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

Area of Science:

• Cardiology
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Short QT syndrome is a heritable arrhythmia disorder associated with sudden cardiac death.
• Alternating hemiplegia of childhood (AHC) patients can present with shortened QT intervals and increased risk of ventricular fibrillation, particularly those with the ATP1A3-D801N variant.

Purpose of the Study:

• To investigate the cardiac mechanism underlying arrhythmias in AHC patients with the ATP1A3-D801N variant.
• To determine if the D801N mutation impairs Na+/K+-ATPase function, leading to calcium overload and altered cardiac action potentials.

Main Methods:

• Utilized in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N).
• Measured action potential duration (APD), intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs).
• Assessed Ca2+ influx via the Na+/Ca2+ exchanger (NCX1) and L-type Ca2+ channel activity.

Main Results:

• iPSC-CMsD801N exhibited shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and increased DADs compared to wild-type.
• Increased Ca2+ influx via NCX1 was observed during depolarization in iPSC-CMsD801N.
• Reduced Na+/K+-ATPase function accelerated L-type Ca2+ channel inactivation, and NCX1 inhibition normalized APD and reduced DADs.

Conclusions:

• The ATP1A3-D801N variant impairs Na+/K+-ATPase, causing calcium overload and arrhythmogenesis in AHC patients.
• Enhanced NCX1 activity contributes to the shortened APD and DADs observed.
• NCX1 inhibition presents a potential therapeutic strategy for arrhythmias in ATP1A3-D801N carriers.