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CARDIOVASCULAR ANESTHESIA

Tumor Necrosis Factor Gene Polymorphism Is Associated with Enhanced Systemic Inflammatory Response and Increased Cardiopulmonary Morbidity After Cardiac Surgery

Departments of Anesthesia and Intensive Care and Clinical Chemistry, Section of Molecular Biology, Sahlgrenska University Hospital, Göteborg, Sweden

Address correspondence and reprint requests to Sven-Erik Ricksten, MD, PhD, Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. Address e-mail to sven-erik.ricksten{at}aniv.gu.se

	Abstract

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Cardiopulmonary bypass induces a systemic inflammatory response characterized by alterations in cardiopulmonary function. Mediators for this morbidity are the cytokines tumor necrosis factor (TNF)- and interleukins. A genomic polymorphism within the TNF locus is associated with increased TNF- levels and high mortality in severe trauma and sepsis. We assessed the relationship of biallelic polymorphisms of the TNF locus in patients undergoing elective cardiac surgery to release of proinflammatory cytokines and cardiopulmonary morbidity. TNF genotypes, plasma concentrations of TNF-, interleukin-6, and cardiopulmonary morbidity were studied in 95 unselected, consecutive patients undergoing routine cardiac surgery. TNF genotypes were determined by the solid-phase minisequencing method. Patients homozygous for the TNFB2 allele (n = 42) displayed larger peak concentrations of TNF- (11.3 ± 1.3 versus 7.8 ± 0.7 pg/mL; P = 0.013) and interleukin-6 (153 ± 27 versus 87 ± 7 pg/mL; P = 0.010) when compared with patients homozygous or heterozygous for TNFB1 (n = 53). The TNFB2 homozygotes had a higher incidence of left ventricular dysfunction (31% versus 9%; P = 0.029; odds ratio 3.84 [95% confidence interval, 1.40–24.3]), postoperative pulmonary dysfunction (24% versus 6%; P = 0.016; odds ratio 5.21 [95% confidence interval, 1.49–18.3]), and a lower pulmonary oxygenation index (29 ± 1.9 versus 36.1 ± 1.8; P = 0.013). Patients homozygous for the TNFB2 allele may develop an enhanced systemic inflammatory response with an increased risk of cardiopulmonary morbidity after cardiac surgery.

IMPLICATIONS: The associations between tumor necrosis factor (TNF) gene polymorphism, plasma cytokines, and cardiopulmonary function after elective cardiac surgery were evaluated. Patients homozygous for the TNFB2 allele displayed larger concentrations of TNF- and interleukin-6 and had an increased risk of developing left ventricular and pulmonary dysfunction compared with TNFB1 homo- or heterozygotes.

	Introduction

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Tumor necrosis factor- (TNF-) is a proinflammatory cytokine that plays a major role in the systemic inflammatory response syndrome and multiple organ dysfunction secondary to surgical intervention, infection, and trauma or ischemia-reperfusion injury (1). In the TNF gene locus, biallelic polymorphisms have been described, e.g., a G-to-A transition at position +252, in the first intron of the TNF-ß gene (TNFB1B2) (2). Polymorphism within the TNF-gene has been shown to be a genomic marker for patients with increased TNF- response and poor prognosis in severe sepsis (3). TNFB2 homozygous individuals display increased circulating TNF plasma concentrations combined with a high mortality rate in severe sepsis and trauma (3,4).

A systemic inflammatory response after cardiac surgery is initiated by tissue injury, endotoxemia, and contact of blood with the foreign surface of the cardiopulmonary bypass (CPB) circuit (5,6). This systemic inflammatory response to CPB induces a spectrum of pathophysiologic changes ranging from mild organ dysfunction to multisystem organ failure (5,6). Soluble mediators of systemic inflammation include plasma proteases, lipids, and cytokines. Increased concentrations of the proinflammatory cytokines TNF-, interleukin-6 (IL-6), and IL-8 during and after CPB have been shown by many studies (5,6). Increased concentrations of TNF-, IL-6, and IL-8 have been associated with cardiopulmonary dysfunction after CPB (5,6).

The aim of the present study was to evaluate the biallelic polymorphism of the TNF-ß gene (TNFB1B2) in patients undergoing elective cardiac surgery with regard to the release of proinflammatory cytokines and postoperative cardiopulmonary morbidity. More specifically, we hypothesized that patients homozygous for TNFB2 have a more pronounced postoperative increase of cytokines and more cardiopulmonary morbidity after cardiac surgery.

