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Cardiovascular Research Advance Access originally published online on June 26, 2008
Cardiovascular Research 2008 79(4):549-550; doi:10.1093/cvr/cvn176
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Erythropoietin in cardioprotection: does it have a future or is it all in the past?

Jawahar L. Mehta1,2,*

1 Division of Cardiovascular Medicine, Gene Therapy Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
2 Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA

* Corresponding author. Tel: +1 501 296 1401; fax: +1 501 686 6180. E-mail address: mehtajl{at}uams.edu

This editorial refers to ‘Post-infarct treatment with an erythropoietin–gelatin hydrogel drug delivery system for cardiac repair’ by H. Kobayashi et al.,1 pp. 611–620, this issue.


   1. Introduction
Top
 1. Introduction
2. Mechanisms of action...
 3. Limitations of and...
 References
 
Over the past two decades, we have seen a gradual reduction in mortality from myocardial infarction due in a large part to the advent of revascularization and other cardioprotective strategies. However, myocardial infarction is still the most common cause of morbidity, related primarily to the loss of left ventricular function and mortality. A host of novel strategies are being examined to limit myocardial infarct size. Towards that goal, several investigators have suggested that erythropoietin (EPO) therapy may hold a new promise. The article by Kobayashi et al. in the current issue of Cardiovascular Research describes a new drug delivery protocol for the use of EPO in the post-myocardial infarction setting.1


   2. Mechanisms of action of erythropoietin in myocardial infarction
Top
 1. Introduction
 2. Mechanisms of action...
3. Limitations of and...
 References
 
2.1 Preclinical studies
It is well known that EPO stimulates the plasma haemoglobin concentration in patients with cancers or renal disease. Receptors for EPO have been shown to be present on vascular smooth muscle cells, endothelial cells, and cardiomyocytes,2 and EPO appears to exert its effect on myocardial function by stimulating EPO receptors on cardiomyocytes.

Previous studies have shown that EPO administration reduces the myocardial infarct size after ischaemia.3,4 Gao et al.5 showed that treatment with a long-acting EPO preparation as late as 24 h after the onset of the ischaemic process provided a significant reduction in myocardial infarct size. Consistent with the limitation of infarct size, EPO therapy in this study improved cardiac reserve and decreased cardiomyocyte apoptosis. van der Meer et al.6 showed that treatment with EPO improved left ventricular function and induced neovascularization in a model of myocardial infarction in rats. This group7 also showed that delayed EPO therapy reduced post-infarct cardiac remodelling at a dose that mobilized endothelial progenitor cells.

Studies in EPO receptor knockout mice have confirmed the role of EPO receptors in cardioprotection.8 These EPO receptor knockout mice when subjected to a brief period of ischaemia–reperfusion showed a larger infarct size and reduced left ventricular function compared with wild-type mice with intact EPO receptor status.

Erythropoietin stimulates new vessel formation in the ischaemic heart.6,9 Myocardial angiogenesis is promoted by EPO via protection of endothelial progenitor cells in the bone marrow from apoptosis, a direct stimulatory effect on myocardial endothelial cells and enhancement of the activity of endothelial progenitor cells. Westenbrink et al.10 showed in an infarct model that EPO mobilized endothelial progenitor cells from the bone marrow to the ischaemic myocardium, where they were incorporated to form new blood vessels.

The clinical implications of these observations, i.e. a delayed window of opportunity, a decrease in apoptosis, an induction of neovascularization, and a reduction in collagen deposition in chronically ischaemic myocardium, are high. These attributes of EPO clearly relate to its role in cardioprotection.

There are, however, concerns that EPO may exert a cardioprotective effect only when large doses of EPO are administered.11 Further, the use of EPO is associated with polycythaemia, and, therefore, significant risk of thrombo-embolic complications.

2.2 Initial clinical studies
There are relatively few studies on the use of EPO in patients with myocardial infarction. Lipsic et al.12 performed a safety study on the effects of a single bolus of EPO (60 000 IU) in patients with acute myocardial infarction. The administration of EPO was not associated with untoward changes in blood pressure and plasma haemoglobin concentration, or any other adverse events, while serum EPO levels increased 200-fold. In keeping with the data in animals, endothelial progenitor cells increased in the EPO-treated patients. These authors have now designed a prospective, randomized, open-label trial with blinded endpoints to examine the effects of EPO in patients with myocardial infarction. These patients will be randomly assigned after a successful percutaneous coronary intervention (PCI) to receive either optimal standard medical care or a single bolus of EPO in addition to standard medical care. At 6 weeks after PCI with or without EPO therapy, a planar radionuclide ventriculography will be performed to determine the changes in left ventricular ejection fraction.13

2.3 The present study
Kobayashi et al.1 examined the effect of local delivery of EPO-containing delivery system (or just the drug-delivery system) applied to the surface of the infarcted area of the rabbit heart. They observed that infarct size was reduced and left ventricular remodelling improved in the EPO-treated animals. These changes were pronounced at 2 weeks to 2 months after myocardial infarction. Further, there was evidence of angiogenesis associated with relevant signals, such as VEGF and activated ERK, Akt, and Stat-3. There was also evidence of metalloproteinase expression and consequent reduction in fibrotic areas in the heart. These studies are important in that they demonstrate the beneficial effects of locally applied (on the infarcted area of he heart) EPO on infarct size and preservation of left ventricular function associated with improvement in cardiac remodelling process. This study also confirms that therapy with EPO can be initiated after the process of myocardial infarction has begun, and the beneficial effects of EPO may become evident during the recovery phase.


