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 (I_K1), disrupting its normal voltage-dependent regulation and severely abbreviating the cardiac action potential. Using a mouse model of SQTS3 carrying the Kir2.1^M301K 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 I_K1 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 I_K1 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.