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(Chest. 2004;125:2232-2237.)
© 2004 American College of Chest Physicians

Association Between the TNF-2 Allele and a Better Survival in Cardiogenic Shock*

Olivier Appoloni, MD; Etienne Dupont, MD, PhD; Marleen Vandercruys, RT; Marc Andrien, BS; Jean Duchateau, MD, PhD and Jean-Louis Vincent, MD, PhD, FCCP

* From the Departments of Intensive Care (Drs. Appoloni and Vincent) and Immunology (Dr. Dupont, Ms. Vandercruys, and Mr. Andrien), Erasme University Hospital, and Department of Immunology (Dr. Duchateau), Brugmann Hospital, Free University of Brussels, Brussels, Belgium.

Correspondence to: Jean-Louis Vincent, MD, PhD, FCCP, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium; e-mail: jlvincen{at}ulb.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Tumor necrosis factor (TNF)-{alpha} has been implicated in the pathophysiology of heart failure. We explored a possible association between TNF-{alpha}, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-ß, and interferon (IFN)-{gamma} cytokine polymorphisms, their in vivo production, and mortality from cardiogenic shock.

Design: Prospective, observational study.

Setting: Thirty-one bed, university, medicosurgical department of intensive care.

Patients: Thirty-three adult patients with cardiogenic shock of recent (< 4 h) onset.

Interventions: None.

Measurements and results: TNF-{alpha}, IL-6, IL-10, TGF-ß1, and IFN-{gamma} plasma levels were measured by enzyme-linked immunosorbent assay. Polymorphisms of TNF-{alpha} within the promoter at position –308a->g, IL-6 within the promoter at position –174c->g, IL-10 within the promoter at position –1082a->g/-819t->c and –819t->c/-592a->c, TGF-ß1 at codon 10t->c and codon 25c->g, and IFN-{gamma} at intron 1 at position + 874t->a were studied. The 33 patients had a mean (± SD) age of 64 ± 17 years and a mean simplified acute physiology score II of 62.3 ± 15.3. Twenty-three patients (70%) died in the ICU, including 21 of 26 patients (81%) in the TNF-1 group but only 2 of 7 patients (29%) in the TNF-2 group (p = 0.016). There were no significant differences in median plasma TNF-{alpha} levels between the TNF-1 and the TNF-2 groups, but TGF-ß1 levels were higher in the survivors than in the nonsurvivors (median, 866 pg/mL; range, 384 to 1,966 pg/mL; vs median, 454 pg/mL; range, 167 to 1,266 pg/mL, respectively; p = 0.02). There were no significant differences in TNF-2 polymorphism between the patients with cardiogenic shock and a group of healthy control subjects (7 of 33 patients vs 13 of 48 subjects, respectively; p = 0.61), but IFN-{gamma} polymorphism was less common in the cardiogenic shock group (p = 0.034).

Conclusions: Patients with the TNF-2 allele have no greater risk of cardiogenic shock but a better survival rate when it develops. Different genetic factors appear to influence the risk of development of, and outcome from, cardiogenic shock.

Key Words: cardiogenic shock • cytokines • interferon-{gamma} • polymorphism • tumor necrosis factor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Cardiogenic shock complicates 5 to 15% of acute myocardial infarctions and carries a dismal prognosis, with short-term mortality ranging from 50 to 80%.1 Although the incidence of acute myocardial infarction has declined, the incidence of cardiogenic shock and its associated mortality has remained unchanged over the past 20 years.2

Tumor necrosis factor (TNF)-{alpha} has been largely implicated in the myocardial depression associated with septic shock,34 as well as in the pathogenesis of heart failure. Blood TNF-{alpha} concentrations are raised in patients with heart failure, and there is a correlation between increasing blood concentrations and severity, symptoms, and survival.56 Animal studies have shown that overexpression7 or chronic infusion8 of TNF-{alpha} can lead to myocarditis, systolic dysfunction, ventricular dilatation and hypertrophy, myocardial fibrosis, myocyte apoptosis, and increased mortality, all of which can be reversed by TNF-{alpha} binding proteins.9 Early human clinical trials have suggested that TNF-{alpha} inhibition may result in an improvement in symptoms and exercise capacity,10 as well as an increase in ejection fraction.1011

Because genetic traits contribute significantly to the global risk of ischemic heart disease (IHD),12 a number of studies have addressed the hypothesis that variations in the genetics of the inflammatory system may increase the risk of disease. Differences in the genetic regulation of inflammatory processes might explain why some people acquire IHD more than others, and why some have a greater inflammatory response than others.12 Several polymorphisms have been identified within the TNF-{alpha} promoter, including one at nucleotide position –308, where the presence of a guanidine defines the common allele (TNF-1), and the presence of an adenosine defines the uncommon allele (TNF-2), which is a more powerful transcriptional activator than the common allele, with a sixfold to sevenfold increase in the inducible level of TNF-{alpha} gene transcription.13 Patients with septic shock and the TNF-2 allele have a higher risk of death,1415 and higher TNF-{alpha} levels than other patients.16 The TNF-2 allele is also overrepresented in patients with end-stage nonischemic myocardial dysfunction when compared with healthy volunteers.17

This study explored whether there is an association between the TNF-2 allele, TNF-{alpha} in vivo production, and mortality from cardiogenic shock. We also studied the relationship between polymorphisms of TNF-{alpha}, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-ß1, interferon (IFN)-{gamma}, and the development of, and mortality from, cardiogenic shock.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
The study included all consecutive patients admitted to the medicosurgical ICU between April 2001 and June 2002 with recent (< 4 h) cardiogenic shock, as defined by evidence of hypotension with a systolic BP < 90 mm Hg for ≥ 1 h not responsive to fluid administration, and associated with hypoperfusion or organ dysfunction and the need for vasopressor agents, such as dopamine at a dose > 5 µg/kg/min, epinephrine, or norepinephrine at any dose. All patients were monitored with a pulmonary artery catheter and had a pulmonary artery balloon occluded pressure ≥ 15 mm Hg, a cardiac index < 2.2 L/min/m2 and/or mixed venous oxygen saturation < 60%, with a hemoglobin concentration > 9 g/dL. Patients were followed up throughout their stay in the ICU.

The control group comprised 48 healthy, Belgian, white, bone marrow donors. TNF-{alpha}, IL-6, IL-10, TGF-ß1, and IFN-{gamma} levels were determined on study admission by enzyme-linked immunosorbent assay (Medgenix Biosource; Nivelles, Belgium). We studied polymorphisms of the following: TNF-{alpha} within the promoter at position –308A->G, IL-6 within the promoter at position –174C->G, IL-10 within the promoter at position –1082A->G/-819T->C and –819T->C/-592A->C, TGF-ß1 at codon 10T->C and codon 25C->G, and IFN-{gamma} at intron 1 at position + 874T->A. Genotypes were analyzed with the Cytokine Genotyping Tray (One Lambda; Canoga Park, CA), which provides sequence-specific oligonucleotide primers for amplification of the selected alleles by polymerase chain reaction. The simplified acute physiology score (SAPS) II18 was measured within 24 h after study entry. The sequential organ failure assessment (SOFA) score19 was calculated at study entry and every day until patient discharge or death.

The study protocol was approved by the Institutional Review Board of Erasme University Hospital. Written informed consent was obtained from each patient or a relative.

Descriptive results of continuous variables are expressed as mean ± SD. Plasma cytokine levels are reported as median and range. Statistical analyses were performed with the Student t test (for normally distributed continuous variables), the Mann-Whitney test and the Kruskal-Wallis test (for nonnormally distributed continuous variables), and the {chi}2 test and Fisher exact test (for categorical variables). A forward stepwise multiple logistic regression analysis was performed to evaluate the independent role of each variable, including all significant or nearly significant data (p < 0.1) from the univariate analysis to determine predictors of mortality. We forced the SOFA score on admission into the model for disease severity adjustment; results are expressed as odds ratios with 95% confidence intervals. We used a two-sided test; p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
We enrolled 33 patients with cardiogenic shock (mean age, 64 ± 17 years). The ICU mortality rate of 70% (23 of 33 patients) was in agreement with the predicted risk of death based on the SAPS II score of 66 ± 22%.

Patients with the TNF-2 allele (including heterozygous patients) had a higher survival rate than those with the TNF-1 allele, as 21 of 26 patients (81%) died in the TNF-1 group but only 2 of 7 patients (29%) in the TNF-2 group (p = 0.016, Table 1 ). The degree of organ dysfunction was also greater in the TNF-1 group than in the TNF-2 group, as shown by a higher SOFA score on ICU admission and during the ICU stay (Table 1). There was a trend toward more severe pulmonary dysfunction in the TNF-1 group than in the TNF-2 group (pulmonary score on ICU admission, 3.6 ± 0.6 vs 3.1 ± 0.7, p = 0.072; pulmonary maximum score, 3.4 ± 0.6 vs 2.9 ± 0.9; p = 0.05).


