Arrhythmias precede cardiomyopathy and remodeling of Ca 2+ handling proteins in a novel model of long QT syndrome

Deletion of QKP1507-1509 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. We generated a knock-in mouse presenting the delQKP1510-1512 mutation (Scn5a ) equivalent to human deletion. Scn5a 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 mice were prolonged. At the age of 4 weeks, Scn5a mice exhibited a remodeling leading to [Ca ] transients with higher amplitude and slower kinetics, combined with enhanced SR Ca load. SERCA2 expression was not altered. However, total phospholamban expression was higher whereas the amount of Ca -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, Scn5a cardiomyocytes showed larger Ca waves, correlated with the presence of afterdepolarizations during action potential recording. Ranolazine partially prevented action potential and QT interval prolongation in 4-week-old Scn5a mice and suppressed arrhythmias. The Scn5a 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.