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European Journal of Heart Failure 2008 10(4):396-403; doi:10.1016/j.ejheart.2008.02.008
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© 2008 European Society of Cardiology

Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure

Kati H. Miettinena,*, Johan Lassusb, Veli-Pekka Harjolab, Krista Siirilä-Warisb, John Melinc, Kari R. Punnonend, Markku S. Nieminenb, Markku Laaksoa and Keijo J. Peuhkurinena

a Department of Medicine, Kuopio University Hospital Kuopio, Finland
b Department of Medicine, Helsinki University Hospital Helsinki, Finland
c Department of Medicine, Jyväskylä Central Hospital Jyväskylä, Finland
d Department of Clinical Chemistry, Kuopio University Hospital Kuopio, Finland

* Corresponding author. Department of Medicine, Kuopio University Hospital, P.O. Box 1777, Puijonlaaksontie 2, FI-70210 Kuopio, Finland. Tel.: +358 17 173422; fax: +358 17 173959. E-mail address: kati.h.miettinen{at}kuh.fi (K.H. Miettinen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Background: Cytokines play an important role in chronic heart failure (HF), but little is known about their involvement in acute decompensated heart failure (ADHF).

Aim: To evaluate the prognostic role of inflammatory cytokines in patients with ADHF.

Methods: Levels of interleukin (IL)-6, tumour necrosis factor alpha (TNF-{alpha}), IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured in 423 patients with ADHF. In addition, appropriate cytokine gene polymorphisms were determined. Survival was followed up to 12 months, and prognostic factors were evaluated.

Results: Elevated levels of IL-6 and TNF-{alpha} were strongly associated with increased 12-month mortality (P < 0.001 for both), whereas the level of IL-10 was predictive only of 6-month mortality (P < 0.01). In multivariate analysis IL-6, chronic renal insufficiency, NT-proBNP, age/10 years' increase and TNF-{alpha} were identified as the most powerful predictors of 12-month mortality. Furthermore, high levels of both IL-6 and NT-proBNP were associated with >7-fold mortality. Cytokine gene polymorphisms were not associated with outcome.

Conclusions: Circulating levels of pro-inflammatory cytokines IL-6 and TNF-{alpha}, and the level of an anti-inflammatory cytokine IL-10, but not their gene polymorphisms, provide novel and important prognostic information in patients with ADHF. Combining measurements of pro-inflammatory cytokines and NT-proBNP seems a promising tool in the prognostic assessment of these patients.

Key Words: Acute heart failure • Cytokines • Prognosis

Received April 5, 2007; Revised November 13, 2007; Accepted February 7, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
While several studies have focused on the pathophysiology and progression of chronic heart failure, relatively little attention has been paid to acute decompensated heart failure (ADHF), which is among the most significant causes of morbidity and mortality in the Western world [1-3]. The short- and long-term prognosis of patients presenting with ADHF is poor, and in a considerable proportion of these patients ADHF is a triggering factor for chronic heart failure (HF) [2].

Several biomarkers have been used in evaluating HF (for review, see [4]). One of the most frequently used markers is the biologically inactive N-terminal portion of the B-type natriuretic peptide, NT-proBNP, which has proven to be a useful tool for diagnostic and prognostic evaluation of both acute and chronic HF [4-7].

A substantial body of evidence supports the concept that immunologic and inflammatory processes play an important role in the pathogenesis and progression of HF [8-13]. In addition, the role of various cytokine gene polymorphisms in the susceptibility and progression of HF has been investigated [14]. However, relatively little is known about the role of cytokines and their genetic regulation in ADHF [15-18].

The current study is part of the national prospective multicenter Finnish Acute Heart Failure Study (FINN-AKVA) [19]. The original aim of this project was to investigate aetiology, triggering factors and modern treatment modalities together with factors affecting morbidity and mortality of ADHF. Here we investigated the prognostic roles of circulating levels of pro- (IL-6, TNF-{alpha}) and anti-inflammatory (IL-10) cytokines together with some other known prognostic factors in HF. The prognostic value of genetic polymorphisms in the promoter regions of the cytokine-encoding genes as well as their association with the circulating cytokine levels were also studied.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Patients and study protocol
The original FINN-AKVA patient cohort includes all consecutive patients hospitalised for ADHF during a three-month period at the beginning of 2004 at five university hospitals, four central hospitals, and five regional hospitals around Finland. A total of 620 patients were recruited and characterized according to the current European Society of Cardiology (ESC) guidelines [20]. The rationale of the FINN-AKVA study, detailed patient characteristics and the criteria for classifying patients have been described previously [19].

In the present study, only patients with either pulmonary oedema or congestive HF were included (n=565), since patients in other classes of ADHF comprised only a minority. We then further selected only patients who had a 48 h blood sample taken. Consequently, the final study population consisted of 120 patients with pulmonary oedema and 303 patients with congestive HF. Among the study population of 423 patients, there were 252 patients (60%) who also had blood samples taken on admission to hospital. Mortality follow-up data was completed for all patients up to 12 months (primary end-point) through the Population Register Centre. All patients gave written informed consent, and the study was carried out in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Helsinki University Central Hospital.

2.2. Vasoactive peptide and cytokine analyses
EDTA blood samples were withdrawn under standardized conditions and stored at –70 °C prior to analysis. Plasma NT-proBNP levels were analysed using a commercially available kit (Roche Diagnostics Elecsys®). Plasma concentrations of IL-6, TNF-{alpha}, and IL-10 were assayed using commercial enzyme-linked immunosorbent assay systems (Quantikine kit, R&D Systems Inc., Minneapolis, USA). The sensitivities of the IL-6, TNF-{alpha}, and IL-10 assays were 0.70 pg/ml, 0.12 pg/ml, and 0.50 pg/ml plasma, respectively.

2.3. Genotyping of the SNPs in IL-6, TNF-{alpha} and IL-10 genes
Genomic data was available for 115 patients (96%) with pulmonary oedema and for 293 patients (97%) with congestive HF. Genotyping was performed either by restriction fragment length polymorphism (IL-6 gene: –174G>C, IL-10 gene: –592C>A) or by TaqMan assays (IL-10 gene: –1082G>A, TNF-{alpha} gene: –308G>A). Details of the genotyping procedures can be obtained from the authors by request.

2.4. Statistical analysis
The data are presented as the median value (range) for continuous variables and as numbers (percentages) for categorical variables. Mann-Whitney-U test was used for statistical comparisons of the study groups, and Spearman rank correlation to test the associations between continuous variables. To study the changes in cytokine levels during hospitalisation (from admission to 48 h) Wilcoxon Signed Ranks test was applied. Cox univariate regression analysis was used to identify variables independently predicting 12-month mortality, and those with P<0.1 were further eligible for the multivariate Cox regression analysis. For biomarkers the median values were used as cut-off points in the model. The results are presented as hazard ratio (HR) with 95% confidence interval (CI). Survival curves were computed with the Kaplan-Meier method, and log-rank test was used to assess differences in survival times between the subgroups. Chi-square or Fisher's exact test was used to compare the differences in categorical data between the patient groups. Kolmogorov-Smirnov test was performed to assess the normality of data distribution. All hypothesis testing was two-tailed, and differences at the level of P<0.05 were considered statistically significant. All statistical analyses were performed using the SPSS software (SPSS version 14.0, SPSS Inc., Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Baseline characteristics
Baseline characteristics of the study population, history of comorbidities, echocardiographic findings and admission medication are described in detail in Table 1. Patients with pulmonary oedema had higher prevalence of coronary artery disease (CAD), type 1 or 2 diabetes, acute myocardial infarction (AMI) on admission, clinical infection on admission, and were on β-blockers significantly more often than patients with congestive HF. For the other clinical variables no significant differences between the patient groups were observed.


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  		Table 1 Baseline characteristics of the study population

 
3.2. Survival analysis
During the 12-month follow-up period 107 patients (25%) died, of which 38 (36%) were diagnosed with pulmonary oedema, and 69 (64%) with congestive HF. The cumulative mortality rates for all patients in this study were 5.4% in hospital (23 deaths), 8.0% at 30 days (34 deaths), 19% at 6 months (79 deaths), and 25% at 12 months (107 deaths). At the time point of 6 months, there were more deaths in the group of patients with pulmonary oedema (25 vs 16%, P<0.05), whereas in-hospital, 30-day, and 12-month mortality rates were similar in both patient groups.

