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

doi:10.3389/fphys.2021.730127

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

Front Physiol. 2022 Jan 27:12:730127. doi: 10.3389/fphys.2021.730127. eCollection 2021.

Authors

Luca Sala¹, Vladislav Leonov^{1

2}, Manuela Mura³, Federica Giannetti¹, Aleksandr Khudiakov¹, Alessandra Moretti^{4

5}, Lia Crotti^{1

6

7}, Massimiliano Gnecchi^{3

8}, Peter J Schwartz¹

Affiliations

¹ Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
² Department of Surgery, Dentistry, Pediatrics and Gynecology, Cardiovascular Science, The University of Verona, Verona, Italy.
³ Coronary Care Unit and Laboratory of Experimental Cardiology, Department of Cardiothoracic and Vascular Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
⁴ First Department of Medicine, Cardiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
⁵ DZHK (German Centre for Cardiovascular Research)-Partner Site Munich Heart Alliance, Munich, Germany.
⁶ Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.
⁷ Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
⁸ Unit of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

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.

Keywords: COVID-19; Long QT Syndrome; hydroxychloroquine; induced pluripotent stem cells; precision medicine; safety pharmacology.