Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation

BackgroundLamin A and C are nuclear filament proteins encoded by the LMNA gene. Mutations in the LMNA gene cause many congenital diseases known as laminopathies, including Emery–Dreifuss muscular dystrophy, Hutchinson–Gilford progeria syndrome, and familial dilated cardiomyopathy (DCM) with conduction disease. A missense mutation (N195K) in the A-type lamins results in familial DCM and sudden arrhythmic death.ObjectiveThe purpose of this study was to investigate the ion current mechanism of arrhythmia and DCM caused by the LaminA-N195K variant.MethodsA homozygous mouse line expressing the Lmna-N195K mutation (LmnaN195K/N195K) that exhibited arrhythmia, DCM, and sudden death was used. Using whole cell patch-clamp technique, we measured action potential duration (APD), Na+ currents (INa) in ventricular myocytes isolated from LmnaN195K/N195K, and wild-type mice.ResultsBoth peak and late INa were significantly (P <.05) increased in LmnaN195K/N195K ventricular myocytes. Similarly, LmnaN195K/N195K ventricular myocytes exhibited significant (P <.005) prolongation of APD (time to 50% [APD50] and 90% [APD90] repolarization) and triggered activity. Acute application of ranolazine inhibited late INa, shortened APD, and abolished triggered activity in LmnaN195K/N195K ventricular myocytes.ConclusionInhibition of late INa may be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation–related DCM