摘要目的探讨以腺病毒(Ad)为载体的血管内皮生长因子165 cDNA(Ad-VEGF165)能否诱导猪缺血心肌血管生成、改善心肌灌注和功能并是否安全. 方法将小型猪行胸廓切开术后将Ameroid constrictor 置于左冠状动脉回旋支近端.3周后随机分成两组,再次行胸廓切开术并将Ad-VEGF165 (n=6)或对照剂以Ad为载体的β-半乳糖酶基因(Ad-Gal,n=6)注入LCX分布区的缺血心肌内,喂养4周.以心电图门控单光子发射计算机断层显像检测心肌灌注和功能,以离体冠状动脉造影检测侧枝血管生成.于载体释放前( 第0天)和释放后第1、3、7、28天抽血行血常规、肝肾功能、心肌酶检测并行血管、心肌、肝脏组织学检查以检测其安全性.结果与对照组和治疗组注射Ad-VEGF165之前相比,给予Ad-VEGF165治疗4周后心肌缺血面积( P＜0.01)、静息最大缺血程度(P＜0.01)明显减小,左心室射血分数(P＜0.01 )和局部室壁运动(P＜0.05)明显改善.冠状动脉造影示治疗组侧枝血管明显多于对照组(P＜0.05).对照组和治疗组血常规、肝肾功能和心肌酶检测示仅第28天时红细胞计数和血尿素氮略有差别(P＜0.05),与载体释放前比较,两组均仅在第1天的肌酸磷酸激酶(P＜0.05)和谷丙转氨酶(P＜0.05)有短暂升高.组织学检测未见LCX动脉粥样硬化斑块形成和肝脏炎症反应,对照组(面积＜10%)和治疗组(面积≤20%)各有1只动物见小面积心肌梗死,未见炎症反应.结论心肌注射Ad-VEGF165可诱导冠状动脉侧枝血管形成、改善心肌灌注和功能并且相当安全, 表明该方法有望成为一种治疗缺血性心脏病的新方法.

abstractsObjective To investigate whether direct administration of adenoviral vectors (Ad) containi ng 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 β-galactosidase cDNA (Ad-Gal, n=6), was di rectly administered into the ischemic myocardium in the circumflex distribution . All animals were sacrificed 4 wk after the second surgery. Myocardial perfus i on and function were assessed by electrocardiogram-gated single photon emission computed tomography (GSPECT) imaging. Ex vivo coronary angiography was perform ed to examine collateral vessels. Toxicity was assessed by blood analyses on th e day just before (day 0) and on day 1, 3, 7, 28 after vector delivery and by va scular, 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 assess ed by coronary angiography was significantly greater in the Ad-VEGF165 group th an in the Ad-Gal group (P＜0.05). General safety parameters, including ro utine blood parameters, liver and kidney function and cardiac specific parameter s 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 ather osclerotic lesion in the circumflex and no inflammation in liver were revealed a nd only a small myocardial necrosis was observed in one Ad-VEGF165 animal (area ≤20%) and one Ad-Gal animal (area＜10%). Conclusions Ad-VEGF165 can induce coronary collateral vessel formation, improve regional my ocardial perfusion and function and is safe by means of direct injection, which suggesting that this strategy may be useful in treating human ischemic heart dis ease.