| Objective: The purpose of the study was to investigate the relationship between Calcineurin and atrial fibrillation (AF), to evaluate the effects of Cyclosporine-A (CsA), an calcineurin inhibitor, on gap-junction protein remodeling of atrial myocardium, and to explore the effects of Cyclosporine-A on electrophysiological properties of atria with AF on a canine model with atrial tachycardiapacing induced AF.Methods: Eighteen healthy adult mongrel dogs weighing 17 to 23.2kg (ranged from 2 to 4 years old) were divided into 3 groups: ①Sham group: no pacemaker was implanted and there were no interventions.②ATP group(atrial tachypacing, ATP): high-speed pacemaker was implanted after IV anesthesia with pentobarbital. A Unipolar pacing lead was inserted through jugular veins into the right atrial appendage under fluoroscopic guidance, and was connected to pacemaker (made by ShangHai Fu Dan University) in subcutaneous pocket in the neck. After 24h post-operative recovery, the pacemaker was started to work at a rate of 400 bpm. ③CsA group: all procedure were the same as ATP group except cyclosporine-A, 10 mg/day/kg was added orally.A closed-chest EPS was performed on each group at baseline and after 8 weeks' rapid pacing. Then the canines were killed and their hearts were removed for study. Transmural atrial free-wall tissue samples were obtained and stored in liquid nitrogen for further study. Activity of Calcineurin phosphatase was measured. Expression and distribution of CalcineurinA_β (CnA_β ), connexin40/connexin43 were detected with methods of immunohistochemistry and western blot.Results: 1. Expression and activity of Calcineurin phosphataseAfter 8 weeks' atrial rapid pacing, the activity of calcineurin enzymatic in atria was increased and the expression of CnA_β protein was enhanced.2. Expression and distribution of atrial connexin40/43 proteinsCompared to Sham group, expression of Cx40 protein in canine atrium was increased markly in ATP group, In CsA group, expression of Cx40 was also increased ,but the changes were much smaller than in ATP group (P< 0.05). In comparison to Sham group, expression of Cx43 was decreased in both ATP and CsA groups, but the changes were much smaller in CsA group than in ATP group (P < 0.05). Increased heterogeneity in the distribution of both Cx40/43 has been observed with regional heterogeneity or with changes in the subcellular distribution and lateralization of connexins in both ATP and CsA group.3. Atrial electrophysiological propertiesCompared to Sham group, ATP and CsA groups had a longer duration of the P wave (P<0.05), shorter AERP (P<0.05), decreased adaptation of AERP (P<0.05), slower CV (P<0.05), shorter WL (P<0.05), longer AF duration. In comparison to ATP group, CsA group had a longer AERP (P<0.05) and a recovering tendency of other parameters but without statistical significance.Conclusion: Our results suggest that calcineurin pathway intervention by CsA has positive effect on tachycardia-induced atrial electrophysiological remodeling and connexin expression, but can not prevent or reversion AF. AF is a complex pathophysiologic process in which many different mechanisms involved in it. Single or fewer signaling pathway interferation has little effect on the initiation and maintenance of AF.
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