Effects of Preoperative Statin Therapy on Cytokines after Cardiac Surgery

Abstract

Introduction: In addition to their lipid-lowering action, it has been demonstrated that statins can exert direct anti-inflammatory effects. We investigated the effect of preoperative statin therapy on systemic inflammatory markers and myocardial NF-κB inhibitor IκB-α after cardiac surgery. Methods: Thirty-six patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass (CPB) with cardioplegia were divided into two groups (statin group, n = 18; control group, n = 18). Plasma concentrations of pro-inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin [IL]-6, IL-8) and anti-inflammatory IL-10 were measured before and 1, 4, 10, and 24 hours (h) after CPB. Phosphorylated IκB-α/total IκB-α ratio was assessed before and after CPB in right atrial biopsies. Results: Baseline and operative data did not differ between groups. Statin therapy was associated with lower preoperative low-density lipoprotein levels compared to control (73 ± 6 vs. 92 ± 6 mg/dL; p = 0.03). Release of IL-6 was attenuated in the statin group at 4 h (2270 ± 599 vs. 5120 ± 656 pg/ml; p < 0.01) and 10 h (1295 ± 445 vs. 3116 ± 487 pg/ml; p < 0.05) compared to the control group. IL-10 increased after surgery in both groups (p < 0.05), but was higher in the statin group at 1 h (66 ± 15 vs. 26 ± 16 pg/mL; p < 0.01). Phosphorylated IκB-α/total IκB-α ratio before CPB did not differ between groups, but was elevated after CPB in both groups (p < 0.05), indicating enhanced degradation of IκB-α. Statin therapy had no effect on TNFα and IL-8. Conclusions: Preoperative statin therapy attenuates the release of pro-inflammatory IL-6 and up-regulates anti-inflammatory IL-10 after cardiac surgery with cardioplegia, but fails to inhibit phosphorylation of myocardial IκB-α.

Statins - inflammatory response - cytokines - cardiovascular surgery

References

• 1 Christenson J T. Preoperative lipid control with simvastatin protects coronary artery bypass grafts from obstructive graft disease.  Am J Cardiol. 2001;  88 896-899
• 2 Knatterud G L, Rosenberg Y, Campeau L. et al . Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators.  Circulation. 2000;  102 157-165
• 3 Pan W, Pintar T, Anton J, Lee V V, Vaughn W K, Collard C D. Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery.  Circulation. 2004;  110 45-49
• 4 Schonbeck U, Libby P. Inflammation, immunity, and HMG‐CoA reductase inhibitors: statins as antiinflammatory agents?.  Circulation. 2004;  109 18-26
• 5 Brull D J, Sanders J, Rumley A, Lowe G D, Humphries S E, Montgomery H E. Statin therapy and the acute inflammatory response after coronary artery bypass grafting.  Am J Cardiol. 2001;  88 431-433
• 6 Lazar H L, Bao Y, Zhang Y, Bernard S A. Pretreatment with statins enhances myocardial protection during coronary revascularization.  J Thorac Cardiovasc Surg. 2003;  125 1037-1042
• 7 Hennein H A, Ebba H, Rodriguez J L. et al . Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization.  J Thorac Cardiovasc Surg. 1994;  108 626-635
• 8 Onai Y, Suzuki J, Kakuta T. et al . Inhibition of Ikappa B phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury.  Cardiovasc Res. 2004;  63 51-59
• 9 Valen G, Paulsson G, Vaage J. Induction of inflammatory mediators during reperfusion of the human heart.  Ann Thorac Surg. 2001;  71 226-232
• 10 Christman J W, Lancaster L H, Blackwell T S. Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy.  Intensive Care Med. 1998;  24 1131-1138
• 11 Dichtl W, Dulak J, Frick M. et al . HMG‐CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.  Arterioscler Thromb Vasc Biol. 2003;  23 58-63
• 12 Chello M, Mastroroberto P, Patti G. et al . Simvastatin attenuates leucocyte-endothelial interactions after coronary revascularisation with cardiopulmonary bypass.  Heart. 2003;  89 538-543
• 13 Liakopoulos O J, Mühlfeld C, Koschinsky M, Coulibaly M O, Schoendube F A, Dörge H. Progressive loss of myocardial contractile function despite unimpaired coronary blood flow after cardiac surgery.  Basic Res Cardiol. 2005;  100 75-83
• 14 Wan S, LeClerc J L, Vincent J L. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation.  Ann Thorac Surg. 1997;  63 269-276
• 15 Massy Z A, Kim Y, Guijarro C, Kasiske B L, Keane W F, O'Donnell M P. Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin.  Biochem Biophys Res Commun. 2000;  267 536-540
• 16 Florens E, Salvi S, Peynet J. et al . Can statins reduce the inflammatory response to cardiopulmonary bypass? A clinical study.  J Card Surg. 2001;  16 232-239
• 17 Sadeghi M M, Collinge M, Pardi R, Bender J R. Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein.  J Immunol. 2000;  165 2712-2718
• 18 Hölschermann H, Schuster D, Parviz B, Haberbosch W, Tillmanns H, Muth H. Statins prevent NF-κB transactivation independently of the IKK-pathway in human endothelial cells.  Atherosclerosis. 2006;  185 240-245
• 19 Rao S, Porter D C, Chen X, Herliczek T, Lowe M, Keyomarsi K. Lovastatin mediated G1 arrest is through inhibition of the proteosome, independent of hydroxymethyl glutaryl-CoA reductase.  Proc Natl Acad Sci USA. 1999;  96 7797-7802
• 20 Ludwig A, Friedel B, Metzkow S. et al . Effect of statins on the proteosomal activity in mammalian endothelial and vascular smooth cell muscle cells.  Biochem Pharmacol. 2005;  70 520-526