title: A 50% reduction of excitability but not of intercellular coupling affects conduction velocity restitution and activation delay in the mouse heart.
abstract: BACKGROUND
  Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction. Clinical studies indicate that SCN5A (excitability) and/or Connexin43 (Cx43, intercellular coupling) expression in heart disease is reduced by approximately 50%. In this retrospective study we assessed the effect of reduced membrane excitability or intercellular coupling on conduction in mouse models of reduced excitability or intercellular coupling.
  
  
  RESULTS
  Epicardial activation mapping of LV and RV was performed on Langendorff-perfused mouse hearts having the following: 1) Reduced excitability: Scn5a haploinsufficient mice; and 2) reduced intercellular coupling: Cx43(CreER(T)/fl) mice, uninduced (50% Cx43) or induced (10% Cx43) with Tamoxifen. Wild type (WT) littermates were used as control. Conduction velocity (CV) restitution and activation delay were determined longitudinal and transversal to fiber direction during S(1)S(1) pacing and S(1)S(2) premature stimulation until the effective refractory period. In both animal models, CV restitution and activation delay in LV were not changed compared to WT. In contrast, CV restitution decreased and activation delay increased in RV during conduction longitudinal but not transverse to fiber direction in Scn5a heterozygous animals compared to WT. In contrast, a 50% reduction of intercellular coupling did not affect either CV restitution or activation delay. A decrease of 90% Cx43, however, resulted in decreased CV restitution and increased activation delay in RV, but not LV.
  
  
  CONCLUSIONS
  Reducing excitability but not intercellular coupling by 50% affects CV restitution and activation delay in RV, indicating a higher safety factor for intercellular coupling than excitability in RV.
authors.affiliation: Division of Heart & Lungs, Department of Medical Physiology, University Medical Center Utrecht, 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: 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; D002462:Cell Membrane / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D005786:Gene Expression Regulation; D006329:Heart Conduction System / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000378:metabolism; D013997:Time Factors
chemical_list: D018031:Connexin 43; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels