Document Detail


Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins.
MedLine Citation:
PMID:  21844076     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Svetlana N Reilly; Raja Jayaram; Keshav Nahar; Charalambos Antoniades; Sander Verheule; Keith M Channon; Nicholas J Alp; Ulrich Schotten; Barbara Casadei
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-08-15
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-08     Completed Date:  2011-11-08     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1107-17     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Animals
Anti-Arrhythmia Agents / therapeutic use*
Arginase / metabolism
Atrial Fibrillation / prevention & control*
Atrioventricular Block / metabolism
Disease Models, Animal
Female
Goats
Heart Atria / drug effects,  metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
Male
Membrane Glycoproteins / biosynthesis
Middle Aged
Mitochondria / enzymology
NADPH Oxidase / biosynthesis,  metabolism
Oxidoreductases / metabolism
Reactive Oxygen Species / metabolism*
rac1 GTP-Binding Protein / metabolism
Grant Support
ID/Acronym/Agency:
090532//Wellcome Trust; FS/11/66/28855//British Heart Foundation; RG/11/15/29375//British Heart Foundation; //British Heart Foundation
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/CYBB protein, human; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Membrane Glycoproteins; 0/Reactive Oxygen Species; EC 1.-/Oxidoreductases; EC 1.6.3.1/CYBA protein, human; EC 1.6.3.1/NADPH Oxidase; EC 3.5.3.1/Arginase; EC 3.6.5.2/rac1 GTP-Binding Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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