title: Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction.
abstract: BACKGROUND
  Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction.
  
  
  METHODS
  We studied 28 CHF patients (age 64 ± 10 yrs, LVEF 29 ± 9%, 89% male) and 12 healthy controls (65 ± 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry.
  
  
  RESULTS
  Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r=-0.41, P=0.01) and soluble tumour necrosis factor receptor 2 (r=-0.38, P=0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P<0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P<0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients.
  
  
  CONCLUSIONS
  The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy.
authors.affiliation: Clinical Cardiology, National Heart & Lung Institute, Imperial College, London, UK. obiokonko@aol.com
authors.forename: Darlington O
authors.initials: DO
authors.lastname: Okonko
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Marley
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.forename: Philip A
authors.initials: PA
authors.lastname: Poole-Wilson
authors.forename: Myrtle Y
authors.initials: MY
authors.lastname: Gordon
mesh_terms: D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation / Q000502:physiology; D004351:Drug Resistance / Q000502:physiology*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006333:Heart Failure / Q000150:complications*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017467:Receptors, Erythropoietin / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; D004921:Erythropoietin; D053612:Janus Kinases