The Cardiovascular Protective Effects of Erythropoietin Stimulating Agents

¹Department of Health Sciences’s Investigation. Sanatorio Metropolitano. Fernando de la Mora. Paraguay. ²Division of Cardiovascular Medicine. Clinical Hospital.Asunción National University. San Lorenzo, Paraguay.

Corresponding Author: Osmar Antonio Centurión, Professor of Medicine. Asuncion National University.Department of Health Sciences’s Investigation. Sanatorio Metropolitano. Teniente Ettiene 215 c/ Ruta Mariscal Estigarribia. Fernando de la Mora, Paraguay, Tel: 595 21 585 540; E-Mail: [email protected]

Received Date: 13 Jul 2017   Accepted Date: 13 Jul 2017    Published Date: 17 Jul 2017  Copyright © 2017 Centurión OA

Citation: Centurión OA and Juan DC. (2017). The Cardiovascular Protective Effects of Erythropoietin Stimulating Agents. Mathews J Cardiol. 2(2): e002.

EDITORIAL

Erythropoietin (EPO) is a member of the class I family of cytokines with a strong ability to stimulate erythropoiesis. The endogenous EPO is mainly synthesized and secreted by the kidney, and the recombinant EPO is utilized in patients suffering from different kinds of anemia [1-3]. EPO influences erythropoiesis by binding to its specific receptor which is expressed on the surface of immature erythroblasts [4]. However, several studies have demonstrated that EPO and EPO receptors are not only expressed in erythroblasts but also in a number of cell types including those within the cardiovascular and nervous system, suggesting that the effects of EPO extend beyond regulation of erythropoiesis. There are different kinds of EPO, namely, epoetin alfa, epoetin beta, and epoetin gamma, which are analogues of recombinant human EPO (rhEPO) derived from a cloned human erythropoietin gene. All of them have the same 165 amino acid sequence with a molecular weight of 30,400 daltons and have the same pharmacological actions as native EPO [1]. The normal serum concentrations of EPO for individuals with normal hematocrit range from 4-27 mU/mL. However, in certain conditions of anemia and hypoxia, EPO levels can be increased 100-1000 times the normal serum EPO concentration [1]. Moreover, the subcutaneous administration of a single 600 U/ kg dose of epoetin alfa to healthy volunteers produced a peak serum concentration of over 1000 mU/mL after 24 hours [5]. A second generation drug, namely, darbepoetin has a threefold longer circulating half-life than rhEPO. It was shown that darbepoetin alfa is 3.6-fold more potent than rhEPO in increasing the hematocrit when each is administered thrice weekly, but when the administration frequency is reduced to once weekly, darbepoetin alfa is approximately 13-fold higher in vivo potency than rhEPO [6, 7]. A third-generation EPO-related molecule called continuous EPO receptor activator (CERA) has been manufac tured. The elimination half-life of CERA in humans is considerably increased to about 130 hours maintaining a stable control of hemoglobin levels with a monthly interval dose [8-10]. The tissue protective effects of EPO, beyond the hematopoietic system, is mediated by activation of homodimeric EPO receptor, but is also believed to be mediated by its actions on the heterotrimeric complex consisting of EPO receptor and the e β-common receptor [8]. Nitric oxide (NO) is a potent vasodilator formed in endothelial cells, and plays a key role in control of the cardiovascular system. It was shown that EPO can exert non-erythropoietic effects in vascular endothelium and is increasingly regarded as a potent tissue protective cytokine. Several studies demonstrated that EPO decreases tissue damage by inhibition of apoptosis and reduction of inflammatory cytokines [11-14]. In-vitro treatment with low dose of rhEPO increased endothelial nitric oxide synthase (eNOS) protein expression in cultured endothelial cells [15-17]. On the other hand, incubation of human coronary artery endothelial cells with high dose of rhEPO for 24 hours inhibited eNOS expression and NO production suggesting that high dose of EPO may have detrimental effects on endothelial function [18, 19]. EPO has a vast variety of cardiovascular effects. It exerts its effects on cardiac as well as the vascular tissues since EPO receptors are expressed in cardiomyocytes, vascular