Abstract 19348: Reduced Cx43 Expression Leads to Increased Fibrosis and Pro-arrhythmia due to Enhanced Fibroblast Activity in Aged and Pressure Overloaded Mice
Background: Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction (Connexin43, Cx43) expression and increased collagen deposition (fibrosis). We hypothesized that reduced Cx43 expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (Transverse Aortic Constriction, TAC) mouse model.
Methods: Cx43fl/fl (control) and Cx43CreER(T)/fl mice (Cx43HZ) were aged to 20 months, or at the age of 3 months either TAC- or SHAM-operated and sacrificed after 16 weeks. Hearts were Langendorff-perfused, and epicardial mapping of LV and RV was performed to determine epicardial conduction velocity (CV), effective refractory period (ERP), and susceptibility for arrhythmias. Cx43 expression, fibroblast proliferation (DDR-2) and activity (pro-collagen peptide III) was determined by Western Blotting and immunohistochemistry. Sirius Red staining was performed to determine collagen content.
Results: Cx43 expression was reduced by half in all Cx43HZ mice compared to their control. Collagen deposition was significantly increased in aged Cx43HZ mice compared to aged control mice (7.38 vs 1.10%). TAC-operation increased fibrosis in control (4.0%) compared to SHAM (0.4%), but was significantly higher in Cx43HZ (10.77%). DDR-2 expression appeared unchanged, but pro-collagen peptide III expression was higher in TAC-operated Cx43HZ mice. Arrhythmia vulnerability was high in aged Cx43HZ mice (67%), in contrast to aged control mice (0%). Aged Cx43HZ mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43HZ mice without. TAC-operation increased arrhythmia susceptibility (35%) in both Cx43HZ and control mice compared to SHAM (0%), and significantly increased heterogeneity of conduction in RV of Cx43HZ mice.
Conclusions: Reduced cellular coupling resulted in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction inhomogeneity and pro-arrhythmia.
- © 2010 by American Heart Association, Inc.