Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity.
Antoniades C., Bakogiannis C., Tousoulis D., Reilly S., Zhang MH., Paschalis A., Antonopoulos AS., Demosthenous M., Miliou A., Psarros C., Marinou K., Sfyras N., Economopoulos G., Casadei B., Channon KM., Stefanadis C.
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. METHODS AND 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.