Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs

• Published in: Journal of the American College of Cardiology Vol. 48; no. 1; pp. 176 - 184
• Main Authors: Hirata, Akio, Minamino, Tetsuo, Asanuma, Hiroshi, Fujita, Masashi, Wakeno, Masakatsu, Myoishi, Masafumi, Tsukamoto, Osamu, Okada, Ken-ichiro, Koyama, Hidekazu, Komamura, Kazuo, Takashima, Seiji, Shinozaki, Yoshiro, Mori, Hidezo, Shiraga, Masamichi, Kitakaze, Masafumi, Hori, Masatsugu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.07.2006; Elsevier Limited
• Subjects: Animals; Antigens, CD34 - analysis; Capillaries - anatomy & histology; Cardiology; Coronary Circulation - drug effects; Coronary vessels; Cytokines; Dogs; Erythropoietin - therapeutic use; Heart attacks; Heart rate; Hemodynamics; Ischemia; Laboratory animals; Leukocytes, Mononuclear - immunology; Myocardial Infarction - blood; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Neovascularization, Physiologic - drug effects; Ostomy; Rodents; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - blood; Veins & arteries; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology; Japan; LCX; MNC; UEA-I; EPO; VEGF; HR; LV; LVEDD; LAD; ABP; LVEDP; MBF; Dil-ac-LDL; EPC; MI
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.04.008

Erythropoietin Enhances Neovascularization of Ischemic Myocardium and Improves Left Ventricular Dysfunction After Myocardial Infarction in Dogs Akio Hirata, Tetsuo Minamino, Hiroshi Asanuma, Masashi Fujita, Masakatsu Wakeno, Masafumi Myoishi, Osamu Tsukamoto, Ken-ichiro Okada, Hidekazu Koyama, Kazuo Komamura, Seiji Takashima, Yoshiro Shinozaki, Hidezo Mori, Masamichi Shiraga, Masafumi Kitakaze, Masatsugu Hori To investigate the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI), we intravenously administered EPO after the permanent ligation of the canine coronary artery. The EPO administered immediately after MI reduced infarct size assessed at 6 h after MI. Moreover, EPO administered 6 h after MI enhanced CD34-positive mononuclear cell mobilization, neovascularization, and myocardial blood flow in the ischemic regions, and prevented worsening of cardiac function without reducing infarct size in the chronic phase. In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase. We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI). Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs). 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. 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. 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.