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BACKGROUND: An altered nitric oxide-redox balance has been implicated in the pathogenesis of atrial fibrillation (AF). Statins inhibit NOX2-NADPH oxidases and prevent postoperative AF but are less effective in AF secondary prevention; the mechanisms underlying these findings are poorly understood. METHODS AND RESULTS: By using goat models of pacing-induced AF or of atrial structural remodeling secondary to atrioventricular block and right atrial samples from 130 patients undergoing cardiac surgery, we found that the mechanisms responsible for the NO-redox imbalance differ between atria and with the duration and substrate of AF. Rac1 and NADPH oxidase activity and the protein level of NOX2 and p22phox were significantly increased in the left atrium of goats after 2 weeks of AF and in patients who developed postoperative AF in the absence of differences in leukocytes infiltration. Conversely, in the presence of longstanding AF or atrioventricular block, uncoupled nitric oxide synthase activity (secondary to reduced BH4 content and/or increased arginase activity) and mitochondrial oxidases accounted for the biatrial increase in reactive oxygen species. Atorvastatin caused a mevalonate-reversible inhibition of Rac1 and NOX2-NADPH oxidase activity in right atrial samples from patients who developed postoperative AF, but it did not affect reactive oxygen species, nitric oxide synthase uncoupling, or BH4 in patients with permanent AF. CONCLUSIONS: Upregulation of atrial NADPH oxidases is an early but transient event in the natural history of AF. Changes in the sources of reactive oxygen species with atrial remodeling may explain why statins are effective in the primary prevention of AF but not in its management.

Original publication

DOI

10.1161/CIRCULATIONAHA.111.029223

Type

Journal article

Journal

Circulation

Publication Date

06/09/2011

Volume

124

Pages

1107 - 1117

Keywords

Aged, Aged, 80 and over, Animals, Anti-Arrhythmia Agents, Arginase, Atrial Fibrillation, Atrioventricular Block, Disease Models, Animal, Female, Goats, Heart Atria, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Membrane Glycoproteins, Middle Aged, Mitochondria, NADPH Oxidase, Oxidoreductases, Reactive Oxygen Species, rac1 GTP-Binding Protein