Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

Roden, Dan M.; Harrington, Robert A.; Poppas, Athena; Russo, Andrea M.

doi:10.1161/circulationaha.120.047521

Cited by 185 publications

(189 citation statements)

References 18 publications

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“…HiPSC-CMs could now serve as a cardiac-specific auxiliary cell type for in vitro pre-clinical efficacy studies for any drug aiming to stymie SARS-CoV-2 proliferation. In parallel, drug-induced arrhythmias and QT-interval prolongation can also be examined for antiviral compounds in pre-clinical development, given that some existing COVID-19 drug treatments exhibit these off-target cardiotoxicities (Roden et al, 2020). Due to the enormity of the current COVID-19 pandemic, and the increasing evidence for associated cardiac symptoms, innovative approaches using technologies such as the hiPSC-CMs presented here will critical to further understand and counteract SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Sharma

García

Arumugaswami

et al. 2020

Preprint

115

152

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words):Coronavirus disease 2019 is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well-understood. We used human induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) as a model system to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and immunofluorescence demonstrated that SARS-CoV-2 can enter and replicate within hiPSC-CMs, localizing at perinuclear locations within the cytoplasm. Viral cytopathic effect induced hiPSC-CM apoptosis and cessation of beating after 72 hours of infection. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating the mechanisms of infection and potentially a cardiac-specific antiviral drug screening platform.was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

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Section: Discussionmentioning

confidence: 99%

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Sharma

García

Arumugaswami

et al. 2020

Preprint

115

152

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“…In addition to renal and hepatic monitoring, the American College of Cardiology has released a position statement advocating for electrocardiographic/QT interval monitoring, correction of hypokalemia >4 mEq/L and hypomagnesemia >2 mg/dL, and avoiding other drugs that prolong QTc, such as azithromycin, when possible. 26 Patients on antiepileptics or who are diabetic should also be closely monitored, but the drugs are not contraindicated for use. Those with underlying conditions of heart disease, or renal or hepatic impairment may still receive the drug, but risks versus benefits should be extensively evaluated prior to doing so.…”

Section: Discussionmentioning

confidence: 99%

Emergency Authorization of Chloroquine and Hydroxychloroquine for Treatment of COVID-19

Piszczatoski

Powell

2020

Ann Pharmacother

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The world is suffering a respiratory pandemic disease caused by a novel coronavirus (2019-nCoV), commonly known as COVID-19 (coronavirus disease 2019). The Food and Drug Administration issued an emergency authorization for chloroquine and hydroxychloroquine as experimental treatments for COVID-19 leading to a shortage of both medications. A literature review conducted in April 2020 shows a lack of high-quality data available, resulting in ambiguous guideline recommendations. Decisions to use either drug should be made with careful consideration of risks versus benefits along with proper monitoring. Because of its higher potency and better safety profile, hydroxychloroquine may be the more reasonable treatment option if treatment is initiated.

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“…This fulfils expectations from its inhibition of IKr and IK1 and translates to the observed electrocardiographic QT prolongations. It is interesting to note that even prior to the Covid-19 pandemic, series of case reports have led to both HCQ and AZM being listed as definite causes of prolonged QT interval and risk of torsade de pointes for patients with long QT syndrome on crediblemeds.org (19).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

Wang¹,

Tian

Lu³

et al. 2020

Preprint

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CLHH, HZ, ML and GLH are joint senior authors Article length: 6234 words, including figure legends and references, excluding abstract and acknowledgements 3 ABSTRACT Aims:We investigate mechanisms for potential pro-arrhythmic effects of hydroxychloroquine (HCQ) alone, or combined with azithromycin (AZM), in Covid-19 management supplementing the limited available experimental cardiac safety data. Methods:We integrated patch-clamp studies utilizing In Vitro ProArrhythmia Assay (CiPA) Schema IC50 paradigms, molecular modelling, cardiac multi-electrode array and voltage (RH237) mapping, ECG studies, and Ca 2+ (Rhod-2 AM) mapping in isolated Langendorff-perfused guinea-pig hearts with human in-silico ion current modelling. Results:HCQ blocked IKr and IK1 with IC50s (10±0.6 and 34±5.0 µM) within clinical therapeutic ranges, INa and ICaL at higher IC50s, leaving Ito and IKs unaffected. AZM produced minor inhibition of INa, ICaL, IKs, and IKr,, sparing IK1 and Ito. HCQ+AZM combined inhibited IKr and IK1 with IC50s of 7.7±0.8 µM and 30.4±3.0 µM, sparing INa, ICaL and Ito. Molecular modelling confirmed potential HCQ binding to hERG. HCQ slowed heart rate and ventricular conduction. It prolonged PR, QRS and QT intervals, and caused prolonged, more heterogeneous, action potential durations and intracellular Ca 2+ transients. These effects were accentuated with combined HCQ+AZM treatment, which then elicited electrical alternans, re-entrant circuits and wave break. Modelling studies attributed these to integrated HCQ and AZM actions reducing IKr and IK1, thence altering cell Ca 2+ homeostasis. Conclusions:Combined HCQ+AZM treatment exerts pro-arrhythmic ventricular events by synergetically inhibiting IKr, IKs with resulting effects on cellular Ca 2+ signalling, and action potential propagation and duration. These findings provide an electrophysiological basis for recent FDA cardiac safety guidelines cautioning against combining HCQ/AZM when treating Covid-19.

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Considerations for Drug Interactions on QTc in Exploratory COVID-19 Treatment

Cited by 185 publications

References 18 publications

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection

Emergency Authorization of Chloroquine and Hydroxychloroquine for Treatment of COVID-19

Mechanistic insights into ventricular arrhythmogenesis of hydroxychloroquine and azithromycin for the treatment of COVID-19

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