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

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 μg/kg/3 weeks, MI-EPO-high) or a low-dose (0.4 μg/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 b 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 b 0.05 compared to MI). The improved cardiac function was associated with increased capillary growth (38% in MI-EPO-high (p b 0.01) and 27% in MI-EPO-low (p b 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.

Erythropoietin protects against doxorubicin-induced heart failure

“…In this regard, Hamid et al (17) found that EPO treatment improved the myocardial performance in doxorubicin-induced cardiomyopathy, which was associated with an increase in HCT levels in their EPO control rats (23). In another study, it has been found that low-dose of EPO improves cardiac function in experimental heart failure without increasing HCT levels; however, some of the beneficial effects were less pronounced in the "low-dose group" than "high dose group" in this study, which might indicate that some of the beneficial effects are related to increased HCT levels and consequently increased oxygen delivery (22). Thus the optimal dose and timing of EPO treatment during chemotherapy are very important and still need to be defined.…”

Erythropoietin Prevention Trial of Coronary Restenosis and Cardiac Remodeling After ST-Elevated Acute Myocardial Infarction (EPOC-AMI) - A Pilot, Randomized, Placebo-Controlled Study -

“…Lipsic et al compared these effects of low-dose EPO (0.4 μg/kg for 3 weeks) to a high EPO dose (40 μg/kg for 3 weeks, 100-fold higher), with previously established effects on cardiac function in post-MI heart failure of rats. 21 Similar to high-dose EPO, low-dose EPO induced neovascularization and attenuated the unfavorable switch to slow β-MHC isoforms. However, in contrast to high-dose EPO, LVEDP was not significantly attenuated in the low-dose group compared to the untreated MI.…”

“…Lipsic et al reported that low dose (0.4 μg/kg) EPO analogue darbepoetin-alfa improved cardiac function and induced neovascularization in post-MI heart failure of rats, the effect of which was similar to higher dose (40 μg/kg) administration. 21 Lower doses of EPO was shown to confer vascular and tissue protection in the kidney, 22 and its safety is approved by the general use in autologous blood collection. 23 Therefore, our pilot study was designed to investigate the effects of short-term low-dose EPO administration on the neointimal hyperplasia in PCI-treated coronary arteries and infarct size (primary endpoints) and cardiac function (second endpoint) in the patients with ST-elevated AMI.…”

Endogenous Erythropoietin and Outcome in Heart Failure

“…20 -23 These effects are seen even when erythropoietin is administered in low doses that do not increase hematocrit. 24 These extrahematopoietic effects may be useful in HF and may prevent cardiac function loss after myocardial infarction. Presently, a randomized multicenter trial is evaluating the effect of a single bolus of erythropoietin administered after a first acute myocardial infarction on left ventricular function.…”