CLINICAL RESEARCH: MYOCARDIAL INFARCTION
High Serum Erythropoietin Level Is Associated With Smaller Infarct Size in Patients With Acute Myocardial Infarction Who Undergo Successful Primary Percutaneous Coronary Intervention
Shigeto Namiuchi, MD*,
Yutaka Kagaya, MD ,*,
Jun Ohta, MD,
Nobuyuki Shiba, MD,
Masafumi Sugi, MD*,
Masayoshi Oikawa, MD*,
Hiroyuki Kunii, MD*,
Hidetsugu Yamao, MD*,
Nobuo Komatsu, MD*,
Mitsuru Yui, MD*,
Hiroko Tada, MD,
Masahito Sakuma, MD,
Jun Watanabe, MD,
Toshikatsu Ichihara, MD* and
Kunio Shirato, MD
* Department of Cardiology, Iwaki Kyoritsu General Hospital, Iwaki, Japan
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Manuscript received December 13, 2004;
accepted January 5, 2005.
* Reprint requests and correspondence: Dr. Yutaka Kagaya, Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan (Email: kagaya{at}cardio.med.tohoku.ac.jp).
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Abstract
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OBJECTIVES: We investigated whether a higher serum erythropoietin (EPO) level in patients with acute myocardial infarction (MI) subjected to successful primary percutaneous coronary intervention (PCI) can predict a smaller infarct size determined by creatine kinase (CK) release.
BACKGROUND: Erythropoietin has been shown to protect cardiomyocytes from ischemia-reperfusion injury in rodents.
METHODS: We prospectively studied 101 patients with first MI who received successful primary PCI within 12 h from the onset of MI. Blood samples were collected to examine the serum EPO level after the primary PCI and within 24 h from the onset of MI.
RESULTS: The peak CK level and cumulative CK release were significantly lower in the above-median EPO group than in the below-median EPO group. Thrombolysis In Myocardial Infarction (TIMI) grades and collateral grades before PCI, infarct-related coronary arteries, time to the successful reperfusion from the onset of MI, and serum creatinine levels were similar in the two EPO groups. A stepwise multiple regression analysis revealed that the absolute serum EPO level (mU/ml) as well as TIMI grades after PCI and preinfarction angina was an independent predictor for the cumulative CK release.
CONCLUSIONS: These data suggest that a high endogenous EPO level can predict a smaller infarct size in patients with acute MI subjected to successful primary PCI. This might be attributed to the potentially protective effect of endogenous EPO against ischemia-reperfusion injury in humans.
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Abbreviations and Acronyms
| | BNP = brain natriuretic peptide | | CK = creatine kinase | | EPO = erythropoietin | | LV = left ventricle/ventricular | | MI = myocardial infarction | | PCI = percutaneous coronary intervention | | TIMI = Thrombolysis In Myocardial Infarction |
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Although primary percutaneous coronary intervention (PCI) and thrombolytic therapy improve the survival in patients with acute myocardial infarction (MI) (1), the development of left ventricular (LV) remodeling, subsequent heart failure, and sudden cardiac death remain unsolved public health problems (2). As the infarct size is one of the most important predictors for LV remodeling and survival after MI (3–5), novel strategies to limit the infarct size should provide further advances.
Erythropoietin (EPO) was originally discovered as a principal regulator that promotes the survival, proliferation, and differentiation of erythroid progenitor cells (6). Several investigators reported that anemia is frequently observed in patients with chronic heart failure and is associated with increased morbidity and mortality (7–9). Furthermore, it has been shown that treatment with EPO significantly improved cardiac function, symptoms, and exercise capacity in patients with chronic heart failure (10,11). Recently, findings in several investigations have suggested that EPO has potential effects in cardiovascular diseases beyond the improvement of anemia (12,13); EPO has been shown to induce angiogenesis (14,15), promote neuronal survival after ischemia (6,16), and protect against ischemic vascular injury (17). Heeschen et al. (18) showed that an increased serum EPO level was associated with an increased number of circulating endothelial progenitor cells as well as that of stem cells and progenitor cells in the bone marrow of patients with coronary artery disease. Calvillo et al. (19) and Cai et al. (20) demonstrated that EPO provided a protective effect against ischemia-reperfusion-induced apoptosis of rat cardiac myocytes and attenuated LV remodeling. It is not known, however, whether endogenous EPO has protective effects against ischemia-reperfusion injury in acute MI in humans. The purpose of the present study was to investigate whether a higher serum EPO level after successful primary PCI in acute MI patients can predict a smaller infarct size determined by the creatine kinase (CK) release.
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Methods
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Patients.
The present study was approved by the ethics review boards of Iwaki Kyoritsu General Hospital and Tohoku University Graduate School of Medicine. Written informed consent was obtained from all patients before the study. The eligible patients were those with first acute MI who received successful primary PCI for the infarct-related coronary artery within 12 h from the onset. A total of 316 patients with acute MI were admitted to the Department of Cardiology, Iwaki Kyoritsu General Hospital, from January 2001 to September 2003. The cardiologists who participated in the present study consecutively attended 195 patients among the 316 patients. This was a convenience sample of patients with ST-segment elevation MI who were recruited by research attending physicians while they were on service.
Among the 195 patients with acute MI, 94 patients were not included in the present study for the following reasons: a history of previous MI (n = 26); no PCI performed (n = 16); PCI performed later than 12 h from the onset (n = 19); left main coronary artery disease (n = 4); Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 before PCI (n = 5); previous administration of recombinant human EPO (n = 2); increased CK level due to lower-leg ischemia (n = 4); or the presence of other cardiac or lung diseases, such as atrial fibrillation (n = 7), dilated cardiomyopathy (n = 2), aortic and mitral regurgitation (n = 1), aortic stenosis (n = 1), and lung fibrosis (n = 1). We also excluded six patients because blood sampling for the serum EPO was not performed within 24 h from the onset of MI. Accordingly, we prospectively studied the remaining 101 patients with first MI (age 28 to 87 years) who underwent successful primary PCI within 12 h from the onset of chest pain. Only 2 of the 101 patients received intracoronary thrombolysis. One of them showed TIMI flow grade 3 after the intracoronary thrombolysis and no significant residual stenosis. The other patient received angioplasty after the intracoronary thrombolysis. The serum CK level was determined every 4 h during the first and second days of the admission and then once a day until the values returned to the normal range.
Serum EPO and brain natriuretic peptide (BNP) levels.
Blood samples were prospectively collected to examine the serum EPO level (Recombigen EPO radioimmunoassay kit, Nippon DPC Corporation, Chiba, Japan) 9.9 ± 5.2 h after the onset of acute MI following primary PCI. We divided the 101 patients into two groups using the median value of the serum EPO level (20.3 mU/ml) in the patients. With this definition, 52 patients were classified into the below-median EPO (low EPO) group, and 49 patients into the above-median EPO (high EPO) group because there were two patients with the serum EPO level of 20.3 mU/ml. The investigators were blinded to the EPO levels during the determination of the CK area under the curve and angiographic parameters. As the BNP level in the acute phase of MI has been shown to predict the prognosis of the patients (21–23), we also measured the BNP level (radioimmunoassay) using the same blood samples as those for EPO to investigate whether the BNP level can predict the infarct size.
Left heart catheterization and left ventriculography.
Left heart catheterization and left ventriculography were performed according to the agreement of the patients as well as the decision by physicians, especially in patients hemodynamically unstable or in those for whom a critical amount of contrast medium had been used for primary PCI. Among the 101 study patients, 38 patients in the low EPO group and 39 patients in the high EPO group underwent these studies immediately after successful primary PCI.
Time course of the serum EPO level.
We investigated the time course of the serum EPO level in acute MI in an additional study. For this purpose 18 patients with acute MI who satisfied the inclusion criteria of the present study were investigated. The blood sampling was performed soon after the primary PCI, and 24 h, 48 h, and 14 days after the onset of acute MI.
Statistical analysis.
Data are presented as mean ± SD. The primary end points were the peak CK levels and cumulative CK release. The peak CK level could be obtained at every 4-h blood sampling in all the patients. The cumulative CK release (area under the curve) as an index of the infarct size was computed by numerical integration from the time point for the first blood sampling until that for the last blood sampling when the CK level returned to the normal range for the first time using the trapezoid method with a zero-line of 100 IU/l (24). Comparisons between the two groups were made by Student t test or chi-square test. Statistical analysis for the time course of the serum EPO levels in the two groups was performed using two-way analysis of variance (ANOVA) with repeated measures. A stepwise multiple regression analysis was used to assess the possible determinants of the peak CK level and cumulative CK release. For the analysis, adjustments were performed with the following variables: the gender, hemoglobin content, creatinine level, oxygen saturation, serum BNP level, current smoking, presence of preinfarction angina within 24 h from the onset of MI, time to PCI from the onset of MI, culprit lesion, TIMI grades before primary PCI, collateral flow before primary PCI, TIMI grades after PCI, and serum EPO level (absolute values in mU/ml). Values of p < 0.05 were considered significant. We used software for the statistics (StatView version 5.0, SAS Institute, San Francisco, California).
