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Eur J Cardiothorac Surg 2008;34:332-337. doi:10.1016/j.ejcts.2008.03.015
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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TNF-{alpha} gene promoter polymorphism at nucleotide –308 and the inflammatory response and oxidative stress induced by cardiac surgery: role of heart failure and medical treatment

Manuel Galiñanesa,*, Martha Jamesb, Veryan Coddb, Amar Baxia, Leonidas Hadjinikolaoua

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).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: 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. Methods: 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 24 h after initiation of CPB. Results: 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 mitoKATP 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. Conclusions: 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 mitoKATP channel opener nicorandil prior to surgery significantly reduced basal TNF-{alpha} values and also the oxidative stress induced by surgery.

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


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Polymorphisms of pro-inflammatory cytokines have been correlated to higher secretion of biologically active products. TNF-{alpha}, a proinflammatory cytokine produced by macrophages but also by cardiomyocytes, mediates systemic responses to sepsis and injury and has been shown to be elevated in several pathological conditions including rheumatoid arthritis, atherogenesis and chronic heart failure [1–3]. Increased TNF-{alpha} can depress cardiac contractile function [4] and cause cell death [5] and because of these effects it has also been implicated in the pathophysiology of cardiopulmonary bypass (CPB) [6].

A single nucleotide polymorphism (G/A) at position –308 in the TNF-{alpha} promoter has been previously described, with G being the common allele. The uncommon A allele has been shown to be a significantly stronger activator of transcription in vitro [7]. It is possible that the effect of this allele when associated with conditions such as heart failure, where TNF-{alpha} production is also increased [3], may exacerbate the response to CPB and thus pose a greater risk for cardiac surgery. Oxygen free radicals are also increased by CPB [8] and, since these have been linked to the production of inflammatory factors [9], it may be speculated that a greater oxidative stress during cardiac surgery will lead to increased production of TNF-{alpha}. Therefore, the aims of the present study were to investigate: (i) whether the TNF-{alpha} G/A polymorphism is associated with increase production of TNF-{alpha} 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.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Study patients and blood sampling
The study was approved by the local ethics committee and written consent was obtained from each patient. One hundred consecutive patients with coronary artery disease alone or in combination with aortic or mitral valve disease entered the study. None of the patients were receiving steroids or immunosuppressant drugs. Standard anesthesia and surgical procedures were followed in all study patients. Blood cardioplegia at a ratio of 4:1 was used for myocardial protection, 1000 ml as the first dose and then 500 ml every 20–30 min. Blood samples (10–15 ml) were obtained from the venous central line before surgery (prior to anesthesia, following premedication and before the administration of IV heparin), before CPB and 30 min, and 4 and 24 h after the initiation of CPB and collected in anticoagulant tubes. Patients were followed up for the first 6 weeks after surgery coinciding with their outpatient clinic visit. The clinical status and occurrence of postoperative complications were recorded at this time.

2.2 Polymerase chain reaction and DNA sequencing
A 107 bp fragment of the TNF-{alpha} promoter (position –327 to –220 bp) was amplified by PCR using the same primers as described by Wilson et al. [10]. Cycling conditions were 94 °C 1 min, 59 °C 1 min, 72 °C 1 min for 30 cycles. The resulting product was checked by agarose gel electrophoresis and purified using QIA quick PCR clean up kit (Qiagen). The resulting DNA was then submitted for sequencing at University of Leicester PNACL.

2.3 Assessment TNF-{alpha} in plasma
TNF-{alpha} was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) with a commercially available kit according to the manufacturer's instructions (BD Biosciences, Cowley, Oxford, UK).

