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Background: Mortality and morbidity after acute myocardial infarction (AMI) remain high even when myocardial reperfusion is successful. Erythropoietin (EPO) protects against experimental MI., Methods: The aim of this single-centre study was to investigate the effects of short-term high-dose erythropoietin on peripheral blood cells (PBCs) and infarct size in 30 patients with a first uncomplicated AMI undergoing percutaneous coronary intervention (PCI) who were randomly assigned to treatment with EPO (33 × 10(3)IU before PCI, and 24 and 48 h after admission), or placebo. We considered short-term CD34+ cell mobilisation, quantitative PBC gene expression in the apoptotic, angiogenic and inflammatory pathways, and enzymatically estimated infarct size. Echocardiographic and cardiac magnetic resonance studies were performed in the acute phase and six months later., Results: CD34+ cell mobilisation 72 h after admission was greater in the EPO-treated patient group (93 cells/μl [36-217] vs 22 cells/μl [6-51]; p = 0.002), who also showed higher expression of the anti-apoptotic AKT and NFkB, the pro-angiogenic VEGFR-2, and the EPO-R genes, and lower expression of the pro-apoptotic CASP3 and TP53 and pro-inflammatory IL12a genes. Moreover, they showed smaller infarct size (30% reduction in CK-MB release; p = 0.025), and a favourable pattern of left ventricular remodelling., Conclusions: Short-term high-dose EPO administration in patients with AMI treated by PCI and standard anti-platelet therapy increases the levels of circulating CD34+ cells, shifts PBC gene expression towards anti-apoptotic, pro-angiogenic and anti-inflammatory pathways, and decreases infarct size. The clinical relevance of these results needs to be confirmed in specifically tailored trials., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)