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European Journal of Heart Failure 2003 5(5):609-614; doi:10.1016/S1388-9842(03)00104-1
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© 2003 European Society of Cardiology

Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure

Thomas Peschela, Martin Schönauera, Holger Thielea, Stefan Ankerb, Gerhard Schulera and Josef Niebauera,*

a Herzzentrum der Universität Leipzig Strümpellstraße 39, 04289 Leipzig, Germany
b Royal Brompton Hospital London, UK and Franz Volhard Klinik, Charité Berlin-Buch Berlin, Germany

* Corresponding author. Tel.: +49-341-8650; fax: +49-341-865-1461. E-mail address: j.niebauer{at}medizin.uni-leipzig.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 6. Conclusions
 References
 
Aims: To test the hypothesis that during acute heart failure endotoxin might be increased in hepatic veins as a sign of bacterial or endotoxin translocation from the bowel into the blood stream.

Methods and results: In patients with acute heart failure (NYHA IV; n=17) levels of endotoxin, soluble (s) CD14, tumor necrosis factor {alpha} (TNF{alpha} and interleukin 6 (IL6)) were measured in blood drawn from an antecubital vein on admission and compared with age-matched patients with stable chronic heart failure (n=21) and healthy volunteers (n=9). All levels were systemically elevated during acute heart failure (all P<0.05); once patients were stable enough to undergo cardiac catheterization, endotoxin was found to be significantly higher in hepatic veins (0.62±0.05 EU/ml) than left ventricles (0.46±0.04 EU/ml; P<0.05), whereas sCD14, TNF{alpha} and IL6 were not different between these sites. At follow-up (29±6 days) endotoxin but not sCD14, TNF{alpha} or IL-6 was significantly lower as compared to baseline (P<0.05).

Conclusions: Higher levels of endotoxin in hepatic veins as compared to the left ventricle during acute heart failure are suggestive of bacterial or endotoxin translocation from the bowel into the blood stream. This may lead to new treatment strategies. The lack of difference in TNF{alpha} levels between the pulmonary artery and the left ventricle sheds doubt on the heart as a source of systemically elevated TNF{alpha} levels.

Key Words: Cytokines • Edema • Heart failure • Inflammation

Received November 12, 2002; Revised February 3, 2003; Accepted June 16, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 6. Conclusions
 References
 
It has been observed during the past decade that circulating inflammatory cytokines such as soluble (s) CD14, tumor necrosis factor (TNF){alpha}, and interleukin 6 (IL-6) are elevated in chronic heart failure [1–7] and that many features of the syndrome of chronic heart failure can be explained by their known biological effects [7]. Indeed, nitric oxide as well as inflammatory cytokines such as TNF{alpha} can induce effects that mimic various clinical features of heart failure, including progressive left ventricular dysfunction, pulmonary edema, left ventricular remodeling, and cardiomyopathy, rendering cytokines likely to be in part responsible for disease progression in patients with heart failure [8]. Furthermore, recent reports have shown that pro-inflammatory cytokines such as soluble TNF receptor 1 may be of greater prognostic importance than hemodynamics and clinical status [9]. This is of importance, since novel treatment strategies at reducing against cytokines are becoming available [10]. Nevertheless, the source of systemically elevated TNF{alpha} levels has yet to be found.

If the heart or the lungs were the main source of elevated TNF{alpha}, then levels would be expected to be higher in the pulmonary artery or left ventricle than in the hepatic vein. Also, we have previously reported elevated levels of endotoxin during acute cardiac decompensation, which were associated with augmented TNF{alpha} levels [11]. This supports the hypothesis that the elevated levels might be caused by acute venous congestion with subsequently altered gut permeability for bacteria, endotoxin, or both, which would then lead to translocation of these materials into the circulation via the hepatic veins [12]. Thus, it was the aim of this study to measure levels of endotoxin and TNF{alpha} in the hepatic veins and to compare them to endotoxin levels in other regions of the circulation, namely the pulmonary artery and the left ventricle.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations
 6. Conclusions
 References
 
2.1. Participants
Patient characteristics are shown in Table 1. We prospectively studied 9 healthy volunteers, 21 out-patients with stable chronic heart failure and 17 patients who were admitted to our intensive care unit with acute heart failure. The healthy volunteers were hospital staff and relatives of patients who agreed to participate. Patients with stable heart failure were recruited during outpatient clinics. The decompensated patients included in this study were consecutive patients who met the inclusion criteria during the study period. The diagnosis of acute heart failure was based on clinical symptoms. On admission this diagnosis was confirmed by echocardiography and then following 9±7 h of clinical stabilization, by cardiac catheterization, and was found to be due to ischemic or idiopathic cardiomyopathy (left ventricular ejection fraction measured by echocardiography and/or left ventriculography of <40%). Healthy volunteers did not undergo cardiac catheterization for ethical reasons. We only enrolled decompensated patients with either first onset heart failure or patients with acute deterioration of known heart failure. Patients with acute coronary syndrome, myocardial infarction, myocarditis or pulmonary embolism were not eligible to be enrolled in this study. After discharge, patients were seen in our outpatient clinic for a follow-up visit (29±6 days).


