Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction

Darlington O. Okonko, Stephen B. Marley, Stefan D. Anker, Philip A. Poole-Wilson, Myrtle Y. Gordon

Research output: Contribution to journalArticlepeer-review

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)359-364
Number of pages6
JournalInternational Journal of Cardiology
Volume164
Issue number3
DOIs
Publication statusPublished - Apr 15 2013

Keywords

  • Anaemia
  • Erythropoietin resistance
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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