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J Thorac Cardiovasc Surg 2000;120:720-728
© 2000 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits

From the Departments of Physiology,^a Internal Medicine,^b and Surgery^c and the Reserch Center for Genetic Engineering and Cell Transplantation,^d Tokai University School of Medicine, Isehara, Japan; and the Department of Cardiology,^e Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Supported by Grants-in-Aid for Scientific Research (09670756 and 10470171) from the Ministry of Education, Science, Sports and Culture of Japan; "Research for the Future" Program by The Japan Society for the Promotion of Science (JSPS-RFTF97I00201); New Energy and Industrial Technology Development Organization; The Science Frontier Program of MESSC of Japan; Tokai University School of Medicine Project Research and Research Aid; and The Ichiro Kanehara Foundation.

Address for reprints: Hidezo Mori, MD, PhD, Department of Physiology, Tokai University School of Medicine, Isehara 259-1193, Japan (E-mail: coronary{at}keyaki.cc.u-tokai.ac.jp).

Objectives: Restoration of coronary blood flow by angiogenesis may offer a new approach to intractable ischemic heart disease. In the present study, we investigated the angiogenic effects of gene transfer of vascular endothelial growth factor 165 on microvascular myocardial ischemia.
Methods: A rabbit model of microvascular myocardial ischemia was created by plugging coronary microvessels with microspheres (15 µm in diameter, 2.8 x 10⁵/kg, n = 29). Gene transfer was performed by semi-selective intracoronary injection of recombinant adenovirus expressing vascular endothelial growth factor 165 forty minutes after microsphere injection (n = 9).
Results: Microsphere injection reduced myocardial perfusion (78% ± 9% of baseline tissue flow) and diminished myocardial contraction (61% ± 12% of the baseline ejection fraction) and cardiac performance (elevated left ventricular end-diastolic pressure and decreased systemic flow) in the acute phase. At 17 ± 3 days, gene transfer of vascular endothelial growth factor 165 had had the following effects: (1) promoted coronary angiogenesis as evidenced by myocardial flow above the baseline (121% ± 24%), (2) increased vascular density revealed by synchrotron radiation microangiography and histologic analysis, (3) ameliorated the degree of myocardial ischemia as evidenced by myocardial lactate content and the extent of histologic necrosis, and (4) restored heart function as evidenced by increased ejection fraction (95% ± 10%), reduced left ventricular end-diastolic pressure, and restored body weight.
Conclusions: In vivo vascular endothelial growth factor 165 gene transfer promoted angiogenesis and was an effective approach to treating microvascular myocardial ischemia.

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