	Methods

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The Human Ethics Committee of the Medical Faculty, University of Göteborg, approved this study, and the patients gave written informed consent for genetic analysis. One-hundred patients undergoing elective cardiac surgery were enrolled from the February 1 to April 30, 1999. Complete data were obtained from 95 patients, which were included in the study. Because of the low frequency of the TNFB1B1 genotype (see Results), our patients were divided in two groups: (a) patients homozygous for TNFB2 (TNFB2B2) and (b) patients homozygous (TNFB1B1) or heterozygous (TNFB1B2) for TNFB1.

Anesthesia was induced with thiopentone, fentanyl, and pancuronium and maintained with fentanyl, nitrous oxide, and enflurane. CPB was performed using a COBE Duo membrane oxygenator (COBE, Arvada, CO) after administration of heparin (300 IU/kg). The activated clotting time was maintained at above 400 s. The circuit was primed with 1500 mL of Ringer’s lactate solution and 200 mL of 15% mannitol, and a nonpulsatile flow of 2.4 L · min^-1 · m^-2 was used. In all patients, hypothermia (32°C–34°C) and cold hyperkalemic blood cardioplegia were used during CPB. After separation from CPB (36.5°C–37°C) anticoagulation was reversed with protamine sulfate, given at a ratio of 1 mg:100 IU of heparin. Inotropic drugs were not used prophylactically in any of the patients before the first weaning attempt from CPB. Initiation of treatment with inotropic drug with or without intraaortic balloon counterpulsation was at the discretion of the attending anesthesiologist and surgeon based on hemodynamic and echocardiographic findings during and after weaning from CPB. Aprotinin was administered during surgery in two patients being homozygous for TNFB2 and in three patients being homo- or heterozygous for TNFB1. None of the patients received steroids or nonsteroidal antiinflammatory drugs before surgery.

Blood samples for assay of the two inflammatory mediators were taken (a) before surgery, immediately before the induction of anesthesia, (b) after 30 min of CPB, (c) at the end of CPB, (d) 2 h after CPB, and (e) 24 h after CPB. Blood samples were drawn into tubes with ethylene diamine tetraacetic acid. All tubes were centrifuged and frozen within 30 min after sampling and stored at -80°C. TNF- and IL-6 were assayed with a commercially available quantitative "sandwich" enzyme immunoassay technique (Biotrak cytokines human ELISA systems, Biotrak, Amersham, United Kingdom).

Analysis of the genotype of the TNF-ß gene was performed after surgery in all patients. Genomic DNA was isolated from peripheral blood cells and analyzed for the polymorphism of the TNF-ß gene by the solid-phase minisequencing method described by Syvänen et al. (7). In the present study, fluorescent ddNTPs were used, and the extended minisequencing detection primers were analyzed by capillary electrophoresis and laser-induced fluorescence.

Amplified genomic DNA from the TNF-ß gene was obtained by multiplex polymerase chain reaction (PCR) using the sense primer 5'-CTCTGACTCTCCATCTGTCA-3' and the antisense primer biotin 5'-GAAGGGG ACAAGATGCAGTCA-3'. Minisequencing primers for the polymorphism 252G/A in the TNF-ß gene were 5'-GGAGGCTGAACCCCGTCC-‘3 and 5'-T (7) CATTCTCTGTTT CTGCCATG-3', respectively. The T (7) is added to the last primer to increase the difference in migration of the two minisequencing primers by capillary electrophoresis. After amplification, 20 µL of the PCR products were added to 96-well streptavidin-coated microtiter plates (Wallac AB, Sweden) and incubated for 1.5 h at 37°C. The bound DNA fragments were denatured with 50 µL of 0.05 M NaOH for 5 min at room temperature. The microtiter plates were washed three times with buffer II containing 0.1% Tween and 0.15 mM NaCl. A 20-µL solution containing 0.05 U of Thermo Sequenase DNA polymerase, fluorescent ddNTP (Thermo Sequenase, Dye Terminator Kit, Amersham, US) and 0.5–15 pmol of specific detection primer was added. The minisequences reaction was allowed to proceed in the wells for 10 min at 58°C. After the reaction, the plates were washed three times with buffer II, and the extended sequence primers were released from the PCR products by incubation with 20 µL of formamide at 45°C for 5 min. The primers were separated and analyzed by capillary electrophoresis and laser-induced fluorescence in an ABI 310 genetic analyzer (Perkin Elmer, Sweden).

Perioperative left ventricular dysfunction (LVD) was defined as the need for inotropic support with or without intraaortic balloon counterpulsation during and after weaning from CPB and on arrival at the cardiothoracic intensive care unit (ICU). Arterial blood gas analysis was performed, and the oxygenation index (OI) was calculated (arterial PO₂ divided by inspired fraction of oxygen) on arrival at the ICU. Postoperative pulmonary dysfunction was defined as an OI <20 kPa (normal levels, 60 kPa). Postoperative peak serum values of creatinine, aspartate aminotransferase, alanine aminotransferase, and bilirubin were noted as well as length of stay (LOS) in the ICU and ICU mortality. A complicated postoperative course in ICU was defined as a LOS in the ICU 2 days, death in the ICU, or both.

To estimate the sample size, a power analysis revealed that 45 patients in each of the two groups were required to be included to detect a 30% intergroup difference in peak plasma TNF-, at a power of 0.8, an = 0.05, and a SD of the underlying population of 6 U (obtained from previous studies).

Results are expressed as mean (SEM). Continuous variables were evaluated by means of Student’s t-test or nonparametric tests where appropriate. Categorical data were analyzed by Fisher’s exact test. The potential differential effects of cardiac surgery on the evolution of TNF- and IL-6 during and after surgery between groups were evaluated by a two-way analysis of variance (ANOVA) followed by a means comparison contrast analysis. A P < 0.05 was considered significant. Differential effects of cardiac surgery on the distribution of ICU LOS between groups were estimated by the nonparametric Wald-Wolfowitz runs test. The odds ratio and the 95% confidence interval (CI) for perioperative LVD and postoperative pulmonary dysfunction were calculated.

	Results

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The genotype distribution was TNFB1 homozygotes 9% (n = 9), TNFB1B2 heterozygotes 46% (n = 44), and TNFB2 homozygotes 44% (n = 42). Genotype distribution was in Hardy-Weinberg equilibrium and comparable to those reported in previous studies (4,5) and to healthy blood donors of our hospital. TNF genotypesdid not differ with respect to age, sex, body mass index, preoperative risk score, incidence of preoperative congestive heart failure, types of surgery, CPB time, or aortic cross-clamp time (Tables 1 and 2 ).

View larger version (13K): [in this window] [in a new window]   Figure 1. Plasma concentrations of tumor necrosis factor (TNF)- before, during, and after cardiac surgery with cardiopulmonary bypass (CPB). Patients homozygous for the TNFB2 allele (TNFB2B2) displayed a more pronounced perioperative increase in TNF- compared with patients homozygous or heterozygous for the TNFB1 allele (TNFB1B1 or TNFB1B2). (A) Before the induction of anesthesia, (B) 30 min of CPB, (C) end of CPB, (D) 2 h after CPB, and (E) = 24 h after CPB. Values are expressed as mean ± SEM. *P < 0.05; ***P < 0.001.

View larger version (14K): [in this window] [in a new window]   Figure 2. Plasma concentrations of interleukin (IL)-6 before, during, and after cardiac surgery with cardiopulmonary bypass (CPB). Patients homozygous for the tumor necrosis factor (TNF)B2 allele displayed a more pronounced perioperative increase in IL-6 compared with patients homozygous or heterozygous for the TNFB1 allele. (A) Before the induction of anesthesia, (B) 30 min of CPB, (C) end of CPB, (D) 2 h after CPB, and (E) 24 h after CPB. Values are expressed as mean ± SEM. **P < 0.01; ***P < 0.001.

The mean ICU LOS was 1.68 ± 0.31 days for TNFB2 homozygotes and 1.15 ± 0.08 days for the TNFB1 homo- or heterozygotes (not significant [ns]). The corresponding values for hospital LOS were 10.14 ± 0.70 and 9.75 ± 0.46, respectively (ns). The LOS in ICU was significantly (P = 0.001) distributed to longer ICU LOS in the TNFB2 homozygotes (Fig. 3). ICU mortality was 2.4% (1 of 42) versus 3.8% (2 of 53) (ns), and the incidence of complicated postoperative course in ICU was 21.4% (9 of 42) versus 7.5% (4 of 53) in TNFB2 homozygotes and TNFB1 homo- or heterozygotes (P = 0.071), respectively.

View larger version (13K): [in this window] [in a new window]   Figure 3. The length of stay (LOS) in the intensive care unit (ICU) was significantly (P = 0.001) distributed to longer lengths of ICU stay in the tumor necrosis factor (TNF)B2 homozygotes compared with TNFB1 homo- or heterozygotes.

	Discussion

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The gene encoding for the cytokine TNF-ß is located on the human chromosome 6. A biallelic genomic restriction fragment length polymorphism occurs in the first intron of the TNF-ß gene at position 258 with a guanine (TNFB1) to adenine (TNFB2) transposition (2). Endotoxin-stimulated monocytes from donors homozygous for the TNFB2 allele secrete more TNF- than individuals heterozygous or homozygous for the TNFB1 allele (8). In a previous study in patients with severe sepsis of infectious origin (peritonitis, pancreatitis, pneumonia, or mediastinitis), patients homozygous for TNFB2 have increased circulating TNF- concentrations, multiple organ failure scores, and mortality compared with heterozygous (TNFB1B2) patients (3). TNF- serum concentrations and the development of nosocomial sepsis in multiply-injured patients are also significantly increased in patients homozygous for the allele TNFB2 compared with heterozygous and TNFB1 homozygous individuals (4).

TNF- depresses cardiac contractility and induces dilated cardiomyopathy in transgenic mice overexpressing TNF- (9–11). The presence of TNF receptors has been identified in adult human cardiac myocytes (12), and overexpression of TNF- can produce LVD and cardiomyopathy in humans (13,14). Increased levels of TNF- have consistently been demonstrated in patients with severe congestive heart failure (15), and increasing concentrations of TNF- are related to the severity of the disease process (16) as well as mortality (15). It has therefore been suggested that cytokines, particularly TNF-, may be responsible for the development and progression of heart failure (17,18).

Eighty percent of patients with New York Heart Association (NYHA) class III or IV heart failure have increased levels of TNF- (mean level, 6–7 pg/mL) (15,16). In the present study, peak concentrations of TNF- after cardiac surgery were 2.5–3 times larger than preoperative control values reaching levels at or more than (9–10 pg/mL) those seen in NYHA class III or IV heart failure patients (15,16). One possible explanation for the increased incidence of LV failure in TNFB2 homozygotes could therefore be the enhanced inflammatory response with increased expression of cytokines in response to cardiac surgery and CPB compared with patients homo- or heterozygous for the TNFB1 allele. The impaired lung function in the TNFB2 homozygotes after cardiac surgery could be caused by the more frequent incidence of LVD in this group, the deleterious pulmonary effects of the systemic inflammatory reaction, or both. CPB provokes a greater pulmonary than systemic inflammatory response, and pulmonary immune mediators correlate significantly with decreased arterial oxygenation after cardiac surgery (19,20).

It has been shown that soluble TNF receptors prevent and reverse the negative inotropic effect of TNF- both in vitro (21) and in vivo (22). Treatment with soluble TNF receptors improves LV function and remodeling as well as the functional status of patients with NYHA class III–IV heart failure (23,24). It is tempting to speculate that perioperative inhibition of the inflammatory response, particularly increased levels of TNF-, in cardiac surgical patients might attenuate the potentially deleterious effects of cytokines on cardiopulmonary function. Both pharmacological strategies (glucocorticoids and protease inhibitors) and mechanical strategies (hemofiltration and heparin-bonded circuits) have proved to effectively attenuate the increase in TNF- and ILs after cardiac surgery (6), although very few studies have evaluated the effects of antiinflammatory strategies on end-organ function.

One limitation of the present study is that data from patients with the TNFB1B1 and the TNFB1B2 genotypes were pooled. The main reason for this is the fact that the frequency of the TNFB1B1 genotype is relatively small (<10%), which has been demonstrated in numerous studies (3,4). The heterozygous and homozygous TNFB1-patients (TNFB1B1 or TNFB1B2) do not appear to have a differentiated response in terms of TNF- concentrations during trauma or sepsis (3,4), thus motivating the pooling of data from these two groups.

In conclusion, we have shown that the polymorphism of the TNF-ß gene is related to the release of proinflammatory cytokines and the risk of developing postoperative cardiopulmonary morbidity in patients undergoing elective cardiac surgery. Patients homozygous for the TNFB2 allele develop a more pronounced perioperative increase in plasma concentrations of TNF- and IL-6, and they have an increased risk of developing perioperative LV failure and postoperative pulmonary dysfunction. Given our results, typing of the polymorphic TNF gene may be another important complementary tool to select patients at high risk of developing vital organ dysfunction after cardiac surgery with CPB.

	Acknowledgments

 
Supported, in part, by the Swedish Medical Research Council (No. 13156), The Medical Faculty of Gothenburg (LUA), Gothenburg Medical Association and Sahlgrenska University Hospital Foundations.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Tomasdottir, H. Articles by Ricksten, S.-E. Search for Related Content PubMed PubMed Citation Articles by Tomasdottir, H. Articles by Ricksten, S.-E. Related Collections Economics and Health Care Research Postanesthetic Care Unit Complications Monitoring (Cardiac)

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999