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  		Table 1.. Comparison of the Clinical Features and Outcomes of Cardiogenic Shock Patients With the Two TNF Genotypes*

 
The IFN-{gamma} polymorphism within the intron 1 at position + 874 T/T (high in vitro production) was underrepresented in the cardiogenic group compared to the control group (p = 0.034) [Table 2 ]. There were no significant differences in median plasma TNF-{alpha} levels, between the TNF-1 group (14 pg/mL; range, 0 to 228 pg/mL) and the TNF-2 group (16 pg/mL; range, 0 to 117 pg/mL; p = 0.91), and also between the survivors (19 pg/mL; range, 0 to 171 pg/mL) and nonsurvivors (12 pg/mL; range, 0 to 228 pg/mL; p = 0.18).


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  		Table 2.. Comparison of the Different Genotypes Between the Two Groups of Patients*

 
There were no associations between plasma levels of the different cytokines studied (ie, phenotypes) and their polymorphisms (ie, genotypes), but plasma TGF-ß1 levels were higher in the 10 survivors (median, 866 pg/mL; range, 384-1966 pg/mL) than in the 23 nonsurvivors (median, 454 pg/mL; range, 167 to 1,266 pg/mL; p = 0.02) [Fig 1 ]. There was no significant difference in the TGF-ß1/TNF-{alpha} ratio between survivors (median, 53 pg/mL; range, 3.9 to 792 pg/mL) and nonsurvivors (median, 55 pg/mL; range, 5.6 to 352 pg/mL; p = 0.94), or the TNF-{alpha}/IL-10 ratio: median, 1 pg/mL (range, 0.1 to 5.6 pg/mL) vs median, 1.4 (range, 0.1 to 77 pg/mL, respectively; p = 0.44).



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  		Figure 1.. TGF-ß1 levels in survivors (open boxes) and in nonsurvivors (shaded boxes). Data are presented as box plots (median values with interquartile range; extreme values, 10% and 90%; circles indicate values > 90%, p = 0.02).

 
To confirm that the TNF-2 allele might be an independent predictor of severity during cardiogenic shock, we used a multiple logistic regression model adjusted for disease severity to determine the predictive factors for mortality (Table 3 ). This analysis showed that the TNF-2 polymorphism was associated with an increased relative risk of death. For an identical SOFA score on ICU admission, patients with the TNF-2 allele had a 10.4-fold increased risk of death.


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  		Table 3.. Multivariate Logistic Regression Model With Adjusted Odds Ratio for Mortality

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
This study indicates for the first time that the rare TNF-2 allele of the TNF-{alpha} promoter is a strong independent factor associated with better survival from cardiogenic shock. The clinical implications of this finding are important. If we identified patients with the TNF-1 allele early who had developed cardiogenic shock, we could treat them more aggressively with invasive procedures such as intra-aortic balloon pump or other assist devices used as "bridge to transplant."

Association studies are all conceived to show a relation between allele "A" and a multifactorial disease "D" whenever the frequency of A differs between patients and control subjects. An association between A and D, however, might arise for at least three reasons: firstly, A truly affects the susceptibility to D; second, A is closely linked to the real allele involved in the pathogenesis of D, producing an association known as "linkage disequilibrium"; and third, people with D or without D are genetically different and coincidentally also differ in the frequency of A (population stratification).20 In the specific case of myocardial infarction that could lead to cardiogenic shock, given its high early mortality, possible alleles associated with rapidly fatal infarction might be underestimated among survivors (survival bias).

Our main observation is the opposite to that in patients with septic shock, where the TNF-2 allele is associated with a higher risk of death,1415 and higher TNF-{alpha} levels than the TNF-1 allele.16 One may wonder why the TNF-2 allele has persisted at such a high-population frequency despite conferring this survival disadvantage in septic patients. As with other ostensibly detrimental gene mutations that persist in the human population (eg, the sickle-cell trait), an unrecognized selective advantage may exist for carriers of the TNF-2 allele; indeed, the present study shows that the TNF-2 allele offers a survival advantage in cardiogenic shock. We found no significant relation between the TNF-{alpha} polymorphism and the plasma TNF-{alpha} levels, reflecting the small number of patients in this study, or the possibility that in certain conditions the TNF-{alpha} promoter gene is repressed and thus inhibits the inducible level of TNF-{alpha} gene transcription. The last hypothesis could explain the clinical difference issues between genomics and proteomics. In certain conditions, as in septic shock, the TNF-2 allele is expressed which leads to high TNF-{alpha} production and higher mortality rates in these patients. However, there could be a lack of TNF-2 expression in cardiogenic shock patients that leads to lower TNF-{alpha} production and higher survival rates in this particular population. Although TNF-{alpha} is expressed in the failing heart, TNF-{alpha} levels in the myocardium are known to be different from those in the plasma.10 Because circulating levels of TNF-{alpha} are also affected by other factors, such as clearance and production by nonmyocardial tissues, they may not reflect the true cytokine burden to the failing heart.

