title: Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice.
abstract: BACKGROUND
  Reduced expression of connexin43 (Cx43) and sodium channel (Nav1.5) and increased expression of collagen (fibrosis) are important determinants of impulse conduction in the heart.
  
  
  OBJECTIVE
  To study the importance and interaction of these factors at very low Cx43 expression, inducible Cx43 knockout mice with and without inducible ventricular tachycardia (VT) were compared through electrophysiology and immunohistochemistry.
  
  
  METHODS
  Cx43(CreER(T)/fl) mice were induced with tamoxifen and killed after 2 weeks. Epicardial activation mapping was performed on Langendorff-perfused hearts, and arrhythmia vulnerability was tested. Mice were divided into arrhythmogenic (VT+; n = 13) and nonarrhythmogenic (VT-; n = 10) animals, and heart tissue was analyzed for Cx43, Nav1.5, and fibrosis.
  
  
  RESULTS
  VT+ mice had decreased Cx43 expression with increased global, but not local, heterogeneity of Cx43 than did VT- mice. Nav1.5-immunoreactive protein expression was lower in VT+ than in VT- mice, specifically at sites devoid of Cx43. Levels of fibrosis were similar between VT- and VT+ mice. QRS duration was increased and epicardial activation was more dispersed in VT+ mice than in VT- mice. The effective refractory period was similar between the 2 groups. Premature stimulation resulted in a more severe conduction slowing in VT+ than in VT- hearts in the right ventricle. Separate patch-clamp experiments in isolated rat ventricular myocytes confirmed that the loss of Cx43 expression correlated with the decreased sodium current amplitude.
  
  
  CONCLUSIONS
  Global heterogeneity in Cx43 expression and concomitant heterogeneous downregulation of sodium-channel protein expression and sodium current leads to slowed and dispersed conduction, which sensitizes the heart for ventricular arrhythmias.
authors.affiliation: Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands. J.A.Jansen@umcutrecht.nl
authors.forename: John A
authors.initials: JA
authors.lastname: Jansen
authors.forename: Maartje
authors.initials: M
authors.lastname: Noorman
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.forename: Mèra
authors.initials: M
authors.lastname: Stein
authors.forename: Sanne
authors.initials: S
authors.lastname: de Jong
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Toon A
authors.initials: TA
authors.lastname: van Veen
authors.forename: Jacques M
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.forename: Harold V
authors.initials: HV
authors.lastname: van Rijen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012306:Risk; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000473:pathology
chemical_list: D018031:Connexin 43; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; D003094:Collagen
references.citation: Circulation. 2004 Mar 2;109(8):1048-55
references.pmid: 14967725
references.citation: Physiol Rev. 2004 Apr;84(2):431-88
references.pmid: 15044680
references.citation: J Biol Chem. 2004 Sep 24;279(39):40748-54
references.pmid: 15272007
references.citation: Eur J Heart Fail. 2010 Sep;12(9):913-21
references.pmid: 20534605
references.citation: Circ Res. 2011 Jul 8;109(2):193-201
references.pmid: 21617128
references.citation: Mol Cell Biochem. 2003 Jan;242(1-2):135-44
references.pmid: 12619876
references.citation: Cardiovasc Res. 2006 Nov 1;72(2):241-9
references.pmid: 16914125
references.citation: Am J Physiol. 1990 Oct;259(4 Pt 2):H1254-63
references.pmid: 1699438
references.citation: Circulation. 2005 Sep 27;112(13):1927-35
references.pmid: 16172272
references.citation: Clin Sci (Lond). 1996 Jun;90(6):447-52
references.pmid: 8697713
references.citation: J Cardiovasc Electrophysiol. 2002 Sep;13(9):865-70
references.pmid: 12380923
references.citation: Neth Heart J. 2008 Oct;16(10):356-8
references.pmid: 18958260
references.citation: J Cardiovasc Electrophysiol. 1999 Oct;10(10):1361-75
references.pmid: 10515561
references.citation: J Mol Cell Cardiol. 2005 Mar;38(3):475-83
references.pmid: 15733907
references.citation: Circulation. 2001 Sep 4;104(10):1194-9
references.pmid: 11535579
references.citation: Cardiovasc Res. 2009 Jul 1;83(1):52-60
references.pmid: 19389723
references.citation: Circ Res. 2009 Sep 11;105(6):523-6
references.pmid: 19661460
references.citation: J Cardiovasc Electrophysiol. 1999 Oct;10(10):1390-401
references.pmid: 10515564
references.citation: FASEB J. 2003 Sep;17(12):1592-608
references.pmid: 12958166
references.citation: J Mol Cell Cardiol. 2004 Jan;36(1):101-10
references.pmid: 14734052
references.citation: Circulation. 2001 Dec 18;104(25):3069-75
references.pmid: 11748102
references.citation: Circ Res. 2001 Feb 16;88(3):333-9
references.pmid: 11179202
references.citation: Circ Res. 2011 Feb 4;108(3):294-304
references.pmid: 21164104
references.citation: Am J Cardiol. 1998 Mar 15;81(6):790-2
references.pmid: 9527097
references.citation: J Cardiovasc Electrophysiol. 2006 May;17(5):567-73
references.pmid: 16684038
references.citation: Heart Rhythm. 2008 Mar;5(3):438-48
references.pmid: 18313604
references.citation: Circ Res. 2007 Sep 28;101(7):703-11
references.pmid: 17673670