2.4 Assessment of peroxynitrite in peripheral blood lymphocytes
Using 1.5 ml Eppendorf tubes, 50 µl of dihydrorhodamine 123 were added to and mixed gently with 500 µl of blood followed by incubation for 30 min at 37 °C. The content was then resuspended in 15 ml tubes containing 7.5 ml of PBS. This was then added on top of 4 ml of lymphoprep (Axis-shield, Dundee, UK), the preparation was centrifuged at 800 x g for 20 min at room temperature. The lymphocyte fraction was then removed, diluted with 12 ml of PBS in another 15 ml tube and centrifuged at 250 x g for 12 min at room temperature. The supernatant was resuspended in 2 ml of 0.2% saline, then after adding 2 ml of 1.9% saline solution cells were incubated for 1 min at room temperature. Cells were resuspended and after adding 0.9% saline to obtain a 12 ml volume the preparation was again centrifuged at 250 x g for 12 min at room temperature. 40 µl of the cell pellet were placed in an Eppendorf tube, fixed by adding 500 µl of 4% paraformaldehyde and then stored in a flow cytometer tube at 4 °C until analysis. Negative controls were obtained using 5 ml of blood that were mixed with 3 ml of PBS before being added on top of 4 ml of lymphoprep in a 15 ml tube followed by centrifugation at 800 x g for 20 min at room temperature. Without adding dihydrorhodamine 123, the lymphocyte fraction was removed, diluted with 10 ml of PBS in a 15 ml tube and centrifuged at 250 x g for 12 min at room temperature. Thereafter the protocol was identical to the one described above in the presence of dihydrorhodamine 123. The mean absorbance of peroxynitrite was measured using a Coulter Epics XL.MCL flow cytometer (Beckman Coulter Diagnostics, High Wycombe, Buckinghamshire, UK).

2.5 Statistical analysis
Results were expressed as mean ± SEM. A sample size big enough to identify the difference of 1 standard deviation with a power of 80% at a probability level of <0.05 was selected. This entailed a minimum of 17 patients to be identified with the G/A genotype and for most of the possible comparisons. Analysis was performed using the SPSS statistical programme (SPSS version 10.0). The nonparametric tests Mann–Whitney U-test for two independent samples, Kruskal–Wallis one-way analysis for several independent variables, Wilcoxon signed-rank test for two related samples and Friedman's test for several related samples were performed where appropriate. The TNF-{alpha} plasma and peroxynitrite in peripheral blood lymphocytes values followed a log-normal distribution and, because of this, they were subjected to logarithmic transformation before the multiple regression analysis. Forward stepwise multiple regression analysis was used to identify the effect of multiple variables on TNF-{alpha} and peroxynitrite values. R 2 adjusted was used as criterion for the selection of the best-fit model. Probability values less than 0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Of the 100 study patients, 34 were identified with the G/A genotype, whereas 65 were G/G and 1 was A/A. Table 1 shows the patients’ characteristics and Table 2 the postoperative data.


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  		Table 1 Patient demographics and preoperative medications
 

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  		Table 2 Patients postoperative data
 
The plasma TNF-{alpha} mean values for all the study patients were 2.05 ± 0.13 ln(mmol/l + 1) before surgery (baseline). They significantly decreased to 1.61 ± 0.17 ln(mmol/l + 1) following anesthesia and the initiation of surgery but before CPB (p < 0.05) with further reduction to 1.20 ± 0.20 ln(mmol/l + 1) after 30 min of the initiation of CPB (p < 0.05). Values returned to preoperative levels 4 h after surgery (2.03 ± 0.14 ln(mmol/l + 1), p = NS vs baseline) and then decreased again 24 h after CPB (1.60 ± 0.18 ln(mmol/l + 1), p < 0.05). Despite the changes, Fig. 1a demonstrates that the plasma TNF-{alpha} values before surgery were similar in the G/A and G/G groups and that the response to surgery and CPB was identical in the two groups.


Figure 1
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  		Fig. 1. TNF-{alpha} plasma values (a) and peroxynitrite content in blood lymphocytes (b) before surgery, before cardiopulmonary bypass (CPB) and at various times after the initiation of CPB according to the TNF-{alpha} genotype.

 
Peroxynitrite mean values for the entire study population were 0.70 ± 0.08 ln(mmol/l + 1) at baseline, they increased by almost two-fold to 1.30 ± 0.09 ln(mmol/l + 1) following anesthesia and the initiation of surgery (p < 0.05), remained elevated throughout CPB, and then exhibited a further increase to 1.55 ± 0.10 ln(mmol/l + 1) 24 h after CPB (p < 0.05). Again, despite these changes, Fig. 1b shows that the peroxynitrite values were identical in the G/A and G/G groups before surgery and that they were also similar during anesthesia and surgery, however values were slightly higher in the G/A group than in the G/G group by 24 h after surgery, a difference that failed to achieve statistical significance.

As expected, Fig. 2a shows that TNF-{alpha} values were higher in patients with greater NYHA class (e.g. advanced heart failure) and that they remained more elevated in the NYHA III class group during and following surgery. Interestingly, peroxynitrite values were unaffected by NHYA class (Fig. 2b).


Figure 2
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  		Fig. 2. TNF-{alpha} plasma values (a) and peroxynitrite content in blood lymphocytes (b) before surgery, before cardiopulmonary bypass (CPB) and at various times after the initiation of CPB according to the NYHA class. * p < 0.05 versus the NYHA 1 group.

 
Analysis of the role of preoperative medications demonstrated that the mitoKATP channel opener nicorandil (at a dose of 20 ml twice a day administered for at least 3 months before surgery) reduced TNF-{alpha} values before surgery and blunted the increase in peroxynitrite caused by surgery (Fig. 3a and b). Table 3 shows the multiple regression analysis on clinical predictors of the greater plasma TNF-{alpha} levels before surgery and demonstrates that only the NYHA class and the use of nicorandil were related to the preoperative TNF-{alpha} levels. The postoperative outcome variables, which are described in Table 2, were not related to either TNF-{alpha} polymorphorphism or TNF-{alpha} and peroxynitrite values, neither to the type of medication received, including nicorandil.


Figure 3
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  		Fig. 3. TNF-{alpha} plasma values (a) and peroxynitrite content in blood lymphocytes (b) before surgery, before cardiopulmonary bypass (CPB) and at various times after the initiation of CPB in subjects receiving or not the mitoKATP channel opener nicorandil. * p < 0.05 versus the group without nicorandil.

 

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  		Table 3 Multiple regression analysis on clinical predictors of the baseline (preoperative) TNF-{alpha} plasma levels
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study has demonstrated that the TNF-{alpha} gene promoter polymorphism G/A at position –308 does not influence TNF-{alpha} plasma levels during cardiac surgery and CPB, and that is not associated with greater oxidative stress (as measured by peroxynitrite content in peripheral blood lymphocytes) or incidence of perioperative complications. In addition, it has shown that the high TNF-{alpha} values seen with advanced symptoms of heart failure do not influence the oxidative stress seen during cardiac surgery. However, the anti anginal agent mitoKATP channel opener nicorandil reduced the basal TNF-{alpha} values and suppressed the oxidative stress caused by cardiac surgery. The relevance and clinical implications of these results are discussed below.

TNF-{alpha} is a cytokine with a wide range of proinflammatory activities, and it occupies a pivotal role in the initiation and amplification of the inflammatory cascade in clinical conditions such as rheumatoid arthritis and atherogenesis [1,2]. Patients with rheumatoid arthritis show up to a five-fold increased cardiovascular mortality, and anti-TNF-{alpha} treatment has been shown to improve the clinical course and outcome of subjects with this disease [11]. Over-production of TNF-{alpha} by the heart is induced by myocardial ischemia [12], as occurs during cardiac surgery, and this can cause additional myocardial dysfunction [13]. Accordingly, some investigators have suggested that abolition of TNF-{alpha} production in knockout mice [14] and anti-TNF-{alpha} therapies reduce postischemic cardiac dysfunction [15]. However, other investigators have reported contrary results and showed that TNF-{alpha} does not modulate ischemia/reperfusion injury or even that it plays an important role in cardioprotection [16]. From these results it is possible to argue that TNF-{alpha} has dual and opposite actions that might depend on the amount of the cytokine produced and the clinical condition, circumstances that need to be fully elucidated before therapeutic interventions for clinical use are designed. While this is defined, the present study has clearly shown that the presence of the G/A polymorphyism in humans does not significantly modify the changes in TNF-{alpha} plasma values observed during cardiac surgery.

