Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs

BACKGROUND: There is evidence suggesting involvement of oxidative stress, inflammation, and calcineurin/nuclear factor of activated T cell pathways in atrial fibrillation. This study evaluated the efficacy of anti-inflammatory and calcineurin-inhibitory drugs on promotion of atrial fibrillation by atrial tachycardia-induced remodeling in dogs. METHODS AND RESULTS: Dogs were subjected to atrial tachypacing at 400 bpm in the absence and presence of treatment with prednisone (15 or 50 mg/day) or ibuprofen (anti-inflammatory) or cyclosporine-A (calcineurin inhibitor). Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. A final open-chest study was performed on day 8. Serum C-reactive protein was measured by ELISA and nitric oxide synthase by Western blotting. The mean duration of induced atrial fibrillation was markedly increased by tachypacing alone, from 26+/-8 to 962+/-317 s (p<0.01), and the atrial effective refractory period was decreased from 117+/-4 to 73+/-7 ms (p<0.001; cycle-length 300 ms). Tachypacing-induced effective refractory period shortening and atrial fibrillation promotion were unaffected by ibuprofen or cyclosporine-A; however, both doses of prednisone suppressed tachypacing-remodeling effects (atrial fibrillation duration to 96+/-60 s and 28+/-11 s at higher and lower doses, respectively; effective refractory period to 101+/-6 ms for higher-dose and 105+/-3 ms for lower-dose group). In addition, prednisone (but not ibuprofen or cyclosporine) significantly decreased C-reactive protein concentrations and attenuated the increase in endothelial nitric oxide synthase expression caused by atrial tachypacing. CONCLUSIONS: Prednisone prevents the electrophysiological and atrial fibrillation-promoting effects of atrial tachycardia-remodeling, possibly by an anti-inflammatory action, whereas the less potent anti-inflammatory ibuprofen and the calcineurin inhibitor cyclosporine-A are without effect.