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European Journal of Heart Failure 2007 9(6-7):574-578; doi:10.1016/j.ejheart.2007.02.005
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© 2007 European Society of Cardiology

Intestinal paracellular permeability is not affected in chronic congestive heart failure

M. Schaufelbergera,*, I. Ekmanb, E. Björnssonc, E. Kalaitzakisc and T. Ekmand

a Department of Internal Medicine, Sahlgrenska University Hospital, Östra, 416 85 Gothenburg, Sweden
b Institute of Health and Care Sciences, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden
c Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden
d Department of Internal Medicine and Oncology, Sahlgrenska University Hospital, Göteborg, Sweden

* Corresponding author. Tel: +46 31 3434000; fax: +46 31 259254. E-mail address: maria.schaufelberger{at}hjl.gu.se


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Background: In chronic heart failure (CHF) it has been proposed that a dysfunction of the gastrointestinal barrier could lead to translocation of endotoxin into the systemic circulation. A secondary inflammatory reaction, observed as increased levels of cytokines, could negatively affect cardiac function. The aims of this paper were therefore to determine whether patients with CHF have a disturbed mucosal barrier and whether it was possible to detect endotoxin in venous blood.

Methods: Nineteen stable patients with CHF (New York Heart Association II–III, EF≤40% or EF>40% and earlier hospitalisation for heart failure) were investigated. Twenty healthy subjects (HS group) and 25 patients, who were admitted for bone marrow transplantation (BMT group), served as controls. Gastrointestinal permeability was assessed by a 51Cr-EDTA absorption test.

Results: Eleven patients with and eight without peripheral oedema were included. Median age was 76.5 years. Intestinal permeability was 1.82±1.96% in the CHF patients and 1.54±.59% and 1.9±.9% in HS and BMT groups, respectively (p=0.4 and p=0.7, CHF vs HS and BMT, respectively). No difference was found between patients with and without oedema and endotoxins were below the detection limit in all patients.

Discussion: This study does not support the hypothesis that patients with CHF have a dysfunctional gastrointestinal barrier, at least as assessed by the 51Cr-EDTA resorbtion test.

Key Words: Heart failure • Intestinal permeability • Endotoxin1

Received November 16, 2006; Revised December 14, 2006; Accepted February 1, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
During the past 20 years, treatment of chronic heart failure (CHF) has mainly focused on blocking activated neurohormones. Although effective new treatment modalities have been introduced, mortality remains high [1]. To prevent further deterioration of cardiac function, mechanisms responsible for this deterioration should be explored. Cytokines, such as TNF-{alpha} and IL-6, which have a direct negative inotropic effect on the myocardium, are increased in CHF [2], but the mechanisms for this increase have not been determined. Understanding the source of these cytokines might provide new therapeutic strategies.

The gastrointestinal barrier protects the host from the external milieu (i.e. the gastrointestinal lumen), where pathogenic bacteria, fungi, immunogenic peptides and carcinogens are transported, metabolised and finally excreted. In situations in which this barrier is compromised, such as after cytotoxic or NSAID therapy, luminal components may traverse the intestinal wall and reach sub-mucosal vessels leading to systemic dissemination and septicaemia, i.e. translocation. Cardiac failure, such as in the context of CHF, can also provoke tissue ischaemia [3]; therefore, it would be reasonable to assume that the mucosal barrier could be compromised in CHF as well, which could lead to translocation of endotoxin or other proinflammatory substances. This could provoke a secondary inflammatory response, which has been postulated to explain the increased cytokine production in CHF [4] and could ultimately influence the progression of the disease [5].

Thus far, there are few data on intestinal perfusion and intestinal permeability in CHF [6,7]. In several previous studies of bone marrow transplantation (BMT) and liver cirrhosis, we investigated intestinal permeability with a 51Cr-EDTA absorption test [8,9]. The aim of the present study was to investigate whether patients with CHF had a disturbed mucosal barrier and whether endotoxin could be detected in the systemic circulation as a consequence of this disturbance.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
2.1. Patients
We prospectively enrolled patients with a history of CHF (NYHA II-III). All patients were required to be in a stable condition during the past two weeks (no change in diuretics during this period), with documented left ventricular dysfunction (ejection fraction ≤40% or ejection fraction >40% and a history of hospitalisation for heart failure). Exclusion criteria were concomitant hepatic/renal disorder (S-creatinine >250 umol/l) or fluid retention requiring dose adjustment of diuretics.

