Comments for:

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response to Battaglia from Koch

Submitter: Walter Koch | walter.koch@jefferson.edu

Jefferson Medical College

Published October 15, 2003

Dear Dr. Battaglia,
You raise a very interesting hypothesis in your letter. In fact, we did find and report in our study that EPO stimulates the proliferation of H9c2 cardiomyoblasts. Therefore, it does appear that EPO can induce proliferative responses in fetal cardiomyocytes. Conversely, in a subsequent study, we have found that EPO does not stimulate proliferation of adult cardiac fibroblasts (unpublished data). Thus, the true proliferative effects of EPO on cardiac cells remain to be characterized. Moreover, in response to your comments, we did not specifically address whether EPO exerts any effects on differentiation of immature cardiac cells. In our study, we primarily addressed myocardial apoptosis as a mechanism for the cardioprotection afforded by exogenous EPO. Although it is possible that EPO stimulates the proliferation and differentiation of cardiac stem cells, we did not address this hypothesis in any of our current research. The data on the involvement of stem cells in cardiac repair after ischemia are exciting and perhaps there may be some role for EPO or other cytokines in this process. I do feel that the timeframes that we examined in our study (1-3 days after myocardial infarction) might be too early to detect proliferating and differentiating stem cells although this was the most opportune period to see high levels of apoptosis. Importantly, your hypothesis that EPO may mediate cardiac stem cell proliferation and differentiation akin to current reports document this effect in neural cells could be, and should be, addressed in future studies.
Sincerely, Walter J. Koch

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Tissue Protection by Erythropoietin- the More the Better?

Submitter: Ferdinand H. Bahlmann | bahlmann.ferdinand@mh-hannover.de

Division of Nephrology, Department of Internal Medicine; Hannover Medical School, Germany

Published October 15, 2003

Dear Sir,
The recently published experimental study by Parsa et al. in this Journal is another ring in the chain of evidence that the hematopoietic cytokine erythropoietin (EPO) has important cytoprotective effects such as protection from ischemic injury and inhibition of apoptotic death-related pathways in several cell lines including cardiomyocytes (1, 2). The authors have employed an elegant approach of preconditioning of myocardial tissue with a single shot of recombinant human EPO (rHuEPO) in a rabbit model of myocardial infarction, and could demonstrate direct protective effects of EPO with improved myocardial function in treated animals within 3 days after infarction (2). While the idea of cardioprotection using rHuEPO is fascinating, there are limitations for such a approach in humans, however. Parsa et al. have used a rHuEPO dose of 5,000 units/kg body weight corresponding to about 350,000 units in a 70 kg man: this is about an average cumulative 1.5 year dose in patients treated for renal anemia. Beside the enormous costs of such a treatment, pharmacological rHuEPO doses are likely to cause significant effects on hematocrit and blood flow properties, resulting in well known serious complications of EPO overdose such as vascular thrombosis and even excess mortality (3). Parsa et al. have argued that the beneficial effects of EPO seen within the first 3 days in their experimental setting were obtained without any increase in hematocrit, but the true is that they show a small increase in mean hematocrit level on day 3, and a significant rise of almost 20% (!) already on day 4 after the single rHuEPO shot (Figure 4; result section). The experiment ends here and the survival of animals remains unknown. Such an acute increase in hematocrit could certainly worsen the clinical situation in patients with myocardial ischemia resulting in deleterious outcome (3). Thus this approach must be taken with caution. In contrast, we have recently shown that even low dose rHuEPO treatment markedly stimulates regenerative endothelial progenitor cell recruitment in humans without affecting hematocrit (4). Moreover, chronic low dose therapy with the rHuEPO analogue darbepoetin confered vascular and tissue protection and improved survival of experimental animals in a classic remnant kidney model characterized by severe injury to the macro- and microvascular endothelium leading to progressive vascular sclerosis and finally terminal organ failure (data not published). These effects were mediated, a least in part, via direct stimulation of the pro-survival Akt pathway. Taken together, low dose therapy with rHuEPO or analogues could be a safer and uncomplicated therapeutic strategy for tissue and organ protection.
References
1.Parsa, C.J., Matsumoto, A., Kim, J., Riel, R.U., Pascal, L.S., Walton, G.B., Thompson, R.B., Petrofski, J.A., Annex, B.H., Stamler, J.S., et al. 2003. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112:999-1007.
2.Calvillo, L., Latini, R., Kajstura, J., Leri, A., Anversa, P., Ghezzi, P., Salio, M., Cerami, A., and Brines, M. 2003. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A.
3.Besarab, A., Bolton, W.K., Browne, J.K., Egrie, J.C., Nissenson, A.R., Okamoto, D.M., Schwab, S.J., and Goodkin, D.A. 1998. 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 339:584-590.
4.Bahlmann, F.H., deGroot, K., Spandau,J.-M., Landry,A.L., Hertel, B., Duckert, T., Boehm,S.M., Menne,J., Haller,H., Fliser D. online. Erythropoietin Regulates Endothelial Progenitor Cells. Blood (Online).

Ferdinand H. Bahlmann, M.D., & Danilo Fliser, M.D.
Division of Nephrology, Department of Internal Medicine
Hanover Medical Schools
Carl-Neuberg-Strasse 1
306235 Hanover, Germany
email: bahlmann.ferdinand@mh-hannover.de, fliser.danilo@mh-hannover.de
Fax:49 511 55 23 66 Phone:49 511 532 63 19

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Erythropoietin and cardiac stem cells

Submitter: Massimo Battaglia | mc8445@mclink.it

INeMM CNR, 00133 Rome, Italy

Published October 7, 2003

Parsa et al. (1) have demonstrated that erythropoietin (EPO) administration is associated with reduced infarct size and cardiomyocyte apoptosis, and that its cardioprotective effects are observed without an increase in hematocrit.
However, EPO has been shown to affect in vitro and in vivo the proliferation and differentiation of embryonic and adult neural stem cells (2). In addition, the existence of adult cardiac stem cells that are multipotent and support myocardial regeneration has recently been reported (3).
To what extent do Parsa et al. think that their results have also been the consequence of a direct effect of EPO on proliferation and differentiation of cardiac stem cells?
Massimo Battaglia INeMM CNR, 00133 Rome, Italy
1. Parsa, C.J. et al. 2003. A novel protective effect of erythropoietin in the infarcted heart. J. Clin. Invest. 112:999-1007.
2. Shingo, T. et al. 2001. Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J. Neurosci. 21:9733-9743.
3. Beltrami, A.P.et al. 2003. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763-776.