title: Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction.
abstract: OBJECTIVE
  Reduced excitability and gap junction expression are commonly found in electrically remodelled diseased hearts, but their contribution to slow conduction and arrhythmias is unclear. In this study, we have investigated the effect of isolated and combined reductions in membrane excitability and intercellular coupling on impulse propagation and arrhythmogeneity in genetically modified mice.
  
  
  RESULTS
  Cx43 and Scn5a(1798insD/+) heterozygous (HZ) mice were crossbred to create a mixed offspring: wild-type (WT, n = 15), Cx43 HZ (n = 14), Scn5a(1798insD/+) (Scn5a) HZ (n = 17), and Cx43/Scn5a(1798insD/+) (Cx43/Scn5a) HZ (n = 15) mice. After ECG recording, epicardial activation mapping (208 recording sites) was performed on Langendorff-perfused hearts. Arrhythmia inducibility was tested by one to three premature stimuli and burst pacing. Conduction velocity longitudinal (CV(L)) and transverse (CV(T)) to fibre orientation and dispersion of conduction were determined during S1-S1 pacing (150 ms). Connexin43 (Cx43) and sodium channel Nav1.5 protein expression and myocardial tissue collagen content were determined by immunohistology. Compared with WT animals, P, QRS, and QTc intervals were prolonged in Scn5a HZ and Cx43/Scn5a HZ, but not in Cx43 HZ animals. Scn5a HZ mice showed decreased CV(L) in right ventricle (RV) but not in left ventricle compared with WT. In the RV of Cx43/Scn5a HZ, CV(T) was reduced, but CV(L) was not different from WT. Arrhythmia inducibility was low and not increased in either single- or double-mutant mice.
  
  
  CONCLUSIONS
  Reduction of both electrical coupling and excitability results in normal conduction velocity parallel to fibre orientation but in pronounced conduction slowing transverse to fibre orientation in RV only, although this does not affect arrhythmogeneity.
authors.affiliation: Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Yalelaan 50, Utrecht, The Netherlands.
authors.forename: Mèra
authors.initials: M
authors.lastname: Stein
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
authors.forename: Mohamed
authors.initials: M
authors.lastname: Boulaksil
authors.forename: Maartje
authors.initials: M
authors.lastname: Noorman
authors.forename: Leonie
authors.initials: L
authors.lastname: van Stuijvenberg
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Richard N W
authors.initials: RN
authors.lastname: Hauer
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002462:Cell Membrane / Q000502:physiology*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006329:Heart Conduction System / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007365:Intercellular Junctions / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels