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 (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. Results Both peak and late INawere significantly (P <.05) increased in LmnaN195K/N195Kventricular myocytes. Similarly, LmnaN195K/N195Kventricular 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/N195Kventricular myocytes. Conclusion Inhibition of late INamay be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation–related DCM.
Markandeya, Y. S., Tsubouchi, T., Hacker, T. A., Wolff, M. R., Belardinelli, L., & Balijepalli, R. C. (2016). Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation. Heart Rhythm, 13(11), 2228–2236. https://doi.org/10.1016/j.hrthm.2016.08.007