STATE-OF-THE-ART PAPER
Protective Effects of Erythropoietin in Cardiac Ischemia
From Bench to Bedside
Erik Lip ic, MD, PhD*, ,*,
Regien G. Schoemaker, PhD*,
Peter van der Meer, MD, PhD*,,
Adriaan A. Voors, MD, PhD,
Dirk J. van Veldhuisen, MD, PhD, FACC and
Wiek H. van Gilst, PhD*,
* Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Manuscript received April 5, 2006;
revised manuscript received August 10, 2006,
accepted August 14, 2006.
* Reprint requests and correspondence: Dr. Erik Lipic, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands. (Email: e.lipsic{at}dz.nl).
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Abstract
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Erythropoietin (EPO) is a hypoxia-induced hormone produced in the kidneys that stimulates hematopoiesis in the bone marrow. However, recent studies have also shown important nonhematopoietic effects of EPO. A functional EPO receptor is found in the cardiovascular system, including endothelial cells and cardiomyocytes. In animal studies, treatment with EPO during ischemia/reperfusion in the heart has been shown to limit the infarct size and the extent of apoptosis. In the longer term, EPO may promote ischemia-induced neovascularization, either by stimulating endothelial cells in situ or by mobilizing endothelial progenitor cells from bone marrow. The effects of EPO in the ischemic heart support the concept of EPO as a pleiotropic, tissue-protective agent for other organs expressing the EPO receptor. We recently performed a first randomized clinical study showing the safety and feasibility of EPO administration in patients with acute myocardial infarction. Future clinical studies are warranted to translate the beneficial effects of EPO from basic experiments to cardiac patients.
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Abbreviations and Acronyms
| | CHF = chronic heart failure | | CKD = chronic kidney disease | | EPC = endothelial progenitor cell | | EPO = erythropoietin | | EPO-R = erythropoietin receptor | | I/R = ischemia/reperfusion | | LV = left ventricle/ventricular | | MI = myocardial infarction | | rhEPO = recombinant human erythropoietin |
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Erythropoietin (EPO) is a hematopoietic hormone produced primarily in the kidneys in response to hypoxia (1). Effects of EPO in the bone marrow are mediated by binding to a specific transmembrane receptor (EPO-R), which is expressed primarily by hematopoietic progenitor cells (2). Subsequent dimerization of EPO-R leads to activation of numerous intracellular pathways (PI3K/Akt, mitogen-activated protein kinase [MAPK], STAT-5) associated with cell survival (3). Erythropoietin primarily inhibits the apoptosis of erythroid precursor cells and thus increases their survival. On the other hand, EPO synergistically with other growth factors promotes the proliferation and maturation of erythroid progenitor cells (4).
The synthesis of various forms of recombinant human EPO (rhEPO) represented a breakthrough in the treatment of anemia caused by EPO deficiency due to chronic kidney disease (CKD) (5). At present, rhEPO is approved also for the treatment of cancer patients with anemia of chronic disease or anemia induced by chemotherapy or radiotherapy (6), in patients with myelodysplastic syndromes, and as a prophylactic treatment to reduce the need for transfusions before major surgery (1).
Although EPO is traditionally viewed as a hematopoietic hormone, the finding of EPO-Rs outside the hematopoietic tissue (endothelial cells, neurons, trophoblast cells) prompted the search for nonhematopoietic effects of EPO (1). Experimental studies have shown the protective effect of exogenous EPO treatment in different tissues. Systemic administration of EPO in the rat model of focal brain ischemia reduced the infarct volume by 50% to 75% (7). In the kidney, treatment with EPO significantly reduced the renal injury and dysfunction associated with ischemia/reperfusion (I/R) in rodents (8). Other reports documented the benefit of EPO therapy in the setting of hypoxic retinal disease (9), gastrointestinal ischemia (10), and the cardiovascular system (11–14).
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EPO and EPO-R in the cardiovascular system
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The expression of EPO-R was found in a variety of cell lines originated from the cardiovascular system. In vitro, EPO-R is synthesized and is present on the surface of human vascular endothelial cells (15), and administration of EPO prevents apoptosis of endothelial cells subjected to hypoxia through direct modulation of PI3K/Akt phosphorylation (16). The expression of EPO-R also was shown in neonatal (17) and adult (18) rat cardiac myocytes. Similar to endothelial cells, EPO prevented the apoptosis of cardiomyocytes by means of activating PI3/Akt pathway (17).
In vivo, EPO-R is expressed in normal rat cardiac tissue. Immunostaining for EPO-R is predominantly observed in interstitial cells, including endothelial cells and fibroblasts, with weak expression in cardiomyocytes (19). Recently, EPO-R expression was confirmed also in human heart tissue. Both ventricular myocytes and endothelial cells in the adult human heart were positive for the EPO-R (20). Expression of EPO itself in the heart, either under normal or hypoxic conditions, has not been reliably established (11).
