TY - JOUR
TI - Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: Implications for the antiarrhythmic effect of statins
AU - Reilly, S.N.
AU - Jayaram, R.
AU - Nahar, K.
AU - Antoniades, C.
AU - Verheule, S.
AU - Channon, K.M.
AU - Alp, N.J.
AU - Schotten, U.
AU - Casadei, B.
JO - CIRCULATION
PY - 2011
VL - 124
TODO - 10
SP - 1107-1117
PB - 
SN - 0009-7322
TODO - 10.1161/CIRCULATIONAHA.111.029223
TODO - acetylsalicylic acid;  angiotensin receptor antagonist;  arginase;  atorvastatin;  beta adrenergic receptor blocking agent;  biopterin;  calcium antagonist;  dipeptidyl carboxypeptidase inhibitor;  diuretic agent;  hydroxymethylglutaryl coenzyme A reductase inhibitor;  mevalonic acid;  mitochondrial oxidase;  n(g) nitroarginine methyl ester;  nitric oxide;  nitric oxide synthase;  p22phox protein;  protein p22;  Rac1 protein;  reactive oxygen metabolite;  reduced nicotinamide adenine dinucleotide phosphate oxidase;  reduced nicotinamide adenine dinucleotide phosphate oxidase 2;  tetrahydrobiopterin;  unclassified drug, adult;  aged;  animal cell;  animal experiment;  animal model;  animal tissue;  antiarrhythmic activity;  article;  atrioventricular block;  cell infiltration;  controlled study;  coronary artery bypass graft;  disease activity;  disease duration;  drug effect;  enzyme activity;  enzyme inhibition;  female;  goat;  heart atrium fibrillation;  heart left atrium;  heart muscle;  heart pacing;  heart right atrium;  heart surgery;  human;  leukocyte;  major clinical study;  male;  nonhuman;  oxidation reduction reaction;  oxidative stress;  postoperative period;  priority journal;  secondary prevention;  sinus rhythm, 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;  rac1 GTP-Binding Protein;  Reactive Oxygen Species
TODO - 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. © 2011 American Heart Association, Inc.
ER -