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Quantifying arrhythmic long QT effects of hydroxychloroquine and azithromycin with whole-heart optical mapping and
Ilija Uzelac1, Abouzar Kaboudian1, Shahriar Iravanian2
1School of Physics, Georgia Institute of Technology, Atlanta, Georgia.
Insights
Hydroxychloroquine and azithromycin treatments for COVID-19 caused dangerous heart rhythm problems. Optical mapping revealed significant proarrhythmic effects, highlighting risks of repurposed drugs.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Drug Safety Evaluation
Background:
- Hydroxychloroquine (HCQ) and azithromycin (AZM) were authorized for COVID-19 treatment, despite limited safety data.
- Repurposed drug safety assessment presents challenges, particularly regarding cardiac risks.
Purpose of the Study:
- To investigate the proarrhythmic effects of HCQ and AZM, alone and combined, at high doses used in COVID-19 trials.
- To elucidate the underlying mechanisms of HCQ and AZM-induced cardiac arrhythmias.
Main Methods:
- Utilized ex vivo optical mapping in Langendorff-perfused guinea pig hearts with voltage-sensitive dyes.
- Employed numerical simulations using guinea pig and human cardiac cell models.
- Incorporated drug effects on ionic currents within cell and tissue models.
Main Results:
- HCQ, alone and with AZM, significantly prolonged QT intervals and increased spatial dispersion of action potential repolarization.
- Proarrhythmic discordant alternans were observed, indicating increased arrhythmia risk.
- AZM alone showed lesser arrhythmic effects; mathematical models did not fully replicate experimental findings.
Conclusions:
- Optical mapping effectively identifies drug-induced proarrhythmic mechanisms at cellular and organ levels.
- Alternative experimental and computational approaches are crucial for assessing risks of new and repurposed drugs during health crises.
- Findings underscore the importance of rigorous cardiac safety evaluations for repurposed medications.
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.
