Abstract 10183: Reduced Heterogeneous Expression Of Cx43 Combined with Decreased Nav1.5 Expression Account for Arrhythmia Vulnerability in Conditional Cx43 Knockout Mice
Background - Reduced Cx43 levels are associated with an increased vulnerability to arrhythmias. We hypothesized that induced Cx43 downregulation of conditional Cx43 KO mice results in more severe and heterogeneous reduction of Cx43, together with decreased Nav1.5 expression, in mice with spontaneous and induced ventricular arrhythmias. For this purpose, we determined electrophysiological and (immuno)histological characteristics of inducible Cx43 KO mice and compared arrhythmogenic (VT+) with non-arrhythmogenic (VT-) mice.
Methods and Results - Cx43 downregulation was induced with Tamoxifen in Cx43CreER(T)/fl mice. Animals were sacrificed 2 weeks after induction. Epicardial activation mapping was performed on Langendorff-perfused hearts, and arrhythmia vulnerability was tested. Mice were subdivided in VT+ (n=13) and VT- (n=10) animals and heart tissue was analyzed for Cx43, Nav1.5 and fibrosis. VT+ mice had decreased Cx43 expression with increased macroscopic, but not microscopic, heterogeneity of Cx43, compared to VT- mice. In addition, Nav1.5 expression was reduced in VT+ versus VT- mice, whereas the amount of fibrosis was comparable. QRS-duration was increased and epicardial activation was more dispersed in VT+ mice than in VT- mice. The effective refractory period (ERP) was similar between both groups. Premature stimulation resulted in a more severe conduction slowing in VT+ compared to VT- hearts in the right ventricle.
Conclusions - In induced conditional Cx43 KO mice, arrhythmogenic animals have a more severe reduction in Cx43, more macroscopic heterogeneity of Cx43 expression and decreased Nav1.5 expression compared to induced animals without arrhythmias. The alterations in reduced and dispersed cell-to-cell coupling together with reduced excitability allows for the occurrence of ventricular arrhythmias.
- © 2011 by American Heart Association, Inc.