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What is the Role of Erythropoietin in Acute Myocardial Infarct? Bridging the Gap Between Experimental Models and Clinical Trials

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Abstract

Erythropoietin (EPO) is the main hormone that regulates erythropoiesis. Beyond its well-known hematopoietic action, EPO has diverse cellular effects in non-hematopoietic tissues. It has been shown to inhibit apoptosis by activating pro-survival pathways in the myocardium, to mobilize endothelial progenitor cells and to inhibit migration of inflammatory cells. EPO has also been shown to have potent pro-angiogenic properties. Numerous experimental data support the cardioprotective effects of EPO in animal models of acute myocardial infarct (AMI). However, these findings are not supported by recent clinical trials designed to investigate the safety and efficacy of EPO in patients with AMI. In this article, we begin by providing a comprehensive review of the cardioprotective effects of EPO in experimental animal models and the molecular mechanisms underlying these effects. We then discuss the EPO data obtained through clinical trials. We compare similarities and differences between the animal and human studies as well as between the different clinical studies in terms of sample size and study design including the dose, the route and the timing of administration as well as confounding factors such as comorbidities and concomitant treatments. Finally, we question the gap between the experimental and the translational clinical data and propose further developments to address these discrepancies and clearly evaluate the role of EPO in the clinical setting of MI.

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Abbreviations

AAR:

Area at risk

ACE:

Angiotensin-converting-enzyme inhibitor

AMI:

Acute myocardial infarction

ARBs:

Angiotensin II receptor blockers

CABG:

Coronary artery bypass graft

CAD:

Coronary artery disease

ESC:

European Society of Cardiology

EPO:

Erythropoietin

EPO-R:

EPO receptor

ERK:

Extracellular signal-regulated kinases

FGF:

Fibroblast growth factor

G-CSF:

Granulocyte colony-stimulating factor

Hb:

Hemoglobin

HGF:

Hepatocyte growth factor

HO:

Heme oxygenase

I:

Ischemia

IGF:

Insulin growth factor

IL:

Interleukin

IM:

Intramuscular

IP:

Intraperitonealy

IS:

Infarct size

IV:

Intravenous

LV:

Left ventricular

LVEF:

Left ventricular ejection fraction

MRI:

Magnetic resonance imaging

NHLBI:

National Heart, Lung, and Blood Institute

PI3K:

Phosphatidylinositol 3-kinase

PCI:

Primary percutaneous coronary intervention

PostC:

Postconditioning

R:

Reperfusion

STEMI:

ST-elevation myocardial infarction

TIMI:

Thrombolysis in myocardial infarction

TNFα:

Tumour necrosis factor-α

VEGF:

Vascular endothelial growth factor

References

  1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110:e82–292.

    Article  PubMed  Google Scholar 

  2. WHO. WHO fact sheet N°310, updated June 2011; 2011.

  3. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–35.

    Article  PubMed  CAS  Google Scholar 

  4. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473–81.

    Article  PubMed  CAS  Google Scholar 

  5. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation. 2005;112:2143–8.

    Article  PubMed  Google Scholar 

  6. Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation. 2008;117:1037–44.

    Article  PubMed  CAS  Google Scholar 

  7. Thuny F, Lairez O, Roubille F, et al. Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:2175–81.

    Article  PubMed  Google Scholar 

  8. Jelkmann W. Biology of erythropoietin. Clin Invest. 1994;72(6 Suppl):S3–10.

    CAS  Google Scholar 

  9. Wu XM, Qian ZM, Zhu L, et al. Neuroprotective effect of ligustilide against ischaemia-reperfusion injury via up-regulation of erythropoietin and down-regulation of RTP801. Brit J Pharmacol. 2011;164:332–43.

    Article  CAS  Google Scholar 

  10. Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001;98:4044–9.

    Article  PubMed  CAS  Google Scholar 

  11. Ruscher K, Freyer D, Karsch M, et al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci. 2002;22:10291–301.

    PubMed  CAS  Google Scholar 

  12. Chong ZZ, Kang JQ, Maiese K. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Brit J Pharmacol. 2003;138:1107–18.

    Article  CAS  Google Scholar 

  13. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101:14907–12.

    Article  PubMed  CAS  Google Scholar 

  14. Grimm C, Wenzel A, Groszer M, et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med. 2002;8:718–24.

    Article  PubMed  CAS  Google Scholar 

  15. Junk AK, Mammis A, Savitz SI, et al. Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2002;99:10659–64.

    Article  PubMed  CAS  Google Scholar 

  16. Chong ZZ, Kang JQ, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation. 2002;106:2973–9.

    Article  PubMed  CAS  Google Scholar 

  17. Hamano Y, Aoki T, Shirai R, et al. Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection. Nephron Exp Nephrol. 2010;114:e69–81.

    Article  PubMed  CAS  Google Scholar 

  18. Patel NS, Sharples EJ, Cuzzocrea S, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int. 2004;66:983–9.

    Article  PubMed  CAS  Google Scholar 

  19. Knudtzon S, Mortensen BT. Growth stimulation of human bone marrow cells in agar culture by vascular cells. Blood. 1975;46:937–43.

    PubMed  CAS  Google Scholar 

  20. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M. Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A. 1990;87:5978–82.

    Article  PubMed  CAS  Google Scholar 

  21. Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.

    Article  PubMed  CAS  Google Scholar 

  22. 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;28:2018–27.

    Article  PubMed  CAS  Google Scholar 

  23. Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105:10925–30.

    Article  PubMed  CAS  Google Scholar 

  24. Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999;126:3597–605.

    PubMed  CAS  Google Scholar 

  25. Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003;100:4802–6.

    Article  PubMed  CAS  Google Scholar 

  26. Parsa CJ, Matsumoto A, Kim J, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest. 2003;112:999–1007.

    PubMed  CAS  Google Scholar 

  27. Wright GL, Hanlon P, Amin K, Steenbergen C, Murphy E, Arcasoy MO. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB. 2004;18:1031–3.

    CAS  Google Scholar 

  28. Gao E, Boucher M, Chuprun JK, Zhou RH, Eckhart AD, Koch WJ. Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart. Am J Physiol Heart Circ Physiol. 2007;293:H60–8.

    Article  PubMed  CAS  Google Scholar 

  29. Toma C, Letts DP, Tanabe M, Gorcsan 3rd J, Counihan PJ. Positive effect of darbepoetin on peri-infarction remodeling in a porcine model of myocardial ischemia-reperfusion. J Mol Cell Cardiol. 2007;43:130–6.

    Article  PubMed  CAS  Google Scholar 

  30. Namiuchi S, Kagaya Y, Ohta J, et al. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol. 2005;45:1406–12.

    Article  PubMed  CAS  Google Scholar 

  31. Ueda K, Takano H, Niitsuma Y, et al. Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice. J Clin Invest. 2010;120:2016–29.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang D, Zhang F, Zhang Y, et al. Erythropoietin enhances the angiogenic potency of autologous bone marrow stromal cells in a rat model of myocardial infarction. Cardiology. 2007;108:228–36.

    Article  PubMed  CAS  Google Scholar 

  33. Kawachi K, Iso Y, Sato T, et al. Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Hear Vessel. 2012;27:79–88.

    Article  Google Scholar 

  34. Rathod DB, Salahudeen AK. Nonerythropoietic properties of erythropoietin: implication for tissue protection. J Investig Med. 2011;59:1083–5.

    PubMed  CAS  Google Scholar 

  35. Chateauvieux S, Grigorakaki C, Morceau F, Dicato M, Diederich M. Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol. 2011;82:1291–303.

    Article  PubMed  CAS  Google Scholar 

  36. Hand CC, Brines M. Promises and pitfalls in erythopoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J Investig Med. 2011;59:1073–82.

    PubMed  CAS  Google Scholar 

  37. Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Int Med. 2008;264:405–32.

    Article  CAS  Google Scholar 

  38. Joyeux-Faure M. Cellular protection by erythropoietin: new therapeutic implications? J Pharmacol Exp Ther. 2007;323:759–62.

    Article  PubMed  CAS  Google Scholar 

  39. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005;293:90–5.

    Article  PubMed  CAS  Google Scholar 

  40. Kagaya Y, Asaumi Y, Wang W, et al. Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target. Tohoku J Exp Med. 2012;227:83–91.

    Article  PubMed  CAS  Google Scholar 

  41. Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108:79–85.

    Article  PubMed  CAS  Google Scholar 

  42. 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 U S A. 2003;100:11612–7.

