0038: SCN5A+/ΔQKP mice: new model of long QT syndrome associated with ventricular arrhythmias and dilated cardiomyopathy

Deletion of QKP1507–1509 amino-acids in the Nav1.5 voltage-gated Na+ channel is associated with a large phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy (DCM) and high incidence of youth sudden death. This mutation does not affect the peak Na+ current but rather increases the late Na+ current. In order to identify the mechanism of DCM in these patients, a knock-in mouse model presenting the equivalent to human QKP1507–1509 mutation, has been generated (Scn5a+/ΔQKP). Four groups of mice were studied: wild-type (Scn5a+/+), heterozygous flp deleter (Scn5a+/+–flp), heterozygous neomycin-ΔQKP (Scn5a+/neo) and Scn5a+/ΔQKP mice. Six-lead ECG were recorded on 3-week-old to 10-week-old mice. Acute Ranolazine treatment (30 mg/kg) was performed on 3-week-old mice. Action potential recording was performed on left atrium and right ventricle of 4-week-old mice. Echocardiography and histological studies were also performed on 4-week-old mice. Scn5a+/ΔQKP mice exhibited high early mortality with 50% of death at the age of 5–6 weeks. ECGs showed that 24/56 Scn5a+/ΔQKP exhibited ventricular extrasystoles and/or non-sustained ventricular tachycardia. Scn5a+/ΔQKP mice in sinus rhythm showed a prolonged QT interval (QTc = 78±6 ms, versus 46±2 ms in controls, n=22). Atrial and ventricular action potential recordings displayed action potential prolongation in Scn5a+/ΔQKP mice. In 4-week-old Scn5a+/ΔQKP mice, echocardiographic and histological analysis displayed cardiac diastolic dysfunction compared to control mice with right ventricle enlargement. Ten-week-old Scn5a+/ΔQKP mice showed signs of hypertrophic remodeling. Treatment with Ranolazine suppressed arrhythmias and QT heterogeneity in Scn5a+/ΔQKP mice. Scn5a+/ΔQKP mice reproduce the phenotype of the human mutation carriers, i.e. long QT syndrome, heart failure and increased risk of sudden death at a young age. We could hypothesize that part of early mortality could be attributed to arrhythmias.