title: Antiarrhythmic Action of Flecainide in Polymorphic Ventricular Arrhythmias Caused by a Gain-of-Function Mutation in the Nav 1.5 Sodium Channel.
abstract: BACKGROUND
  The cardiac sodium channel Nav 1.5, encoded by the gene SCN5A, is associated with a wide spectrum of hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large multigenerational family with exercise-induced polymorphic ventricular arrhythmias. The purpose of this study was to evaluate the molecular and clinical effects of flecainide administration on patients with this syndrome.
  
  
  METHODS
  Eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. The in vitro effects of flecainide were evaluated using the patch-clamp technique with HEK293 cells expressing the Nav 1.5 channel.
  
  
  RESULTS
  The flecainide treatment significantly reduced the frequency of PVCs during and after exercise. Next, the sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups.
  
  
  CONCLUSIONS
  The clinical investigations of the affected patients, as well as the molecular and pharmacological characterization of the SCN5A p.I141V mutation, provide new evidence supporting the association of this mutation with exercise-induced polymorphic ventricular arrhythmias. These data also demonstrate that flecainide may serve as an effective treatment for the defect in Nav 1.5 that leads to an increased sodium window current.
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Mohamed Y
authors.initials: MY
authors.lastname: Amarouch
authors.affiliation: Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Leinonen
authors.affiliation: Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Annukka
authors.initials: A
authors.lastname: Marjamaa
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.affiliation: Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widen
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D005424:Flecainide / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D018408:Patch-Clamp Techniques; D018879:Ventricular Premature Complexes / Q000188:drug therapy*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; D005424:Flecainide
keywords: Nav1.5-I141V; PVCs; cardiac arrhythmias; cardiac sodium channel; flecainide