Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity.
BACKGROUND
Statins improve clinical outcome of patients with atherosclerosis, but their perioperative role in patients undergoing coronary artery bypass grafting (CABG) is unclear. We hypothesized that short-term treatment with atorvastatin before CABG would improve the redox state in saphenous vein grafts (SVGs), independently of low-density lipoprotein cholesterol (LDL)-lowering.


RESULTS
In a randomized, double-blind controlled trial, 42 statin-naïve patients undergoing elective CABG received atorvastatin 40 mg/d or placebo for 3 days before surgery. Circulating inflammatory markers and malondialdehyde (MDA) were measured before and after treatment. SVG segments were used to determine vascular superoxide (O(2)(*-)) and Rac1 activation. For ex vivo studies, SVG segments from 24 patients were incubated for 6 hours with atorvastatin 0, 5, or 50 μmol/L. Oral atorvastatin reduced vascular basal and NADPH-stimulated O(2)(*-) in SVGs (P<0.05 for all versus placebo) and reduced plasma MDA (P<0.05), independently of LDL-lowering and of changes in inflammatory markers. In SVGs exposed to atorvastatin ex vivo, without exposure to LDL, basal and NADPH-stimulated O(2)(·-) were significantly reduced (P<0.01 for both concentrations versus 0 μmol/L) in association with a striking reduction in Rac1 activation and 1 membrane-bound Rac1 and p67(phox) subunit. The antioxidant effects of atorvastatin were reversed by mevalonate, implying a dependence on vascular HMG-CoA reductase inhibition.


CONCLUSIONS
Short-term treatment with atorvastatin 40 mg/d before CABG improves redox state in SVGs, by inhibiting vascular Rac1-mediated activation of NADPH-oxidase. These novel findings suggest that statin therapy should be maintained or initiated in patients undergoing CABG, independently of LDL levels. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
Antoniades
Charalambos
C
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. antoniad@well.ox.ac.uk
Bakogiannis
Constantinos
C
Tousoulis
Dimitris
D
Reilly
Svetlana
S
Zhang
Mei-Hua
MH
Paschalis
Andreas
A
Antonopoulos
Alexios S
AS
Demosthenous
Michael
M
Miliou
Antigoni
A
Psarros
Costas
C
Marinou
Kyriakoula
K
Sfyras
Nikolaos
N
Economopoulos
George
G
Casadei
Barbara
B
Channon
Keith M
KM
Stefanadis
Christodoulos
C
D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000601:surgery; D000069059:Atorvastatin; D001026:Coronary Artery Bypass; D004311:Double-Blind Method; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D011300:Preoperative Care; D011758:Pyrroles / Q000008:administration & dosage*; D012501:Saphenous Vein / Q000378:metabolism; D013481:Superoxides / Q000097:blood; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D011758:Pyrroles; C107953:RAC1 protein, human; D013481:Superoxides; D008315:Malondialdehyde; D000069059:Atorvastatin; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein