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EXPERIMENTAL STUDY

Efficacy of intracoronary or intravenous VEGF₁₆₅ in a pig model of chronic myocardial ischemia

Kaori Sato, MD^* , Tiangen Wu, MD^*, Roger J. Laham, MD^*, Robert B. Johnson, MD^*, Pamela Douglas, MD, FACC^*, Jianyi Li, MSc, Frank W. Sellke, MD, Stuart Bunting, PhD, Michael Simons, MD, FACC^* and Mark J. Post, MD, PhD^*

^* Angiogenesis Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Division of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Genentech, Inc., South San Francisco, California, USA

Manuscript received October 20, 1999; revised manuscript received September 12, 2000, accepted October 16, 2000.

Reprint requests and correspondence: Dr. Mark J Post, Angiogenesis Research Center, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, Massachusetts 02215
mpost{at}caregroup.harvard.edu

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 VEGF₁₆₅ is one of the most potent pro-angiogenic growth factors, VEGF₁₆₅ treatment 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 rhVEGF₁₆₅ in 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 VEGF₁₆₅ 0.25 µg/kg/min, 2) slow (200 min) intravenous VEGF₁₆₅ 0.05 µg/kg/min, 3) rapid intracoronary VEGF₁₆₅ 0.25 µg/kg/min, 4) rapid intracoronary VEGF₁₆₅ 0.25 µg/kg/min + nitro-L-arginine methyl ester hydrochloride (L-NAME) or 5) rapid vehicle infusion.

RESULTS

Intracoronary and intravenous VEGF₁₆₅ induced 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 VEGF₁₆₅ groups. 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 VEGF₁₆₅ significantly 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 VEGF₁₆₅ was not effective in augmenting either myocardial flow or function in this model.

Abbreviations and Acronyms   ANOVA = analysis of variance   IC = intracoronary   IV = intravenous   LAD = left anterior descending artery   LCX = left coronary circumflex artery   L-NAME = N-nitro-L-arginine methyl ester hydrochloride   LV = left ventricle, left ventricular   MANOVA = multivariate analysis of variance   NO = nitric oxide   NOS = nitric oxide synthase   SNP = sodium nitroprusside   VEGF = vascular endothelial growth factor

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