Since interventions (such as CABG or PCI) may significantly influence survival, we further analyzed the data by dividing the study patients into groups undergoing invasive (either CABG, n=15 or PCI, n=18; 7.8% of total) or non-invasive (n=390) treatment during the hospitalisation period. Kaplan-Meyer analysis showed that patients treated invasively tended to have better one-year survival (P=0.089) than those treated non-invasively.

3.3. Levels of biomarkers at 48 h from admission
Circulating levels of biomarkers at 48 h from admission are shown in Table 2. Patients with pulmonary oedema had significantly higher levels of NT-proBNP, IL-6 and IL-10 than patients with congestive HF, whereas TNF-{alpha} levels were similar in both groups. Plasma IL-6/IL-10 ratio was also higher among patients with pulmonary oedema.


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  		Table 2 Circulating levels of biomarkers at 48 h from admission

 
Differences in the levels of the biomarkers at 48 h according to patients' clinical characteristics were also studied. Higher IL-6 levels were associated with higher incidence of AMI on admission (20.9 vs 12.7 pg/ml, P<0.001), history of CAD (15.1 vs 13.7 pg/ml, P<0.05), and clinical infection on admission (28.2 vs 12.4 pg/ml, P<0.001). TNF-{alpha} levels were higher in patients presenting with history of HF (1.63 vs 1.39 pg/ml, P<0.001), AMI (1.75 vs 1.46 pg/ml, P<0.05), CAD (1.62 vs 1.34, P<0.001) and chronic renal insufficiency (1.99 vs 1.47 pg/ml, P<0.001), and clinical infection on admission (1.65 vs 1.49 pg/ml, P<0.05). TNF-{alpha} levels were also higher among patients on β-blockers (1.57 vs 1.37 pg/ml, P<0.01) or diuretics (1.60 vs 1.36 pg/ml, P<0.001) prior to hospitalisation. Elevated levels of IL-10 were associated only with the presence of clinical infection on admission (2.46 vs 1.55 pg/ml, P<0.01). Higher NT-proBNP levels were associated with history of HF (4630 vs 3480 pg/ml, P<0.05), CAD (4310 vs 3570 pg/ml, P<0.05), AMI (5030 vs 3620 pg/ml, P<0.01) and chronic renal insufficiency (6210 vs 3850 pg/ml, P<0.05), and AMI (5690 vs 3610 pg/ml, P<0.001) and use of diuretics on admission (4820 vs 3620 pg/ml, P<0.05).

In the group undergoing invasive treatment, significantly higher levels of IL-6 (27.1 vs 13.6 pg/ml, P<0.01), and a trend towards higher IL-10 levels (2.86 vs 1.67 pg/ml, P=0.091), were observed. The observed difference(s) in the cytokine levels may, however, simply reflect the higher incidence of AMI among invasively treated patients (49 vs 19%, P<0.001) [21].

3.4. Cytokines and patient outcome
Patients were stratified into tertiles on the basis of their cytokine levels at 48 h. The lower, middle and upper tertiles for IL-6 were <8.80 pg/ml, 8.80-24.0 pg/ml, and >24.0 pg/ml, respectively, for TNF-{alpha}<1.20 pg/ml, 1.20-1.94 pg/ml, and >1.94 pg/ml, respectively, and for IL-10<0.97 pg/ml, 0.97-2.76 pg/ml, and >2.76 pg/ml, respectively. Kaplan-Meier survival curves indicated poor outcome for ADHF patients with high levels of IL-6 and TNF-{alpha} (12-month mortality, P<0.001 for both) (Fig. 1). High level of IL-10 was predictive of 6-month (P<0.01), but not of 12-month mortality.


Figure 01
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  		Fig. 1 Kaplan-Meier survival curves for ADHF patients stratified by tertiles of plasma IL-6 (A), TNF-{alpha} (B) and IL-10 (C) at 48 h from admission. Lowest tertiles are shown in solid lines, middle tertiles in dashed lines, and highest tertiles in dotted lines. ADHF = acute decompensated heart failure; IL = interleukin; NS = not significant; TNF-{alpha} = tumour necrosis factor alpha.

