B-AB13-04 A PATIENT-SPECIFIC RE-ENGINEERED CARDIOMYOCYTE MODEL CONFIRMS THE CIRCUMSTANCE-DEPENDENT ARRHYTHMIA RISK ASSOCIATED WITH THE AFRICAN-SPECIFIC COMMON SCN5A POLYMORPHISM (P.SER1103TYR): IMPLICATIONS FOR THE INCREASED SUDDEN DEATHS OBSERVED IN BLACKS DURING THE COVID-19 PANDEMIC

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Background

During the early stages of the COVID-19 pandemic, many cities throughout the world observed a marked increase in sudden cardiac death (SCD). The p.S1103Y-SCN5A common variant, present in ∼8-10% 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

In light of the FDA’s Emergency Use Authorization of hydroxychloroquine (HCQ), a potential QT-prolonging drug, we sought to ascertain the effects of acidosis and 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) were generated using CRISPR/Cas9 technology. FluoVolt voltage sensing dye was used to assess APD90 values in p.S1103Y-SCN5A-iPSC-CMs compared to isogenic control 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 significant difference in APD90 values of p.S1103Y-SCN5A iPSC-CMs (398 ± 7 ms, n=21) versus isogenic control (395 ± 6 ms, n=21, p = NS). The APD90 was prolonged significantly in p.S1103Y-SCN5A iPSC-CMs (477 ± 5 ms, Δ+79 ms, n=15, p < 0.0001) but not in isogenic control (377 ± 6 ms, Δ-21 ms, n=15, p = NS) at pH 6.9. Notably, while there was no change in APD90 values in isogenic control iPSC-CMs (394 ± 6 ms, n=15, p = NS), there was significant

Conclusion

Although the African-specific p.S1103Y-SCN5A common variant had no effect on APD under baseline conditions, the physiologic stress of either acidosis or HCQ treatment prolonged significantly the APD in patient-specific, re-engineered heart cells. Further study is needed to determine if the p.S1103Y-SCN5A common polymorphism and its circumstance-dependent reduction in repolarization reserve has contributed to the increased rate of SCDs and the racial outcome disparities observed during the

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