| First Author | Montnach J | Year | 2018 |
| Journal | J Mol Cell Cardiol | Volume | 123 |
| Pages | 13-25 | PubMed ID | 30144447 |
| Mgi Jnum | J:266290 | Mgi Id | MGI:6196197 |
| Doi | 10.1016/j.yjmcc.2018.08.019 | Citation | Montnach J, et al. (2018) Arrhythmias precede cardiomyopathy and remodeling of Ca(2+) handling proteins in a novel model of long QT syndrome. J Mol Cell Cardiol |
| abstractText | 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(+/DeltaQKP)) equivalent to human deletion. Scn5a(+/DeltaQKP) mice showed prolonged QT interval, conduction defects and ventricular arrhythmias at the age of 2weeks, and, subsequently, structural defects and premature mortality. The mutation increased Na(+) window current and generated a late Na(+) current. Ventricular action potentials from Scn5a(+/DeltaQKP) mice were prolonged. At the age of 4weeks, Scn5a(+/DeltaQKP) 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(+/DeltaQKP) 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(+/DeltaQKP) mice and suppressed arrhythmias. CONCLUSION: The Scn5a(+/DeltaQKP) 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. |
