Details

Autor(en) / Beteiligte

• Montnach, Jérôme
• Chizelle, Franck F.
• Belbachir, Nadjet
• Castro, Claire
• Li, Linwei
• Loussouarn, Gildas
• Toumaniantz, Gilles
• Carcouët, Agnès
• Meinzinger, Anne Julia
• Shmerling, Doron
• Benitah, Jean-Pierre
• Gómez, Ana Maria
• Charpentier, Flavien
• Baró, Isabelle

Titel

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

Ist Teil von

• Journal of molecular and cellular cardiology, 2018-10, Vol.123, p.13-25

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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+/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 [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, Scn5a+/ΔQKP cardiomyocytes showed larger Ca2+ 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. 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. •A new SCN5A long QT syndrome mouse model recapitulates the human clinical phenotype.•The pathological late Na+ current contributes to the cardiac electrical dysfunctions.•The arrhythmias precede structural defects and key Ca2+ handling proteins remodeling.•Ranolazine, a late Na+ current inhibitor, reduces action potential and QT prolongation.