Background
During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, a marked increase in sudden cardiac death (SCD) was observed. The p.S1103Y-SCN5A common variant, which is present in ∼8% of individuals of African descent, may be a circumstance-dependent, SCD-predisposing, proarrhythmic polymorphism in the setting of hypoxia-induced acidosis or QT-prolonging drug use.
Objective
The purpose of this study was to ascertain the effects of acidosis and hydroxychloroquine (HCQ) on the action potential duration (APD) in a patient-specific induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of p.S1103Y-SCN5A.
Methods
iPSC-CMs were generated from a 14-year-old p.S1103Y-SCN5A-positive African American male. The patient’s variant-corrected iPSC-CMs (isogenic control [IC]) were generated using CRISPR/Cas9 technology. FluoVolt voltage-sensitive dye was used to assess APD90 values in p.S1103Y-SCN5A iPSC-CMs compared to IC before and after an acidotic state (pH 6.9) or 24 hours of treatment with 10 μM HCQ.
Results
Under baseline conditions (pH 7.4), there was no difference in APD90 values of p.S1103Y-SCN5A vs IC iPSC-CMs (P = NS). In the setting of acidosis (pH 6.9), there was a significant increase in fold-change of APD90 in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (P <.0001). Similarly, with 24-hour 10 μM HCQ treatment, the fold-change of APD90 was significantly higher in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (P <.0001).
Conclusion
Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD90 under baseline conditions, the physiological stress of either acidosis or HCQ treatment significantly prolonged APD90 in patient-specific, re-engineered heart cells.
【저자키워드】 Long QT syndrome, Drug-induced long QT syndrome, Induced pluripotent stem cell–derived cardiomyocyte, p.Ser1103Tyr-SCN5A, 【초록키워드】 COVID-19, Treatment, coronavirus disease, pandemic, Hydroxychloroquine, Stress, variant, polymorphism, cells, African, male, death, HCQ, African American, early stage, physiological, significant increase, individual, no difference, Effect, objective, SCD, Result, was used, significantly, condition, increase in, significantly higher, had no, conditions, 24 hour, APD, baseline, 【제목키워드】 COVID-19 pandemic, polymorphism, risk, arrhythmia, death, SCN5A, individual,