TNF-α gene promoter polymorphism at nucleotide −308 and the inflammatory response and oxidative stress induced by cardiac surgery: role of heart failure and medical treatment☆

Abstract

Increased TNF-alpha during cardiac surgery is thought to be responsible for perioperative complications. The TNF-alpha gene promoter polymorphism G/A at position -308 has been associated with enhanced TNF-alpha secretion, as has been heart failure. Therefore, the aims of this study were to investigate: (i) whether the TNF-alpha G/A polymorphism is associated with exacerbation of TNF-alpha plasma levels during cardiac surgery; (ii) whether TNF-alpha production is further increased by heart failure and influenced by medical treatment; and (iii) whether this polymorphism is associated with increased oxidative stress and perioperative complications. The TNF-alpha gene promoter polymorphism was studied in 100 consecutive patients undergoing cardiac surgery. Of them, 65 were identified with the common allele G/G, whereas 34 patients were with the G/A polymorphism and 1 was A/A. TNF-alpha plasma levels (ELISA) and peroxynitrite content in peripheral blood lymphocytes (flow cytometry) were measured before surgery, before cardiopulmonary bypass (CPB), and 30 min, 4 and 24h after initiation of CPB. The changes observed in TNF-alpha plasma levels during cardiac surgery were unaffected by the G/A polymorphism. TNF-alpha values were elevated before surgery in patients with more advanced NYHA class (1.66+/-0.14, 2.29+/-0.06 and 2.57+/-0.11 ln(mmol/l+1), for NYHA I, II and III; p=0.004) but again they were not correlated with the G/A polymorphism. Peroxynitrite content in lymphocytes was similar upon the initiation of surgery in the G/A and G/G groups and also in all NYHA class groups, and thereafter levels were similarly increased by surgery in all groups. However, analysis of the effect of preoperative medication showed that the mitoK(ATP) channel opener nicorandil reduced TNF-alpha values before surgery and blunted the increase in peroxynitrite caused by surgery. Perioperative complications were not related to either TNF-alpha polymorphism or TNF-alpha and peroxynitrite levels. The TNF-alpha gene promoter polymorphism G/A at position -308 does not influence TNF-alpha plasma levels during cardiac surgery, is not associated with greater oxidative stress, and does not result in a greater incidence of perioperative complications. However, importantly, treatment with the mitoK(ATP) channel opener nicorandil prior to surgery significantly reduced basal TNF-alpha values and also the oxidative stress induced by surgery.