Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit

Erik Lipsic, B Daan Westenbrink, Peter van der Meer, Pim van der Harst, Adriaan A Voors, Dirk J van Veldhuisen, Regien G Schoemaker, Wiek H van Gilst

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Erythropoietin (EPO) may improve cardiac function and induce neovascularisation in experimental models of chronic heart failure (CHF). However, the increased haematocrit associated with EPO treatment might exert concomitant deleterious effects.

AIM: To investigate the haematocrit independent effects of EPO on cardiac function.

METHODS AND RESULTS: Rats underwent permanent coronary artery ligation to induce myocardial infarction (MI) or sham surgery. Three weeks after MI, rats were randomly allocated to treatment with vehicle (MI) or the long-acting EPO analogue darbepoetin alfa administered in a high (40 microg/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 microg/kg/3 weeks, MI-EPO-low). After 9 weeks, haemodynamic parameters, myocardial histology and Myosin Heavy Chain (MHC) isoforms were determined. High-dose EPO resulted in a significant increase in haematocrit (p<0.01) while low-dose EPO had no effect on haematocrit levels. EPO significantly improved cardiac function in both EPO groups, reflected by increased left ventricular (LV)-developed pressure and improved contractility (dP/dt(max)) and relaxation (dP/dt(min)) indices of the LV at 9-weeks (all p<0.05 compared to MI). The improved cardiac function was associated with increased capillary growth (38% in MI-EPO-high (p<0.01) and 27% in MI-EPO-low (p<0.05)) and an attenuated switch to slow beta-MHC isoforms in both EPO groups.

CONCLUSIONS: EPO improves cardiac function and induces neovascularisation at a dose that does not increase haematocrit, thereby circumventing the possible deleterious effects of increased erythropoiesis.

Original languageEnglish
Pages (from-to)22-9
Number of pages8
JournalEuropean Journal of Heart Failure
Volume10
Issue number1
DOIs
Publication statusPublished - Jan 2008
Externally publishedYes

Keywords

  • Animals
  • Apoptosis/drug effects
  • Capillaries
  • Coronary Vessels
  • Darbepoetin alfa
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Erythropoietin/analogs & derivatives
  • Heart Failure/blood
  • Hematinics/therapeutic use
  • Hematocrit
  • Male
  • Myocardial Contraction/drug effects
  • Neovascularization, Physiologic
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome

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