Higher doses of HCQ used in COVID-19 patients (an order of magnitude higher than the standard dose for malaria) coupled with pre-existing cardiac conditions increase the risk of cardiovascular side effects. Despite its safety at concentrations used for the treatment of the above conditions, the recent application of HCQ alone or in combination with azithromycin (AZM) in coronavirus disease-2019 (COVID-19) therapy has raised clinical safety concerns. Hydroxychloroquine (HCQ), an analogue of chloroquine, is an anti-parasitic and immunosuppressant treating malaria, rheumatoid arthritis, and systemic lupus erythematosus ( White, 2007). Our porcine heart slices provide a powerful platform to investigate mechanisms of drug cardiotoxicity. These findings indicate that HCQ and AZM alter cardiac function beyond QT prolongation with significant contractile dysfunction in intact cardiac tissue. Furthermore, pre-treating porcine heart slices with the L-type calcium channel agonist Bay K8644 prevented the effect of both drugs, while administration of Bay K8644 after drugs interventions largely reversed the effects, suggesting a mechanism involving inhibition of L-type calcium channels. Combination of HCQ and AZM induced a dose-dependent effect similar to HCQ alone. However, AZM monotherapy decreased contractile force and contraction kinetics only at higher concentrations (30 µM). Our results show that clinically relevant concentrations of HCQ monotherapy (1–10 µM) reduced contractile force and contraction kinetics in porcine slices in a dose-dependent manner. Here, we evaluated the cardiotoxic effect of HCQ and AZM applied alone or in combination on cardiac contractility by measuring contractile force and contraction kinetics in heart slices prepared from porcine hearts. Our group has pioneered the living heart slice preparation, an ex-vivo platform that maintains native cardiac tissue architecture and physiological electrical and contractile properties. HCQ and AZM have been associated with QT interval prolongation and drug-induced arrhythmias, however other cardiotoxicity mechanisms remain largely unexplored. The cardiotoxicity risk of hydroxychloroquine (HCQ) and azithromycin (AZM) has been the subject of intensive research triggered by safety concerns in COVID-19 patients. 2School of Biosciences and Medicine, University of Surrey, Guildford, United Kingdom.1School of Medicine, Jiangsu Vocational College of Medicine, Yancheng, China.Johnson 2 Changhao Wu 2 Patrizia Camelliti 2*
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