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Results
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Clinical and angiographic characteristics.
The baseline clinical characteristics of the low and high EPO groups are summarized in Table 1. The hemoglobin content in the blood was slightly but significantly lower in the high EPO group than in the low EPO group. The serum BNP level was significantly higher in the high EPO group than in the low EPO group. The body mass index was slightly but significantly higher in the high EPO group than in the low EPO group. Current smoking was less frequent and preinfarction angina within 24 h from the onset was more frequent in the high EPO group than in the low EPO group. The time from the onset to the successful reperfusion was similar in the low and high EPO groups. The angiographic characteristics were similar in the two EPO groups (Table 2).
Peak CK level and cumulative CK release.
As shown in Figure 1, both the peak CK levels and cumulative CK release of the high EPO group were significantly lower than those of the low EPO group. Figure 2 shows the relationship between the log serum EPO level and cumulative CK release in all the 101 patients enrolled in the present study. It is obvious that the patients with the higher cumulative CK release are located more frequently at the lower serum EPO level side than at the higher serum EPO level side, although the correlation between the two parameters is not strong.
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Figure 1 Peak creatine kinase (CK) and cumulative CK release in the below-median (low erythropoietin [EPO], n = 52) and above-median (high EPO, n = 49) EPO groups. Mean ± SD.
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Figure 2 The relationship between the log serum erythropoietin (EPO) level and cumulative creatine kinase (CK) release in all the 101 patients enrolled in the present study. It is obvious that the patients with the higher cumulative CK release are located more frequently at the lower serum EPO level side than at the higher serum EPO level side, although the correlation between the two parameters is not strong.
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LV end-diastolic pressure and left ventriculography.
The LV end-diastolic pressure, LV end-diastolic volume index, and LV ejection fraction measured in the selected patients were similar in the low (n = 38) and high (n = 39) EPO groups immediately after the primary PCI (Fig. 3).
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Figure 3 Results of left heart catheterization and left ventriculography. These measurements were performed according to the agreement of the patients as well as the decision by physicians (see Methods section). Each parameter was obtained from 38 patients in the below-median erythropoietin (EPO) (low EPO) group and 39 patients in the above-median EPO (high EPO) group immediately after the successful primary PCI. Mean ± SD. LV = left ventricular.
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Time course of the serum EPO level.
The time course of the serum EPO level in an additional study in which 18 patients with acute MI who satisfied the inclusion criteria of the present study were investigated is shown in Figure 4. We divided the 18 patients using the initial serum EPO level of 20.3 mU/ml that was the median value of the 101 patients enrolled in the main study. Two-way ANOVA with repeated measures revealed that the serum EPO level during the 14 days was significantly higher in the patients with an initial serum EPO level >20.3 mU/ml (n = 10) than in those with an initial serum EPO level <20.3 mU/ml (n = 8, p = 0.001). The interaction between the difference in the initial serum EPO levels and the time course of the serum EPO level was not statistically significant (p = 0.21).
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Figure 4 The time course of the serum erythropoietin (EPO) levels in an additional study in which 18 patients with acute myocardial infarction (MI) who satisfied the inclusion criteria of the present study were investigated. The blood sampling was performed soon after the primary percutaneous coronary intervention, and 24 h, 48 h, and 14 days after the onset of acute MI. Two-way analysis of variance with repeated measures revealed that the serum EPO level during the 14 days was significantly higher in the patients with an initial serum EPO level >20.3 mU/ml (n = 10) than in those with an initial serum EPO level <20.3 mU/ml (n = 8, p = 0.001). The interaction between the difference in the initial serum EPO levels and the time course of the serum EPO level was not statistically significant (p = 0.21). Mean ± SD. Solid triangles = initial EPO <20.3 mU/ml; open circles = initial EPO >20.3 mU/ml.
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Stepwise multiple regression analysis.
The serum EPO level (absolute values in mU/ml) as well as TIMI flow grade 2 after PCI and the presence of preinfarction angina within 24 h of the onset of MI was an independent predictor for the cumulative CK release (Table 3). The hemoglobin content and current smoking were not independent predictors for the cumulative CK release. As preinfarction angina was significantly more frequent in the high EPO group than in the low EPO group, we also assessed the possible determinants of the cumulative CK release in patients without preinfarction angina. As shown in Table 4, the serum EPO level (absolute values in mU/ml) as well as TIMI flow grade 2 after PCI and serum BNP level was an independent predictor of the cumulative CK release in those patients. The serum EPO level was not an independent predictor of the peak CK level (p = 0.078).
