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Sutanto, H; Heijman, J.
Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin
FRONT PHYSIOL. 2020; 11: 587709 Doi: 10.3389/fphys.2020.587709
Web of Science PubMed FullText FullText_MUG

Leading authors Med Uni Graz: Heijman Jordi
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Abstract:: The antimalarial drug, chloroquine (CQ), and antimicrobial drug, azithromycin (AZM), 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 CQ and AZM. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of CQ and AZM 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 1,000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol (ISO)-induced changes in ion-channel function. In the canine ventricular model at 1 Hz pacing, therapeutic doses of CQ and AZM (5 and 20 mu M, 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 mu M ISO counteracted the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of ISO. Similarly, CQ and AZM 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 mu M ISO at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the I-Ca,I-L window current produced afterdepolarizations, which were exacerbated by ISO. In both models, reduced extracellular K+ reduced the repolarization reserve and increased drug effects. In conclusion, CQ- and AZM-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).
Find related publications in this database (Keywords): arrhythmia; computational modeling; COVID-19; chloroquine; azithromycin; beta-adrenergic; electrophysiology-basic