doi: 10.1161/hh1801.097644
© 2001 American Heart Association, Inc.
UltraRapid Communication |
Ascorbate Attenuates Atrial Pacing-Induced Peroxynitrite Formation and Electrical Remodeling and Decreases the Incidence of Postoperative Atrial Fibrillation
From the College of Pharmacy and the Dorothy M. Davis Heart and Lung Research Institute (C.A.C., R.S.B., S.P., J.A.B., D.R.V.W.), Ohio State University, Columbus, Ohio; Department of Cardiovascular Medicine (M.K.C., A.K., S.P., D.R.V.W.), Cleveland Clinic Foundation, Cleveland, Ohio; College of Veterinary Medicine (T.N., H.N., R.L.H.), Ohio State University, Columbus, Ohio; and Kaufmann Center for Heart Failure and Department of Cardiothoracic Surgery (P.M.M.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to David R. Van Wagoner, PhD, Department of Cardiovascular Medicine, FF-10, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5069. E-mail vanwagd{at}ccf.org
Atrial fibrillation (AF), the most common chronic arrhythmia, increases the risk of stroke and is an independent predictor of mortality. Available pharmacological treatments have limited efficacy. Once initiated, AF tends to self-perpetuate, owing in part to electrophysiological remodeling in the atria; 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-induced atrial electrophysiological remodeling and in the occurrence of AF following cardiac surgery. In chronically instrumented dogs, we found that rapid (400 min-1) atrial pacing was associated with attenuation of the atrial effective refractory period (ERP). Treatment with ascorbate, an antioxidant and peroxynitrite decomposition catalyst, did not directly modify the ERP, 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 attenuated 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 ascorbate had a 16.3% incidence of postoperative AF, compared with 34.9% in control subjects. In combination, these studies suggest that oxidative stress underlies early atrial electrophysiological remodeling and offer novel insight 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.
Key Words: atrial fibrillation • antioxidant • ascorbate • oxidative stress • cardiac surgery
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