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  		Table 1 Patient characteristics

 
On admission patients’ medication consisted of a combination of the following drugs: angiotensin converting enzyme inhibitors (53%), β-blockers (35%), diuretics (53%), digoxin (12%), aspirin (29%) and warfarin (6%).

No patient or volunteer had a history of rheumatoid arthritis or cancer. Furthermore, no patient showed clinical signs of infection and all three-blood cultures drawn on admission and during the following 24 h were negative.

The research protocol was approved by the ethics committee of the University of Leipzig, and procedures followed were in accordance with institutional guidelines. All patients and volunteers gave written informed consent.

2.2. Assays
Baseline blood samples were collected from an antecubital vein 15 min after admission to the intensive care unit and during follow-up visits. A polyethylene catheter was inserted into an antecubital vein and 8 ml of blood were drawn into endotoxin-free tubes (Endo Tube ET, Chromogenix AB, Sweden). Thirty-milliliter samples were also taken for biochemical and cytokine measurements. During cardiac catheterization, blood was obtained from hepatic veins, the pulmonary artery and left ventricle. All blood samples were immediately centrifuged and plasma samples were stored at –80 °C until analysis.

Concentrations of endotoxin were measured using a commercially available kit (Limulus Amebocyte Lysate QCL-1000 test kit, BioWhittaker Inc, Walkersville, USA) [11]. The normal concentration of endotoxin for this assay in healthy people is <0.50 EU/ml. The within-assay coefficients of variation at concentrations of 0.35 EU/ml and 0.82 EU/ml were 9.9 and 9.6%; between-assay coefficients of variation were 16.8 and 13.3%, respectively. For repeated blood samples in non-oedematous patients the coefficient of variation was 10.8%. The lower limit of detection was 0.03 EU/ml.

Total TNF{alpha} (Medgenix, Fleurus, Belgium; sensitivity 3.0 pg/ml; test not influenced by soluble TNF receptors), interleukin 6 (R&D Systems, Minneapolis, MN, USA; lower limit of detection of the assay was 0.0094 pg/ml) and soluble CD14 (IBL, Hamburg, Germany) were measured by ELISA.

2.3. Statistical analysis
We assessed normality of distribution with the Kolmogorow–Smirnov test. Unpaired and paired Student's t-tests, ANOVA with Fisher's post-hoc test (with allowance for multiple testing), and the Mann–Whitney U-test were used where appropriate. Data are presented as mean±S.E. We also used univariate–correlation and multivariate–correlation analyses to establish the relation between variables. A commercially available statistical software program was used (StatView 5.0, Abacus Concepts Inc., Berkeley, CA, USA). A P-value of <0.05 was accepted as statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations
 6. Conclusions
 References
 
In Table 1 baseline characteristics of patients and healthy volunteers are shown. There were no significant differences observed with regard to age and body weight. All decompensated patients were in NYHA class IV and had an impaired left ventricular ejection fraction in echocardiograms (34±2%) as well as in angiograms (33±4%). Pulmonary artery pressures (PAP systolic/mean/diastolic: 39±2/24±2/16±2 mmHg) and wedge pressures (PCWP mean: 12±2 mmHg) were elevated in these decompensated patients and their cardiac output was diminished (3.7±0.3 l/min). In Table 2, baseline levels of humoral variables, as well as markers of pro-inflammatory cytokine activation are given. As expected from patients clinical status, sodium levels were diminished and markers of kidney and liver function were elevated. During the acute phase of heart failure, levels of endotoxin, sCD14, TNF{alpha} and IL6 were significantly elevated compared to patients with stable heart failure (all at least P<0.05; Table 2).


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  		Table 2 Results on admission

 
Once stabilization was achieved, cardiac catheterization was performed only in patients with heart failure and blood samples were obtained from hepatic veins, the pulmonary artery and left ventricle. Endotoxin levels were highest in hepatic veins and here significantly increased compared to levels measured in the left ventricle (P<0.02; Fig. 1), suggesting possible endotoxin translocation from the gut into the circulation. There were no significant differences found for sCD14, TNF{alpha} and IL6 (P=n.s.). Levels of endotoxin, sCD14, TNF{alpha} and IL6 were not different between the pulmonary artery and the left ventricle (P=n.s., Table 3; Fig. 1).


