title: Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure.
abstract: Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.
authors.affiliation: Clinical Cardiology, National Heart & Lung Institute, Imperial College School of Medicine, London, United Kingdom. s.genth@ic.ac.uk
authors.forename: Sabine
authors.initials: S
authors.lastname: Genth-Zotz
authors.forename: Stephan
authors.initials: S
authors.lastname: von Haehling
authors.forename: Aidan P
authors.initials: AP
authors.lastname: Bolger
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kalra
authors.forename: Roland
authors.initials: R
authors.lastname: Wensel
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Coats
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
mesh_terms: D000328:Adult; D000368:Aged; D002100:Cachexia / Q000097:blood*; D004731:Endotoxins / Q000097:blood / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D004731:Endotoxins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha