title: Myocardial redox state predicts in-hospital clinical outcome after cardiac surgery effects of short-term pre-operative statin treatment.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the role of the myocardial redox state in the development of in-hospital complications after cardiac surgery and the effect of statins on the myocardial redox state.
  
  
  BACKGROUND
  Statins improve clinical outcome after cardiac surgery, but it is unclear whether they exert their effects by modifying the myocardial redox state.
  
  
  METHODS
  We quantified myocardial superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)) and their enzymatic sources in samples of the right atrial appendage (RAA) from 303 patients undergoing cardiac surgery who were followed up until discharge, and in 42 patients who were randomized to receive 3-day treatment with atorvastatin 40 mg/d or placebo before surgery. The mechanisms by which atorvastatin modifies myocardial redox state were investigated in 26 RAA samples that were exposed to atorvastatin ex vivo.
  
  
  RESULTS
  Atrial O(2)(-) (derived mainly from nicotinamide adenine dinucleotide phosphate [NADPH] oxidases) and ONOO(-) were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O(2)(-) and ONOO(-) production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase.
  
  
  CONCLUSIONS
  There is a strong independent association between myocardial O(2)(-)/ONOO(-) and in-hospital complications after cardiac surgery. Both myocardial O(2)(-) and ONOO(-) are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103).
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. antoniad@well.ox.ac.uk
authors.forename: Charalambos
authors.initials: C
authors.lastname: Antoniades
authors.forename: Michael
authors.initials: M
authors.lastname: Demosthenous
authors.forename: Svetlana
authors.initials: S
authors.lastname: Reilly
authors.forename: Marios
authors.initials: M
authors.lastname: Margaritis
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Zhang
authors.forename: Alexios
authors.initials: A
authors.lastname: Antonopoulos
authors.forename: Kyriakoula
authors.initials: K
authors.lastname: Marinou
authors.forename: Keshav
authors.initials: K
authors.lastname: Nahar
authors.forename: Raja
authors.initials: R
authors.lastname: Jayaram
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.forename: Constantinos
authors.initials: C
authors.lastname: Bakogiannis
authors.forename: Rana
authors.initials: R
authors.lastname: Sayeed
authors.forename: Costas
authors.initials: C
authors.lastname: Triantafyllou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Koumallos
authors.forename: Costas
authors.initials: C
authors.lastname: Psarros
authors.forename: Antigoni
authors.initials: A
authors.lastname: Miliou
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D006348:Cardiac Surgical Procedures / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D016001:Confidence Intervals; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage*; D017052:Hospital Mortality / Q000639:trends; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D011183:Postoperative Complications / Q000517:prevention & control; D011237:Predictive Value of Tests; D011300:Preoperative Care / Q000379:methods; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin