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


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


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.
Lipsic
Erik
E
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands.
Westenbrink
B Daan
BD
van der Meer
Peter
P
van der Harst
Pim
P
Voors
Adriaan A
AA
van Veldhuisen
Dirk J
DJ
Schoemaker
Regien G
RG
van Gilst
Wiek H
WH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002196:Capillaries; D003331:Coronary Vessels; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D006397:Hematinics / Q000627:therapeutic use*; D006400:Hematocrit; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D018919:Neovascularization, Physiologic; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa