title: Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation.
abstract: 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.
  
  
  
  The purpose of this study was to investigate the ion current mechanism of arrhythmia and DCM caused by the LaminA-N195K variant.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Inhibition of late INamay be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation-related DCM.
authors: Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin.
authors: Yogananda S
authors: YS
authors: Markandeya
authors: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd., Osaka, Japan.
authors: Tadashi
authors: T
authors: Tsubouchi
authors: Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin.
authors: Timothy A
authors: TA
authors: Hacker
authors: Meriter UnityPoint Heart and Vascular Institute, Madison, Wisconsin.
authors: Matthew R
authors: MR
authors: Wolff
authors: Gilead Sciences, Foster City, California.
authors: Luiz
authors: L
authors: Belardinelli
authors: Cellular and Molecular Arrhythmia Research Program, Department of Medicine, University of Wisconsin, Madison, Wisconsin. Electronic address: rcb@medicine.wisc.edu.
authors: Ravi C
authors: RC
authors: Balijepalli
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D034904:Lamin Type A / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000069458:Ranolazine / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
chemical_list: D034904:Lamin Type A; C576142:Lmna protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000069458:Ranolazine
keywords: Cardiac arrhythmia; Lamin A/C mutation; Late sodium current; Ranolazine; Ventricular myocyte