Ruel Marc, Wu Gui Fu, Khan Tanveer A, Voisine Pierre, Bianchi Cesario, Li Jianyi, Li Jian, Laham Roger J, Sellke Frank W
Center for Minimally Invasive Surgery, Harvard Medical School, Boston, MA, USA.
Circulation. 2003 Sep 9;108 Suppl 1:II335-40. doi: 10.1161/01.cir.0000087903.75204.ad.
Discrepancy exists between the potent effects of therapeutic angiogenesis in laboratory animals and the marginal results observed in patients with advanced coronary artery disease. In vitro and small animal data suggest that angiogenesis may depend on locally available nitric oxide (NO), but the impact of endothelial dysfunction on therapeutic angiogenesis in the myocardium has been unclear. We compared the effects of clinically applicable angiogenesis methods in swine in which endothelial dysfunction was experimentally induced to that observed in normal swine.
Miniswine were fed either a regular (N=13) or hypercholesterolemic diet (N=13) for 20 weeks. Hypercholesterolemic swine showed coronary endothelial dysfunction on videomicroscopy. Animals from both groups received 100 microg of perivascular sustained-release fibroblast growth factor (FGF)-2 in the lateral myocardial territory, previously made ischemic by placement of an ameroid constrictor around the circumflex artery. After 4 weeks of FGF-2 therapy, lateral myocardial perfusion was significantly lower in hypercholesterolemic than in normocholesterolemic swine, both at rest and during pacing (0.44+/-0.04 versus 0.81+/-0.15 mL/min/g at rest, respectively; P=0.006; and 0.50+/-0.06 versus 0.71+/-0.10 mL/min/g during pacing; P=0.02). Hypercholesterolemic swine showed no net increase in perfusion from FGF-2 treatment. Endothelial cell density and FGF receptor-1 expression were significantly lower in the lateral territory of hypercholesterolemic versus normocholesterolemic animals.
The cardiac angiogenic response to FGF-2 treatment using clinically applicable methods was markedly inhibited in hypercholesterolemic swine with coronary endothelial dysfunction. These findings suggest that coronary endothelial dysfunction is major obstacle to the efficacy of clinical angiogenesis protocols and constitutes a target toward making angiogenesis more effective in patients with advanced coronary disease.
治疗性血管生成在实验动物中具有显著效果，但在晚期冠状动脉疾病患者中观察到的效果却很有限，两者存在差异。体外和小动物实验数据表明，血管生成可能依赖于局部可利用的一氧化氮（NO），但内皮功能障碍对心肌治疗性血管生成的影响尚不清楚。我们比较了在实验性诱导内皮功能障碍的猪和正常猪中，临床适用的血管生成方法的效果。
小型猪分别喂食常规饮食（N = 13）或高胆固醇饮食（N = 13）20周。高胆固醇血症猪在视频显微镜下显示冠状动脉内皮功能障碍。两组动物均在外侧心肌区域接受100微克血管周围缓释成纤维细胞生长因子（FGF）-2，该区域先前通过在回旋动脉周围放置阿梅罗氏缩窄环造成缺血。FGF-2治疗4周后，高胆固醇血症猪外侧心肌灌注在静息和起搏时均显著低于正常胆固醇血症猪（静息时分别为0.44±0.04 vs 0.81±0.15毫升/分钟/克；P = 0.006；起搏时为0.50±0.06 vs 0.71±0.10毫升/分钟/克；P = 0.02）。高胆固醇血症猪经FGF-2治疗后灌注无净增加。高胆固醇血症动物外侧区域的内皮细胞密度和FGF受体-1表达显著低于正常胆固醇血症动物。
在患有冠状动脉内皮功能障碍的高胆固醇血症猪中，使用临床适用方法对FGF-2治疗的心脏血管生成反应明显受到抑制。这些发现表明，冠状动脉内皮功能障碍是临床血管生成方案疗效的主要障碍，也是使血管生成在晚期冠心病患者中更有效的一个靶点。
