Quantifying arrhythmic long QT effects of hydroxychloroquine and azithromycin with whole-heart optical mapping and simulations

Heart Rhythm O2

Abouzar Kaboudian, PhD¹  Elizabeth M. Cherry, PhD²  Neal Bhatia, MD, FHRS³  Robert F. Gilmour, Jr., PhD⁴  Jimena G. Siles-Paredes, MSc⁴  Flavio H. Fenton, PhD⁵  Shahriar Iravanian, MD, MSE⁶  Hiroshi Ashikaga, MD, PhD⁶  Ilija Uzelac, PhD, MBA⁶  James C. Gumbart, PhD⁷ 

[1] Address reprint requests and correspondence: Dr Ilija Uzelac, School of Physics, Georgia Institute of Technology, 837 State St, Atlanta, GA 30332.;Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada;Cardiac Arrhythmia Service, Johns Hopkins University School of Medicine, Baltimore, Maryland;Division of Cardiology, Section of Electrophysiology, Emory University Hospital, Atlanta, Georgia;School of Computational Science and Engineering, Georgia Institute of Technology, Atlanta, Georgia;School of Physics, Georgia Institute of Technology, Atlanta, Georgia;Universidad Privada del Valle, Santa Cruz, Bolivia;

关键词: Alternans;    Action potential;    Arrhythmias;    Azithromycin;    COVID-19;    Cardiotoxic drugs;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: In March 2020, hydroxychloroquine (HCQ) alone or combined with azithromycin (AZM) was authorized as a treatment for COVID-19 in many countries. The therapy proved ineffective with long QT and deadly cardiac arrhythmia risks, illustrating challenges to determine the new safety profile of repurposed drugs. Objective: To investigate proarrhythmic effects and mechanism of HCQ and AZM (combined and alone) with high doses of HCQ as in the COVID-19 clinical trials. Methods: Proarrhythmic effects of HCQ and AZM are quantified using optical mapping with voltage-sensitive dyes in ex vivo Langendorff-perfused guinea pig (GP) hearts and with numerical simulations of a GP Luo-Rudy and a human O’Hara-Virag-Varro-Rudy models, for Epi, Endo, and M cells, in cell and tissue, incorporating the drug’s effect on cell membrane ionic currents. Results: Experimentally, HCQ alone and combined with AZM leads to long QT intervals by prolonging the action potential duration and increased spatial dispersion of action potential (AP) repolarization across the heart, leading to proarrhythmic discordant alternans. AZM alone had a lesser arrhythmic effect with less triangulation of the AP shape. Mathematical cardiac models fail to reproduce most of the arrhythmic effects observed experimentally. Conclusions: During public health crises, the risks and benefits of new and repurposed drugs could be better assessed with alternative experimental and computational approaches to identify proarrhythmic mechanisms. Optical mapping is an effective framework suitable to investigate the drug’s adverse effects on cardiac cell membrane ionic channels at the cellular level and arrhythmia mechanisms at the tissue and whole-organ level.

【 授权许可】

Unknown