2.2. Control groups
Two control groups were investigated with the same technique and in the same laboratory. One group consisted of 20 healthy subjects (HS group) with a median age of 52 (43-69) years. The other group consisted of 25 patients who were admitted for bone marrow transplantation (BMT group), with a median age of 58 (53-63). The BMT patients were in remission from acute leukaemia/high grade non-Hodgkin lymphoma or in a chronic phase of chronic myeloid leukaemia. In this patient group, repeated consecutive measures of intestinal permeability had been performed during different phases of their illness; all patients had shown increased paracellular permeability immediately after chemotherapy with normal values as soon as 14 days after intensive chemotherapy.

2.3. Gastrointestinal permeability
Gastrointestinal permeability was assessed using a 51Cr-EDTA absorption test [8-10]. The test solution consisted of 4 MBq of 51CR-labelled edetic acid (51Cr-EDTA, specific activity 1-2 mCi/mg chromium, Amersham International, UK) in 50 ml of water. At 08.00, after an overnight fast, all subjects emptied their bladders and then drank the test solution. Urine was collected for the next 24 h. Three millilitres of the 24-h volume were counted for 5 min in a gamma counter. The 24-h urinary excretion of the 51Cr-EDTA was expressed as a percentage of the dose given orally. To investigate the completeness of urine collection the patients with CHF were given PABA (paraaminobensoic acid) 1 g three times the day before the test and the amount of PABA (renal excretion 100%) in the collected urine was calculated.

The result of the intestinal permeability measurement in the CHF patients was compared with the HS and BMT control groups.

2.4. Endotoxin
Blood samples from patients with CHF were collected in sterile and endotoxin-free vacuum tubes (Chromogenix, Mölndal, Sweden) for the analysis of endotoxin (Chromogenic Limulus Amoebocyte Lysate assay, CLAL, Chromogenix, Mölndal, Sweden). The method has been described elsewhere [11].

2.5. Statistics
All data are presented as mean±SD unless indicated otherwise. Confidence intervals (CIs) were calculated with an alpha value of 0.95. The Mann-Whitney U test for non-parametric data was used for the comparisons between groups. A p-value of <0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Nineteen patients were included (two in NYHA class II and 17 in NYHA class III). The median age was 76.5 (range 50-83) years. Eight patients had no signs of oedema, whereas eleven patients had peripheral oedema (some severe). In fact, two of the patients had peripheral oedema which was assessed as therapy resistant by their physicians. The amount of the total 24-h urine volume collected varied with a median of 79% (range 30-100). Intestinal permeability in the CHF patients was 1.82±1.96% (CI 1.41-2.22%). Table 1 summarises patient characteristics and Table 2 shows the individual results of the 51Cr-EDTA test. Intestinal permeability in the HS group was found to be 1.54±0.59% (CI 1.28-.80%, p=0.4 vs. CHF) [8]; in the BMT group the corresponding value was 1.9±0.9% (CI 1.55-2.25 %, p=0.7 vs CHF) [12]. Fig. 1 depicts the different CIs in graphical form. No difference was observed between patients with and without peripheral oedema (1.83± .77 vs 1.8±1.06%). S-endotoxin was below the detection limit for all patients studied.


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  		Table 1 Characteristics of patients with chronic heart failure (CHF), patients awaiting a bone marrow transplantation (BMT) and healthy subjects

 


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  		Table 2 Individual patient characteristics and results of the 51Cr-EDTA test

 


Figure 01
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  		Fig. 1 Confidence intervals for intestinal permeability in patients with CHF and the two control groups (healthy subjects and patients on a waiting list for bone marrow transplant). CHF; chronic heart failure, BMT; patients in remission from acute leukaemia/high grade non-Hodgkin lymphoma or in a chronic phase of chronic myeloid leukaemia.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgments
 References
 
We investigated whether patients with stable, moderate to severe CHF had a disturbance of gastrointestinal mucosal barrier integrity as assessed by the 51Cr-EDTA resorbtion test. The results for the patients with CHF were within the same range as the HS and BMT groups. Furthermore, no difference was noted between patients with and without peripheral oedema. Consequently, these findings do not lend support to the hypothesis that patients with CHF have an impaired mucosal barrier.

Mucosal barrier integrity has been studied with a variety of tests. Disaccharides such as lactulose or mannitol [13] are common test substances. As an alternative, we used the 51CR-EDTA resorbtion test for several reasons. First, the test solution is tasteless and well tolerated by patients, and second, 51Cr-EDTA is the same size as endotoxin, a molecule of interest in this area of research [6] and permeates, like lactulose, through the paracellular route.

One pivotal study in the field of intestinal permeability concerned coeliac disease. Here, patients with coeliacs, but in clinical remission, were shown to have an increased 51Cr-EDTA resorbtion [14]. Likewise, mucosal barrier function deteriorates during mucosal ischaemia or after the administration of NSAIDs or cytotoxic drugs [15]. This paracellular "leakiness" of the mucosal barrier may permit translocation of luminal components such as bacteria or fungi [16].

CHF has been shown to lead to a hypoperfusion of muscle [7], it has therefore been hypothetized that a corresponding splanchnic hypoperfusion and mucosal ischaemia, induce an intestinal barrier defect and promote translocation. This elicits systemic inflammation characterised by increased production of cytokines such as IL-6 and TNF-alpha [6,8]. As proof of this concept, these cytokines have been shown to increase in patients with CHF and cytokine levels correlate with the severity of the disease [6,7].

To provide evidence for such a tentative sequence of events, the degree of splanchnic perfusion was investigated in a study of patients with CHF. The study demonstrated an increase in gastric intramucosal pCO2 during moderate exercise, indicative of mucosal hypoperfusion [17]. In an endoscopic study, changes in gastric and duodenal mucosa correlated with the mean inferior vena cava and hepatic vein diameters. Thus, it was concluded that venous congestion could also interfere with mucosal integrity [18]. Increased endotoxin levels have been found in acute deteriorated oedematous patients with CHF, with a reduction in endotoxin levels after treatment [5]. However, in the present study, we did not find increased levels of endotoxin, this may be due to the different patient groups studied. Although eleven of our patients were oedematous they were in a stable condition, whereas the patients studied by Niebauer and coworkers [5] had acute heart failure.

One limitation of our study was that patients were assessed as clinically stable. However, more than half of the patients had signs of peripheral oedema. Despite this, there was no difference in permeability between patients with and without oedema.

We compared our results with two control populations, one healthy group (i.e. the HS group) and one group of patients scheduled for BMT (i.e. the BMT group). A criticism concerning the control groups could be that they were younger than the group with CHF. Two studies have investigated the influence of ageing on intestinal permeability [19,20]. In the most recent study [19] the excretion of lactulose and mannitol was found to decrease with increasing age, as was creatinine clearance. It was concluded that there were no indications for increased "leakiness" of the intestine with advancing age; instead, the reduced ability to excrete orally administered lactulose /mannitol could be explained by a reduction in renal clearance [19]. This conclusion challenges the results in our study in that 12 of our 19 patients had elevated creatinine. Thus, it could be argued that the reduced renal capacity to excrete 51Cr-EDTA would obscure a true increase in permeability among our patients. Therefore, we calculated the creatinine clearance according to Cockcroft and Gault [21]. Median creatinine clearance was 62 (range 32-99) ml/min in the CHF patients. T 1/2 for 51Cr-EDTA is normally 2.3 h, however in an elderly patient with a clearance of 31 ml/min it is 6.7 h. Only two of the patients in our study had a clearance below 40 ml/min, thus the loss due to a reduced clearance, could be anticipated to be 1-6% of the total amount excreted after a collection period of 24 h (personal communication: G. Hermansson, MD PhD, unpublished data). We therefore believe that our data concerning intestinal permeability in the present group of patients with CHF are correct. In addition, the values for the control population in this study are in accordance with earlier findings [22].

If luminal components translocate during periods of impaired mucosal defence, one therapeutic alternative would be to eradicate pathogenetic bacteria from the intestinal lumen. Consistent with this hypothesis, selective intestinal decontamination was tested in a pilot trial that included patients with CHF (NYHA III-IV). Luminal concentration of gram-negative bacteria and endotoxin was found to decrease significantly, as did the cytokine production from endotoxin-primed monocytes. However, circulating concentrations of endotoxin and cytokines remained unchanged. Therefore, the ultimate proof of a link between impairment of the mucosal barrier, bacterial translocation and resulting systemic inflammatory response in CHF remains to be established [23].


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgments
 References
 
Cytokines, such as TNF-{alpha}, have a negative effect on the failing heart. To prevent further deterioration in CHF, therapeutic intervention against cytokines has been considered. It has been proposed that damage to the gastrointestinal barrier could result in translocation of endotoxins into the blood, which, in turn, increases the levels of cytokines. Our data do not support this hypothesis. It may be that, in periods of acute decompensation, the permeability changes. Future studies should therefore evaluate CHF patients in different phases of the disease.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
References
 
We acknowledge Gert Hermansson for his contribution to this paper. This work was supported by grants from Swedish Heart and Lung Foundation and Swedish Medical Research Council (Project 0071/2003).


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

  1. Schaufelberger M., Swedberg K., Koster M., Rosen M., Rosengren A. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden; Data from the Swedish Hospital Discharge Registry 1988 to 2000. Eur Heart J (2004) 25:300–307.[Abstract/Free Full Text]
  2. Blum A., Miller H. Role of cytokines in heart failure. Am Heart J (1998) 135:181–186.[CrossRef][Web of Science][Medline]
  3. DeFelice A., Frering R., Horan P. Time course of hemodynamic changes in rats with healed severe myocardial infarction. Am J Physiol (1989) 257:H289–H296.[Web of Science][Medline]
  4. Deitch E.A., Xu D., Franko L., Ayala A., Chaudry I.H. Evidence favoring the role of the gut as a cytokine-generating organ in rats subjected to hemorrhagic shock. Shock (1994) 1:141–145.[Web of Science][Medline]
  5. Niebauer J., Volk H.D., Kemp M., et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet (1999) 353:1838–1842.[CrossRef][Web of Science][Medline]
  6. Deswal A., Petersen N.J., Feldman A.M., Young J.B., White B.G., Mann D.L. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation (2001) 103:2055–2059.[Abstract/Free Full Text]
  7. Rauchhaus M., Doehner W., Francis D.P., et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation (2000) 102:3060–3067.[Abstract/Free Full Text]
  8. Kalaitzakis E., Johansson J., Bjarnason I., Björnsson E., et al. Intestinal permeability in cirrhotic patients with and without ascites. Scand J Gastroenterol (2006) 41:326–330.[CrossRef][Web of Science][Medline]
  9. Bjarnason I., MacPherson A., Hollander D. Intestinal permeability: an overview. Gastroenterology (1995) 108:1566–1581.[CrossRef][Web of Science][Medline]
  10. Tibble J.A., Bjarnason I. Non-invasive investigation of inflammatory bowel disease. World J Gastroenterol (2001) 7:460–465.[Web of Science][Medline]
  11. Ronholm E., Tomasdottir H., Runeborg J., et al. Gastro-intestinal complement activation during human liver transplantation: impact on postoperative liver function. Acta Anaesthesiol Scand (2000) 44:850–857.[CrossRef][Web of Science][Medline]
  12. Johansson J.E., Ekman T. Gastro-intestinal toxicity related to bone marrow transplantation: disruption of the intestinal barrier precedes clinical findings. Bone Marrow Transplant (1997) 19:921–925.[CrossRef][Web of Science][Medline]
  13. Menzies I., Crane R. Assessing intestinal absorptive capacity and permeability in vivo. In: Methods in disease: investigating the gastrointestinal tract—Ed Preedy V.R., Watson R.R., eds. (1998) Greenwich Medical Media Ltd. 41–62.
  14. Bjarnason I., Peters T.J., Veall N. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet (1983) 1:323–325.[Web of Science][Medline]
  15. Mielants H., Goemaere S., De Vos M., et al. Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. J Rheumatol (1991) 18:389–393.[Web of Science][Medline]
  16. Sullivan M.J., Knight J.D., Higginbotham M.B., Cobb F.R. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure. Circulation (1989) 74:245–251.
  17. Krack A., Richartz B.M., Gastmann A., et al. Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure. Eur J Heart Fail (2004) 6:403–407.[Abstract/Free Full Text]
  18. Kaiser R., Kochhar R., Pradeepta K.S., Usha D., Harinder K.B., Varma J.S. An endoscopic study of upper-GI mucosal changes in patients with congestive heart failure. Gastrointest Endosc (2004) 60:887–893.[CrossRef][Web of Science][Medline]
  19. Saltzman J.R., Kowdley K.V., Perrone G., Russell R.M. Changes in small-intestine permeability with aging. J Am Geriatr Soc (1995) 43:160–164.[Web of Science][Medline]
  20. Beaumont D.M., Cobden I., Sheldon W.L., Laker M.F., James O.F. Passive and active carbohydrate absorption by the ageing gut. Age Ageing (1987) 16:294–300.[Abstract/Free Full Text]
  21. Cockcroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[Web of Science][Medline]
  22. Zuckerman M.J., Menzies I.S., Ho H., et al. Assessment of intestinal permeability and absorption in cirrhotic patients with ascites using combined sugar probes. Dig Dis Sci (2004) 49:621–626.[CrossRef][Web of Science][Medline]
  23. Conraads V.M., Jorens P.G., De Clerck L.S., et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail (2004) 6:483–491.[Abstract/Free Full Text]

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