Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias

Abstract

The canine sterile pericarditis model is characterized by impaired conduction and atrial arrhythmia vulnerability. Electrical and structural remodeling processes caused by the inflammatory response likely promote these abnormalities. In the present study, we tested the hypothesis that altered distribution of atrial connexins is associated with markedly abnormal atrial conduction, thereby contributing to vulnerability to atrial flutter (AFL) and atrial fibrillation (AF) induction and maintenance. During rapid pacing and induced, sustained AFL or AF in five sterile pericarditis (SP) and five normal (NL) dogs, epicardial atrial electrograms were recorded simultaneously from both atria (380 electrodes) or from the right atrium (RA) and Bachmann's bundle (212 electrodes). Tissues from RA sites were subjected to immunostaining and immunoblotting to assess connexin (Cx) 40 and Cx43 distribution and expression. Transmural myocyte (alpha-actinin) and fibroblast (vimentin) volume were also assessed by immunostaining. RA pacing maps showed markedly abnormal conduction in SP, with uniform conduction in NL. Total RA activation time was significantly prolonged in SP vs. NL at 300-ms and 200-ms pacing-cycle lengths. Sustained arrhythmias were only inducible in SP [total: 4/5 (AFL: 3/5; AF: 1/5)]. In NL, Cx40, Cx43, alpha-actinin, and vimentin were homogeneously distributed transmurally. In SP, Cx40, Cx43, and alpha-actinin were absent epicardially, decreased midmyocardially, and normal endocardially. SP increased epicardial vimentin expression, suggesting fibroblast proliferation. Immunoblot analysis confirmed reduced expression of Cx40 and Cx43 in SP. The transmural gradient in the volume fraction of Cx40 and Cx43 in SP is associated with markedly abnormal atrial conduction and is likely an important factor in the vulnerability to induction and maintenance of AFL/AF in SP.

The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

“…The canine sterile pericarditis model has been a well established representation of human postoperative AF/AFL for many years. A recent study by Ryu et al (2007), looking at gap junctional changes in the canine sterile pericarditis model, showed differences in the overall expression and transmural distribution of Cx40 and Cx43, similar to the human disease. In this study, the authors concluded that the aforementioned Cx changes are associated with abnormal atrial conduction and can lead to increased AF/AFL vulnerability.…”

The preventive effect of statin therapy on new-onset and recurrent atrial fibrillation in patients not undergoing invasive cardiac interventions

“…This is possibly complemented by the results of the large-scale observational studies demonstrating that statins may impose a counteracting effect on AF in patients not undergoing invasive cardiac interventions as well. The pathophysiological mechanism of AF unrelated to surgery can be attributed to factors such as increased angiotensin II, inflammation, dilatation and fibrosis of the left atrial tissue [9,[50][51][52][53][54].…”

“…Several observational studies suggest that statins may exert anti-arrhythmic effect by inhibiting inflammation and oxidative stress [7][8][9]. Thus, several randomized and non-randomized trials have attempted to demonstrate a relationship between the use of statins and reduction in AF.…”

Impaired mobilization of bone marrow derived CD34 positive mononuclear cells is related to the recurrence of atrial fibrillation after radiofrequency catheter ablation

“…It has been reported that inflammation is sufficient to facilitate the initiation of atrial arrhythmias [21] and an elevated high sensitive C-reactive protein (hsCRP) may predict AF in some patients [22]. Given the extensive tissue damage involved in LA ablation procedures, an acute inflammatory response is likely to occur, and the time course of spontaneous arrhythmia resolution correlates well with the presumed resolution of inflammation after extensive atrial RFCA [23,24].…”