Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure

Atherosclerosis. 2008 Jul;199(1):215-21. doi: 10.1016/j.atherosclerosis.2007.09.039. Epub 2007 Nov 7.


Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-*, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-* treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Anemia / complications
  • Anemia / drug therapy*
  • Biomarkers / blood
  • C-Reactive Protein / immunology
  • C-Reactive Protein / metabolism
  • Chronic Disease
  • Cytokines / blood
  • Cytokines / immunology
  • Darbepoetin alfa
  • Erythropoietin / administration & dosage
  • Erythropoietin / analogs & derivatives*
  • Fas Ligand Protein / blood*
  • Fas Ligand Protein / immunology
  • Female
  • Heart Failure / complications*
  • Hematinics / administration & dosage
  • Humans
  • Intercellular Adhesion Molecule-1 / blood
  • Intercellular Adhesion Molecule-1 / immunology
  • Interleukin-10 / blood*
  • Interleukin-10 / immunology
  • Interleukin-6 / blood
  • Interleukin-6 / immunology
  • Male
  • Middle Aged
  • Solubility
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / immunology
  • Vascular Cell Adhesion Molecule-1 / blood
  • Vascular Cell Adhesion Molecule-1 / immunology
  • fas Receptor / blood*
  • fas Receptor / immunology


  • Biomarkers
  • Cytokines
  • FAS protein, human
  • Fas Ligand Protein
  • Hematinics
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • fas Receptor
  • Erythropoietin
  • Intercellular Adhesion Molecule-1
  • Interleukin-10
  • Darbepoetin alfa
  • C-Reactive Protein