European Heart Journal Advance Access originally published online on July 3, 2006
European Heart Journal 2006 27(15):1767-1768; doi:10.1093/eurheartj/ehl128
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Epo ‘cytokine-doping’ of heart disease patients, will it work?
1 Cardiac Catheterisation Laboratory, The Heart Centre, University Hospital Rigshospitalet, Copenhagen, DK-2100, Denmark
2 Cardiac Stem Cell Research Laboratory, University Hospital Rigshospitalet, Copenhagen, Denmark
* Corresponding author. Tel: +45 35453693; fax: +45 35452705. E-mail address: erikj{at}rh.dk
This editorial refers to ‘Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy’
by S. Hamed et al., on page 1876
Erythropoietin (EPO) is a cytokine for erythrocyte precursors in the bone marrow, and the glycoprotein hormone that regulates red blood cell production. EPO is mainly produced in the kidney and production is induced by hypoxia/ischaemia. The main transcriptional factor is HIF-1, which is also induced by hypoxia/ischaemia in myocardial cells. EPO is also expressed in the heart. However, its expression may only be brief, it has in fact only been shown 24–48 h after permanent coronary artery occlusion in mice hearts.1
EPO was purified from urine for therapeutic use in the 1970s and recombinant EPO (rEPO) has been available since the 1980s as an effective treatment of anaemia, particularly in renal failure patients on dialysis. Although illegal, in international sports, rEPO and its analogues have been used by athletes to effectively increase red cell mass and oxygen transport for improved performance in contests depending on their aerobic potential.
In addition to being a main regulator of erythropoiesis, EPO has, in animal models, been shown to play a protective role against ischaemic injuries in the brain, spinal cord, and skeletal muscle. In addition, EPO seems to have a wide range of cardiovascular system-protective properties, including angiogenic and anti-apoptotic activities in vitro and in vivo, and the capability to increase myocyte proliferation in vitro. Recently, a functional EPO receptor has been identified both in endothelial cells and in ventricular myocytes of the heart.
These findings indicate a possible future role of EPO in the treatment of heart diseases. Animal studies in rodents suggest that EPO exerts a protective effect against infarction and ischaemia-reperfusion injury and also against doxorubicin-induced cardiomyopathy. The mechanisms by which EPO works in these animal models are far from understanding. In fact, a number of rather different agents/interventions including several antioxidants (e.g. Q10, melatonin, vitamin E, C-phycocyanin), thrombopoietin, the immunomodulatory alkaloid swainsonine, and endurance training) have had comparable significant cardioprotective properties in these models.
The results of Hamed et al. clearly show the effect of EPO on mobilized endothelial progenitor cells, suggesting that the protective effects of EPO against the doxorubicin-induced cardiomyopathy, might be exerted by preserving the proliferative, migratory, and adhesive capacity of the endothelial progenitor cells.2,3 In addition, EPO has reduced the doxorubicin-induced decline in heart function. However, it is interesting that there were no significant evidence of fibrosis or apoptosis in the heart in any of the animals with doxorubicin-induced cardiomyopathy whether or not they had been treated with EPO.
Results from larger animals are conflicting. In a porcine model, there was no effect of rEPO on ischaemia-reperfusion injury, whereas a small series of direct myocardial injection of rEPO in a circumflex ameroid constrictor model indicated some effect.4,5
In patients with a first MI, who underwent successful percutaneous coronary revascularization (PCI), high levels of plasma endogenous EPO have been found to be associated with smaller infarcts. In a recent phase-one single centre study of 20 patients with acute MI treated with PCI, an intravenous injection of the long-acting EPO analogue darbepoetin alfa (300 µg) was administered immediately before PCI in 10 of the patients.6 In the control group, serum EPO peaked after 72 h, whereas a prolonged increase was obtained in the treatment group. The authors report a FACS analysis showing an almost three-fold elevation in the numbers of CD34+/CD45– cells in the blood in the treatment group after 72 h. In our opinion, cell numbers in this kind of analyses are small and therefore results should be interpreted with extreme caution. Furthermore, there is a lack of consensus on how to characterize progenitor cells by surface markers. We believe that multipotent mesenchymal stem cells might be of greater relevance to cardiac repair and regeneration, and need to be studied.7
At this point it might be of relevance to recall previous years promising angiogenic and cardioprotective effects of treatment with cytokines as granulocyte-colony stimulating factor (G-CSF) and vascular endothelial growth factors, which have been shown in rodent animal models, and in small patient series. There has been a ‘disappointing’ lack of effect of these substances, when transferred into larger blinded placebo-controlled clinical trials.8–10 We recently performed placebo-controlled and blinded trials on the effects of subcutaneous injection of G-CSF in 78 patients with acute MI treated with PCI, and on the effects of direct myocardial injection of VEGF plasmid in 80 patients with chronic ischaemic heart disease, and have found no ‘convincing effects’ on cardiac magnetic resonance images or single proton emission computerized tomographies.
