Therapeutic angiogenesis in chronically ischemic porcine myocardium: Comparative effects of bFGF and VEGF

Background. Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been used in preclinical studies to induce new blood vessel growth in ischemic cardiac muscle with promising results. However, clinical trials have been much less convincing and further work is needed. This study expands on prior work by comparing the long-term proangiogenic effects of direct intramyocardial (IM) injection of bFGF, as well as IM and intravenous (IV) VEGF in a porcine model of chronic hibernating myocardium. Methods. Mini-swine with proximal 90% left circumflex (LCx) coronary stenosis subtending chronically ischemic, viable (hibernating) myocardium by positron emission tomography (PET) and dobutamine stress echocardiography (DSE) were randomized to IM bFGF (n = 5), IM VEGF ₁₆₅ (n = 5), IV VEGF₁₆₅ (n = 5), IM vehicle (n = 5), or sham redo-thoracotomy (n = 4). The bFGF protein was administered in a total dose of 1.35 μg divided into 30 IM injections. IM VEGF₁₆₅ protein was administered in a total dose of 15 μg/kg divided into 30 injections; IV VEGF₁₆₅ was given at a dose of 50 ng·kg^-1 ·min^-1 for 200 minutes at three 72-hour intervals (30 μg/kg total dose). After 3 and 6 months the PET and DSE studies were repeated, and the animals were sacrificed for tissue vascular density and angiogenic protein analysis. Results. Myocardial blood flow (MBF) by PET was significantly improved 3 months posttreatment in the IM bFGF and IM VEGF ₁₆₅ groups, differences that were sustained at 6 months. There was no significant increase in MBF 3-months posttreatment in the IV VEGF ₁₆₅ group; however, at 6 months MBF was significantly improved. No change in MBF was seen in the IM vehicle or sham groups. Regional wall motion at rest and peak stress in the LCx region demonstrated small but statistically significant improvements by 6 months in the IM bFGF and IV VEGF₁₆₅ groups only; no improvement was seen in the IM VEGF₁₆₅, IM vehicle, or sham groups. Quantitative vascular density was significantly increased in the LCx regions of all treatment groups (IM bFGF, IM VEGF₁₆₅, IV VEGF₁₆₅) 6-months postoperatively. No significant increase in LCx region myocardial bFGF or VEGF protein levels was seen in the treated animals at 6 months. Conclusions. The IM bFGF, IM VEGF₁₆₅, and IV VEGF ₁₆₅ all improve regional perfusion and vascular density 6-months posttherapy in the animal model utilized. Functional improvements were less consistent. Both bFGF and VEGF₁₆₅ may be useful therapies for improving regional perfusion in chronically ischemic myocardium, although combination therapy with additional growth factors or cellular therapies may be necessary if concomitant improvements in function are to be seen.