endothelial cells and smooth muscle cells [20-22]. The clinical dosage required to observe EPO-induced tissue protection is much higher than that required for hematopoietic effects [20-22]. There is robust experimental evidence of beneficial effects with the use of EPO in the cardiovascular system. However, all the plausible mechanisms should be tested in clinical situations to properly evaluate clinical outcomes. There are some adverse events data described in clinical trials in patients with heart failure, kidney disease, myocardial infarction, and stroke [23-26]. The adverse side effects associated with EPO therapy were due to its pleiotropic effects mainly in the cardiovascular system including hypertension, thrombosis and augmented tumor angiogenesis [27-29]. Single-center studies have shown that EPO therapy of anemia in patients with heart failure was associated with improvement in exercise capacity, improved cardiac and renal function and reduced use of diuretics [30, 31]. Other trials evaluated the safety and efficacy of darbepoetin alfa at a dosage of 0.75μg/kg once every 2 weeks in symptomatic heart failure patients [32, 33]. It was demonstrated that the incidence of adverse events in these trials was similar between placeboand darbepoetin alfa-treated patients [34]. However, the significant increase in hemoglobin shown with darbepoetin alfa therapy correlated well with improved health-related quality of life. The results from pre-clinical studies attribute multiple mechanisms of protection by EPO against myocardial disorders besides anemia treatment. Treatment with EPO may decrease apoptosis of myocytes, induce neovascularization by promoting myocardial angiogenesis increasing collateral vessels, reduce collagen deposition in ischemic myocardium, as well as, improve left ventricular function. However, large clinical trials did not demonstrate those benefits [23, 24]. Similarly, trials in patients with anemia and heart failure did not demonstrate improved clinical outcomes and raise concerns about increased complications [25, 26]. It is highly possible that EPO may have failed in these clinical trials because of the employment of insufficient dose. Preclinical studies have frequently used doses in the range of 1,000 to 5,000 IU/kg, while just a dose of 300 IU/ kg were utilized in many large clinical trials. Although this lower dose is adequate for the EPO receptors in the erythroblasts, the EPO receptors found on multiple cell types responsible for cardiovascular protection are different [27-29]. However, the explanation may not be that simple. There is a complex interplay between vascular abnormalities and inflammatory mediators. There are several different cell types involved, and, within each individual cell, there are complex interactions among multiple signaling pathways. On the other hand, the use of higher doses of EPO in those large clinical trials might have had developed adverse effects such as thrombosis and hypertension. In conclusion, experimental and clinical studies have demonstrated that EPO does not only affect the hematopoietic system, but also plays important role in control of the cardiovascular system. EPO has been shown to produce cardiovascular protection by exerting its effects on the endothelial cells and vascular smooth muscle cells. Tissue protective effects of EPO on the vasculature are mediated by decreasing apoptosis of myocytes, by inducing neovascularization, by promoting myocardial angiogenesis increasing collateral vessels, by reducing collagen deposition in ischemic myocardium, and by stimulating endothelial nitric oxide production and vasodilatation. However, these beneficial effects were not demonstrated in large clinical trials, a fact that makes clear the need for insights in this yet developing field. In order to effectively utilize EPO for cardiovascular protection in diseased patients, it will be required a better understanding of the ideal dosage to maximize effectiveness and minimize adverse effects of novel manufactured variations of EPO stimulating agents. There is a necessity of increasing our knowledge of the relevant processes that occur at the cellular level, and to individualize patients for relevant factors that may affect clinical outcome.

