Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs
Akio Hirata, MD*,
Tetsuo Minamino, MD, PhD*,*,
Hiroshi Asanuma, MD, PhD*,
Masashi Fujita, MD*,
Masakatsu Wakeno, MD ,
Masafumi Myoishi, MD,
Osamu Tsukamoto, MD*,
Ken-ichiro Okada, MD*,
Hidekazu Koyama, BS*,
Kazuo Komamura, MD, PhD ,
Seiji Takashima, MD, PhD*,
Yoshiro Shinozaki, MD||,
Hidezo Mori, MD, PhD,
Masamichi Shiraga, MD, PhD ,
Masafumi Kitakaze, MD, PhD, FACC and
Masatsugu Hori, MD, PhD, FACC*
* Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Department of Bioregulatory Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Cardiovascular Division of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
|| Department of Physiological Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
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Figure 1 Experimental protocols to investigate acute effects of erythropoietin (EPO) on myocardial infarct size. LAD = left anterior descending coronary artery; RhEPO = recombinant human erythropoietin.
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Figure 2 Experimental protocols to investigate effects of immediate or delayed treatment with erythropoietin (EPO) on neovascularization and cardiac function. CD34+MNC = CD34-positive mononuclear cell; other abbreviations as in Figure 1.
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Figure 3 Representative left ventricular cross sections at 6 h after myocardial infarction (MI) in dogs with (B) and without (A) erythropoietin (EPO) treatment. (C) Infarct size at 6 h after MI. *p < 0.05 vs. the control group. Open circles = infarct size in each animal.
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Figure 4 (A) Time course of changes in circulating CD34+MNC count after left anterior descending coronary artery (LAD) ligation in different experimental groups. (B) Representative images of double-stained cultured cells (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acetylated low density lipoprotein [Dil-ac-LDL] and Ulex europaeus agglutinin I [UEA-I]) at baseline (a, b) and 1 week after LAD ligation (c, d) from dogs with and without erythropoietin (EPO) treatment immediately after LAD ligation. (C) Quantitative analysis of endothelial progenitor cell culture assay. *p < 0.05 vs. the control group. p < 0.05 vs. baseline.
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Figure 5 (A) Representative immunohistologic staining with an antibody against von Willebrand factor in nonischemic (left circumflex coronary artery [LCX]) (a, b, c, d) and ischemic (left anterior descending coronary artery [LAD]) (e, f, g, h) regions in different experimental groups. Capillary density (B) and capillary-to-myocyte ratio (C) of nonischemic (LCX) and ischemic (LAD) regions in different experimental groups. *p < 0.05 versus the control group. Abbreviations as in Figure 1.
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Figure 6 Regional myocardial blood flow in the ischemic (left anterior descending coronary artery [LAD]) region 90 min and 4 weeks after myocardial infarction in different experimental groups. *p < 0.05 versus the control group. EPO = erythropoietin.
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Figure 7 The time course of changes in left ventricular ejection fraction (LVEF) (A), left ventricular end-diastolic dimension (LVEDD) (B), and left ventricular end-diastolic pressure (LVEDP) (C) in different experimental groups. Statistically significant (p < 0.05) group-by-time interactions (analysis of variance for repeated measurements) are indicated by the following: # = all groups; $ = control x EPO(0) group; & = control x EPO(6h) group; = EPO(0) x EPO(6h) group. (D) Infarct size at 4 weeks after myocardial infarction in different experimental groups. Open circles = infarct size in each animal. *p < 0.05 versus the control group. EPO = erythropoietin.
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