Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat

Objective: It has been postulated that high atrial rate induced changes at the level of the gap junctions ('gap junctional remodeling', i.e, changes i n distribution, intercellular orientation and expression of gap junction pr oteins), could be Dart of the vicious circle of electrophysiologic and stru ctural changes leading to sustained atrial fibrillation (AF). To obtain exp erimental evidence in favour of such a postulate the timing of this remodel ing process was studied in relation to the development of sustained BF in a goat model. Methods and Results: Thin sections from the left (LAA) and rig ht atrial appendage (RAA) from goats in sinus rhythm (SR) or AF, induced th rough programmed endocardial burst pacing for time periods between 0 and 16 weeks, were immunolabeled with antibodies against connexin(Cx)40 and Cx43 and analysed by immunofluorescence and confocal laser scanning microscopy. During SR the distribution pattern for Cx43 was completely homogeneous (LAA and RAA) and for Cx40 mostly homogeneous (LAA: all five goats, RAA: three out of five goats). The distribution pattern for Cx43 remained stable durin g AF, while the Cx40 distribution pattern became increasingly heterogeneous , both in the LAA and RAA, with increasing duration of pacing. This increas e in heterogeneity in Cx40 distribution correlated (Spearman rank order) wi th an increase in stability of AF and the occurrence of structural changes (myolysis) in atrial myocytes. The Cx40/Cx43 immunofluorescence signal rati o in both the LAA and RAA appeared to be significantly lower in AF (1-16 we eks) as compared to SR (0 weeks); going from 0 to 16 weeks average ratios d ecreased 54.5% (n = 5; P = 0.026) in the LAA and 35.8% (n = 5; P = 0.034) i n the RAA. Western blot analyses revealed similar decreases in the total Cx 40/Cx43 protein ratio, on average 50.0% (n = 5; P = 0.008) and 47.8% (n = 5 ; P = 0.02) in the LAA and RAA, respectively. No changes were measured in t he levels of Cx40 or Cx43 mRNA, as was assessed through RT-PCR. Conclusion: The time course of changes in the distribution and content of Cx40 gap jun ctions as observed during endocardial burst pacing of the goat atrium sugge sts that Cx40 gap junctional remodeling might be involved in the pathogenes is of sustained atrial fibrillation. (C) 2000 Elsevier Science B.V. All rig hts reserved.