Hamrick Samantha K, John Kim C S, Tester David J, Giudicessi John R, Ackerman Michael J
Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Department of Cardiovascular Medicine, Clinician-Investigator Training Program, Mayo Clinic, Rochester, Minnesota.
Heart Rhythm. 2022 May;19(5):822-827. doi: 10.1016/j.hrthm.2021.12.029. Epub 2021 Dec 31.
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.
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.
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 APD 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.
Under baseline conditions (pH 7.4), there was no difference in APD 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 APD 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 APD was significantly higher in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (P <.0001).
Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD under baseline conditions, the physiological stress of either acidosis or HCQ treatment significantly prolonged APD in patient-specific, re-engineered heart cells.
在2019冠状病毒病（COVID-19）大流行的早期阶段，观察到心源性猝死（SCD）显著增加。p.S1103Y-SCN5A常见变异存在于约8%的非洲裔个体中，在缺氧诱导的酸中毒或使用延长QT间期药物的情况下，可能是一种依赖于环境的、易导致SCD的促心律失常多态性。
本研究的目的是在患者特异性诱导多能干细胞衍生心肌细胞（iPSC-CM）模型中，确定酸中毒和羟氯喹（HCQ）对p.S1103Y-SCN5A动作电位时程（APD）的影响。
从一名14岁的p.S1103Y-SCN5A阳性非裔美国男性中生成iPSC-CM。使用CRISPR/Cas9技术生成患者变异校正的iPSC-CM（同基因对照[IC]）。在酸中毒状态（pH 6.9）或用10μM HCQ治疗24小时之前和之后，使用FluoVolt电压敏感染料评估p.S1103Y-SCN5A iPSC-CM与IC相比的APD值。
在基线条件下（pH 7.4），p.S1103Y-SCN5A与IC iPSC-CM的APD值无差异（P=无显著性差异）。在酸中毒（pH 6.9）情况下，与IC iPSC-CM相比，p.S1103Y-SCN5A iPSC-CM的APD变化倍数显著增加（P<.0001）。同样，在用10μM HCQ治疗24小时后，与IC iPSC-CM相比，p.S1103Y-SCN5A iPSC-CM的APD变化倍数显著更高（P<.0001）。
尽管非洲特异性p.S1103Y-SCN5A常见变异在基线条件下对APD没有影响，但酸中毒或HCQ治疗的生理应激在患者特异性、重新构建的心脏细胞中显著延长了APD。
