Hariawala M D, Horowitz J R, Esakof D, Sheriff D D, Walter D H, Keyt B, Isner J M, Symes J F
Division of Cardiothoracic Surgery, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
J Surg Res. 1996 Jun;63(1):77-82. doi: 10.1006/jsre.1996.0226.
Several recent studies have demonstrated the potential for improving myocardial perfusion by the continuous administration of angiogenic growth factors. Studies in our laboratory have shown that a single intraarterial or intravenous bolus of the endothelial cell specific mitogen vascular endothelial growth factor (VEGF) can significantly improve perfusion in a rabbit ischemic limb model. To test the efficacy of this therapeutic approach in chronic myocardial ischemia, 18 Yorkshire pigs underwent a left thoracotomy followed by placement of an ameroid constrictor around the proximal circumflex coronary artery. Gradual occlusion of the artery (26 +/- 4 days) was accompanied by identifiable hypokinesis of the posterolateral wall of the left ventricle (2D echo). Thirty days postoperatively, rhVEGF(165) (2 mg; n = 8) or saline (n = 10) was administered directly into the left coronary ostium. Postadenosine myocardial perfusion studies using colored microspheres 30 days later demonstrated superior blood flow in the ischemic zone of the VEGF-treated hearts (ischemic/normal ratio 1.09 vs 0.97, P < 0.05) compared with those receiving saline injection. Four of eight VEGF-treated animals succumbed, however, to severe hypotension following VEGF administration. Therefore 500 micrograms of VEGF were administered intracoronary to five normal pigs. A significant drop in mean arterial pressure (-44.4 +/- 3.2%, P < 0.05 vs baseline) and peripheral resistance (-13.2 +/- 4.5%, P < 0.05 vs baseline) was accompanied by increased heart rate. IV administration of N(omega)-nitro-L-arginine (L-NNA), an EDRF inhibitor, restored blood pressure to baseline. We conclude that a single intracoronary bolus of VEGF is capable of significantly augmenting flow to collateral-dependent ischemic myocardium. The associated hypotension appears to be EDRF-mediated. Further studies are needed to define the best dose and route of administration of VEGF for the treatment of coronary insufficiency.
最近的几项研究表明，通过持续给予血管生成生长因子来改善心肌灌注具有潜力。我们实验室的研究表明，单次动脉内或静脉推注内皮细胞特异性有丝分裂原血管内皮生长因子（VEGF）可显著改善兔缺血肢体模型的灌注。为了测试这种治疗方法在慢性心肌缺血中的疗效，18只约克夏猪接受了左胸切开术，然后在左旋支冠状动脉近端放置阿梅罗伊德缩窄环。动脉逐渐闭塞（26±4天）伴随着左心室后壁可识别的运动减弱（二维超声心动图）。术后30天，将重组人VEGF（165）（2毫克；n = 8）或生理盐水（n = 10）直接注入左冠状动脉口。30天后使用彩色微球进行腺苷后心肌灌注研究表明，与接受盐水注射的心脏相比，VEGF治疗的心脏缺血区血流更好（缺血/正常比值1.09对0.97，P < 0.05）。然而，8只接受VEGF治疗的动物中有4只在给予VEGF后死于严重低血压。因此，向5只正常猪冠状动脉内给予500微克VEGF。平均动脉压显著下降（-44.4±3.2%，与基线相比P < 0.05）和外周阻力下降（-13.2±4.5%，与基线相比P < 0.05），同时心率增加。静脉注射内皮舒张因子抑制剂N（ω）-硝基-L-精氨酸（L-NNA）可使血压恢复到基线水平。我们得出结论，单次冠状动脉推注VEGF能够显著增加依赖侧支循环的缺血心肌的血流量。相关的低血压似乎是由内皮舒张因子介导的。需要进一步研究来确定VEGF治疗冠状动脉供血不足的最佳剂量和给药途径。
