title: Overexpression of SCN5A in mouse heart mimics human syndrome of enhanced atrioventricular nodal conduction.
abstract: BACKGROUND
  In enhanced atrioventricular (A-V) nodal conduction (EAVNC) syndrome, patients have short A-V conduction times. Multiple mechanisms have been proposed to explain EAVNC; however, the electrophysiological or molecular substrate responsible for it remains unclear.
  
  
  OBJECTIVE
  The purpose of this study was to test the hypothesis that overexpression of SCN5A in the mouse heart may provide an animal model mimicking EAVNC.
  
  
  METHODS
  Electrocardiogram, atrial, His bundle, and ventricular electrograms were recorded from wild-type (WT) and transgenic (TG) mice overexpressing human SCN5A. The sodium current and NaV1.5 expression were measured using patch-clamp and immunohistochemistry techniques.
  
  
  RESULTS
  The P-R interval in TG mice (13.6 ± 1.2 ms) was much shorter than that in WT mice (40.2 ± 0.59 ms). In TG isolated hearts, the A-V conduction time (14.4 ± 0.81 ms) during right atrial pacing was also shorter than that in WT hearts (39.5 ± 0.62 ms). Records of His bundle electrograms revealed that atrial-to-His and His-to-ventricular intervals were shorter in TG than in WT hearts. In addition, TG hearts had a shorter Wenckebach cycle length and A-V effective refractory period. The sodium current was 2-fold greater in TG ventricular myocytes than in WT ventricular myocytes. Flecainide prolonged the A-V conduction time in TG hearts to a value close to that in WT hearts. Nifedipine prolonged the atrial-to-His interval in WT hearts but not in TG hearts. Immunohistochemistry studies revealed increased NaV1.5 labeling in TG atrial and ventricular tissues, and NaV1.5 expression in A-V junction and A-V ring regions in TG hearts.
  
  
  CONCLUSIONS
  Enhanced A-V conduction in mice overexpressing SCN5A in the heart mimics the human syndrome of EAVNC. Thus, variants in sodium channel expression in the A-V nodal region may be an electrophysiological substrate responsible for EAVNC.
authors.affiliation: Department of Biology, Gilead Sciences, Fremont, California.
authors.forename: Gong Xin
authors.initials: GX
authors.lastname: Liu
authors.affiliation: Department of Experimental Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
authors.forename: Bastiaan J
authors.initials: BJ
authors.lastname: Boukens
authors.affiliation: Department of Biology, Gilead Sciences, Fremont, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Department of Biology, Gilead Sciences, Fremont, California. Electronic address: Sridharan.Rajamani@gilead.com.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001283:Atrioventricular Node / Q000187:drug effects / Q000503:physiopathology; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D004562:Electrocardiography / Q000379:methods; D006325:Heart Atria / Q000503:physiopathology*; D006329:Heart Conduction System / Q000002:abnormalities; D006352:Heart Ventricles / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse
keywords: Animal model; Enhanced atrioventricular nodal conduction; SCN5A