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

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.
(Copyright © 2018. Published by Elsevier Ltd.)