Why are results in the animal model often impossible to reproduce in clinical trials? There are understandable explanations to these discrepancies. The animals are phenotypically and genetically very similar, relatively young and of the same age and size, and they are exposed to specific and controlled interventions. Furthermore, treatment effects can be established by sacrificing the animals and use microscopic examination and so on. The animal model disease might not appropriately compare with the human expression of a certain disease, and the drug doses used might not be equipotent. In the clinical trials, patients are very different phenotypically and genetically, most often old, with additional and competing diseases. In addition, in the clinical trial, a new intervention is added ‘on top’ of a number of other potent well accepted treatments and/or drug regimens, which might dilute the effect of the new treatment. Properly sized patient materials, carefully blinded, and placebo-controlled study design might compensate, to some extent, for these problems.
Considering years of extensive experiences with rEPO in different clinical settings, it should be possible to clarify relatively soon the specific safety issues in heart disease patients, and to move forward and evaluate whether some of the impressive effects of EPO in the doxorubicin-induced cardiomyopathy, as shown by Hamed et al., could be ‘transferred’ from animals to the treatment of patients with heart disease.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehl044 
References
- Mengozzi M, Latini R, Salio M, Sfacteria A, Piedimonte G, Gerwien JG, Leist M, Siren AL, Ghezzi P, Chimenti S. (2006) Increased erythropoietin production after myocardial infarction in mice. Heart 92:838–839.
[Free Full Text] - Hamed S, Barshack I, Luboshits G, Wexler D, Deutsch V, Keren G, George J. (2006) Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy. Eur Heart J 27:1876–1883 First published on May 26, 2006, doi:10.1093/eurheartj/ehl044.
[Abstract/Free Full Text] - Li L, Takemura G, Li Y, Miysata S, Esaki M, Okada H, Kanamori H, Khai NC, Maruyama R, Ogino A, Minatougi S, Fujiwara T, Fujiwara H. (2006) Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation 113:535–543.
[Abstract/Free Full Text] - Kristensen J, Maeng M, Rehling M, Berg JS, Mortensen UM, Nielsen SS, Nielsen TT. (2005) Lack of acute cardioprotective effect from preischaemic erythropoietin administration in a porcine coronary occlusion model. Clin Phys Funct Imag 25:305–310.
- Krause KT, Jaquet K, Geide S, Schneider C, Mandel C, Stoll HP, Hertting K, Harle T, Kuck KH. Percutaneous endocardial injection of erythropoietin: assessment of cardioprotection by electromechanical mapping. Eur J Heart Fail Published online ahead of print February 4, 2006.
- Lip
ic E, van der Meer P, Voors AA, Westenbrink BD, van den Heuvel AFM, de Boer HC, van Zonneveld AJ, Schoemaker RG, van Gilst WH, Zijlstra F, van Veldhuise DJ. 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 Published online ahead of print April 22, 2006. - Wang Y, Johnsen HE, Mortensen S, Bindslev L, Jørgensen E, Kastrup J. (2006) Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with ST-elevation myocardial infarction treated with percutaneous coronary intervention. Heart 92:768–774.
[Abstract/Free Full Text] - Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349.
[Abstract/Free Full Text] - Ripa RS, Jørgensen E, Wang Y, Thune JJ, Nilsson JC, Søndergaard L, Johnsen HE, Køber L, Grande P, Kastrup J. (2006) Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction. Result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113:1983–1992.
[Abstract/Free Full Text] - Kastrup J, Jørgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, Botker HE, Dudek D, Drvota V, Hesse B, Thuesen L, Blomberg P, Gyongyosi M, Sylven C. (2005) the Euroinject One Group. Direct intramyocardial plasmid vascular endothelial growth factor-A(165) gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: The Euroinject One trial. J Am Coll Cardiol 45:982–988.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy
- Saher Hamed, Iris Barshack, Galia Luboshits, Dov Wexler, Varda Deutsch, Gad Keren, and Jacob George
EHJ 2006 27: 1876-1883.[Abstract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  M. Minetti, L. Agati, and W. Malorni The microenvironment can shift erythrocytes from a friendly to a harmful behavior: Pathogenetic implications for vascular diseases Cardiovasc Res, July 1, 2007; 75(1): 21 - 28. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||