Abstract
IntroductionComputer 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.Methods and ResultsEpicardial 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: Cx43CreER(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 S1S1 pacing and S1S2 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.ConclusionReducing 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.
Highlights
Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction
Reduced Membrane Excitability Conduction velocity restitution and activation delay curves of WT and Scn5a heterozygous Scn5a (HZ) animals are depicted in figure 2 (A to D)
This sudden increase in CVL in RV of Scn5a HZ animals close to the effective refractory period was accompanied by a significant increase in activation delay
Summary
Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction. These studies show that if impulse conduction is challenged, either by reducing membrane excitability [5,7] or intercellular coupling [6], the effect on impulse conduction at basic cycle length is minor These data suggest that the heart has ‘conduction reserve’ [8,9,10], and that single factors determining impulse conduction either need to be modified to the extreme [6], or moderately in combination [4,5,7], in order to exceed the myocardial conduction reserve and cause impulse propagation impairment. This suggests that RV conduction reserve is lower than that of LV, leaving the RV more vulnerable to impulse propagation impairment in the mouse heart
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