An entirely new concept of EPO-mediated protection was introduced by Leist et al. (21), through generating mutants of EPO, which do not bind to the classical dimeric EPO-R and lack hematopoietic activity but nevertheless maintain their protective properties in various models of tissue and organ ischemia. This could suggest existence of different types of receptors needed for hematopoietic and nonhematopoietic effects of EPO. Recently, a putative cell surface receptor configuration mediating the tissue-protective EPO effects was identified, consisting of the EPO-receptor and beta-common receptor, which is present also in the myocardium (22).
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Acute cardioprotective effects of EPO
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In hematopoietic and nonhematopoietic tissues alike, EPO was shown to activate pathways leading to inhibition of apoptosis. Apoptosis, one of the major forms of cell death, has been implicated in different cardiovascular diseases. In myocardial infarction (MI), apoptosis might be a determinant of the final infarct size, and its extent depends on the presence of postischemic reperfusion (23).
Recently, numerous ex vivo (in isolated rodent and rabbit hearts) and in vivo studies have shown a protective role of EPO during ischemic and I/R injury in the heart (Table 1).
Pretreatment of adult rats with EPO (5,000 IU/kg) 24 h preceding I/R increased the functional recovery of isolated hearts during reperfusion (11). This was accompanied by protection against apoptosis, as measured by the number of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive cells and activity of proapoptotic marker caspase-3. The mechanism of EPO-mediated protection was shown by blockade of these effects with a specific inhibitor of the PI3K/Akt pathway (24). The involvement of signal transducing pathways was further elucidated by Shi et al. (25) in a rabbit isolated-heart model in which the cardioprotective effects of EPO were abolished by inhibitors of 2 different MAPK (p38 and p42/44). In the same study, potassium channel inhibitors also blocked the EPO effects, indicating a role of potassium channels in EPO-mediated preservation of heart function, possibly cause by reduction of calcium overload. Hanlon et al. (26) showed the importance of another protein kinase, protein kinase C (PKC), in EPO-mediated cardioprotection. Interestingly, although activation of PKC by EPO is required before and during ischemia, postischemic cardioprotection is dependent on PI3K/Akt and MAPK pathways (26,27). In a study performed by our group, perfusion of isolated rat hearts with EPO during I/R attenuated the deterioration of left ventricular pressure and coronary flow during the reperfusion (19). Erythropoietin in this setting also reduced cellular damage (purine outflow) and the number of cells entering apoptosis (active caspase-3 positive).
Although inhibition of apoptosis is widely accepted as a mechanism for EPO-mediated protection against acute ischemic injury, other possibilities should also be considered. Pretreatment with EPO was shown to inhibit the I/R-induced myocardial inflammatory response (28) by preventing the switching of myocytes to a proinflammatory phenotype, possibly also through up-regulation of nitric oxide production. Erythropoietin also can improve the cardiac function by directly modulating the cardiac Na+/K+ pump (29) or stimulating the production of atrial natriuretic peptide in cardiac atrium (30).
In the first in vivo study, Calvillo et al. (12) used a rat model of coronary I/R. Administration of EPO (5,000 IU/kg/day) for 7 consecutive days after reperfusion reduced the loss of cardiomyocytes by 50%, an extent sufficient to normalize hemodynamic function. However, the hematocrit increased by 20% to 30% by the end of the study, and such a change alone may lead to improved cardiac function merely by improving the delivery of oxygen.
In a rabbit model of MI, treatment with EPO at the time of permanent coronary ligation resulted in a trend toward reduced infarct size and improvement of cardiac contractility and relaxation when measured 3 days later. Moreover, the cardiac inotropic reserve, studied in response to beta-adrenergic receptor agonist, was significantly enhanced in the EPO-treated group (14). In addition, EPO administration in an in vivo I/R was also found to be beneficial, resulting in a significant reduction of infarct size, expressed as a percentage of total ischemic area at risk (31). This protection was associated with the mitigation of myocardial cell apoptosis. Furthermore, in line with the results from ex vivo experiments, reduction of infarct size in vivo is dependent on the activation of pro-survival pathways PI3K/Akt and MAPK (27).
The results of these studies raised 2 clinically important issues: that of the timing and the dosage of EPO administration. In a study performed by our group (13), EPO reduced infarct size and inhibited apoptosis when administered before the actual ischemic episode to until after the onset of reperfusion, providing a broad window of opportunity for the potential treatment of acute coronary syndromes. Because most of the previous experimental studies used high doses of EPO (1,000 to 5,000 IU/kg), Hirata et al. (32) approached the issue of minimal EPO dose still rendering cardioprotection. The EPO treatment in a canine model of I/R reduced infarct size in a dose-dependent manner, establishing the lowest effective dose of 100 IU/kg.
