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PRECLINICAL STUDY

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.

Manuscript received June 14, 2005; revised manuscript received November 10, 2005, accepted November 30, 2005.

^_* Reprint requests and correspondence: Dr. Tetsuo Minamino, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. (Email: minamino{at}medone.med.osaka-u.ac.jp).

OBJECTIVES: We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI).

BACKGROUND: Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs).

METHODS: We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs. Control animals received saline immediately after the ligation.

RESULTS: The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 ± 6.0% vs. 22.9 ± 2.2%). One week after MI, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 ± 1.9%) group was significantly higher than that in either the control (41.9 ± 0.9%) or the EPO(1wk) (42.6 ± 1.2%) group but significantly lower than that in the EPO(0) group (56.1 ± 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups.

CONCLUSIONS: In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Abbreviations and Acronyms   ABP = arterial mean blood pressure   Dil-ac-LDL = 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled acetylated low density lipoprotein   EPC = endothelial progenitor cell   EPO = erythropoietin   HR = heart rate   LAD = left anterior descending coronary artery   LCX = left circumflex coronary artery   LV = left ventricle/ventricular   LVEDD = left ventricular end-diastolic dimension   LVEDP = left ventricular end-diastolic pressure   MBF = myocardial blood flow   MI = myocardial infarction   MNC = mononuclear cell   UEA-I = Ulex europaeus agglutinin I   VEGF = vascular endothelial growth factor

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