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European Journal of Heart Failure 2006 8(2):141-146; doi:10.1016/j.ejheart.2005.05.010
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© 2006 European Society of Cardiology

Circulating levels of tumor necrosis factor-{alpha} correlate positively with severity of peripheral oedema in patients with right heart failure

Majed Odeha,c,*, Edmond Sabob,c and Arie Olivena,c

a Department of Internal Medicine B and, Bnai Zion Medical Center P.O. Box 6477, Haifa 31063, Israel
b Institute of Pathology, Carmel Medical Center Haifa, Israel
c Technion Faculty of Medicine, Israel Institute of Technology Haifa, Israel

* Corresponding author. Department of Internal Medicine B and, Bnai Zion Medical Center, P.O. Box 6477, Haifa 31063, Israel. Tel.: +972 4 8359775; fax: +972 4 8371393. E-mail address: majed.odeh{at}b-zion.org.il


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: Several previous studies have shown that circulating levels of tumor necrosis factor-{alpha} (TNF) are elevated in patients with advanced congestive heart failure. However, the relationship between circulating levels of TNF and severity of peripheral oedema in these patients has not been previously evaluated.

Aims: To investigate the relationship between circulating levels of TNF, and severity of peripheral oedema in patients with right-sided heart failure (RHF).

Methods and results: Circulating levels of TNF were measured in 15 healthy volunteers, and in 83 patients with RHF with various levels of peripheral oedema. At presentation, 13 patients had no peripheral oedema (grade 0), 22 patients had mild peripheral oedema (grade 1), 23 patients had moderate peripheral oedema (grade 2), and 25 patients had severe peripheral oedema (grade 3). The values of circulating TNF levels (mean±S.E.M.) at presentation in the control group and in the RHF patients (oedema grades 0—3) were 2.98±0.21, 4.22±0.55, 4.67±0.29, 7.66±0.44, and 10.94±0.67 pg/mL respectively. There was a significant difference between the groups (p<0.0001, ANOVA), and a significant positive correlation was found between circulating TNF levels and severity of peripheral oedema (r=0.77, p<0.0001).

Conclusion: A significant relationship is present between circulating levels of TNF and severity of peripheral oedema in patients with RHF.

Key Words: Tumor necrosis factor-{alpha} • Peripheral oedema • Bowel-wall oedema • Congestive heart failure • Right-sided heart failure • Left-sided heart failure

Received February 5, 2005; Revised April 4, 2005; Accepted May 16, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
A number of clinical and experimental studies have demonstrated that circulating levels of tumor necrosis factor-P (TNF) are elevated in humans and animals with advanced heart failure [1-3]. This proinflammatory cytokine has since been strongly implicated in the pathogenesis of this cardiac disease [4-6], and it has been shown that elevated TNF levels are an independent predictor of mortality in patients with advanced heart failure [7,8]. Indeed, when expressed at sufficiently high concentrations, TNF produces progressive left ventricular dysfunction, pulmonary oedema, left ventricular remodeling, cardiac myocyte hypertrophy and apoptosis, and cardiomyopathy [4-6].

The majority of previous studies of TNF in congestive heart failure (CHF) have focused mainly on left-sided heart failure (LHF), and only a few studies have dealt with right-sided heart failure (RHF) [9-11]. There are no published data on the relationship between serum levels of TNF and severity of peripheral oedema or right ventricular ejection fraction (RVEF) in patients with RHF.

The main aim of this study was to investigate the relationship between circulating levels of TNF in peripheral venous blood and certain parameters of RHF, including severity of peripheral oedema, RVEF and NYHA functional class, in patients with RHF related to ischemic heart disease (IHD) or idiopathic dilated cardiomyopathy (IDC).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study population
Fifteen volunteers, who were defined as healthy according to history and physical examination (8 men and 7 women; aged 40 to 80 years) were selected as the control group. Eighty-three patients with RHF and RVEF <35%, range 8-34% (47 men and 36 women; aged 46 to 91 years) were selected as the experimental group. RVEF and left ventricular ejection fraction (LVEF) were determined using the multigated acquisition (MUGA) technique. Of these 83 patients, thirteen were out-patients with stable RHF and no peripheral oedema, and were controlled by oral medical therapy. The remaining 70 RHF patients had recent onset decompensation, as evidenced by development of peripheral oedema despite adequate oral medical therapy, and requiring admission to the hospital for therapeutic intervention. All patients also had chronic stable LHF (LVEF <45%, range 12-44%) of varying severity, but with no signs and symptoms of acute decompensation, such as dyspnea at rest, pulmonary congestion or pleural effusions on physical examination and chest radiography. Patients were excluded from the study if they had had a myocardial infarction within the previous 3 months or had current clinical evidence of unstable angina pectoris, acute or chronic infection, autoimmune or inflammatory disease, cancer, hypoalbuminemia, or any other disease causing peripheral oedema other than RHF. All patients were on stable medical therapy for at least 1 month before enrolling in the study. No patient had received anti-inflammatory drugs within the preceding 2 weeks. The only intervention in all decompensated patients was intravenous diuretic therapy.

The experimental group underwent routine clinical evaluation of heart failure, including history and physical examination, echocardiogram and MUGA scan. The cause of RHF was IHD in 69 patients and IDC in 14 patients. The severity of peripheral oedema was evaluated and graded in the standing position as follows: grade 0, in the absence of leg oedema; grade 1 (or mild), leg oedema up to the ankles; grade 2 (or moderate), leg oedema above the ankles and below the knees; and grade 3 (or severe), leg oedema up to and above the knees. Thirteen patients (7 men and 6 women, aged 46 to 82 years) had grade 0 peripheral oedema at presentation, 22 patients (14 men and 8 women, aged 56 to 88 years) were grade 1, 23 patients (12 men and 11 women, aged 48 to 91 years) were grade 2, and 25 patients (14 men and 11 women, aged 55 to 88 years) were grade 3.

Five milliliters of anticubital venous blood was collected at presentation from all control subjects and all patients for TNF assay. All decompensated patients were treated with intravenous furosemide in addition to their previous medications. Twenty patients, who improved from grade 2 or 3 to grade 0 or 1 peripheral oedema following treatment, underwent re-evaluation of TNF levels 5 to 8 days after presentation. Serum TNF levels at presentation were compared with post-improvement levels in these 20 patients. The study conforms with the principles outlined in the Declaration of Helsinki and was approved by the ethics committee of Bnai Zion Medical Center, all subjects gave informed consent.

2.2. Measurement of TNF concentration
Samples of peripheral venous blood (after clotting at 4 °C) were centrifuged at 2500 rpm and 4 °C for 10 min. The serum was stored immediately at –70 °C prior to TNF assay. TNF concentrations were measured using a commercially available (Quantikine HS, R and D Systems, Minneapolis, MN, USA) solid-phase high sensitivity enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. This assay employs the quantitative sandwich enzyme immunoassay technique. A monoclonal antibody specific for TNF was pre-coated onto a microplate. Standards and samples were pipetted into the well and any TNF present was bound by the immobilized antibody. After washing away any unbound substances, an enzyme-linked polyclonal antibody specific for TNF was added to the wells. Following a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added to the wells. After an incubation period, an amplifier solution was added to the wells and colour developed in proportion to the amount of TNF bound in the initial steps. The colour development was stopped and the intensity of the colour was measured. The samples were compared against the standards curve to determine the amount of TNF present. All samples were coded so that the investigator performing the assay was blinded to their identity. Results were expressed in pg/mL; the lower detection limit was 0.18 pg/mL.

2.3. Statistical analysis
Data were expressed as mean±standard error of mean (S.E.M.) values, and 95% confidence intervals (CIs) for means and proportions were calculated. Normality of variables was evaluated using the Kolmogorov-Smearnov test. Comparison between multiple unpaired groups was performed using the one way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test. Paired and unpaired samples for dependent and independent groups respectively, were compared using the Student t-test. The equality of variances was tested using the Levene's test. Correlations were evaluated using the Pearson's coefficient of correlation for parametric variables, and the Spearman's coefficient of correlation for nonparametric variables. Two-tailed p values of 0.05 or less were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
The mean ages of the control group and groups with grade 0, grade 1, grade 2, and grade 3 peripheral oedema were comparable (68.5±3.1, 68.9±2.8, 71.1±1.9, 71.0±2.0, and 70.6±1.8 years respectively, p=0.46). There was no significant difference in sex distribution between the groups (p=0.94). Mean circulating levels of TNF (and 95% CIs for means) at presentation, in the control group, in patients without peripheral oedema, (grade 0), in all patients with peripheral oedema (grades 1 to 3 combined), and according to the grade of peripheral oedema are presented in Table 1. TNF levels were significantly higher in the oedema group compared to the patients without oedema and the control group (p<0.0001). A significant difference in circulating levels of TNF was found between the controls and each grade of peripheral oedema (p<0.0001, ANOVA, Fig. 1). All comparisons showed a significant difference except for the comparison between the control group and the grade 0 group, and between the grade 0 group and the grade 1 group. A strong significant positive correlation was also found between circulating levels of TNF and the severity of peripheral oedema (r=0.77, p<0.0001).


