Inhibition of the cardiac angiogenic response to surgical FGF-2 therapy in a swine endothelial dysfunction model

Background - 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. Methods and Results - 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 mug 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. Conclusions - 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.