Abstract 3860: Arrhythmia Vulnerability of Aged Haploinsufficient Cx43 Mice is Determined by Heterogeneous Downregulation of Cx43 Combined with Increased Fibrosis

Abstract

Background: Reduced gap junction expression and increased collagen deposition are commonly found in ventricles of electrically remodeled diseased hearts. Their interactive contribution to slow conduction and increased arrhythmogeneity is, however, unclear. In this study, we investigated the effect of increased fibrosis with normal or reduced levels of the ventricular gap junction protein Cx43 on impulse propagation and arrhythmogeneity. Methods: 11 Cx43fl/fl (Control) and 13 Cx43CreER(T)/fl mice (expressing only 50% of Cx43 protein compared to control; Cx43HZ) were aged to 20 months. Epicardial activation mapping (208 electrode terminals) of right (RV) and left (LV) ventricle was performed on Langendorff perfused hearts. Effective refractory period (ERP) was determined by premature stimulation and arrhythmia inducibility was tested by 1–3 premature stimuli and burst pacing. Epicardial conduction velocity longitudinal (CVL) and transverse (CVT) to fiber orientation and inhomogeneity of conduction was determined during S1S1 pacing (150 ms). Cx43, N-cadherin expression, and tissue collagen content was determined by (immuno)histology and Western blotting. Results: Sustained ventricular arrhythmias were induced in 0/11 control and 8/13 Cx43HZ mice (p<0.01). CVL and CVT were unchanged, except for CVT in RV, which was decreased from 48.2±2 to 39.3±1.8 cm/s (Control vs Cx43HZ, p<0.05). In RV, ERP was decreased from 78.2±6.0 to 53.1±3.3 ms (Control vs Cx43HZ, p<0.05). In both RV and LV, inhomogeneity of conduction was significantly higher in Cx43HZ mice with arrhythmias (VT+), compared to both Control and Cx43HZ mice without arrhythmias (VT−). Cx43 expression levels were comparable between VT+ and VT- Cx43HZ mice, though strongly reduced compared to Control. However, Cx43 distribution was very heterogeneous in VT+ mice with large areas devoid of Cx43 while N-cadherin was unaffected, indicating the presence of intact intercalated disks. Compared to Control interstitial fibrosis was increased in Cx43HZ mice, but more pronounced in VT+ Cx43HZ mice when compared to Cx43HZ VT- mice. Conclusions: Combined heterogeneous reduction of Cx43 and increased fibrosis strongly enhance arrhythmogenic vulnerability in aged haploinsufficient Cx43 mice.