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  		Table 1 General characteristics, serum TNF levels, RVEF, LVEF, and NYHA functional class according to patient group (means and 95% CIs for means)

 


Figure 1
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  		Fig. 1 Mean serum levels of tumor necrosis factor-P (TNF) in the control group and according to the grade of peripheral edema at presentation before intervention. All group comparisons showed a significant difference (p<0.0001, ANOVA).

 
The 20 patients who underwent repeat evaluation of circulating levels of TNF following improvement in peripheral oedema due to intervention, showed a significant decrease in circulating levels of TNF from 9.3±0.78 pg/mL (95% CI: 7.66-10.93) at presentation to 5.14±0.36 pg/mL (95% CI: 4.39-5.89) following improvement (p<0.0001, Fig. 2).


Figure 2
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  		Fig. 2 Comparison between serum levels of tumor necrosis factor-P (TNF) in 20 patients who had grade 2 (Mod.=moderate) or grade 3 (Sev.=severe) peripheral oedema at presentation, and who became grade 0 (Abs.=absence) or grade 1 (Mild) after intervention. The two groups were significantly different (p<0.0001).

 
Mean values (and 95% CIs for means) of RVEF and LVEF according to the severity of peripheral oedema are presented in Table 1. A significant inverse correlation was found between circulating levels of TNF and values of RVEF (r=–0.5, p<0.0001, Fig. 3). When this correlation was evaluated for each peripheral oedema group separately, only of the grade 2 and grade 3 groups showed a significant inverse correlation (r=–0.42, p=0.043, and r=–0.41, p=0.04 respectively). No significant correlation was found between circulating levels of TNF and LVEF in these patients (r=–0.11, p=0.32).


Figure 3
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  		Fig. 3 Correlation between serum levels of tumor necrosis factor-P (TNF) and right ventricular ejection fraction (RVEF) in all patients. A significant inverse correlation was found between the two variables (r=–0.50, p<0.0001).

 
Mean circulating levels of TNF (and 95% CIs for means) according to NYHA functional class are presented in Table 2. A significant difference was found between the classes for circulating levels of TNF at presentation (p<0.0001, ANOVA). All comparisons showed a significant difference except for; the control group versus NYHA class I, NYHA class I versus NYHA class II, and NYHA class III versus NYHA class IV (Table 2). A significant positive correlation was found between circulating levels of TNF and severity of functional disability represented by the NYHA functional classes (r=0.61, p<0.0001). A significant inverse correlation was found between NYHA functional class and RVEF (r=–052, p<0.0001), however, no significant correlation was found between NYHA functional class and LVEF (r=–0.06, p=0.6).


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  		Table 2 Number of subjects and mean serum levels of TNF and 95% CIs for means in the control group and according to NYHA functional class

