Author + information
- Received May 9, 2011
- Revision received August 5, 2011
- Accepted August 8, 2011
- Published online January 3, 2012.
- Charalambos Antoniades, MD, PhD⁎,†,⁎ (, )
- Michael Demosthenous, MD†,
- Svetlana Reilly, MD, DPhil⁎,
- Marios Margaritis, MD⁎,
- Mei-Hua Zhang, PhD⁎,
- Alexios Antonopoulos, MD†,
- Kyriakoula Marinou, MD, PhD‡,
- Keshav Nahar, BSc⁎,
- Raja Jayaram, MD⁎,
- Dimitris Tousoulis, MD, PhD†,
- Constantinos Bakogiannis, MD†,
- Rana Sayeed, MD§,
- Costas Triantafyllou, MD∥,
- Nikolaos Koumallos, MD∥,
- Costas Psarros, MSc†,
- Antigoni Miliou, MSc, PhD†,
- Christodoulos Stefanadis, MD, PhD†,
- Keith M. Channon, MD⁎ and
- Barbara Casadei, MD, DPhil⁎
- ↵⁎Reprint requests and correspondence:
Dr. Charalambos Antoniades, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom
Objectives 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 (O2−) 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 O2− (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 O2− 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 O2−/ONOO− and in-hospital complications after cardiac surgery. Both myocardial O2− 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)
This study was funded by the European Commission, within the 7th Framework Programme (Marie Curie Reintegration Grant under Grant Agreement No. 224832 [STATINS-REDOX] to Dr. Antoniades); by an FP7 Grant (European Network for Translational Research in Atrial Fibrillation [EUTRAF] under Grant Agreement No. 261057 to Dr. Casadei); by the British Heart Foundation (to Drs. Antoniades [FS/11/66/28855] and Channon); by the Leducq Foundation (to Drs. Reilly, Channon, and Casadei); and by the Oxford National Institute for Health Research Biomedical Research Centre (to Drs. Jayaram, Channon, and Casadei). Dr. Casadei has received an unrestricted research grant from Pfizer. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. Drs. Antoniades and Demosthenous contributed equally to the study.
- Received May 9, 2011.
- Revision received August 5, 2011.
- Accepted August 8, 2011.
- American College of Cardiology Foundation