EPC mobilization after erythropoietin treatment in acute ST-elevation myocardial infarction: the REVEAL EPC substudy
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Erythropoietin (EPO) was hypothesized to mitigate reperfusion injury, in part via mobilization of endothelial progenitor cells (EPCs). The REVEAL trial found no reduction in infarct size with a single dose of EPO (60,000 U) in patients with ST-segment elevation myocardial infarction. In a substudy, we aimed to determine the feasibility of cryopreserving and centrally analyzing EPC levels to assess the relationship between EPC numbers, EPO administration, and infarct size. As a prespecified substudy, mononuclear cells were locally cryopreserved before as well as 24 and 48–72 h after primary percutaneous coronary intervention. EPC samples were collected in 163 of 222 enrolled patients. At least one sample was obtained from 125 patients, and all three time points were available in 83 patients. There were no significant differences in the absolute EPC numbers over time or between EPO- and placebo-treated patients; however, there was a trend toward a greater increase in EPC levels from 24 to 48–72 h postintervention in patients receiving ≥30,000 U of EPO (P = 0.099 for CD133+ cells, 0.049 for CD34+ cells, 0.099 for ALDHbr cells). EPC numbers at baseline were inversely related to infarct size (P = 0.03 for CD133+ cells, 0.006 for CD34+ cells). Local whole cell cryopreservation and central EPC analysis in the context of a multicenter randomized trial is feasible but challenging. High-dose (≥30,000 U) EPO may mobilize EPCs at 48–72 h, and baseline EPC levels may be inversely associated with infarct size.
KeywordsErythropoietin Endothelial progenitor cells Myocardial infarction Cryopreservation
The authors would like to thank Peter Hoffmann for thoughtful editorial and logistical support. The REVEAL study was supported by Intramural Research Program contract HHS-N-260-2005-00010-C from the National Institute on Aging, Bethesda, MD, USA. The first author was the recipient of a Duke Pepper Older Americans Independence Center Research Career Development Program in Aging Research Award (5P30AG028716), Durham, NC, USA.
Conflict of interest
Dr. Povsic has received grants from Baxter International, Regado Biosciences, and Theragen. Dr. Najjar has received research funding from HeartWare. Dr. Hasselblad has received salary support via Grants from Eli Lilly and Medicure Inc. administered through Duke University. Dr. Heitner reported that New York Methodist Hospital received compensation for his work as a principal investigator for a study; also, he has received compensation for his expert testimony in an individual malpractice case, Grant support from the Empire Clinical Research Investigator Program, and compensation for serving on a steering committee for a trial. Dr. Raman has received Grant support from the National Institutes of Health and from Siemens Corporation. Dr. Barsness has been a consultant for Hoffmann-La Roche, Inc. and Baxter Healthcare Corporation, and has received research funding from Gilead Sciences, Inc. Dr. Patel has served as a board member for Genzyme’s advisory board and Bayer Healthcare, and as a consultant for Ikaria. Dr. Kim was an inventor on a U.S. patent for Delayed Enhancement MRI, which is owned by Northwestern University. Dr. Harrington’s complete listing of disclosure information is available at https://www.dcri.org/about-us/conflict-of-interest/COI-Harrington_2012.pdf. Dr. Rao received research funding from Novartis, Cordis Corporation, and Ikaria; and was a consultant for Sanofi-Aventis, Bristol-Meyers Squibb, Astra- Zeneca, Daiichi Sankyo-Lilly, and Terumo USA. The other authors report no disclosures.
- 5.Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, Koster J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG (2007) Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 28:2018–2027PubMedCrossRefGoogle Scholar
- 7.Melloni C, Rao SV, Povsic TJ, Melton L, Kim RJ, Kilaru R, Patel MR, Talan M, Ferrucci L, Longo DL, Lakatta EG, Najjar SS, Harrington RA (2010) Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial. Am Heart J 160:795–803PubMedCrossRefGoogle Scholar
- 8.Najjar SS, Rao SV, Melloni C, Raman SV, Povsic TJ, Melton L, Barsness GW, Prather K, Heitner JF, Kilaru R, Gruberg L, Hasselblad V, Greenbaum AB, Patel M, Kim RJ, Talan M, Ferrucci L, Longo DL, Lakatta EG, Harrington RA (2011) Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA 305:1863–1872PubMedCrossRefGoogle Scholar
- 9.Gentry T, Foster S, Winstead L, Deibert E, Fiordalisi M, Balber A (2007) Simultaneous isolation of human BM hematopoietic, endothelial and mesenchymal progenitor cells by flow sorting based on aldehyde dehydrogenase activity: implications for cell therapy. Cytotherapy 9:259–274PubMedCrossRefGoogle Scholar
- 12.Olson W, Smolkin M, Farris E, Fink R, Czarkowski A, Fink J, Chianese-Bullock K, Slingluff C (2011) Shipping blood to a central laboratory in multicenter clinical trials: effect of ambient temperature on specimen temperature, and effects of temperature on mononuclear cell yield, viability and immunologic function. J Transl Med 9:26PubMedCrossRefGoogle Scholar
- 15.Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L (2005) Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 105:199–206PubMedCrossRefGoogle Scholar
- 16.Paczkowska E, Larysz B, Rzeuski R, Karbicka A, Jałowiński R, Kornacewicz-Jach Z, Ratajczak MZ, Machaliński B (2005) Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. Eur J Haematol 75:461–467PubMedCrossRefGoogle Scholar
- 17.Wang Y, Johnsen HE, Mortensen S, Bindslev L, Ripa RS, Haack-Sorensen M, Jorgensen E, Fang W, Kastrup J (2006) Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Heart 92:768–774PubMedCrossRefGoogle Scholar
- 18.Wojakowski W, Tendera M, Michalowska A, Majka M, Kucia M, Maslankiewicz K, Wyderka R, Ochala A, Ratajczak MZ (2004) Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 110:3213–3220PubMedCrossRefGoogle Scholar
- 20.Leone AM, Rutella S, Bonanno G, Abbate A, Rebuzzi AG, Giovannini S, Lombardi M, Galiuto L, Liuzzo G, Andreotti F, Lanza GA, Contemi AM, Leone G, Crea F (2005) Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function. Eur Heart J 26:1196–1204PubMedCrossRefGoogle Scholar