Repurposing polyamines to prevent life-threatening arrhythmias in Short QT Syndrome type 3.

Short QT Syndrome type 3 (SQTS3) is an inherited disorder marked by an abnormally short QT interval on ECG and a high risk of life-threatening arrhythmias, for which effective targeted therapies are lacking. SQTS3 is caused by Kir2.1 mutations that enhance the outward component of the strong inward rectifier potassium current (IK1), disrupting its normal voltage-dependent regulation and severely abbreviating the cardiac action potential. Using a mouse model of SQTS3 carrying the Kir2.1M301K mutation, we examine whether administration of polyamines, the fundamental blockers of Kir2.1 channels, could restore the normal QT interval and prevent arrhythmia. Male mutant mice display reduced IK1 rectification, reduced sodium channel function, QT interval shortening, and a high susceptibility to induced ventricular tachycardia. Here, we show that systemic polyamine administration restores strong IK1 rectification, rescues sodium current density, prolongs action potential duration and QT interval, and significantly reduces arrhythmia inducibility, identifying a potential therapeutic approach for SQTS, a life-threatening disease.