REFERENCES

1. Jelkmann W. (1992). Erythropoietin: structure, control of production, and function. Physiol Rev. 72(2): 449-489.
2. Janmaat ML, Heerkens JL, de Bruin AM, Klous A, et al. (2010). Erythropoietin accelerates smooth muscle cellrich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood. 115(7): 1453-1460.
3. Kanagy NL, Perrine MF, Cheung DK and Walker BR. (2003). Erythropoietin administration in vivo increases vascular nitric oxide synthase expression. J Cardiovasc Pharmacol. 42(4): 527-533.
4. Noguchi CT, Bae KS, Chin K, Wada Y, et al. (1991). Cloning of the human erythropoietin receptor gene. Blood. 78: 2548-2556.
5. Ramakrishnan R, Cheung WK, Wacholtz MC, Minton N, et al. (2004). Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers. J Clin Pharmacol. 44(9): 991-1002.
6. Macdougall I. (2001). An overview of the efficacy and safety of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant. 16(Suppl 3): 14-21.
7. Egrie JC, Dwyer E, Browne JK, Hitz A, et al. (2003). Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol. 31(4): 290-299.
8. Macdougall IC and Eckardt KU. (2006). Novel strategies for stimulating erythropoiesis and potential new treatments for anaemia. Lancet. 368(9539): 947-953.
9. Locatelli F, Villa G, de Francisco AL, Albertazzi A, et al. (2007). Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration. Curr Med Res Opin. 23(5): 969-979.
10. Provenzano R, Besarab A, Macdougall IC, Ellison DH, et al. (2007). The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study. Clin Nephrol. 67(5): 306-317.
11. Iversen PO, Nicolaysen A, Kvernebo K, Benestad HB, et al. (1999). Human cytokines modulate arterial vascular tone via endothelial receptors. Pflugers Arch. 439(1-2): 93-100.
12. Rui T, Feng Q, Lei M, Peng T, et al. (2005). Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1. Cardiovasc Res. 65(3): 719-727.
13. Burger D, Lei M, Geoghegan-Morphet N, Lu X, et al. (2006). Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovasc Res. 72(1): 51-59.
14. Li Y, Takemura G, Okada H, Miyata S, et al. (2006). Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res. 71(4): 684-694.
15. Wu XC, Johns EJ and Richards NT. (1999). Relationship between erythropoietin and nitric oxide in the contraction of rat renal arcuate arteries and human umbilical vein endothelial cells. Clin Sci (Lond). 97(4): 413-419.
16. Banerjee D, Rodriguez M, Nag M and Adamson JW. (2000). Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity. Kidney Int. 57(5): 1895-1904.
17. Beleslin-Cokic BB, Cokic VP, Yu X, Weksler BB, et al. (2004). Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood. 104(7): 2073-2080.
18. Scalera F, Kielstein JT, Martens-Lobenhoffer J, Postel SC, et al. (2005). Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol. 16(4): 892- 898.
19. Wang XQ and Vaziri ND. (1999). Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension. 33(3): 894-899.
20. Brines M and Cerami A. (2006). Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 70(2): 246-250.
21. Anagnostou A, Liu Z, Steiner M, Chin K, et al. (1994). Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA. 91(9): 3974-3978.
22. Ammarguellat F, Gogusev J and Drueke TB. (1996). Direct effect of erythropoietin on rat vascular smooth-muscle cell via a putative erythropoietin receptor. Nephrol Dial Transplant. 11(4): 687-692.
23. Najjar SS, Rao SV, Melloni C, Raman SV, et al. (2011). REVEAL Investigators: Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 305(18): 1863-1872.
24. Prunier F, Bière L, Gilard M, Boschat J, et al. (2012). 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. 163(2): 200-207.
25. Swedberg K, Young JB, Anand IS, Cheng S, et al. (2013). Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 368: 1210-1219.
26. Ghali JK, Anand IS, Abraham WT, Fonarow GC, et al. (2008). Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 117: 526-535.
27. Steppich B, Groha P, Ibrahim T, Schunkert H, et al. (2017). Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial. BMC Cardiovascular Disorders. 17: 38-45.
28. Garimella PS, Katz R, Patel KV, Kritchevsky SB, et al. (2016). Association of Serum Erythropoietin with Cardiovascular Events, Kidney Function Decline and Mortality: The Health ABC Study. Circ Heart Fail. 9(1): e002124.
29. Zhang H, Zhang P, Zhang Y, Yan J, et al. (2016). Effects of erythropoiesis-stimulating agents on heart failure patients with anemia: a meta-analysis. Adv Interv Cardiol. 12(3): 247-253.
30. Namiuchi S, Kagaya Y, Ohta J, Shiba N, et al. (2005). 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. 45(9): 1406-1412.
31. Palazzuoli A, Silverberg D, Iovine F, Capobianco S, et al. (2006). Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am Heart J. 152(6): 1096-1099.
32. Ponikowski P, Anker SD, Szachniewicz J, Okonko D, et al. (2007). Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 49(7): 753-762.
33. Ghali JK, Anand IS, Abraham WT, Fonarow GC, et al. (2008). Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 117(4): 526-535.
34. Klapholz M, Abraham WT, Ghali JK, Ponikowski P, et al. (2009). The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure. Eur J Heart Fail. 11(11): 1071-1077.