Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure

BackgroundHeterogeneity of repolarization and conduction is a potential source of arrhythmogenesis. In heart failure (HF), intercellular coupling is reduced and heterogeneities may become evident because of reduced intercellular coupling.ObjectiveThis study sought to investigate connexin43 (Cx43) expression, conduction velocity (CV), refractoriness and inducibility of arrhythmias at multiple sites of the left ventricle during HF.MethodsHF was induced by pressure-volume overload in rabbits. Epcardial and intramural mapping was performed in isolated perfused hearts following programmed stimulation. Myocytes were enzymatically dissociated and studied using D-4-ANEPPS fluorescence. Western blotting and immunohistochemistry was performed to quantify heterogeneity of Cx43 expression.ResultsCx43 was heterogeneously reduced in the midmyocardial, but not in the sub epicardium layer of the left ventricular free wall in HF compared to control rabbits. In HF, subepicardial and midmyocardial refractory periods (RPs) were increased compared to control rabbits (148 ± 3 ms and 143 ± 3 versus 131 ± 2 and 129 ± 2 ms, respectively, both P < 0.001). Also, transmural dispersion of RPs was larger in HF (30 ± 4 ms) than in control rabbits (24 ± 3 ms, P < 0.05). Intrinsic dispersion of action potential duration in isolated myocytes was similar in HF and control rabbits. Transmural CV was heterogeneous, although the mean CV was not different between groups. Arrhythmias were more easily inducible in HF, especially from midmyocardium.ConclusionIn HF, midmyocardial Cx43 expression is heterogeneously reduced. This is associated with increased transmural dispersion in refractoriness and conduction, and with increased arrhythmia inducibility.