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

Background: Lamin 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.

Objective: The purpose of this study was to investigate the ion current mechanism of arrhythmia and DCM caused by the LaminA-N195K variant.

Methods: A homozygous mouse line expressing the Lmna-N195K mutation (Lmna) that exhibited arrhythmia, DCM, and sudden death was used. Using whole cell patch-clamp technique, we measured action potential duration (APD), Na currents (I) in ventricular myocytes isolated from Lmna, and wild-type mice.

Results: Both peak and late I were significantly (P <.05) increased in Lmna ventricular myocytes. Similarly, Lmna ventricular myocytes exhibited significant (P <.005) prolongation of APD (time to 50% [APD] and 90% [APD] repolarization) and triggered activity. Acute application of ranolazine inhibited late I, shortened APD, and abolished triggered activity in Lmna ventricular myocytes.

Conclusion: Inhibition of late I may be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation-related DCM.