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Table 4. Stepwise Multiple Regression Analysis of Variables Associated With the Cumulative CK Release in Patients Without Preinfarction Angina
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Discussion
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We demonstrated for the first time that, in patients with first MI who underwent successful primary PCI within 12 h from the onset, a high serum EPO level was associated with a smaller infarct size as determined by the cumulative CK release. Furthermore, a stepwise multiple regression analysis revealed that the serum EPO level (absolute values in mU/ml) was an independent predictor for the cumulative CK release. Even in patients without preinfarction angina, the serum EPO level was an independent predictor. The serum EPO level was not an independent predictor of the peak CK level (p = 0.078). This might be explained at least partially by the well-known fact that the peak CK level is more affected by a variety of circumstances that interfere with the release of CK from the necrotic tissue (25).
Mechanisms for different serum EPO levels.
Erythropoietin is primarily synthesized by the kidney, and the serum EPO level increases exponentially as the hemoglobin content decreases (26,27). In the present study, the hemoglobin content was slightly but significantly increased in the low EPO group compared with the high EPO group. The mechanism for the different serum EPO levels observed in the present study, therefore, is probably the response to the different baseline hemoglobin levels. Furthermore, current smoking was more frequent in the low EPO group than in the high EPO group in the present study. Tanabe et al. (28) demonstrated that smoking was associated with low serum EPO levels in healthy volunteers, presumably due to an elevated red cell volume. Although further studies are needed to determine the precise mechanism for the different serum EPO levels, it is possible that current smoking increased the hemoglobin content in the blood, and affected the serum EPO levels of the patients in the low EPO group. As both the current smoking and hemoglobin content were not independent predictors of the infarct size, we believe that the serum EPO is more important as a predictor of the infarct size than current smoking and the hemoglobin contents. In our preliminary study, we measured the serum EPO levels in the blood taken from the coronary sinus of five patients with acute MI after successful primary PCI. There was no difference in the EPO levels between blood from the coronary sinus and that from the aorta (data not shown). It is unlikely, therefore, that the higher EPO level in the selected patients can be attributed to the increased EPO production in ischemic myocardium.
Beneficial effect of high serum EPO level.
The results of the present clinical study may be consistent with those of animal experiments by Cai et al. (20). They demonstrated that exposure of mice to intermittent hypoxia resulted in the protection of hearts against ischemia-reperfusion injury 24 h later. They also found that this protective effect was lost in mice heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor-1 alpha, and that among mRNAs encoded by hypoxia-inducible factor target genes, only EPO mRNA as well as EPO protein was significantly increased after intermittent hypoxia. Calvillo et al. (19) demonstrated that recombinant human EPO administered daily for seven days reduced cardiac-myocyte loss and ameliorated LV remodeling in rats with coronary artery ligation and reperfusion. It is possible, therefore, that the high endogenous EPO level in selected patients of the present study ameliorated the cardiac-myocyte death after ischemia and reperfusion. Recently, Heeschen et al. (18) demonstrated that, in patients with coronary artery disease, the serum EPO level was significantly correlated with the number and function of circulating endothelial progenitor cells. It is also possible, therefore, that the high serum EPO in selected patients of the present study mobilized endothelial progenitor cells and increased neovascularization, which could not be visualized by coronary arteriography. Finally, the high serum EPO level possibly recruited cells capable of differentiating into immature cardiac myocytes, the implantation of which has been shown to attenuate LV remodeling in a rat MI model (29,30).
It is possible that the grouping according to the above-median or below-median values might have erroneously produced the differences between the two groups. However, the results were almost the same even when we divided the patients into two groups using the mean plus two standard deviations of the serum EPO levels of the control patients who had received elective PCI for stable angina and had no residual coronary artery stenosis (data not shown). Furthermore, multivariate analysis revealed that the serum EPO levels can independently predict the infarct size determined by CK release. We, therefore, believe that our conclusion was not elicited erroneously by the arbitrary grouping. Finally, as shown in Figure 2, which demonstrates the relationship between the log serum EPO level and cumulative CK release in all the 101 patients, it is obvious that the patients with the higher cumulative CK release are located more frequently at the lower serum EPO level side than at the higher serum EPO level side. The correlation between the two parameters, however, was not strong (r = –0.262, p = 0.008). One possible explanation for this may be the TIMI grade after PCI, a much stronger predictor for the cumulative CK release as shown in the Table 3 scattered data plots.