The incidence of the TNF-{alpha} gene promoter polymorphism G/A at position –308 seen in our study is similar to the one reported by other investigators [17,18]. However, in our study the presence of G/A polymorphism was not associated with a poor clinical outcome after cardiac surgery; that contrasts with studies performed in other systems and clinical conditions in which the G/A polymorphism has been shown to increase the risk of developing chronic renal failure [17] and fibrosing alveolitis [19]. The controversy is further fuelled by the finding that the G/A polymorphism does not increase the risk of cardiogenic shock and that in fact subjects with this complication have a better survival rate when it develops [18]. The reason for this disease-specific response and apparently conflicting results is unknown and needs to be clarified.

It is well recognized that TNF-{alpha}, in concert with other neurohormones, contributes to the progression of heart failure. The administration of TNF-{alpha} to experimental animals and the transgenic over-expression of TNF-{alpha} replicate the heart failure phenotype and also supports an important role of the cytokine in the development of this condition. As expected, our results showed that patients with more severe symptoms of heart failure exhibited the highest TNF-{alpha} plasma levels. However, our study also shows that patients with elevated TNF-{alpha} plasma values do not have additional increases during and following cardiac surgery, and that high TNF-{alpha} values are not associated with a greater incidence in perioperative complications, results that do not support the use of anti-cytokine therapy against TNF-{alpha} in cardiac surgery.

The present study has also shown that there is a significant increase in oxidative stress upon the initiation of surgery, which is consistent with previous results from our laboratory [8]. However, the TNF-{alpha} G/A polymorphism and the presence of greater TNF-{alpha} plasma values, as occurred in patients with more severe symptoms of heart failure, were not correlated with the degree of the oxidative stress response seen during cardiac surgery. Since there is evidence that inflammatory responses can be induced via activation of redox-sensitive transcription factors [9], our results would suggest that the production of TNF-{alpha} may be unaffected when the degree of oxidative stress is at the levels observed in our study. This is a concept that if definitely proven may influence the design of therapeutical strategies and deserves further investigation.

The most striking finding of this study was the significant reduction in TNF-{alpha} production prior to cardiac surgery and the suppression of the increased in peroxynitrite caused by surgery in patients treated with the mitoKATP channel opener nicorandil. These unexpected results are difficult to interpret since opening of the mitoKATP channels causes a decrease in the mitochondrial membrane potential, that in turn leads to a reduction of mitochondrial calcium overload [20] and increased production of oxygen free radicals by the mitochondria [21]. Indeed, opening of the mitoKATP channels increases superoxide generation from complex I of the electron transport chain [22], however it should be pointed out that during reoxygenation mitoKATP channel opening has the opposite effect and attenuates oxidative stress [23]. Our laboratory has demonstrated that opening of the mitoKATP channels is essential for the cardioprotection obtained by ischemic and pharmacological preconditioning in the human myocardium [24] but also that the chronic administration of a mitoKATP channel opener like nicorandil renders the myocardium unresponsive to the preconditioning stimuli [25]. Overall it appears that the permanent opening of the mitoKATP channels by chronic administration of nicorandil can induce benefits by reducing oxidative stress and the production of inflammatory factors such as TNF-{alpha} during cardiac surgery but that at the same time it may abrogate the cardioprotective effect of preconditioning. Therefore, at present, it is unclear whether the net effect of nicorandil in patients undergoing cardiac surgery is beneficial or detrimental, or whether these opposed actions cancel out the effect of the other. A large proportion of patients with coronary artery disease and hypertension are receiving nicorandil (20% in our study) and this important issue needs to be elucidated by future studies.


   Acknowledgments
 
We would like to thank Dr Bashir Matata and Mr Maqsood Elahi for their assistance and Mrs Nicola Harris for help with the preparation of the manuscript.


   Footnotes
 
{star} This work was partly funded by the British Heart Foundation (Grant PG/02/095) and by a contribution from Professor Manuel Galiñanes.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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