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bioRxiv · 10.1101/2025.09.10.675300

Repurposing polyamines to prevent arrhythmias in Short QT Syndrome type 3, a potentially lethal disease

Moreno-Manuel, A. I.·Cruz, F. M.·Macias, A.·Cabrera-Borrego, E.·Jalife, J.
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Abstract

Short QT Syndrome type 3 (SQTS3) is a channelopathy characterized by the abbreviation of the QT interval on electrocardiogram and life-threatening arrhythmias. SQTS3 is caused by gain-of-function mutations in KCNJ2, which codes the strong inward rectifier potassium channel Kir2.1 responsible for the repolarizing current IK1. Inward- going rectification of IK1 is due to a voltage-dependent block by intracellular magnesium and polyamines. We evaluated the therapeutic potential of extrinsic polyamine administration to restore normal cardiac repolarization and prevent life-threatening arrhythmias in an AAV9-mediated mouse model of SQTS3 carrying the Kir2.1M301K mutation, which shortens the QT interval to a minimum of 194ms in patients. Compared to Kir2.1WT, the QT interval was significantly shortened in Kir2.1M301K mice. Intracardiac stimulation induced long-lasting, high-frequency ventricular tachycardia. Patch-clamping demonstrated an extremely abbreviated action potential duration (APD) in Kir2.1M301K cardiomyocytes due to a Kir2.1 lack of inward rectification. These IK1 defects decreased INa density and NaV1.5 expression. The mechanistically targeted Kir2.1 blockage by exogenous polyamines (spermine intraperitoneally or spermidine orally) prolonged the APD and the QT interval, and significantly reduced arrhythmia inducibility in Kir2.1M301K mice. Polyamines significantly reduced the IK1 gain-of-function, an effect that alleviated the INa reduction in mutant cardiomyocytes. Therefore, repurposing polyamine administration might be a novel and effective therapeutic strategy for managing cardiac arrhythmias in SQTS3 patients.

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Moreno-Manuel, A. I., Cruz, F. M., Macias, A., Cabrera-Borrego, E., Jalife, J.. 2025-09-16. Repurposing polyamines to prevent arrhythmias in Short QT Syndrome type 3, a potentially lethal disease. https://doi.org/10.1101/2025.09.10.675300

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