Figure 1
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  		Fig. 1 In patients with decompensated heart failure invasive assessment of endotoxin levels was performed in blood obtained from the hepatic vein, pulmonary artery and left ventricle. Highest levels were found in hepatic veins and these levels were significantly increased as compared to the left ventricle.

 


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  		Table 3 Invasive measurements in decompensated patients

 
At follow-up (29±6 days), levels of endotoxin were significantly lower than during the acute phase of acute heart failure (P<0.05; Table 4). Absolute values of sCD14, TNF{alpha} and IL-6 were lowest at discharge but statistically not different from baseline.


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  		Table 4 Admission vs. follow-up in decompensated patients

 
No simple correlations were found between plasma creatinine or urea concentrations and endotoxin at baseline, nor between changes in markers of kidney function over time, compared with changes in endotoxin or cytokine concentrations over time (data not shown). Therefore, a bias due to latent abnormalities of kidney function in individual patients is unlikely.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations
 6. Conclusions
 References
 
The main findings of this study are:

  1. Endotoxin and TNF{alpha} levels are systemically elevated during acute heart failure as compared to patients with stable heart failure.
  2. Higher levels of endotoxin in the hepatic vein as compared to the left ventricle during acute heart failure, lend further support to the hypothesis that bacterial or endotoxin translocation from the bowel into the blood stream might occur.
  3. The lack of difference between TNF{alpha} levels measured in the hepatic vein, pulmonary artery and left ventricle does not question whether there is an upregulated expression of cytokines in the myocardium, but sheds doubt on the heart and/or lung as a source of systemically elevated TNF{alpha} levels.

4.1. Endotoxin translocation
It has previously been postulated that acute venous congestion with subsequently altered gut permeability for bacteria, endotoxin, or both, may lead to translocation of these materials into the circulation [12]. Indeed, in patients with acute heart failure, elevated levels of endotoxin, sCD14, TNF{alpha} and IL-6 have recently been reported [11]. Provided endotoxin spills over into the circulation, one would not only expect to measure systemically elevated levels of endotoxin, but also increased levels in the hepatic vein as compared to other regions of the circulation. Therefore, we set out to assess endotoxin levels not only systemically, but also in the hepatic vein, pulmonary artery and left ventricle.

We identified a group of patients with an acute episode of acute heart failure, in whom levels of endotoxin, sCD14, TNF{alpha} and IL-6 were elevated [1–7,11]. We measured increased levels of endotoxin and confirmed our initial finding that patients with an episode of acute heart failure have elevated systemic levels of endotoxin, sCD14, TNF{alpha} and IL-6 as compared to age-matched patients with stable CHF and healthy volunteers.

Further to our initial report, we now observed significantly higher levels of endotoxin in hepatic veins as compared to the pulmonary arteries and the left ventricle, lending further support to the hypothesis of endotoxin translocation from the gut into the circulation. Since bacteremia, which is also associated with elevated endotoxin levels, might also occur in these patients, blood cultures were drawn on admission and during the following 24 h. All blood cultures, however, remained negative, thus ruling out relevant bacteremia. Endotoxin levels were found to be similar to those reported earlier [11]. It may be speculated that invasively measured endotoxin levels would have been even higher, if cardiac catheterization had been performed on admission. However, since cardiac decompensation was not due to myocardial infarction, patients first had to be stabilized before undergoing cardiac catheterization in order to minimise procedural risk. Stabilisation was mainly done using intensive diuretic therapy, which has previously been shown to lead to reduced levels of endotoxin, and this could explain why invasively measured endotoxin levels did not quite match baseline levels [11].

Our finding that levels of endotoxin, but not sCD14, TNF{alpha} or IL-6, improve after 4 weeks of optimized therapy is in line with current literature. Similar results have been reported in patients with chronic heart failure as well as left ventricular decompensation, where stabilization and optimized treatment was not associated with a reduction in TNF{alpha} until 3–6 months after stabilization [2,4,13–16]. This may be due to a concentration effect, resulting from the loss of up to 12 kg 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 cytokine decrease immediately after clinical improvement may be due to a change in monocyte or macrophage lipopolysaccharide sensitivity, where ‘normalized’ endotoxin concentrations may still cause increased cytokine production. Indeed, such an increased cellular sensitivity to lipopolysaccharides has been documented in patients with an acute episode of decompensated heart failure [17].

