AUTHOR=Sutanto Henry , Heijman Jordi 

TITLE=Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

JOURNAL=Frontiers in Physiology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.587709

DOI=10.3389/fphys.2020.587709

ISSN=1664-042X

ABSTRACT=The antimalarial drug chloroquine and antimicrobial drug azithromycin have received significant attention during the COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection), and may influence the electrophysiological effects of chloroquine and azithromycin. 

Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of chloroquine and azithromycin using detailed in silico models of ventricular electrophysiology. Concentration-dependent alterations in ion-channel function were incorporated into the Heijman canine and O’Hara-Rudy human ventricular cardiomyocyte models. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 1000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol-induced changes in ion-channel function. 

In the canine ventricular model at 1 Hz pacing, therapeutic doses of chloroquine and azithromycin (5 and 20 µM, respectively) individually prolonged AP duration (APD) by 33% and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 µM isoproterenol counteracted the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of isoproterenol. Similarly, chloroquine and azithromycin individually prolonged APD by 43% and 29% in the human ventricular cardiomyocyte model, while their combination prolonged APD by 76% without causing early afterdepolarizations. Consistently, 1 µM isoproterenol at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the ICa,L window current produced afterdepolarizations, which were exacerbated by isoproterenol. In both models, reduced extracellular K+ reduced the repolarization reserve and increased drug effects. 

In conclusion, chloroquine- and azithromycin-induced proarrhythmia is promoted by conditions with reduced repolarization reserve. Sympathetic stimulation limits drug-induced APD prolongation, suggesting the potential importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).