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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.
Hamrick, Samantha K; John Kim, C S; Tester, David J; Giudicessi, John R; Ackerman, Michael J.
  • Hamrick SK; 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, Win
  • John Kim CS; 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, Win
  • Tester DJ; 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, Win
  • Giudicessi JR; 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, Win
  • Ackerman MJ; 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, Win
Heart Rhythm ; 19(5): 822-827, 2022 05.
Article in English | MEDLINE | ID: covidwho-1587705
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, 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Arrhythmias, Cardiac / Myocytes, Cardiac / Black People / Induced Pluripotent Stem Cells / NAV1.5 Voltage-Gated Sodium Channel Type of study: Experimental Studies / Observational study / Prognostic study Topics: Variants Limits: Adolescent / Humans / Male Language: English Journal: Heart Rhythm Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Arrhythmias, Cardiac / Myocytes, Cardiac / Black People / Induced Pluripotent Stem Cells / NAV1.5 Voltage-Gated Sodium Channel Type of study: Experimental Studies / Observational study / Prognostic study Topics: Variants Limits: Adolescent / Humans / Male Language: English Journal: Heart Rhythm Year: 2022 Document Type: Article