0417 : SCN5A+/ΔQKP mice present late sodium current associated with long QT syndrome, dilated cardiomyopathy and ranolazine-sensitive spontaneous ventricular arrhythmias

Deletion of QKP1507-1509 amino-acids in SCN5A gene product, the main cardiac Na+ channel Nav1.5, is associated with a large phenotypic spectrum of long QT syndrome (LQT3), dilated cardiomyopathy (DCM) and high incidence of youth sudden death. This mutation does not affect the peak Na+ current (INa) but rather increases the late/persistent Na+ current (INaL). In order to investigate the mechanisms implicated in the phenotype observed on the mutation carriers, a knock-in mouse model presenting the equivalent QKP1510-1512 mutation has been generated (Scn5a+/ΔQKP). Mouse ECGs were recorded weekly from the age of 3 weeks. Na+ current was recorded with the whole cell patch-clamp technique in ventricular myocytes isolated from 4-week-old mice. Histological analysis was performed in paraffin sections of hearts of 4-week-old mice. At the age of 3 weeks, mice were treated with acute administration of ranolazine (30mg/kg i.p.) or β- blocker propranolol (0.3-1-3mg/kg i.p.) to suppress arrhythmias. Scn5a+/ΔQKP mice in sinus rhythm displayed a prolonged QT interval (QTc = 64±2ms vs. 42±1ms in controls) with a high incidence of spontaneous ventricular extrasystoles and/or non-sustained tachycardia, leading to early mortality. Structural analysis showed right ventricular DCM. Voltage-dependent activation and inactivation properties were significantly altered in Scn5a+/ΔQKP mice, leading to an increase in the arrhythmogenic Na+ window current. INaL was enhanced by more than 2-fold in myocytes from Scn5a+/ΔQKP mice compared to control mice. At 3 weeks, ranolazine significantly decreased QTc and suppressed arrhythmias whereas propranolol alone had no beneficial effects. Scn5a+/ΔQKP mice recapitulate a large part of the diverse clinical phenotype of patients carrying the equivalent mutation. Our results show that the mutation induces a late Na+ current involved in the arrhythmogenic process. Ranolazine, rather than β-blockers, could be a good candidate for pharmacological treatment.