Arrhythmias precede cardiomyopathy and remodeling of Ca2+ handling proteins in a novel model of long QT syndrome.
J Mol Cell Cardiol
; 123: 13-25, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-30144447
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 ANDRESULTS:
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 2â¯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 4â¯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.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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
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Cálcio
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Cardiomiopatias
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
França