Thromb Haemost 2012; 107(04): 769-774
DOI: 10.1160/TH11-08-0552
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Erythropoietin-induced progenitor cell mobilisation in patients with acute ST-segment-elevation myocardial infarction and restenosis

Andreas Stein
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Felix Mohr
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Magdalena Laux
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Stefanie Thieme
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Barbara Lorenz
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Mirijam Cetindis
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Janina Hackl
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Philipp Groha
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Gabriele Demetz
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Stefanie Schulz
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Julinda Mehilli
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Albert Schömig
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Adnan Kastrati
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
,
Ilka Ott
1   Deutsches Herzzentrum der Technischen Universität München, München, Germany
› Author Affiliations
Further Information

Publication History

Received: 24 August 2011

Accepted after major revision: 05 January 2012

Publication Date:
29 November 2017 (online)

Summary

Erythropoietin improves myocardial function and enhances re-endothelialisation. Aim of this study was to analyse progenitor cell mobilisation and restenosis in patients from the Regeneration of Vital Myocardium in ST-Segment Elevation Myocardial Infarction by Erythropoietin (REVIVAL-3) study. Patients with STEMI undergoing percutaneous coronary intervention (PCI) were randomly assigned to Epoetin beta (EPO) (n=68) or placebo (n=70). Drug-eluting stents (DES) were utilised in 93% of patients receiving EPO and in 95% of patients receiving placebo (p=0.83). Serial venous blood samples were drawn; CD133+ progenitor cells were quantified by four-colour flow cytometry and cytokines interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor (TNF) alpha were analysed by cytometric bead array. Fortyeight hours after PCI a significant increase in CD133+ progenitor cells was observed in the EPO group. Yet, no differences in plasma cytokines were found. Quantitative coronary angiography after six months revealed an increase in segment diameter stenosis in the EPO group (32 ± 19% vs. 26 ± 14%, p=0.046). However, this increase in neointima generation was not associated with progenitor cell mobilisation. EPO in patients with STEMI treated with PCI is associated with an increase in diameter stenosis that is not associated with circulating progenitor cells.

ClinicalTrials.gov Identifier: NCT00390832

 
  • References

  • 1 Latini R, Brines M, Fiordaliso F. Do non-hemopoietic effects of erythropoietin play a beneficial role in heart failure?. Heart Fail Rev 2008; 13: 415-423.
  • 2 Brunner S, Winogradow J, Huber BC. et al. Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow-derived progenitor cells via the cxcr-4/sdf-1 axis. Faseb J 2009; 23: 351-361.
  • 3 Fiordaliso F, Chimenti S, Staszewsky L. et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci USA 2005; 102: 2046-2051.
  • 4 Hirata A, Minamino T, Asanuma H. et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol 2006; 48: 176-184.
  • 5 Moon C, Krawczyk M, Ahn D. et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci USA 2003; 100: 11612-11617.
  • 6 van der Meer P, Lipsic E, Henning RH. et al. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 2005; 46: 125-133.
  • 7 Westenbrink BD, Lipsic E, van der Meer P. et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 2007; 28: 2018-2027.
  • 8 Besarab A, Bolton WK, Browne JK. et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584-590.
  • 9 Pfeffer MA, Burdmann EA, Chen CY. et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361: 2019-2032.
  • 10 Singh AK, Szczech L, Tang KL. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085-2098.
  • 11 Ott I, Schulz S, Mehilli J. et al. Erythropoietin in patients with acute st-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: A randomized, double-blind trial. Circ Cardiovasc Interv 2010; 03: 408-413.
  • 12 Urao N, Okigaki M, Yamada H. et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via aktendothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res 2006; 98: 1405-1413.
  • 13 Asahara T, Takahashi T, Masuda H. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J 1999; 18: 3964-3972.
  • 14 Heimfeld S, Fogarty B, McGuire K. et al. Peripheral blood stem cell mobilization after stem cell factor or g-csf treatment: Rapid enrichment for stem and progenitor cells using the ceprate immunoaffinity separation system. Transplant Proc 1992; 24: 2818.
  • 15 Kessinger A, Bishop MR, Jackson JD. et al. Erythropoietin for mobilization of circulating progenitor cells in patients with previously treated relapsed malignancies. Exp Hematol 1995; 23: 609-612.
  • 16 Schomig K, Busch G, Steppich B. et al. In terleu kin-8 is associated with circulating cd133+ progenitor cells in acute myocardial infarction. Eur Heart J 2006; 27: 1032-1037.
  • 17 Minatoguchi S, Takemura G, Chen XH. et al. Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment. Circulation 2004; 109: 2572-2580.
  • 18 Harada M, Qin Y, Takano H. et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the jakstat pathway in cardiomyocytes. Nat Med 2005; 11: 305-311.
  • 19 Sugano Y, Anzai T, Yoshikawa T. et al. Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction. Cardiovasc Res 2005; 65: 446-456.
  • 20 Zohlnhofer D. G-CSF for left ventricular recovery after myocardial infarction: Is it time to face reality?. Cardiovasc Drugs Ther 2008; 22: 343-345.
  • 21 Zohlnhofer D, Kastrati A, Schomig A. Stem cell mobilization by granulocyte-colony-stimulating factor in acute myocardial infarction: Lessons from the revival-2 trial. Nat Clin Pract Cardiovasc Med 2007; 04 (Suppl. 01) S106-109.
  • 22 Stein A, Zohlnhofer D, Pogatsa-Murray G. et al. Expression of CXCR4, VLA-1, LFA-3 and transducer of erb in G-CSF-mobilised progenitor cells in acute myocardial infarction. Thromb Haemost 2010; 103: 638-643.
  • 23 Janmaat ML, Heerkens JL, de Bruin AM. et al. Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood 2010; 115: 1453-1460.
  • 24 Li Y, Takemura G, Okada H. et al. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res 2006; 71: 684-694.
  • 25 Li JJ, Ren Y, Chen KJ. et al. Impact of c-reactive protein on in-stent restenosis: A meta-analysis. Tex Heart Inst J 2010; 37: 49-57.
  • 26 Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity c-reactive protein assay. Clin Chem 1999; 45: 2136-2141.
  • 27 Sen S, McDonald SP, Coates PT, Bonder CS. Endothelial progenitor cells: Novel biomarker and promising cell therapy for cardiovascular disease. Clin Sci 2010; 120: 263-283.