Efficacy and safety of therapeutic angiogenesis from direct myocardial administration of an adenoviral vector expressing vascular endothelial growth factor 165.
OBJECTIVE
To investigate whether direct administration of adenoviral vectors (Ad) containing the complementary deoxyribonucleic acid (cDNA) of vascular endothelial growth factor 165 (Ad-VEGF165) induces porcine coronary collateral vessel formation, improves regional myocardial perfusion and function and is safe.


METHODS
Three weeks after miniature swine underwent left thoracotomy and placement of an Ameroid constrictor on the left circumflex coronary artery (LCX), Ad-VEGF165 (n = 6) or the control, Ad expressing beta-galactosidase cDNA (Ad-Gal, n = 6), was directly administered into the ischemic myocardium in the circumflex distribution. All animals were sacrificed 4 wk after the second surgery. Myocardial perfusion and function were assessed by electrocardiogram-gated single photon emission computed tomography (GSPECT) imaging. Ex vivo coronary angiography was performed to examine collateral vessels. Toxicity was assessed by blood analyses on the day just before (day 0) and on day 1, 3, 7, 28 after vector delivery and by vascular, myocardial and liver histology after sacrifice.


RESULTS
GSPECT imaging 4 wk after administration of Ad-VEGF165 demonstrated significant reduction in ischemic area (P < 0.01) and rest ischemic severity (P < 0.01) and significant improvement in the left ventricular ejection fraction (P < 0.01) and regional wall motion (P < 0.05) compared with that of Ad-Gal and before administration of Ad-VEGF165. Collateral vessel development assessed by coronary angiography was significantly greater in the Ad-VEGF165 group than in the Ad-Gal group (P < 0.05). General safety parameters, including routine blood parameters, liver and kidney function and cardiac specific parameters demonstrated no difference between Ad-VEGF165 and Ad-Gal animals except for the red blood cell count on day 28 (P < 0.05) and blood urea nitrogen on day 7 (P < 0.05). Only transient elevations in creatine phosphokinase (P < 0.05) and aspartate transaminase (P < 0.05) on day 1 were revealed compared with that before vector administration in both groups. Histologically, no atherosclerotic lesion in the circumflex and no inflammation in liver were revealed and only a small myocardial necrosis was observed in one Ad-VEGF165 animal (area < or = 20%) and one Ad-Gal animal (area < 10%).


CONCLUSIONS
Ad-VEGF165 can induce coronary collateral vessel formation, improve regional myocardial perfusion and function and is safe by means of direct injection, which suggesting that this strategy may be useful in treating human ischemic heart disease.
Department of Cardiology, the Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China.
Duanzhen
D
Zhang
Luyue
L
Gai
Ruiyun
R
Fan
Wei
W
Dong
Yingfeng
Y
Wen
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003097:Collateral Circulation; D017023:Coronary Angiography; D003331:Coronary Vessels / Q000503:physiopathology; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D004562:Electrocardiography; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000502:physiology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D008222:Lymphokines / Q000235:genetics* / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013552:Swine; D013556:Swine, Miniature; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D008222:Lymphokines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors