Hydroxychloroquine and QT prolongation: reassuring data in approved indications

Pareek, Anil; Sharma, Tarun; Mehta, Ravi Tejraj

doi:10.1093/rap/rkaa044

Cited by 9 publications

(5 citation statements)

References 7 publications

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“…More modest or negligible effects are instead evoked in hiPSC-CMs from healthy donors, particularly at concentrations close to those used to treat rheumatic disease; this was consistent with data from clinical studies (Abella et al, 2021). Despite the highly controversial and debated (lack of) effectiveness for the prevention or treatment of COVID-19 (Axfors et al, 2021), the use of HCQ in a population of healthy individuals should not be stigmatized, as this compound has been successfully used for decades for the treatment of malaria, systemic lupus erythematosus and rheumatoid arthritis with more benefits than harm for patients (Wallace et al, 2012;Pareek et al, 2020), without significant increases in TdP risk at standard concentrations used in rheumatology (Taylor and White, 2004) and mainly only in association with co-prescribed QT-prolonging drugs and very high HCQ dosages (causal association) (Saint-Gerons and Tabarés-Seisdedos, 2021). Our report confirms this evidence.…”

Section: Discussionsupporting

confidence: 60%

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

Sala

Leonov

Mura

et al. 2021

Preprint

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In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 patients due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring may be challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after subchronic exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrate that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation in vitro and triggered arrhythmias that halted the beating at high concentration. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD values. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to quickly assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.

show abstract

Section: Discussionsupporting

confidence: 60%

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

Sala

Leonov

Mura

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Despite the highly controversial and debated (lack of) effectiveness for the prevention or treatment of COVID-19 ( Axfors et al, 2021 ), the use of HCQ in a population of healthy individuals should not be stigmatized, as this compound has been successfully used for decades for the treatment of malaria, systemic lupus erythematosus and rheumatoid arthritis with more benefits than harm for patients ( Wallace et al, 2012 ; Pareek et al, 2020 ), without significant increases in TdP risk at standard concentrations used in rheumatology ( Taylor and White, 2004 ) and mainly only in association with co-prescribed QT-prolonging drugs and very high HCQ dosages (causal association) ( Saint-Gerons and Tabarés-Seisdedos, 2021 ). Our report confirms this evidence.…”

Section: Discussionmentioning

confidence: 99%

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

et al. 2022

View full text Add to dashboard Cite

In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring is challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrated that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation and halted the beating at high concentration due to the combined effect of HCQ on multiple ion currents. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs. asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.

show abstract

“…Despite the highly controversial and debated (lack of) effectiveness for the prevention or treatment of COVID-19 (Axfors et al, 2021), the use of HCQ in a population of healthy individuals should not be stigmatized, as this compound has been successfully used for decades for the treatment of malaria, systemic lupus erythematosus and rheumatoid arthritis with more benefits than harm for patients (Wallace et al, 2012;Pareek et al, 2020), without significant increases in TdP risk at standard concentrations used in rheumatology (Taylor and White, 2004) and mainly only in association with coprescribed QT-prolonging drugs and very high HCQ dosages (causal association) (Saint-Gerons and Tabarés-Seisdedos, 2021). Our report confirms this evidence.…”

Section: Discussionmentioning

confidence: 99%

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: The case of hydroxychloroquine in COVID-19

Sala

Leonov²,

Mura³

et al. 2022

Vascular Pharmacology

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Hydroxychloroquine and QT prolongation: reassuring data in approved indications

Cited by 9 publications

References 7 publications

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: the case of hydroxychloroquine in COVID-19

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

Use of hiPSC-derived cardiomyocytes to rule out proarrhythmic effects of drugs: The case of hydroxychloroquine in COVID-19

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