Recently, Fiordaliso et al. (33) definitely separated the hematopoietic and nonhematopoietic effects of EPO by using a carbamylated derivate of EPO, lacking erythropoietic activity. The carbamylated derivate of EPO administration prevented cardiomyocyte loss and improved left ventricular (LV) function after I/R injury in rats.
Importantly, the effects of EPO administration persist over a longer period after the ischemic insult. Moon et al. (34) found that a single dose of EPO (3,000 IU/kg) immediately after coronary artery ligation in rats reduced the infarct size to 15% to 25% that of untreated animals examined 8 weeks later. This reduction in myocardial damage was accompanied by prevention of LV dilation and improved LV ejection fraction, as measured by repeated echocardiography. It seems that EPO may protect the myocardium also against more severe insults, such as permanent coronary occlusion, and this effect becomes even more pronounced with time.
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Long-term effect of EPO in the heart
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Current therapy in patients after MI is focused on prevention of ventricular remodeling and development of heart failure. Myocardial regeneration may offer possibilities that could improve cardiac function in these patients. Although regeneration of cardiomyocytes by proliferation or transdifferentiation seems limited (35), the formation of new vessels in noninfarcted parts may indirectly save cardiomyocytes and lead to improvement of ventricular function.
Two processes contribute to postnatal formation of blood vessels. Angiogenesis is the sprouting of new vessels from existing ones, whereas vasculogenesis refers to formation of blood vessels from endothelial progenitor cells (EPCs). These cells are undifferentiated cells in peripheral tissues, or derived from bone marrow, possessing the ability to mature into the cells lining the lumen of a blood vessel.
The EPCs also are mobilized in patients during acute cardiac ischemic events (36). Recently, increased levels of circulating EPCs were associated with reduced risk of death from cardiovascular causes in patients with confirmed coronary artery disease (37). In the BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial, intracoronary infusion of autologous bone marrow cells (CD34+) after MI resulted in improved global LV ejection fraction 6 months after cell transfer (38). However, the difference in LV ejection fraction was less convincing during the long-term follow-up (39).
Erythropoietin was found to be a potent stimulus for EPC mobilization, which was associated with neovascularization of ischemic tissue (40). The effect of EPO on the formation of new vessels has also been observed in an experimental model of stroke; EPO treatment, initiated 24 h after induction of stroke, increased the density of microvessels at the stroke boundary and improved neurological function (41).
We addressed this issue in the heart, evaluating the effect of EPO treatment on new vascular formation in an experimental heart failure model (42). Rats were subjected to coronary artery ligation, and therapy with the high-dose EPO analog darbepoetin (40 µg/kg/3 weeks) was initiated 3 weeks after MI. Although not reducing infarct size, EPO treatment significantly improved cardiac function. This improvement was coupled with an increased capillary-to-myocyte ratio, indicating neovascularization.
In the clinical setting, treatment with rhEPO causes a significant mobilization and functional activation of EPCs in patients with renal anemia, as well as in healthy subjects (43). Interestingly, serum levels of EPO were also significantly correlated with the number of circulating EPCs in patients with established coronary artery disease (40).
In addition to stimulating and mobilizing EPCs, directly enhancing angiogenesis by EPO could also lead to neovascularization; EPO stimulates proliferation of endothelial cells in situ and their differentiation into vascular structures (44). In cultured human myocardial tissue, EPO stimulated capillary outgrowth comparable with that of vascular endothelial growth factor (45).
However, the doses used in the previous studies, when applied to a clinical situation, could cause an EPO overdose that may lead to hypertension, seizures, vascular thrombosis, and death, possibly related to abruptly increased hematocrit values (46). This would be of an even greater concern in patients with an already elevated cardiovascular risk.
This considerable clinical problem was addressed by Bahlmann et al. (47). In their model of progressive renal disease, treatment with the low-dose EPO analog darbepoetin conferred tissue protection and preserved capillary network in the kidney, but did not increase the hematocrit level. In a recent study performed by our group, we studied the effects of low (nonerythropoietic)-dose darbepoetin in a rat model of post-MI heart failure. We showed that darbepoetin treatment preserves cardiac function, even in doses not affecting the hematocrit level. This is associated with an increased number of circulating EPCs and an increased capillary-to-myocyte ratio (48). Stimulation of EPCs, without increasing the number of red blood cells, implies specific EPO dose-effect relationships in different bone marrow cells.
Although time-limited treatment with high-dose EPO may be beneficial and safe during acute ischemic injury, if prolonged therapy is required (heart failure), drug regimens using low-dose EPO may be more suitable in avoiding the adverse effects of the treatment. In this regard the nonhematopoietic EPO derivates could also prove valuable; however, their effect on vasculogenesis and/or angiogenesis is not yet established.
