© 2008 European Society of Cardiology
Low-dose erythropoietin improves cardiac function in experimental heart failure without increasing haematocrit
icDepartment of Cardiology, University Medical Center Groningen, University of Groningen The Netherlands
* Corresponding author. Department of Cardiology, Thoraxcenter, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 3613876; fax: +31 50 3614391. E-mail address: b.d.westenbrink{at}thorax.umcg.nl (B. D. Westenbrink)
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Abstract |
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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 µ/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 µ/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/dtmax) and relaxation (dP/dtmin) 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 β-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.
Key Words: Capillaries • Heart failure • Ventricular function
Received May 24, 2007; Revised August 31, 2007; Accepted October 16, 2007
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