4.2. Transmyocardial gradient
Increased expression of tumor necrosis factor (TNF{alpha}) has been found in cardiac tissue of patients with chronic heart failure undergoing heart transplantation and the failing heart has been suggested as the cause of immune activation [6]. Indeed, several laboratories have convincingly shown that TNF{alpha} and nitric oxide synthase are expressed by the failing human heart, which confirms that the heart is a potential site of production of inflammatory mediators [7,18–20]. Raised TNF{alpha} concentrations in cardiac tissue of patients with endstage chronic heart failure may, however, also be due to cardiomyocytes or tissue monocytes releasing increased amounts of cytokines upon stimulation by lipopolysaccharides because of decompensation or hypersensitive cardiomyocytes. In cardiomyocytes of end-stage heart failure patients awaiting heart transplantation or assist devices (especially in patients with ischaemic chronic heart failure) increased baseline and lipopolysaccharide-stimulated TNF{alpha} production has been reported [21]. Whether TNF{alpha} expressed by cardiac tissue is released in sufficient amounts to explain increased systemic levels remains elusive [1,3,22].

In the present study, levels of sCD14, TNF{alpha} and IL-6 were not different between the hepatic veins, pulmonary artery and left ventricle. We could thus not find a transmyocardial gradient, which is in line with three other reports that also assessed intrarcardiac levels of pro-inflammatory cytokines [1,3,22]. Munger et al. measured plasma levels of TNF{alpha}, IL-1, IL-6 and soluble IL-2 of arterial and coronary sinus blood in patients with mild to moderate heart failure and could not detect any transmyocardial gradient [22]. Similarly, Petretta et al. measured levels of cytokines in the ascending aorta, coronary sinus, inferior vena cava and hepatic vein [1], and Deliargyris et al. drew blood samples from the femoral artery, femoral vein, left main coronary artery and coronary sinus [3]. Both studies failed to detect transmyocardial gradients for TNF{alpha} and IL-6 in chronic heart failure. Although these findings and our report do not argue against myocardial expression of inflammatory cytokines, which undoubtedly occurs, they do, however, imply limited contribution of myocardial production to the elevation of systemic cytokine levels.

Although Petretta et al. concluded that no cardiac or gut production of cytokines occurs in mild to severe heart failure [1] neither of these studies attempted to measure endotoxin levels systemically or in the hepatic vein, which would have been indicative of endotoxin or bacterial translocation from the gut into the circulation. Therefore, these results do not rule out endotoxin translocation.

4.3. Peripheral hypoxia
A further potential site of cytokine production that might contribute considerably to systemically elevated cytokine levels is the skeletal muscle. During peripheral hypoxia, which is a hallmark symptom of chronic heart failure, measures of increased oxidative stress have been found to correlate with soluble TNF{alpha} receptor-1 and receptor-2 concentrations [23], and peak leg blood flow after ischaemia in clinically stable patients with chronic heart failure has been shown to be inversely related to TNF{alpha} plasma concentrations [24]. This effect may be due to both a hypoxia-induced increase in TNF{alpha} production or toxic effects of TNF{alpha} on endothelial function [25]. Also, elevated IL-6 plasma concentrations as reported in this study, can be attributed to peripheral hypoxia [26]. Although increased levels of inflammatory cytokines have been shown to be associated with hypoxia, no report has yet shown that hypoxia itself leads to raised concentrations of TNF{alpha}, procalcitonin, or soluble TNF receptor-1 or receptor-2.

Soluble CD14 receptors are, by contrast, characteristic of endotoxin action, but not of hypoxic disorders [27]. Although, in this study absolute numbers were lowest after recompensation, this did not reach statistical significance. This is quite expected though, since the complex of endotoxin and endotoxin-binding protein activates monocytes and tissue macrophages via the CD14 and Toll-like receptor proteins [28], which stimulates the production of TNF{alpha} and other cytokines. Previous studies suggested that increased soluble CD14 concentrations might be related to endotoxemia [29]. Shed, and therefore soluble, CD14 receptors are thought to reflect the amount of endotoxin/cell interaction in the longer term.


   5. Study limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
6. Conclusions
 References
 
For ethical reasons, invasive measurements were only performed in patients with decompensated heart failure, and not in patients with stable heart failure or healthy volunteers. Therefore, the possibility that endotoxin levels may have also been higher in the hepatic veins of healthy volunteers cannot be excluded. However, this does not seem very likely, since baseline endotoxin levels were in the normal range whereas levels in patients with decompensated heart failure were almost twice as high.


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 6. Conclusions
References
 
We have shown that endotoxemia occurs during acute episodes of congestive heart failure and that normalization of endotoxin concentrations can be achieved using intensive diuretic treatment. Furthermore, we report that invasively measured endotoxin levels are highest in the hepatic vein, which is in keeping with the hypothesis of endotoxin translocation from the gut into the circulation. The lack of difference in TNF{alpha} levels measured in the hepatic vein, pulmonary artery and left ventricle sheds doubt on the heart and/or lung as a source of systemically elevated TNF{alpha} levels.

Taken together, these findings may stimulate various new treatment options directed against bacteria in the bowel, the translocation process, endotoxin itself, or the binding sites of bacterial endotoxin on immune competent cells.


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

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