What is the clinical evidence from this study?

Study design: Other. Population: Short QT syndrome associated with ATP1A3-D801N variant (n=2). Intervention: ORM-10103 (NCX1 inhibitor) vs. Vehicle. Primary outcome: Action potential duration and delayed afterdepolarizations.

What question did this study set out to answer?

The aim is to investigate how the D801N variant in ATP1A3 contributes to cardiac arrhythmias and calcium overload.

April 10, 2026Open Access

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

Q: What does this research mean for the field?

The ATP1A3-D801N variant causes cardiac arrhythmogenesis through NCX1-mediated calcium overload, leading to shortened action potential duration and delayed afterdepolarizations that can be rescued by NCX1 inhibition. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

In patient-derived cardiomyocytes, the ATP1A3-D801N variant caused shortened action potential duration and delayed afterdepolarizations via calcium overload, which was rescued by NCX1 inhibition with ORM-10103.

Key Points

The aim is to investigate how the D801N variant in ATP1A3 contributes to cardiac arrhythmias and calcium overload.
Utilized in silico modeling and patient-derived iPSC cardiomyocytes (iPSC-CMsD801N)
Measured action potential duration (APD) and calcium levels in iPSC-CMsD801N and wild-type (WT) cells
Assessed ion channel function and calcium influx during depolarization
Applied pharmacologic inhibition of NCX1 with ORM-10103 to evaluate its effect on APD and afterdepolarizations
iPSC-CMsD801N exhibited shorter APD and higher intracellular calcium levels compared to WT
Observed delayed afterdepolarizations (DADs) in iPSC-CMsD801N
Increased Ca²+ influx via NCX1 during depolarization in the variant group
Pharmacologic inhibition of NCX1 normalized APD and reduced DADs

Structured PICO

Does pharmacologic inhibition of NCX1 with ORM-10103 normalize action potential duration and reduce delayed afterdepolarizations in patient-derived iPSC-CMs with the ATP1A3-D801N variant?

Population

Patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from individuals with alternating hemiplegia of childhood (AHC) heterozygous for the ATP1A3-D801N variant, and in silico models

Intervention

Pharmacologic inhibition of NCX1 with ORM-10103

Comparator

Untreated iPSC-CMsD801N and Wild-type (WT) iPSC-CMs

Outcome

Action potential duration (APD), intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs)surrogate

The ATP1A3-D801N variant causes arrhythmogenesis via NCX1-mediated calcium overload, identifying NCX1 as a potential therapeutic target for these patients.

Limitations

Immaturity of iPSC-CMs, which lack well-developed T-tubules.
Did not directly assess the effect of the missense allele on the function of WT subunits.
Lack of an animal model that adequately recapitulates the cardiac pathology due to low Atp1a3 expression in animal hearts.
Systemic inhibition of NCX1 may affect exchanger function in noncardiac tissues.

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 Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.

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