D801N in ATP1A3-encoded Na/K-ATPase alpha 3 causes cardiac arrhythmogenesis through sodium-calcium exchanger–mediated calcium overload

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Abstract
Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na + /K + -ATPase function, causing Ca 2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMs D801N ), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca 2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca² + influx via the Na + /Ca 2+ exchanger (NCX1) during depolarization was observed in iPSC-CMs D801N . Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca 2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca 2+ -mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.
Funding Information
  • Doris Duke Charitable Foundation (CSDA-2020098)
  • National Heart, Lung, and Blood Institute (R01-HL160654,R01-HL166217)
  • National Institute of General Medical Sciences (T32 GM007171)

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