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Clinical implications
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Erythropoietin has been successfully used in clinical practice for more than 2 decades, for the most part to treat anemia in patients with CKD, caused by diminished production of endogenous EPO. In these patients, anemia is an established risk factor for cardiovascular disease outcomes (49). Numerous smaller studies in predialysis and dialysis patients have shown a beneficial effect of anemia treatment with EPO on various surrogate cardiovascular end points (50,51). However, no conclusive data from randomized controlled trials exist establishing the impact of anemia treatment on cardiovascular and total mortality in patients with CKD (52). A recently started TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study will determine the effect of darbepoetin treatment on cardiovascular events in CKD patients (52).
Anemia is also commonly observed in patients with chronic heart failure (CHF) and is related to the severity of the disease (53). Although the cause of anemia in these patients is multifactorial, inadequate EPO production and a blunted response to EPO in the bone marrow play a major role (54). Consequently, elevated EPO levels are associated with the severity of CHF and are a prognostic marker for impaired survival, independent of hemoglobin levels (55). It seems that, although increased in absolute terms, EPO levels in anemic CHF patients are still relatively low to adequately stimulate the hematopoiesis in bone marrow. Higher levels of hematopoiesis inhibitors, such as N-acetyl-seryl-aspartyl-lysyl-proline, could also counterbalance the effects of EPO (56). In a number of small studies, normalization of hemoglobin levels with EPO in CHF patients was associated with improved LV ejection fraction (57) and enhanced exercise capacity (58). Although this amelioration partly could be attributed to hemoglobin elevation and thus the increased oxygen-binding capacity of blood, the nonhematopoietic effects of EPO must also be considered. Recently, 2 larger placebo-controlled phase II studies with EPO treatment in anemic CHF patients were conducted that also suggested potential beneficial effects both in terms of quality of life and clinical end points. For this reason, a larger trial aimed at assessing its effect on morbidity and mortality is now being initiated (59).
The nonhematopoietic tissue-protective properties of EPO also may be beneficial in treatment of patients with acute coronary syndromes. Currently, the emphasis in the treatment of MI is on early reperfusion and hence limiting the damage of cardiac ischemia. However, development of post-MI heart failure remains a major challenge despite optimal therapy. Erythropoietin could on one hand acutely protect myocardial cells against I/R-induced injury, and on the other hand could attenuate the cardiac remodeling by stimulating the EPCs. Interestingly, high levels of endogenous EPO in patients with a first MI who underwent successful primary coronary intervention were found to be associated with smaller infarcts, which was interpreted by the investigators as a possible endogenous, protective mechanism (60).
We recently performed a first safety and feasibility study with darbepoetin treatment in patients with an acute MI (61). In this single-center, investigator-initiated, prospective study we randomized 22 nonanemic patients with a first acute MI to 1 bolus of 300 µg darbepoetin alfa or no additional medication before primary coronary intervention. Administration of darbepoetin was both safe and well tolerated. In the darbepoetin group, serum EPO levels increased to 130 to 270 times that of controls within the first 24 h. Darbepoetin administration led to only small and nonsignificant changes in hematocrit levels, whereas EPCs (CD34+/CD45–) were significantly increased at 72 h. Despite a nonsignificantly longer time to treatment and more extensive baseline area at risk (cumulative ST-segment elevation) in the darbepoetin-treated group, LV ejection fraction after 4 months was similar in the 2 groups (52 ± 3% in darbepoetin vs. 48 ± 5% in control group, p = NS), indicating a possible positive effect of darbepoetin treatment on longer-term infarct healing and/or cardiac remodeling.
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Conclusions
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The traditionally hematopoietic hormone EPO is increasingly recognized as a pleiotropic cytokine, with effects reaching much further than stimulating red blood cell production. Although already used in cardiology to correct anemia in CHF patients, the nonhematopoietic effects of EPO also may be beneficial in nonanemic cardiovascular patients.
From the experimental studies, EPO seems to influence 2 crucial processes during cardiac ischemic injury, first by acutely reducing the infarct size and inhibiting the apoptosis, and second by promoting new vessels formation over a longer time frame (Fig. 1). In clinics, randomized trials should translate the results of experimental studies and investigate the effectiveness of EPO treatment in various patient populations (acute MI, CHF).
Although treatment with EPO is generally well tolerated and safe, it may be associated with adverse effects such as hypertension and thromboembolism. These side effects are related mainly to high-dose chronic EPO treatment, associated with increased hematocrit. Using variants of EPO without hematopoietic effect but retaining tissue protective activity could be useful in a clinical situation in which multiple EPO administrations would be warranted.
Future studies should determine a place for EPO in the treatment of acute and chronic cardiac ischemia, which may have widespread implications for managing heart patients.
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Footnotes
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Experimental studies performed by our group were partly supported by an unrestricted educational grant from Amgen, Inc. (Thousand Oaks, California).
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