Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation

Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pha rmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the at ria; however, the fundamental mechanisms underlying this process are still unclear. We have recently demonstrated that chronic human AF is associated with increased atrial oxidative stress and peroxynitrite formation; we have now tested the hypothesis that these events participate in both pacing-ind uced atrial electrophysiological remodeling and in the occurrence of AF fol lowing cardiac surgery. In chronically instrumented dogs, we found that rap id (400 min(-1)) atrial pacing was associated with attenuation of the atria l effective refractory period (ERP). Treatment with ascorbate, an antioxida nt and peroxynitrite decomposition catalyst, did not directly modify the ER P, but attenuated the pacing-induced atrial ERP shortening following 24 to 48 hours of pacing. Biochemical studies revealed that pacing was associated with decreased tissue ascorbate levels and increased protein nitration (a biomarker of peroxynitrite formation). Oral ascorbate supplementation atten uated both of these changes. To evaluate the clinical significance of these observations, supplemental ascorbate was given to 43 patients before, and for 5 days following, cardiac bypass graft surgery. Patients receiving asco rbate had a 16.3% incidence of postoperative AF, compared with 34.9% in con trol subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insi ght into the etiology and potential treatment of an enigmatic and difficult to control arrhythmia. The full text of this article is available at http: //www.circresaha.org.