TY - JOUR
T1 - Patient-specific, re-engineered cardiomyocyte model confirms the circumstance-dependent arrhythmia risk associated with the African-specific common SCN5A polymorphism p.S1103Y
T2 - Implications for the increased sudden deaths observed in black individuals during the COVID-19 pandemic
AU - Hamrick, Samantha K.
AU - John Kim, C. S.
AU - Tester, David J.
AU - Giudicessi, John R.
AU - Ackerman, Michael John
N1 - Funding Information:
We would like to thank the team in the Mayo Clinic Microscopy and Cell Analysis Core facility in Rochester, Minnesota, for their dedication to quality assistance and care with the equipment. Funding Sources: This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Disclosures: Dr Ackerman is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, and Pfizer. However, none of these entities were involved in this study in any manner. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Funding Information:
Funding Sources: This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Disclosures: Dr Ackerman is a consultant for Abbott, ARMGO Pharma, Boston Scientific, Daiichi Sankyo, Invitae, LQT Therapeutics, Medtronic, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, and Pfizer. However, none of these entities were involved in this study in any manner. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Publisher Copyright:
© 2021 Heart Rhythm Society
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Drug-induced long QT syndrome
KW - Induced pluripotent stem cell–derived cardiomyocyte
KW - Long QT syndrome
KW - p.Ser1103Tyr-SCN5A
UR - http://www.scopus.com/inward/record.url?scp=85123830914&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123830914&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2021.12.029
DO - 10.1016/j.hrthm.2021.12.029
M3 - Article
C2 - 34979239
AN - SCOPUS:85123830914
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
ER -