Arrhythmias precede cardiomyopathy and remodeling of Ca2+ handling proteins in a novel model of long QT syndrome

Aim: Deletion of QICP1507-1509 amino-acids in SCN5A gene product, the voltage-gated Na+ channel Nav1.5, has been associated with a large phenotypic spectrum of type 3 long QT syndrome, conduction disorder, dilated cardiomyopathy and high incidence of sudden death. The aim of this study was to develop and characterize a novel model of type 3 long QT syndrome to study the consequences of the QKP1507-1509 deletion. Methods and results: We generated a knock-in mouse presenting the delQKP1510-1512 mutation (Scn5a(+/)(Delta QKP)) equivalent to human deletion. Scn5a(+/)(Delta QKP) mice showed prolonged QT interval, conduction defects and ventricular arrhythmias at the age of 2 weeks, and, subsequently, structural defects and premature mortality. The mutation increased Na+ window current and generated a late Na+ current. Ventricular action potentials from Scn5a(+/)(Delta QKP) mice were prolonged. At the age of 4 weeks, Scn5a(+/)(Delta QKP) mice exhibited a remodeling leading to [Ca2+](i) transients with higher amplitude and slower kinetics, combined with enhanced SR Ca2+ load. SERCA2 expression was not altered. However, total phospholamban expression was higher whereas the amount of Ca2+-calmodulin-dependent kinase II (CaMKII)-dependent T17-phosphorylated form was lower, in hearts from 4-week-old mice only. This was associated with a lower activity of CaMKII and lower calmodulin expression. In addition, Scrt5a(+/)(Delta QKP) cardiomyocytes showed larger Ca2+ waves, correlated with the presence of after-depolarizations during action potential recording. Ranolazine partially prevented action potential and QT interval prolongation in 4-week-old Scri5a(+/)(Delta QKP) mice and suppressed arrhythmias. Conclusion: The Scri5a(+/)(Delta QKP) mouse model recapitulates the clinical phenotype of mutation carriers and provides new and unexpected insights into the pathological development of the disease in patients carrying the QKP1507-1509 deletion.