Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin
Henry Sutanto, Jordi Heijman
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).