Abstract Body (Do not enter title and authors here): Background: Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic channelopathy caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier K⁺ channel Kir2.1 responsible for I_K1. Patients with SQTS3 have life-threatening arrhythmias by mechanisms that are poorly understood. In ventricular cardiomyocytes, intrinsic polyamine blockade of Kir2.1 channels produces inward rectification, controlling the final phase of action potential (AP) repolarization to the resting potential.
Hypothesis and objectives: We investigated the electrophysiologic and arrhythmogenic mechanisms of SQTS3 using an in-vivo cardiac-specific mouse model of Kir2.1^M301K identified in a patient with the most extreme QT interval shortening reported in the literature. We hypothesized that exogenous administration of the long-chain polyamine spermine would prevent arrhythmias by increasing inward rectification and prolonging the AP duration (APD) and the QT interval in the Kir2.1^M301K mouse model.
Results: On ECG, the QT interval of Kir2.1^M301K mice was significantly short compared with wildtype mice (p<0.0001), recapitulating the electrical phenotype of the patient. Intracardiac programmed stimulation in Kir2.1^M301K mice resulted in rapid and long-lasting ventricular tachycardia episodes (p<0.001). Patch-clamping demonstrated extremely abbreviated AP in Kir2.1^M301K cardiomyocytes due to lack of inward-going rectification and increased I_K1 at voltages positive to -80mV (p<0.0001). Interestingly, the Kir2.1^M301K mutation reduced the voltage-gated cardiac Na⁺ current I_Na density (p<0.0001) reducing Na_V1.5 availability during the AP upstroke and the excitability. With super-resolution microscopy we showed that some pools of Kir2.1 and Na_V1.5 place close to each other at the sarcolemma. Spermine treatment (10mg/Kg/day i.p.) for 20 days prolonged the QT interval in Kir2.1^M301K and significantly reduced arrhythmia inducibility. Spermine prolonged the APD of Kir2.1^M301K cardiomyocytes and alleviated the I_K1 gain-of-function and I_Na defects caused by the mutation.
Conclusions: The mouse model of cardiac-specific Kir2.1^M301K successfully replicates the electrophysiological phenotype of the SQTS3 patient, providing a strong validation of our study's findings. The potential of exogenous administration of spermine as a novel and effective therapeutic strategy for the management of cardiac arrhythmias in SQTS3 patients is a promising avenue for further research and development.