Abstract 8731: Ventricular Tachycardias in Compensated Hypertrophic Rats Are Polymorphic: Strong Evidence of Increased Spatial Heterogeneity of Non-phosphorylated Cx43 as Part of the Arrhythmogenic Substrate
Introduction: Hypertrophic remodeling is known to increase the propensity of ventricular tachyarrhythmias leading to sudden death in patients. To study the mechanism underlying these fatal arrhythmias, we analyzed electrical and structural cardiac remodeling as well as arrhythmogeneity during early compensated hypertrophy in a rat model of chronic pressure overload.
Methods: 26 Wistar rats were subjected to either transverse aortic constriction (TAC, n=13) or sham operation (n=13). Four weeks after operation, rats were subjected to echo- and electrocardiography. Epicardial (208 sites) and transmural (30 sites) ventricular activation mapping was performed in Langendorff perfused hearts. Subsequently, hearts were processed for (immuno)histological and Western blot (WB) analyses.
Results: TAC rats displayed compensated hypertrophy with preserved LV function. QRS-duration increased significantly by 14% to 20.4±0.38 ms. Epicardial conduction velocity (CV) was unaltered. However, LV transmural CV was significantly reduced by 36% to 37.6±2.9 cm/s. Moreover, epicardial impulse propagation was more dispersed in TAC. ERP increased by 14% to 67.5±3.3 ms in LV. Sustained polymorphic ventricular tachycardias (VT) were induced from LV in 8/13 TAC and in 0/13 sham. Electrical activation patterns of LV and RV during VT showed variable sites of earliest epicardial activation and altering sites of functional conduction block. Wandering epicardial reentrant activation was sporadically observed. WB data revealed a significantly decreased total amount of Cx43 in TAC combined with a shift towards the non-phosphorylated isoform of Cx43. Moreover, Cx43 expression was heterogeneous in arrhythmogenic animals. Areas deprived of Cx43 showed increased expression of non-phosphorylated Cx43. It is known that de-phosphorylation of Cx43 results in conduction disorders. Interstitial fibrosis increased uniformly in TAC by 67%.
Conclusions: In TAC rats with compensated cardiac hypertrophy, transmural conduction was impaired. This was caused by decreased total Cx43 combined with increased heterogeneity of intramural Cx43 expression and regional substitution with non-phosphorylated Cx43. This may result in the increased vulnerability to polymorphic VTs.
- © 2010 by American Heart Association, Inc.