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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.
Highlights
Drug repurposing is a key strategy aimed to identify new applications for compounds that have already been approved by regulatory authorities
A genotype-dependent effect was observed and it became evident in two conditions: after the acute (2 h) exposure to 10 μM HCQ, hiPSC-CMs from the two controls showed no effect on the spontaneous beating while ∼20% of the monolayers from the LQT1, ∼35% of the Jervell and Lange-Nielsen syndrome (JLNS) and ∼50% of the monolayers from the very severe CALM-LQTS temporarily halted the beating, which only partially recovered at longer timepoints (Figure 2)
We have demonstrated that HCQ can induce corrected FPD (cFPD) prolongation, with effects becoming important in susceptible subjects, at concentrations similar to those used in COVID-19 trials
Summary
Drug repurposing is a key strategy aimed to identify new applications for compounds that have already been approved by regulatory authorities. HCQ prolongs the QT interval (Saleh et al, 2020), with effects exacerbated in the presence of factors such as plasma electrolyte imbalance (e.g., hypokalemia) and fever, both frequently present in patients with COVID-19, or secondary organ dysfunction For these reasons, HCQ is classified by the CredibleMeds R database (Woosley et al, 2021) as a drug with a known risk of causing Torsades de Pointes (TdP) and which has to be avoided in patients with the congenital Long QT Syndrome (cLQTS) (Schwartz and Ackerman, 2013). The proarrhythmic potential of HCQ seems further enhanced by its administration in combination with Azhithromycin, a macrolide antibiotic proposed for the treatment of COVID-19 which can cause TdPs (Mercuro et al, 2020; Fiolet et al, 2021)
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