title: Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract.
abstract: BACKGROUND
  In patients with Brugada syndrome, arrhythmias typically originate in the right ventricular outflow tract (RVOT). The RVOT develops from the slowly conducting embryonic outflow tract.
  
  
  OBJECTIVE
  We hypothesize that this embryonic phenotype is maintained in the fetal and adult RVOT and leads to conduction slowing, especially after sodium current reduction.
  
  
  RESULTS
  We determined expression patterns in the embryonic myocardium and performed activation mapping in fetal and adult hearts, including hearts from adult mice heterozygous for a mutation associated with Brugada syndrome (Scn5a1798insD/+). The embryonic RVOT was characterized by expression of Tbx2, a repressor of differentiation, and absence of expression of both Hey2, a ventricular transcription factor, and Gja1, encoding the principal gap-junction subunit for ventricular fast conduction. Also, conduction velocity was lower in the RVOT than in the right ventricular free wall. Later in the development, Gja1 and Scn5a expression remained lower in the subepicardial myocardium of the RVOT than in RV myocardium. Nevertheless, conduction velocity in the adult RVOT was similar to that of the right ventricular free wall. However, in hearts of Scn5a1798insD/+ mice and in normal hearts treated with ajmaline, conduction was slower in the RVOT than in the right ventricular wall.
  
  
  CONCLUSIONS
  The slowly conducting embryonic phenotype is maintained in the fetal and adult RVOT and is unmasked when cardiac sodium channel function is reduced.
authors: Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors: Bas J
authors: BJ
authors: Boukens
authors: Marc
authors: M
authors: Sylva
authors: Corrie
authors: C
authors: de Gier-de Vries
authors: Carol Ann
authors: CA
authors: Remme
authors: Connie R
authors: CR
authors: Bezzina
authors: Vincent M
authors: VM
authors: Christoffels
authors: Ruben
authors: R
authors: Coronel
mesh_terms: D000367:Age Factors; D000818:Animals; D053840:Brugada Syndrome / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology*; D006329:Heart Conduction System / Q000196:embryology* / Q000503:physiopathology*; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism* / Q000502:physiology; D009924:Organ Culture Techniques; D016278:Ventricular Function, Right / Q000502:physiology*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse
keywords: Brugada; Cx43; RVOT; Scn5a; development