 
Excluding patients with clinical infection from the analyses had no significant effect on survival according to either cytokine tertiles or genetic variants (see below). Similarly, Kaplan-Meier survival analysis performed after excluding patients undergoing invasive procedures during hospitalisation gave identical results compared to the analysis performed for the entire study group, showing that medically treated patients (n=390) in the highest tertiles of IL-6, TNF-{alpha} and IL-10 had the highest one-year mortality, and that those in the lowest tertiles had the lowest mortality (P<0.001 for IL-6, P<0.001 for TNF-{alpha}, and P<0.05 for IL-10).

3.5. Combining NT-proBNP and cytokines in risk evaluation
Combining tertiles of cytokines and NT-proBNP enabled even more comprehensive risk stratification, with 12-month mortality rates ranging from 0 to 46% (Fig. 2). Patients with the lowest levels of both NT-proBNP and cytokines (either IL-6, TNF-{alpha} or IL-10) had the lowest mortality rate, whereas a high risk of death within 12 months was associated with highly elevated levels of both biomarkers. The lower, middle and upper tertiles for NT-proBNP used in the risk stratification were <2620 pg/ml, 2620-6400 pg/ml, and >6400 pg/ml, respectively.


Figure 02
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  		Fig. 2 12-month mortality rates in dual biomarker tertile analyses. (A) IL-6 and NT-proBNP, (B) TNF-{alpha} and NT-proBNP, and (C) IL-10 and NT-proBNP. NT-proBNP = N-terminal pro-brain natriuretic peptide. Other abbreviations as in Fig. 1.

 
3.6. Cytokine gene polymorphisms
No differences in the genotype distributions and allele frequencies, or altered levels of circulating cytokines at 48 h from admission with respect to the gene polymorphisms investigated were observed between the patient groups of pulmonary oedema and congestive HF. Furthermore, none of the genetic variants studied were associated with either the survival time or the frequency of deaths at any time point. In addition, no differences in the genotype distributions with respect to gender, EF, chronic renal insufficiency, or history of CAD, type 1 or 2 diabetes, or AMI were observed (data not shown). The only differences with respect to genetic polymorphisms were observed in patients presenting with (1) chronic AF, with the –174C allele of the IL-6 gene being more common in patients with than without chronic AF (86 vs 74%, P<0.05), (2) previously diagnosed HF, with the –308A allele of the TNF-{alpha} gene being more common in patients with than without previous HF (29 vs 19%, P<0.05), and (3) a history of hypertension, with the –1082A allele of the IL-10 gene being more common in patients with than without a history of hypertension (84 vs 75%, P<0.05).

To assess whether the effect of a given polymorphism on circulating cytokine levels was "masked" by the presence of a modifying intervention (CABG/PCI), we reanalyzed the data after excluding those patients from the analyses. It was found that the influence of various gene polymorphisms on either circulating cytokine levels or survival course was not affected by the procedures (P=NS for all). It has to be noted, however, that the number of patients undergoing invasive procedures in this study was relatively low.

3.7. Biochemical markers with prognostic impact
After multivariate adjustment in the Cox proportional hazard model, IL-6 level>14.2 pg/ml at 48 h from admission was the most powerful predictor of 12-month mortality, followed by chronic renal insufficiency, NT-proBNP level>4080 pg/ml, age/10 years' increase and TNF-{alpha} level>1.51 pg/ml (Table 3).


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  		Table 3 Variables predicting 12-month mortality in Cox proportional hazard regression analysis in patients with ADHF

 
3.8. Changes in biomarkers during hospitalisation
To assess changes in circulating cytokine levels during the first two days of treatment in hospital we performed a subanalysis of patients in whom both admission and 48 h blood samples were taken (n=252). The analysis showed that between admission and 48 h there were small but significant changes in the levels of IL-6 (from 16.9 to 15.4 pg/ml, P<0.01) and TNF-{alpha} (from 1.40 to 1.56 pg/ml, P<0.001), with a simultaneous decline in NT-proBNP levels (from 5620 to 4230 pg/ml, P<0.001). IL-10 levels, however, remained unchanged.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
Despite the high mortality and morbidity rates associated with ADHF, relatively little is known about the regulation of cardiovascular homeostasis in this condition. It is well established that inflammation plays a major role in the development and progression of chronic HF [8-13]. However, only a few previous studies have elucidated the role of the inflammatory system, and specifically the prognostic role of inflammatory mediators, in ADHF.

