title: Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Reilly
authors.forename: Raja
authors.initials: R
authors.lastname: Jayaram
authors.forename: Keshav
authors.initials: K
authors.lastname: Nahar
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Sander
authors.initials: S
authors.lastname: Verheule
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Alp
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001119:Arginase / Q000378:metabolism; D001281:Atrial Fibrillation / Q000517:prevention & control*; D054537:Atrioventricular Block / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006041:Goats; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C086986:CYBA protein, human; D001119:Arginase; D020830:rac1 GTP-Binding Protein