tetano
Editor, Senior Moderator
Heart Rhythm
. 2021 Dec 31;S1547-5271(21)02521-2.
doi: 10.1016/j.hrthm.2021.12.029. Online ahead of print.
A Patient-Specific Re-Engineered Cardiomyocyte Model Confirms the Circumstance-Dependent Arrhythmia Risk Associated with the African-Specific Common SCN5A Polymorphism (p.S1103Y): Implications for the Increased Sudden Deaths Observed in Black Individuals During the COVID-19 Pandemic
Samantha K Hamrick[SUP] 1 [/SUP], Cs John Kim[SUP] 1 [/SUP], David J Tester[SUP] 1 [/SUP], John R Giudicessi[SUP] 2 [/SUP], Michael J Ackerman[SUP] 3 [/SUP]
Affiliations
Abstract
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, present in ∼8% of individuals of African descent, may be a circumstance-dependent, SCD-predisposing, pro-arrhythmic polymorphism in the setting of hypoxia-induced acidosis or QT-prolonging drug use.
Objective: To ascertain the effects of acidosis and hydroxychloroquine (HCQ) on the action potential duration (APD) in a patient-specific induced pluripotent stem cell 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 sensing 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 versus isogenic control 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 < 0.0001). Similarly, with 24h 10 μM HCQ treatment, the fold-change of APD90 was significantly higher in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (p < 0.0001).
Conclusions: Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD90 under baseline conditions, the physiologic stress of either acidosis or HCQ treatment significantly prolonged the APD90 in patient-specific, re-engineered heart cells.
Keywords: DI-LQTS; LQTS; and p.S1103Y-SCN5A; drug-induced long QT syndrome; iPSC-CM; induced pluripotent stem cell-derived cardiomyocyte; long QT syndrome; p.Ser1103Tyr-SCN5A.
. 2021 Dec 31;S1547-5271(21)02521-2.
doi: 10.1016/j.hrthm.2021.12.029. Online ahead of print.
A Patient-Specific Re-Engineered Cardiomyocyte Model Confirms the Circumstance-Dependent Arrhythmia Risk Associated with the African-Specific Common SCN5A Polymorphism (p.S1103Y): Implications for the Increased Sudden Deaths Observed in Black Individuals During the COVID-19 Pandemic
Samantha K Hamrick[SUP] 1 [/SUP], Cs John Kim[SUP] 1 [/SUP], David J Tester[SUP] 1 [/SUP], John R Giudicessi[SUP] 2 [/SUP], Michael J Ackerman[SUP] 3 [/SUP]
Affiliations
- PMID: 34979239
- DOI: 10.1016/j.hrthm.2021.12.029
Abstract
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, present in ∼8% of individuals of African descent, may be a circumstance-dependent, SCD-predisposing, pro-arrhythmic polymorphism in the setting of hypoxia-induced acidosis or QT-prolonging drug use.
Objective: To ascertain the effects of acidosis and hydroxychloroquine (HCQ) on the action potential duration (APD) in a patient-specific induced pluripotent stem cell 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 sensing 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 versus isogenic control 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 < 0.0001). Similarly, with 24h 10 μM HCQ treatment, the fold-change of APD90 was significantly higher in p.S1103Y-SCN5A iPSC-CMs compared to IC iPSC-CMs (p < 0.0001).
Conclusions: Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD90 under baseline conditions, the physiologic stress of either acidosis or HCQ treatment significantly prolonged the APD90 in patient-specific, re-engineered heart cells.
Keywords: DI-LQTS; LQTS; and p.S1103Y-SCN5A; drug-induced long QT syndrome; iPSC-CM; induced pluripotent stem cell-derived cardiomyocyte; long QT syndrome; p.Ser1103Tyr-SCN5A.