    Article  PubMed  CAS  Google Scholar 

  43. Tramontano AF, Muniyappa R, Black AD, et al. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun. 2003;308:990–4.

    Article  PubMed  CAS  Google Scholar 

  44. Cai Z, Semenza GL. Phosphatidylinositol-3-kinase signaling is required for erythropoietin-mediated acute protection against myocardial ischemia/reperfusion injury. Circulation. 2004;109:2050–3.

    Article  PubMed  CAS  Google Scholar 

  45. Schlecht-Bauer D, Antier D, Machet MC, Hyvelin JM. Short- and long-term cardioprotective effect of darbepoetin-alpha: role of Bcl-2 family proteins. J Cardiovasc Pharmacol. 2009;54:223–31.

    Article  PubMed  CAS  Google Scholar 

  46. Xu B, Dong GH, Liu H, Wang YQ, Wu HW, Jing H. Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock Protein 70 and attenuation of nuclear factor-kappaB. Ann Clin Lab Sci. 2005;35:161–8.

    PubMed  CAS  Google Scholar 

  47. Joyeux-Faure M, Ramond A, Beguin PC, Belaidi E, Godin-Ribuot D, Ribuot C. Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart. Fundam Clin Pharmacol. 2006;20:51–6.

    Article  PubMed  CAS  Google Scholar 

  48. Burger D, Lei M, Geoghegan-Morphet N, Lu X, Xenocostas A, Feng Q. Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovasc Res. 2006;72:51–9.

    Article  PubMed  CAS  Google Scholar 

  49. Burger D, Xiang F, Hammoud L, Lu X, Feng Q. Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2009;296:H84–93.

    Article  PubMed  CAS  Google Scholar 

  50. Mihov D, Bogdanov N, Grenacher B, Gassmann M, Zund G, Bogdanova A, et al. Erythropoietin protects from reperfusion-induced myocardial injury by enhancing coronary endothelial nitric oxide production. Eur J Cardiothorac Surg. 2009;35:839–46.

    Article  PubMed  Google Scholar 

  51. Roubille C, Martel-Pelletier J, Haraoui B, Tardif J-C, Pelletier J-P. Biologics and cardiovascular system: a double edged sword. Antiinflamm Antiallergy Agents Med Chem. 2013;12:68–82.

    PubMed  CAS  Google Scholar 

  52. Brines M. The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors. Blood Purif. 2010;29:86–92.

    Article  PubMed  CAS  Google Scholar 

  53. Fiordaliso F, Chimenti S, Staszewsky L, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2005;102:2046–51.

    Article  PubMed  CAS  Google Scholar 

  54. Rui T, Feng Q, Lei M, et al. Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1. Cardiovasc Res. 2005;65:719–27.

    Article  PubMed  CAS  Google Scholar 

  55. Tada H, Kagaya Y, Takeda M, et al. Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion. Cardiovasc Res. 2006;71:466–77.

    Article  PubMed  CAS  Google Scholar 

  56. Asaumi Y, Kagaya Y, Takeda M, et al. Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice. Circulation. 2007;115:2022–32.

    Article  PubMed  CAS  Google Scholar 

  57. Burger DE, Xiang FL, Hammoud L, Jones DL, Feng Q. Erythropoietin protects the heart from ventricular arrhythmia during ischemia and reperfusion via neuronal nitric-oxide synthase. J Pharmacol Exp Ther. 2009;329:900–7.

    Article  PubMed  CAS  Google Scholar 

  58. van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur J Heart Fail. 2004;6:853–9.

    PubMed  Google Scholar 

  59. Bullard AJ, Govewalla P, Yellon DM. Erythropoietin protects the myocardium against reperfusion injury in vitro and in vivo. Basic Res Cardiol. 2005;100:397–403.

    Article  PubMed  CAS  Google Scholar 

  60. Diwan V, Kant R, Jaggi AS, Singh N, Singh D. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem. 2008;315:195–201.

    Article  PubMed  CAS  Google Scholar 

  61. Parsa CJ, Kim J, Riel RU, et al. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac fibroblasts. J Biol Chem. 2004;279:20655–62.

    Article  PubMed  CAS  Google Scholar 

  62. Rafiee P, Shi Y, Su J, Pritchard Jr KA, Tweddell JS, Baker JE. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic Res Cardiol. 2005;100:187–97.

