Endotoxin and immune activation in chronic heart failure: a prospective cohort study

Summary

Background

Immune activation in patients with chronic heart failure may be secondary to endotoxin (lipopolysaccharide) action. We investigated the hypothesis that altered gut permeability with bacterial translocation and endotoxaemia would be increased in patients with oedema secondary to congestive heart failure.

Methods

We compared 20 patients who had chronic heart failure with recent-onset peripheral oedema (mean age 64 years [SD 10], New York Heart Association [NYHA] class 3·3 [0·7]), 20 stable non-oedematous patients with chronic heart failure (mean age 63 years [19], NYHA class 2·6 [0·7]), and 14 healthy volunteers (mean age 55 years [16]). Biochemical markers of endotoxaemia, inflammation, and immune activation were measured. Ten patients were studied within 1 week of complete resolution of oedema. Five patients survived longer than 6 months and were restudied again after remaining free of oedema for more than 3 months.

Findings

Mean endotoxin concentrations were higher in oedematous patients with chronic heart failure than in stable patients with chronic heart failure (0·74 [SD 0·45] vs 0·37 EU/mL [0·23], p=0·0009) and controls (0·46 EU/mL [0·21], p=0·02). Oedematous patients had the highest concentrations of several cytokines. After short-term diuretic treatment, endotoxin concentrations decreased from 0·84 EU/mL [0·49] to 0·45 EU/mL [0·21], p<0·05) but cytokines remained raised. After freedom of oedema for more than 3 months after oedema resolved, endotoxin concentrations remained unchanged from the previous visit (0·49 EU/mL [0·06], p=0·45).

Interpretation

Raised concentrations of endotoxin and cytokines are found in patients with chronic heart failure during acute oedematous exacerbation. Intensified diuretic treatment can normalise endotoxin concentrations. Our preliminary findings suggest that endotoxin may trigger immune activation in patients with chronic heart failure during oedematous episodes.

Introduction

Some patients with chronic heart failure have features such as cardiac cachexia that may be due to activation of the immune system.1, 2 Increased expression of tumour necrosis factor α (TNFα) 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.³ No link between a pathogenic process and cytokine activation has been documented in human beings with heart failure or in animal models. The cause of increased cytokine production in patients with heart failure remains unknown.

We have previously suggested that bacterial endotoxin, lipopolysaccharide, contributes to immune activation in chronic heart failure.⁴ Acute venous congestion could lead to altered gut permeability for bacteria, endotoxin, or both, and to translocation of these materials into the circulation. In the circulation, lipopolysaccharide is bound by a serum protein, termed lipopolysaccharide-binding protein (LBP).⁵ The lipopolysaccharide-LBP complex can interact with the CD14 membrane protein and Toll-like signalling receptors to start a signalling cascade that leads to increased cytokine production (figure 1). The extracellular domain of the CD14 receptor is shed after interaction and serum concentrations are thought to reflect the amount of endotoxin and cell interaction. The lipopolysaccharide-LBP ratio has been shown to be crucial for the immunostimulatory effects of lipopolysaccharide.⁶ High concentrations of LBP, as seen during the acute-phase response, can completely block lipopolysaccharide effects in vitro and in a murine sepsis model.⁷ Furthermore, patients with high concentrations of soluble CD14 (which shows endotoxin-cell interaction and shedding of CD14 from the cell membrane⁸) have strikingly increased concentrations of TNFα, soluble TNF receptor-1 and receptor-2, and intracellular-adhesion molecule-1.⁴

The degree of bowel-wall oedema cannot be directly measured. The relation between central haemodynamics and the pathophysiological features of chronic heart failure is weak.⁹ In animal models there is a poor relation between intracardiac pressures and intestinal perfusion.¹⁰ We therefore separated patients according to the presence or absence of a reliable marker of acute venous congestion due to cardiac failure, namely peripheral oedema. Bowelwall oedema that could cause altered gut permeability and bacterial (ie, endotoxin) translocation is most likely to occur with moderate to severe peripheral oedema.

Our main aim in this study was to measure endotoxin and cytokine concentrations in patients with chronic heart failure during an acute exacerbation with peripheral oedema and after short-term and long-term treatment with diuretics.