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The results of this study demonstrate that in oedematous patients with RHF due to IHD or IDC, circulating levels of TNF are significantly higher than in patients without oedema and in healthy volunteers. No significant difference was found between non-oedematous patients and the healthy volunteers. These results are similar to the findings of a previous study in this regard [9]. Furthermore, this study demonstrated, for the first time, the presence of a positive relationship between circulating levels of TNF and severity of peripheral oedema in patients with RHF (Fig. 1) which represents severity of right ventricular decompensation in these patients. A reduction in the severity of peripheral oedema from grade 2 or 3 (moderate or severe) to grade 0 or 1 (absent or mild) following intensive diuretic treatment for a few days, was accompanied by a significant decrease in circulating levels of TNF (Fig. 2). This effect on TNF levels was not observed by Niebauer, et al., [9] who demonstrated similar effects on plasma levels of endotoxin but not on plasma levels of TNF in oedematous patients with RHF. The authors suggested that this difference in effect on plasma levels of endotoxin and TNF, may be due to a concentration effect from the loss of body water or long-term activation of monocytes or macrophages after brief exposure to an endotoxin stimulus during a phase of clinical deterioration with increased venous congestion. Alternatively, the lack of TNF decrease immediately after clinical improvement may be due to a change in monocyte or macrophage lipopolysaccharide sensitivity (i.e., "normalized" endotoxin concentrations may still cause increased cytokine production) [9]. However, why should such a concentration effect influence TNF levels but not endotoxin levels? Furthermore, this phenomenon of decreased levels of circulating endotoxin without a concomitant decrease in TNF levels has not been observed in other conditions associated with high levels of endotoxin and TNF, such as sepsis, [12-14] acute heatstroke, [15] and decompensated liver cirrhosis [16]. A similar disparity has been reported in the medical literature for TNF in LHF. While in some studies stabilization and optimized treatment of patients with acute LHF was not accompanied by reduction in circulating TNF levels, [17-20] a significant reduction was observed in others [21-24]. These differences merit further investigation.

No significant correlation was found between circulating levels of TNF and values of LVEF in our patients, this is consistent with previous studies [1,25-27]. However, a significant inverse correlation was observed between circulating levels of TNF and values of RVEF (Fig. 3). This correlation with RVEF has not been previously evaluated. These different results between LVEF and RVEF regarding correlation with circulating levels of TNF might be related to the presence of acute decompensation of the right ventricle without acute decompensation of the left ventricle in our patients. Indeed, when this correlation was evaluated for each peripheral oedema group separately, only patients with grade 2 and grade 3 (moderate and severe) peripheral oedema showed a significant correlation between circulating levels of TNF and RVEF. This issue needs further evaluation.

A significant relationship was found between circulating levels of TNF and the severity of functional disability represented by NYHA functional class. While circulating levels of TNF in patients with NYHA functional class III or IV were significantly higher than those of patients in NYHA class I or II, no significant difference was found between NYHA functional class I and II, or between NYHA functional class III and IV (Table 2). These results are consistent with results of several previous studies [7,9,27-31]. A significant inverse correlation was found between NYHA functional class and RVEF, while no significant correlation was found between NYHA functional class and LVEF. There are no previous data in the medical literature on the relationship between NYHA functional class and RVEF in patients with CHF. In patients with LHF, it is expected that those with higher NYHA functional classes are characterized by a more markedly decreased LVEF, as reported recently by Petretta et al. [27]. However, data from two previous studies did not show a such relationship, and are consistent with our results [30,31]. The results of Petretta et al. [27] may be related to their small sample size compared to our study and to the two other previous studies [30,31]. This relationship also merits further investigation.

The origin of the increased circulating TNF concentration in CHF is controversial and remains unknown. While some experimental and clinical studies have shown that the myocardium could be the source of increased production and high circulating levels of TNF, [30,32-34] other studies do not support this theory and suggest that other peripheral organs, such as the bowel-wall, are the main source of the increased circulating TNF levels in CHF [2,3,9,35,36]. In these later studies, [2,3,9,35,36] it was suggested that bowel oedema due to mesenteric venous congestion, which may develop in heart failure, particularly in advanced stages, causes bacterial translocation and endotoxin release from the bowel into the circulation leading to elevated circulating endotoxin levels. Endotoxin, as a main stimulator for TNF production, in turn, causes elevated concentration of circulating TNF. Since bowel-wall oedema, which could cause altered gut permeability and subsequent bacterial and/or endotoxin translocation, is most likely to occur with moderate to severe peripheral oedema, [9] our results showing that circulating levels of TNF are significantly increased only in patients with moderate to severe peripheral oedema may support the above suggestion.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our results have demonstrated, for the first time, a positive relationship between circulating levels of TNF and severity of peripheral oedema in patients with RHF due to IHD or IDC. A decrease in the severity of peripheral oedema in these patients was accompanied by a significant decrease in circulating levels of TNF. Our results demonstrate, also for the first time, the presence of a significant inverse correlation between circulating levels of TNF and values of RVEF. Since the severity of peripheral oedema may indirectly represent the severity of bowel-wall oedema in patients with CHF, these results may support the hypothesis that the oedematous bowel-wall could be a source of the high circulating levels of TNF in advanced CHF.


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

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