Although patients were included consecutively, the main limitation of this study is the small sample size; thus, the increased survival rate in the TNF-2 group could be fraught with statistical problems leading to a ß error. Additionally, the small contribution of a single novel polymorphism to the overall risk of a multifactorial disorder such as IHD might be obscured by the presence of one or more dominant classical risk factors. It is well known that a new genetic risk factor is more likely to emerge within homogeneous groups of patients in whom it has a similar role. Identifying such homogeneous groups might be difficult, requiring rigorous control not only for age, sex, race, and ethnic grouping but also for clinical features and biochemical markers linked to specific pathogenic mechanisms.

There are several mechanisms of TNF-{alpha}–mediated heart failure, including a reduction in intracellular Ca++,21 direct negative inotropic effects,22 interference with nitric oxide synthase,22 cardiomyocyte apoptosis,23 or increased production of superoxide anions.24 However, TNF-{alpha} production may be secondary to heart failure and not a causative factor. Peripheral hypoperfusion and ischemia may lead to increased bowel permeability causing bacterial translocation, endotoxin release, and increased systemic TNF-{alpha} production.25 Baumgarten et al26 showed that in mice, sustained hemodynamic overloading provokes a transient increase in proinflammatory cytokines (TNF-{alpha}, IL-1ß, and IL-6) and cytokine receptor gene expression; however, the decrease in proinflammatory cytokine gene expression occurred in the absence of changes in loading conditions, suggesting that the gene expression of proinflammatory cytokines in the heart is regulated, at least in part, by load-dependent and load-independent mechanisms.

We found no differences in the frequency of the TNF-2 allele between the 33 patients with cardiogenic shock and healthy volunteers. Densem et al17 also observed no differences in the frequency of the TNF-2 allele between 175 heart transplant recipients regardless of disease etiology and 212 healthy volunteers. However, we did find that the IFN-{gamma} polymorphism within the intron 1 at position + 874 T/T, which is associated with high in vitro production, was overrepresented in the control group compared with the cardiogenic group. This finding is supported by a study27 that showed that a lack of IFN-{gamma} due to depletion with an antibody or to a genetic deficiency exacerbated murine myocarditis. The disease-limiting effect of IFN-{gamma} might be explained by its ability to control the expansion of activated T-lymphocytes.

We found that plasma TGF-ß1 levels were higher in survivors than in nonsurvivors even when adjusted for the SOFA score. Aukrust et al28 found that patients with severe congestive heart failure had abnormal levels of anti-inflammatory cytokines, with decreased levels of TGF-ß1 and inadequately raised IL-10 in relation to elevated TNF-{alpha} concentrations, thus showing a marked imbalance favoring inflammatory effects. In our study, survivors produced higher levels of TGF-ß1 compared to nonsurvivors, but there were no significant differences in terms of TGF-ß1/TNF-{alpha} or TNF-{alpha}/IL-10 ratios. Another study29 showed that TGF-ß1 could antagonize the harmful actions of TNF-{alpha} and protect the myocardium.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Patients with the TNF-2 allele have no greater risk of cardiogenic shock, but have a better survival rate when cardiogenic shock develops. The IFN-{gamma} polymorphism within the intron 1 at position + 874 T/T is associated with a greater incidence of cardiogenic shock but is not associated with a better survival in these patients.

Prospective multicenter studies and the analysis of haplotypes may overcome some of the limitations of population association studies.30 With the advent of DNA microchips and with further studies on the functional relevance of the single polymorphism, it should be possible to draw a more accurate profile of the inflammatory gene variants in cardiogenic shock.


   Footnotes
 
Abbreviations: IFN = interferon; IHD = ischemic heart disease; IL = interleukin; SAPS = simplified acute physiologic score; SOFA = sequential organ failure assessment; TGF = transforming growth factor; TNF = tumor necrosis factor

Received for publication July 7, 2003. Accepted for publication December 4, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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