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

Luca Sala, Vladislav Leonov, Manuela Mura, Federica Giannetti, Aleksandr Khudiakov, Alessandra Moretti, Lia Crotti, Massimiliano Gnecchi, Peter J. Schwartz

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Article number730127
JournalFrontiers in Physiology
Volume12
DOIs
StatePublished - 27 Jan 2022
Externally publishedYes

Keywords

  • COVID-19
  • Long QT Syndrome
  • hydroxychloroquine
  • induced pluripotent stem cells
  • precision medicine
  • safety pharmacology

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