PropertyValue
?: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 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 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 μM ISO at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the I(Ca,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).
is ?:annotates of
?:creator
?:doi
  • 10.3389/fphys.2020.587709
?:doi
?:journal
  • Front_Physiol
?:license
  • cc-by
?:pdf_json_files
  • document_parses/pdf_json/d5b2c481a1fea5d4d32c6304260885f113538dda.json
?:pmc_json_files
  • document_parses/pmc_json/PMC7642988.xml.json
?:pmcid
?:pmid
?:pmid
  • 33192602.0
?:publication_isRelatedTo_Disease
?:sha_id
?:source
  • Medline; PMC
?:title
  • Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin
?:type
?:year
  • 2020-10-22

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