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

^a Cardiac Surgery Unit, Department of Cardiovascular Sciences, The Glenfield Hospital, University of Leicester, Leicester LE3 9QP, UK
^b Cardiology Unit, Department of Cardiovascular Sciences, The Glenfield Hospital, University of Leicester, Leicester LE3 9QP, UK

Received 4 September 2007; received in revised form 29 January 2008; accepted 11 March 2008.

^_* Corresponding author. Tel.: +44 116 256 3032; fax: +44 116 250 2449. (Email: mg50{at}le.ac.uk).

Background: Increased TNF- during cardiac surgery is thought to be responsible for perioperative complications. The TNF- gene promoter polymorphism G/A at position –308 has been associated with enhanced TNF- secretion, as has been heart failure. Therefore, the aims of this study were to investigate: (i) whether the TNF- G/A polymorphism is associated with exacerbation of TNF- plasma levels during cardiac surgery; (ii) whether TNF- 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. Methods: The TNF- 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- 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 24 h after initiation of CPB. Results: The changes observed in TNF- plasma levels during cardiac surgery were unaffected by the G/A polymorphism. TNF- 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- values before surgery and blunted the increase in peroxynitrite caused by surgery. Perioperative complications were not related to either TNF- polymorphism or TNF- and peroxynitrite levels. Conclusions: The TNF- gene promoter polymorphism G/A at position –308 does not influence TNF- 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- values and also the oxidative stress induced by surgery.

Key Words: TNF- polymorphism • Inflammatory reaction • Oxidative stress • Cardiopulmonary bypass • Cardiac surgery • Man