Suzuki et al. [17] reported that measurement of IL-6 level was useful for the evaluation of patients with ADHF; but unfortunately, that was not a prognostic study. Another recent study by Chin et al. [16] showed that IL-6 levels in patients admitted for ADHF were predictive of six month mortality, but only a small number of patients were included (n=77). In the study of Mueller et al. [18] inflammation, assessed by high C-reactive protein (CRP) levels at the time of acute HF presentation, was strongly associated with adverse short- and long-term clinical outcomes. The prognostic importance of TNF-{alpha} or IL-10 was not assessed in any of these studies. In the present study, ADHF patients hospitalised for pulmonary oedema or congestive HF with elevated plasma levels of IL-6, TNF-{alpha} and/or IL-10 measured two days after hospital admission were found to carry a considerable risk of death within the subsequent 12 months. Furthermore, elevated cytokine levels were found to be associated with previously diagnosed HF, CAD, AMI or chronic renal insufficiency, as well as the presence of AMI or clinical infection on admission.

Similarly to the vasoactive peptide NT-proBNP, which is widely used in the clinical evaluation of different stages of HF [4-7], the circulating levels of IL-6 and IL-10 measured at 48 h after hospital admission in this study were able to differentiate patients with congestive HF from those with pulmonary oedema. In addition, plasma IL-6/IL-10 ratio was significantly higher among patients with pulmonary oedema, reflecting stronger imbalance between the pro- and anti-inflammatory cytokine responses in these patients. Previously, circulatory IL-6 levels have been reported to reflect the disease status in ADHF [17]. The dual biomarker analysis combining cytokines and NT-proBNP, appeared to be a very useful tool in the prognostic assessment of ADHF patients in our study. A correlation between BNP and IL-6 responses and tissue repair during the early phase after AMI has also been observed previously [21], suggesting a specific interaction between the vasoactive peptide and inflammatory systems [22].

Patients undergoing invasive procedures (CABG/PCI) during the hospitalisation period had significantly higher levels of IL-6 - probably due to the higher incidence of AMI [21] - but had better one-year survival rate than those without any interventions, emphasizing the importance of early invasive treatment in the high-risk group of patients with AMI and subsequently highly elevated IL-6 levels. Most importantly, even after excluding patients with invasive treatment from the survival analyses, significant differences in one-year survival between patients in the highest and lowest cytokine tertiles still existed, which further highlight the importance of cytokine signalling in ADHF.

Satoh et al. [23] showed that activation of inflammatory mechanisms may have an essential role in the development of heart failure after AMI. In the present study, patients with a history of AMI prior to hospitalisation for ADHF had significantly higher levels of the pro-inflammatory cytokine TNF-{alpha} at 48 h from admission compared to patients without AMI. In addition, patients suffering from AMI at the time of admission had significantly higher IL-6, but not TNF-{alpha}, levels than patients without AMI, reflecting a specific inflammatory response to tissue injury. Previously, Puhakka et al. [21] have reported an increase in circulating IL-6 levels 24 h after thrombolysis in patients with AMI, whereas no changes in TNF-{alpha} levels were observed.

In the present study, changes in the cytokine levels during hospitalisation were studied in a subset of patients in whom both admission and 48 h samples were taken. During the first two days of treatment a slight, but significant decrease in the level of IL-6 was observed. However, TNF-{alpha} levels showed a simultaneous increase. Recently, Suzuki et al. [17] reported that in patients with acute pulmonary oedema (n=73) IL-6 levels peaked at 12 h after hospital admission, and declined thereafter, whereas TNF-{alpha} and IL-1β remained unchanged throughout the observation period. Vanderheyden et al. [15] also studied the changes in IL-6 and TNF-{alpha} levels during the compensation process in a small group of patients with ADHF, and reported that there was a trend for IL-6 to decline, while no changes in TNF-{alpha} levels were observed at recompensation. These two small studies thus support the results of our study, suggesting that IL-6 may act as an acute phase reactant in ADHF.