    Article  PubMed  CAS  Google Scholar 

  63. Kobayashi H, Miura T, Ishida H, et al. Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion. Clin Exp Pharmacol Physiol. 2008;35:812–9.

    Article  PubMed  CAS  Google Scholar 

  64. Olea FD, Vera Janavel G, De Lorenzi A, et al. High-dose erythropoietin has no long-term protective effects in sheep with reperfused myocardial infarction. J Cardiovasc Pharmacol. 2006;47:736–41.

    Article  PubMed  CAS  Google Scholar 

  65. Kristensen J, Maeng M, Rehling M, et al. Lack of acute cardioprotective effect from preischaemic erythropoietin administration in a porcine coronary occlusion model. Clin Physiol Funct Imaging. 2005;25:305–10.

    Article  PubMed  CAS  Google Scholar 

  66. Vilarinho KA, de Oliveira PP, Saad MJ, et al. Erythropoietin protects the systolic function of neonatal hearts against ischaemia/reperfusion injury. Eur J Cardiothorac Surg. 2013;43:156–62.

    Article  PubMed  Google Scholar 

  67. Voors AA, Belonje AM, Zijlstra F, et al. A single dose of erythropoietin in ST-elevation myocardial infarction. Eur Heart J. 2010;31:2593–600.

    Article  PubMed  CAS  Google Scholar 

  68. Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305:1863–72.

    Article  PubMed  CAS  Google Scholar 

  69. Taniguchi N, Nakamura T, Sawada T, et al. Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study. Circ J. 2010;74:2365–71.

    Article  PubMed  Google Scholar 

  70. Ozawa T, Toba K, Suzuki H, et al. Single-dose intravenous administration of recombinant human erythropoietin is a promising treatment for patients with acute myocardial infarction - randomized controlled pilot trial of EPO/AMI-1 study. Circ J. 2010;74:1415–23.

    Article  PubMed  CAS  Google Scholar 

  71. Ferrario M, Arbustini E, Massa M, et al. High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol. 2011;147:124–31.

    Article  PubMed  Google Scholar 

  72. Ludman AJ, Yellon DM, Hasleton J, et al. Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart. 2011;97:1560–5.

    Article  PubMed  CAS  Google Scholar 

  73. Prunier F, Biere L, Gilard M, et al. Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation myocardial infarction: results of the erythropoietin in myocardial infarction trial. Am Heart J. 2012;163:200–7.

    Article  PubMed  CAS  Google Scholar 

  74. Thibault H, Piot C, Ovize M. Postconditioning in man. Heart Fail Rev. 2007;12:245–8.

    Article  PubMed  CAS  Google Scholar 

  75. Morel O, Perret T, Delarche N, et al. Pharmacological approaches to reperfusion therapy. Cardiovasc Res. 2012;94:246–52.

    Article  PubMed  CAS  Google Scholar 

  76. Sack MN, Murphy E. The role of comorbidities in cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16:267–72.

    Article  PubMed  CAS  Google Scholar 

  77. Penna C, Tullio F, Moro F, Folino A, Merlino A, Pagliaro P. Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats. Basic Res Cardiol. 2010;105:181–92.

    Article  PubMed  Google Scholar 

  78. Przyklenk K. Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts: the co-morbidity conundrum. Drug Aging. 2011;28:331–43.

    Article  Google Scholar 

  79. Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J Surg Res. 2008;145:287–94.

    Article  PubMed  CAS  Google Scholar 

  80. Xu YC, Xue FS, Liao X, et al. Combined morphine and limb remote ischaemia postconditioning may produce an enhanced cardioprotection. Med Hypotheses. 2009;73:302–5.

    Article  PubMed  CAS  Google Scholar 

  81. Iliodromitis EK, Andreadou I, Prokovas E, Zoga A, Farmakis D, Fotopoulou T, et al. Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation. Basic Res Cardiol. 2010;105:193–203.

    Article  PubMed  CAS  Google Scholar 

  82. Kocsis GF, Pipis J, Fekete V, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Am J Physiol Heart Circ Physiol. 2008;294:H2406–9.

    Article  PubMed  CAS  Google Scholar 

  83. Messadi-Laribi E, Griol-Charhbili V, Gaies E, et al. Cardioprotection and kallikrein-kinin system in acute myocardial ischaemia in mice. Clin Exp Pharmacol Physiol. 2008;35:489–93.

    Article  PubMed  CAS  Google Scholar 

  84. Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2011;106:925–52.

    Article  PubMed  CAS  Google Scholar 

  85. Roubille F, Lairez O, Mewton N, et al. Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol. 2012;107:275.

    Article  PubMed  Google Scholar 

  86. Roubille F, Tardif JC. Cardioprotection - time to take into account clinical complexity: the case of antiplatelet agents. Cardiovasc Drugs Ther. 2013;27:105–7.

    Article  PubMed  Google Scholar 

  87. Baker JE, Kozik D, Hsu AK, Fu X, Tweddell JS, Gross GJ. Darbepoetin alfa protects the rat heart against infarction: dose–response, phase of action, and mechanisms. J Cardiovasc Pharmacol. 2007;49:337–45.

    Article  PubMed  CAS  Google Scholar 

  88. Suh JW, Chung WY, Kim YS, et al. The effect of intravenous administration of erythropoietin on the infarct size in primary percutaneous coronary intervention. Int J Cardiol. 2011;149:216–20.

    Article  PubMed  Google Scholar 

  89. Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004;62:74–85.

    Article  PubMed  CAS  Google Scholar 

  90. Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2007;293:H1654–61.

    Article  PubMed  CAS  Google Scholar 

  91. Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M. Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation. 2008;117:2761–8.

    Article  PubMed  CAS  Google Scholar 

  92. Talan MI, Ahmet I, Lakatta EG. Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window? PLoS One. 2012;7:e34819.

    Article  PubMed  CAS  Google Scholar 

  93. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005;111:194–7.

    Article  PubMed  CAS  Google Scholar 

  94. Fujita M, Asanuma H, Hirata A, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. Am J Physiol Heart Circ Physiol. 2007;292:H2004–8.

    Article  PubMed  CAS  Google Scholar 

  95. Roubille F, Franck-Miclo A, Covinhes A, et al. Delayed postconditioning in the mouse heart in vivo. Circulation. 2011;124:1330–6.

    Article  PubMed  Google Scholar 

  96. Adams JA, Bassuk JA, Arias J, et al. Acute effects of “delayed postconditioning” with periodic acceleration after asphyxia induced shock in pigs. Pediatr Res. 2008;64:533–7.

    Article  PubMed  Google Scholar 

  97. Ren C, Gao X, Niu G, Yan Z, Chen X, Zhao H. Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS One. 2008;3:e3851.

    Article  PubMed  CAS  Google Scholar 

  98. Leconte C, Tixier E, Freret T, et al. Delayed hypoxic postconditioning protects against cerebral ischemia in the mouse. Stroke. 2009;40:3349–55.

    Article  PubMed  Google Scholar 

  99. Lipsic E, van der Meer P, Henning RH, et al. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol. 2004;44:473–9.

    Article  PubMed  CAS  Google Scholar 

  100. Moon C, Krawczyk M, Paik D, Lakatta EG, Talan MI. Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: dose response and therapeutic window. Cardiovasc Drugs Ther. 2005;19:243–50.

    Article  PubMed  CAS  Google Scholar 

  101. Basalay M, Barsukevich V, Mastitskaya S, et al. Remote ischaemic pre- and delayed postconditioning - similar degree of cardioprotection but distinct mechanisms. Exp Physiol. 2012;97:908–17.

    Article  PubMed  CAS  Google Scholar 

  102. Lipsic E, van der Meer P, Voors AA, et al. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study. Cardiovasc Drugs Ther. 2006;20:135–41.

    Article  PubMed  CAS  Google Scholar 

  103. 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;3:408–13.

    Article  PubMed  CAS  Google Scholar 

  104. Roubille F, Micheau A, Combes S, Piot C. Intracoronary administration of darbepoetin-alpha at onset of reperfusion in acute myocardial infarction: results of the randomized Intra-Co-EpoMI Trial. Arch Cardiovasc Dis. 2013;106:135–45.

    Article  PubMed  Google Scholar 

  105. Kanellakis P, Pomilio G, Agrotis A, Gao X, Du XJ, Curtis D, et al. Darbepoetin-mediated cardioprotection after myocardial infarction involves multiple mechanisms independent of erythropoietin receptor-common beta-chain heteroreceptor. Brit J Pharmacol. 2010;160:2085–96.

    Article  CAS  Google Scholar 

  106. Mueller C, Wodack K, Twelker K, Werner N, Custodis F, Nickenig G. Darbepoetin improves endothelial function and increases circulating endothelial progenitor cell number in patients with coronary artery disease. Heart. 2011;97:1474–8.

    Article  PubMed  CAS  Google Scholar 

  107. Tilling L, Hunt J, Donald A, Clapp B, Chowienczyk P. Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion. Clin Sci. 2012;122:329–36.

    Article  PubMed  CAS  Google Scholar 

  108. Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents (ESA). Clin J Am Soc Nephrol. 2009;4:470–80.

    Article  PubMed  CAS  Google Scholar 

  109. Vaziri ND. Thrombocytosis in EPO-treated dialysis patients may be mediated by EPO rather than iron deficiency. Am J Kidney Dis. 2009;53:733–6.

    Article  PubMed  Google Scholar 

  110. Peterson TE, Katusic ZS. EPO tecting the endothelium. Brit J Pharmacol. 2007;150:823–5.

    Article  CAS  Google Scholar 

  111. Tilling L, Clapp B. Erythropoietin: a future therapy for failing hearts? Heart Fail Rev. 2012;17:475–83.

    Article  PubMed  CAS  Google Scholar 

  112. Elmahdy H, El-Mashad AR, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010;125:e1135–42.

    Article  PubMed  Google Scholar 

  113. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.

    PubMed  CAS  Google Scholar 

  114. Wustenberg T, Begemann M, Bartels C, et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry. 2011;16:26–36.

    Article  PubMed  CAS  Google Scholar 

  115. Talving P, Lustenberger T, Kobayashi L, et al. Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: a matched case control study. Ann Surg. 2010;251:1–4.

    Article  PubMed  Google Scholar 

  116. Fujiwara N, Nakamura T, Sato E, et al. Renovascular protective effects of erythropoietin in patients with chronic kidney disease. Intern Med. 2011;50:1929–34.

    Article  PubMed  CAS  Google Scholar 

  117. Sorg H, Harder Y, Krueger C, Reimers K, Vogt PM. The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use. Med Res Rev. 2013;33:637–64.

    Article  PubMed  CAS  Google Scholar 

  118. Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647–56.

    Article  PubMed  CAS  Google Scholar 

  119. Robertson CS, Cherian L, Shah M, et al. Neuroprotection with an erythropoietin mimetic peptide (pHBSP) in a model of mild traumatic brain injury complicated by hemorrhagic shock. J Neurotrauma. 2012;29:1156–66.

    Article  PubMed  Google Scholar 

  120. Pankratova S, Kiryushko D, Sonn K, et al. Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor. Brain. 2010;133:2281–94.

    Article  PubMed  Google Scholar 

  121. Dumont F, Bischoff P. Non-erythropoietic tissue-protective peptides derived from erythropoietin: WO2009094172. Expert Opin Ther Pat. 2010;20:715–23.

    Article  PubMed  CAS  Google Scholar 

  122. Li J, Xu H, Gao Q, Wen Y. Effect of erythropoiesis-stimulating agents in acute ST-segment elevation myocardial infarction: a systematic review. Eur J Clin Pharmacol. 2012;68:469–77.

    Article  PubMed  CAS  Google Scholar 

  123. Badalzadeh R, Mohammadi M, Najafi M, Ahmadiasl N, Farajnia S, Ebrahimi H. The additive effects of ischemic postconditioning and cyclosporine-A on nitric oxide activity and functions of diabetic myocardium injured by ischemia/reperfusion. J Cardiovasc Pharmacol Ther. 2012;17:181–9.

    Article  PubMed  CAS  Google Scholar 

  124. Boucher M, Pesant S, Lei YH, et al. Simultaneous administration of insulin-like growth factor-1 and darbepoetin alfa protects the rat myocardium against myocardial infarction and enhances angiogenesis. Clin Transl Sci. 2008;1:13–20.

    Article  PubMed  CAS  Google Scholar 

  125. Hausenloy DJ, Baxter G, Bell R, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol. 2010;105:677–86.

    Article  PubMed  Google Scholar 

  126. Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, Kuck KH. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res. 2002;64:326–33.

    Article  PubMed  CAS  Google Scholar 

  127. Schneider MD. EPO and super-EPO: erythropoietins direct neoangiogenesis by cardiac progenitor cells. Cell Stem Cell. 2011;9:95–6.

    Article  PubMed  CAS  Google Scholar 

  128. Treguer F, Donal E, Tamareille S, et al. Speckle tracking imaging improves in vivo assessment of EPO-induced myocardial salvage early after ischemia-reperfusion in rats. Am J Physiol Heart Circ Physiol. 2010;298:H1679–86.

    Article  PubMed  CAS  Google Scholar 

  129. Heinisch BB, Vcelar B, Kapiotis S, et al. The effect of erythropoietin on platelet and endothelial activation markers: a prospective trial in healthy volunteers. Platelets. 2012;23:352–8.

    Article  PubMed  CAS  Google Scholar 

  130. Fuste B, Serradell M, Escolar G, et al. Erythropoietin triggers a signaling pathway in endothelial cells and increases the thrombogenicity of their extracellular matrices in vitro. Thromb Haemost. 2002;88:678–85.

    PubMed  Google Scholar 

  131. Stohlawetz PJ, Dzirlo L, Hergovich N, et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood. 2000;95:2983–9.

    PubMed  CAS  Google Scholar 

  132. Luft FC. Erythropoietin and arterial hypertension. Clin Nephrol. 2000;53 Suppl 1:S61–4.

    PubMed  CAS  Google Scholar 

  133. Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis. 1999;33:821–8.

    Article  PubMed  CAS  Google Scholar 

  134. Teng R, Calvert JW, Sibmooh N, et al. Acute erythropoietin cardioprotection is mediated by endothelial response. Basic Res Cardiol. 2011;106:343–54.

    Article  PubMed  CAS  Google Scholar 

  135. Liu X, Xie W, Liu P, Duan M, Jia Z, Li W, et al. Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion. Life Sci. 2006;78:2255–64.

    Article  PubMed  CAS  Google Scholar 

  136. Hotta H, Miura T, Miki T, et al. Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts. Circ Res. 2010;106:129–32.

    Article  PubMed  CAS  Google Scholar 

  137. Tamareille S, Ghaboura N, Treguer F, et al. Myocardial reperfusion injury management: erythropoietin compared with postconditioning. Am J Physiol Heart Circ Physiol. 2009;297:H2035–43.

    Article  PubMed  CAS  Google Scholar 

  138. Shen Y, Wang Y, Li D, et al. Recombinant human erythropoietin pretreatment attenuates heart ischemia-reperfusion injury in rats by suppressing the systemic inflammatory response. Transplant Proc. 2010;42:1595–7.

    Article  PubMed  CAS  Google Scholar 

  139. Hirata A, Minamino T, Asanuma H, et al. Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts. Cardiovasc Drugs Ther. 2005;19:33–40.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Fédération Française de Cardiologie (FR). The authors apologize to the authors whose works couldn’t be quoted because of space limitations.

Conflicts of Interest

Dr Roubille has no conflict of interest related to this study. Dr Prunier has received a grant form Amgen for a previous work (Prunier Am J Physiol 2007). Dr Tardif’s laboratory has received research grants from Roche.

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Authors and Affiliations

  1. Montreal Heart Institute, Université de Montréal, Montreal, Canada

    François Roubille

  2. Cardiology Department, University Hospital of Montpellier, Montpellier, France

    François Roubille, Florence Leclercq & Christophe Piot

  3. Inserm, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, INSERM, U661, Universités de Montpellier 1 and 2, Montpellier, France

    François Roubille, Stéphanie Barrère-Lemaire & Christophe Piot

  4. Laboratoire Cardioprotection, Remodelage et Thrombose, Université d’Angers, Angers, France

    Fabrice Prunier

  5. Service de Cardiologie, Centre Hospitalier Universitaire Angers, Angers, France

    Fabrice Prunier

  6. Montreal Heart Institute, Montreal, Quebec, Canada

    Ekaterini A. Kritikou, Eric Rhéaume, David Busseuil & Jean-Claude Tardif

  7. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Eric Rhéaume & Jean-Claude Tardif

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Roubille, F., Prunier, F., Barrère-Lemaire, S. et al. What is the Role of Erythropoietin in Acute Myocardial Infarct? Bridging the Gap Between Experimental Models and Clinical Trials. Cardiovasc Drugs Ther 27, 315–331 (2013). https://doi.org/10.1007/s10557-013-6461-1

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