title: 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.
abstract: 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.
authors.affiliation: Second Department of Cardiology and Heart Failure Unit, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
authors.forename: Kallirrhoe
authors.initials: K
authors.lastname: Kourea
authors.forename: John T
authors.initials: JT
authors.lastname: Parissis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Farmakis
authors.forename: Fotios
authors.initials: F
authors.lastname: Panou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Paraskevaidis
authors.forename: Koula
authors.initials: K
authors.lastname: Venetsanou
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.forename: Dimitrios Th
authors.initials: DT
authors.lastname: Kremastinos
mesh_terms: D000368:Aged; D000740:Anemia / Q000150:complications / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood / Q000276:immunology; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D053222:Fas Ligand Protein / Q000097:blood* / Q000276:immunology; D005260:Female; D006333:Heart Failure / Q000150:complications*; D006397:Hematinics / Q000008:administration & dosage; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood* / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012995:Solubility; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood / Q000276:immunology; D019014:fas Receptor / Q000097:blood* / Q000276:immunology
chemical_list: D015415:Biomarkers; D016207:Cytokines; C491901:FAS protein, human; D053222:Fas Ligand Protein; D006397:Hematinics; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019014:fas Receptor; D004921:Erythropoietin; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D000068256:Darbepoetin alfa; D002097:C-Reactive Protein