   3. Limitations of and concerns about therapy with erythropoiesis-stimulating agents
Top
 1. Introduction
 2. Mechanisms of action...
 3. Limitations of and...
References
 
There are major concerns about the use of erythropoiesis-stimulating agents in general. Several studies have shown rapid tumour growth or shortened survival of patients with breast, non-small cell lung, head and neck, lymphoid, or cervical cancers, who had received EPO compared with patients who did not. Erythropoiesis-stimulating agent administration is also associated with increased risks of venous thrombo-embolic phenomena and mortality.14 These concerns have recently been brought to the attention of healthcare providers, patients, and the Food and Drug Administration.15 Thus, caution is necessary when clinical trials with EPO in patients with myocardial infarction are conducted, and one must be vigilant for known and unknown side effects of this potential life-saving strategy.

The authors of the present study provide the valuable piece of information that systemic application of EPO is not required for cardioprotection after myocardial infarction. Nevertheless, local application of EPO as proposed here also has limitations in its clinical feasibility, as this delivery system would be applicable to relatively few patients. The authors claim that EPO patches might be used as adjunct therapy when coronary artery bypass grafting is applied. Further, they show that local application of EPO is devoid of systemic side effects. They also demonstrate that the improvement in cardiac remodelling is associated with expression of pro-survival and pro-angiogenic signals.


   Notes
 
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.


   References
Top
 1. Introduction
 2. Mechanisms of action...
 3. Limitations of and...
 References
 

  1. Kobayashi H, Minatoguchi S, Yasuda S, Bao N, Kawamura I, Yamaki T, et al. Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair. Cardiovasc Res (2008) 79:611–620.[Abstract/Free Full Text]
  2. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. J Am Med Assoc (2005) 293:90–95.[Abstract/Free Full Text]
  3. Lipsic E, Schoemaker RG, van der Meer P, Voors AA, van Veldhuisen DJ, van Gilst WH. Protective effects of erythropoietin in cardiac ischemia: from bench to bedside. J Am Coll Cardiol (2006) 48:2161–2167.[Abstract/Free Full Text]
  4. Bogoyevitch MA. An update on the cardiac effects of erythropoietin cardioprotection by erythropoietin and the lessons learnt from studies in neuroprotection. Cardiovasc Res (2004) 63:208–216.[Abstract/Free Full Text]
  5. 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–H68.[Abstract/Free Full Text]
  6. van der Meer P,, Lipsic E, Henning RH, Boddeus K, van der Velden J, Voors AA., 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.[Abstract/Free Full Text]
  7. Prunier F., Pfister O, Hadri L, Liang L, Del Monte F, Liao R, et al. Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells. Am J Physiol Heart Circ Physiol (2007) 292:H522–H529.[Abstract/Free Full Text]
  8. Tada H, Kagaya Y, Takeda M, Ohta J, Asaumi Y, Satoh K, et al. Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion. Cardiovasc Res (2006) 71:466–477.[Abstract/Free Full Text]
  9. Fujita M, Tambara K. Recent insights into human coronary collateral development. Heart (2004) 90:246–450.[Abstract/Free Full Text]
  10. Westenbrink BD, Lipsic E, van der Meer P, van der Harst P, Oeseburg H, Du Marchie Sarvaas GJ, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J (2007) 16:2018–2027.
  11. Riksen NP, Hausenloy DJ, Yellon DM. Erythropoietin: ready for prime-time cardioprotection. Trends Pharmacol Sci (2008) 29:258–267.[CrossRef][Medline]
  12. Lipsic E, van der Meer P, Voors AA, Westenbrink BD, van den Heuvel AF, de Boer HC, 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) 20:135–141.[CrossRef][Web of Science][Medline]
  13. Belonje AM, Voors AA, van Gilst WH, Anker SD, Slart RH, Tio RA, Zijlstra F, van Veldhuisen DJ, HEBE III investigators. Effects of erythropoietin after an acute myocardial infarction: rationale and study design of a prospective, randomized, clinical trial (HEBE III). Am Heart J (2008) 155:817–822.[CrossRef][Web of Science][Medline]
  14. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. J Am Med Assoc (2008) 299:914–924.[Abstract/Free Full Text]
  15. Mitka M. New limits advised for anemia drugs. J Am Med Assoc (2008) 299:2016.[Free Full Text]

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Post-infarct treatment with an erythropoietin–gelatin hydrogel drug delivery system for cardiac repair
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Cardiovasc Res 2008 79: 611-620. [Abstract] [Full Text] [PDF]




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