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

Abstract Aim 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. Methods and results We generated a knock-in mouse presenting the delQKP1510–1512 mutation ( Scn5a +/ΔQKP ) equivalent to human deletion. Scn5a +/ΔQKP 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 +/ΔQKP mice were prolonged. At the age of 4 weeks, Scn5a +/ΔQKP mice exhibited a remodeling leading to [Ca 2+ ] i transients with higher amplitude and slower kinetics, combined with enhanced SR Ca 2+ load. SERCA2 expression was not altered. However, total phospholamban expression was higher whereas the amount of Ca 2+ -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 +/ΔQKP cardiomyocytes showed larger Ca 2+ 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 +/ΔQKP mice and suppressed arrhythmias. Conclusion The Scn5a +/ΔQKP 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.