID-19 infected cardiac tissue, the cardiomyocyte's ionic current parameters are varied based on the clinical study reported by Wang et al, [21], and listed in Table 3. To the best of the author's knowledge, prior art studies have not considered the role of temperature (fever) arising due to COVID-19; in this study, we configure the computational model of the ventricular tissue with an elevated temperature of 313.15 Kelvin.…”

Science's Response to CoVID‐19

“…Hydroxychloroquine was given limited emergency use authorization by the FDA in combination with azithromycin, which was subsequently revoked [249] . More recently, (hydroxy)chloroquine has been declared ineffective in numerous CoVID‐19 trials [250] . Analysis across numerous publications indicates little beneficial effect of hydroxychloroquine on CoVID‐19.…”

“…Most studies above have focused on approved drugs, although some included molecules in “preclinical” evaluation. Given the situation, preclinical molecules were unlikely to lead to a timely solution, but, we believe that focusing solely on approved drugs was likely too narrow [250] . To explain this logic, we breakdown the trials process.…”

Science’s Response to COVID-19

“…233 Analysis across numerous publications indicates little beneficial effect of hydroxychloroquine on CoVID-19. The use of hydroxychloroquine with azithromycin may actually increase mortality 249 and negative symptoms associated with both drugs. 250 Some interest remains in (hydroxy)chloroquine serving as a prophylactic treatment against CoVID-19, 251 although recent reports are not encouraging.…”