It is interesting that preinfarction angina was significantly more frequent in the high EPO group than in the low EPO group. Preinfarction angina has been shown to be associated with a smaller infarct size in patients subjected to reperfusion therapy presumably because of ischemic preconditioning (31,32). The results of the present study are consistent with those of earlier studies because preinfarction angina was an independent predictor for the cumulative CK release. As shown in Table 4, the absolute serum EPO level was an independent predictor of the cumulative CK release also in the patients who had not experienced preinfarction angina. Furthermore, the serum EPO level was similar in the patients with preinfarction angina and those without preinfarction angina (27.6 ± 14.2 mU/ml vs. 26.6 ± 25.7 mU/ml, respectively, p = 0.85). We believe, therefore, that the favorable effect of the high endogenous serum EPO level cannot be explained by preconditioning effects elicited by preinfarction angina.
Because we do not know the baseline serum EPO levels before the onset of MI, it is unclear whether or not the higher serum EPO levels demonstrated in some patients of the present study had been triggered by acute MI. The time course of the plasma EPO level assessed in a separate study with a small number of the acute MI patients revealed that the serum EPO level during the 14 days was significantly higher in the patients with an initial serum EPO level >20.3 mU/ml than in those with an initial serum EPO level <20.3 mU/ml (Fig. 4). It is possible, therefore, that the protective effect of a higher serum EPO level against ischemia-reperfusion injury, which has been reported in several animal experiments (19,20), was maintained during the acute phase of MI. As the infarct size is one of the most important factors to determine LV remodeling after MI, we cannot tell whether the high serum EPO levels demonstrated in some patients with acute MI were also beneficial in terms of the amelioration of the post-MI LV remodeling.
Clinical implication.
As discussed in the previous section, Cai et al. (20) demonstrated that exposure of mice to intermittent hypoxia resulted in the protection of hearts against ischemia-reperfusion injury, and that this beneficial effect could be attributed to the increased EPO production in the kidney. Although the peak serum EPO level may have been lower in the present study than in the animal experiment by Cai et al. (20), the elevated serum EPO level seems to have lasted longer (Fig. 4), and might have elicited favorable effects in these patients. In this regard, additional studies to assess the usefulness of therapeutic application of human recombinant EPO to enhance the serum EPO levels in acute MI patients may be considered. However, we should be cautious concerning the possible prothrombotic potential of EPO (33), although the results of a preliminary study in patients with acute stroke were very promising (34).
Study limitations.
First, we cannot exclude the possibility that the high serum EPO levels in the selected patients in the present study were epiphenomenon reflecting some unknown mechanisms that reduced the infarct size. Second, we did not use an imaging modality, such as single photon emission tomography for assessment of the infarct size of the patients. Third, we did not investigate other humoral factors or the level of circulating endothelial progenitor cells, which might affect the infarct size. Fourth, we performed blood sampling for the serum EPO level only once. Although we determined the time course of the serum EPO levels in an additional study with a small number of the acute MI patients, we do not know the precise time course of the serum EPO levels in the 101 patients enrolled in the present study, and the results might have differed if we had performed the blood sampling at a different time point. Finally, the present study was based on a small convenience sample of acute MI patients. A further study with a random sample of a larger population is required to draw a more definite conclusion.
Conclusions.
The results of the present study suggest that a high endogenous EPO level (absolute value) can predict a smaller infarct size in patients with acute MI subjected to successful primary PCI. This might be attributed to the potentially protective effect of endogenous EPO against ischemia-reperfusion injury in humans, although further study is required to determine its precise mechanism.
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Acknowledgments
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The authors thank Mr. Brent Bell for reading the manuscript.
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Footnotes
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This study was supported, in part, by grants-in-aid for science research (15590715) from the Ministry of Education, Science, Sports, and Culture of Japan.
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D. E. Burger, F.-L. Xiang, L. Hammoud, D. L. Jones, and Q. Feng
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D Mocini, P Muso, E Guendouz, L De Marco, L Mele, R Cini, P Sordini, A Alois, A Costantino, S Arima, et al.
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C. Casals-Pascual, R. Idro, N. Gicheru, S. Gwer, B. Kitsao, E. Gitau, R. Mwakesi, D. J. Roberts, and C. R. J. C. Newton
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PNAS,
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W. Husemann, M. Fobker, M. Pohlen, C. Bruch, M. Hausberg, G. Breithardt, and H. Reinecke
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M. Nakano, K. Satoh, Y. Fukumoto, Y. Ito, Y. Kagaya, N. Ishii, K. Sugamura, and H. Shimokawa
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S. M. Davidson and D. M. Yellon
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E. R. Gross and G. J. Gross
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S. Namiuchi and Y. Kagaya
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Serum Erythropoietin Levels and Infarct Size
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A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, G. S. Ginsburg, B. H. Greenberg, W. Y.W. Lew, D. Sahn, and S. Tsimikas
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Abstract
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