OBJECTIVES

We sought to optimize vascular endothelial growth factor (VEGF) treatment for therapeutic angiogenesis in myocardial ischemia, we explored the efficacy of five different regimens.

BACKGROUND

Although VEGF₁₆₅is one of the most potent pro-angiogenic growth factors, VEGF₁₆₅treatment for myocardial ischemia has been hampered by low efficacy and dose-limiting hypotension after systemic or intracoronary delivery.

METHODS

This study evaluated the effect of intravenous or intracoronary rhVEGF₁₆₅in the presence or absence of nitric oxide (NO) synthase inhibition in a porcine model of chronic myocardial ischemia. Forty-two Yorkshire pigs with chronically occluded left circumflex coronary arteries were randomly assigned to receive 10 μg/kg of VEGF₁₆₅: 1) rapid (40 min) intravenous VEGF₁₆₅0.25 μg/kg/min, 2) slow (200 min) intravenous VEGF₁₆₅0.05 μg/kg/min, 3) rapid intracoronary VEGF₁₆₅0.25 μg/kg/min, 4) rapid intracoronary VEGF₁₆₅0.25 μg/kg/min + nitro-L-arginine methyl ester hydrochloride (L-NAME) or 5) rapid vehicle infusion.

RESULTS

Intracoronary and intravenous VEGF₁₆₅induced hypotension. Intracoronary VEGF-induced hypotension was blocked by L-NAME. Coronary angiography three weeks after treatment showed improvement in collateral index in both intracoronary groups but not the intravenous VEGF₁₆₅groups. Likewise, myocardial blood flow and microvascular function in the ischemic territory improved in both intracoronary groups but not in the intravenous groups. Global and regional myocardial function showed no significant improvements in any groups.

CONCLUSIONS

Intracoronary infusion of VEGF₁₆₅significantly improves blood flow to the ischemic myocardium. Concomitant administration of L-NAME inhibits VEGF-induced hypotension while most likely preserving VEGF-induced angiogenesis. Intravenous infusion of VEGF₁₆₅was not effective in augmenting either myocardial flow or function in this model.