Several studies have evaluated the influence of various polymorphisms in the genes encoding for cytokines on disease susceptibility and progression of HF [14]. We found that in our patient cohort neither circulating cytokine levels nor survival were associated with gene variants in the cytokine-encoding genes. This was true also for patients treated non-invasively, showing that the invasive procedure did not mask the effect(s) of gene polymorphism(s) on either cytokine levels or survival. However, given the complex network regulating cytokine expression at the cellular level, the true impact of a single polymorphism on the expression of a given gene is hard to assess. Since in the present study we did not measure gene expression at the tissue level, the true influence of genetic regulatory elements on circulating cytokine levels could not be evaluated. Still, it is noteworthy that patients previously diagnosed with HF more often had the –308A allele of the TNF-{alpha} gene than patients with new-onset HF. In addition, although the –308G>A polymorphism was not associated with circulating TNF-{alpha} levels in the entire study population, patients with a history of HF had higher TNF-{alpha} levels than patients with new-onset HF. Given that –308A allele is a much stronger transcriptional activator than the common allele (–308G) [24,25], it is possible that the observed difference in TNF-{alpha} levels is partly influenced by genetic predisposition.

Since the functional diversity of cytokines is determined by the extent of cytokine production as well as the expression of cytokine receptor molecules, the inflammatory responses in different individuals may vary. In addition, it has been suggested that administration of adrenergic blockers for the treatment of HF improves myocardial function through modulation of inflammatory cytokine production, thereby limiting their detrimental effects on the heart [4,26,27]. In the present study, patients on β-blockers prior to hospitalisation were found to have slightly higher TNF-{alpha} levels at 48 h from admission. This may, however, be due to the higher prevalence of CAD, previous AMI and/or chronic HF among those patients. Treatment with ACE inhibitors and/or angiotensin II type I receptor antagonists did not have any influence on circulating cytokine levels. Recent reports suggest that statins confer cardiovascular benefit by their ability to modulate immuno-inflammatory processes [28]. We did not, however, observe any differences in cytokine levels at admission between patients with and without statins. It is noteworthy, however, that only one third of the patients were on statins on admission to hospital. The anti-inflammatory properties of diuretics have not been properly studied, but in an in vitro study the diuretic ethacrynic acid was shown to exert anti-inflammatory effects by inhibiting the secretion of IL-6 and IL-10 [29]. We did not observe any differences in IL-6 and IL-10 levels in patients with and without diuretics on admission. However, TNF-{alpha} levels were higher in the diuretic users. The higher NT-proBNP concentration among patients on diuretics most likely reflects the higher percentage of patients previously diagnosed with HF or the existence of more severe HF.

In our study population, clinical infection on admission was observed in one quarter of patients. This was also manifested by increased levels of circulating cytokines in these patients. Excluding patients with clinical infection did not, however, change the results in the analyses, suggesting an independent and specific role of cytokine activation in ADHF.

4.1. Conclusions
The results of the present study suggest that inflammation is not only associated with the clinical severity of ADHF, but also has a significant prognostic role. High levels of the pro-inflammatory cytokines IL-6 and TNF-{alpha}, and to some extent also the anti-inflammatory cytokine IL-10, were found to be highly predictive of poor outcome. Although circulatory markers of inflammation provide novel and important prognostic information in ADHF, the polymorphisms studied affecting the promoter regions of the genes encoding for cytokines do not seem to do so. Combining measurements of NT-proBNP and pro-inflammatory cytokine levels during the early hospitalisation period of patients presenting with ADHF may be valuable clinical tool in the prognostic assessment of these patients.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
The authors thank Raija Isomäki and Tero Hongisto for their excellent technical assistance in the cytokine assays, and Kaija Eirola, Minna Kinnunen, Leena Uschanoff and Teemu Kuulasmaa for conducting the genetic analyses. This study was supported by the Finnish Foundation for Cardiovascular Research, Paolo Foundation, Aarne Koskelo Foundation, Ida Montin Foundation, Orion Pharma, and by the EVO research grants of Kuopio University Hospital. Roche Diagnostics provided kits for analysis of NT-proBNP.


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

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