Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium

Both VEGF protein and VEGF DNA in combination:with an adenoviral vector hav e been shown to enhance collateral formation in a porcine model of chronic myocardial ischemia. We sought to determine whether direct intramyocardial injection of naked DNA encoding for VEGF could similarly improve myocardial perfusion. Initially, 23 nonischemic pigs received either 200 mu g of plas mid DNA encoding beta-galactosidase (pCMV beta, n = 11) or 500 mu g of phVE GF165 (n = 12) into four separate sites in the myocardium via a small anter olateral thoracotomy incision in the fourth intercostal:space, Two addition al groups of pigs received an intramyocardial injection of either phVEGF165 (n = 6) or pCMV beta (n = 7) 3 to 4 weeks after implantation of an ameroid constrictor around the left circumflex coronary artery. The injections cau sed no change in heart rate or blood pressure, and no ventricular arrhythmi as or histologic evidence of inflammation. VEGF protein was detected by Wes tern blot in VEGF-treated animals, with the strongest bands closest to the injection site. Plasma VEGF concentration (ELISA) increased from 3 +/- 2 to 27 +/- 13 pg/ml (p = 0.035) by day 4 after treatment. No increase in VEGF protein was noted in pCMV beta-treated animals whereas these did stain posi tive for beta-Gal. Resting myocardial blood flow (colored microspheres) was significantly reduced in the ischemic versus nonischemic territory in cont rol animals (1.07 +/- 0.05 versus 1.32 +/- 0.05; p < 0.05) but not VEGF-tre ated pigs (1.32 +/- 0.24 versus 1.13 +/- 0.12; p = NS). Maximal vasodilatat ion with adenosine significantly increased flow to the ischemic region in V EGF-treated pigs (2.16 +/- 0.57 versus 1.32 +/- 0.24; p < 0.05) but not con trols (1.31 +/- 0.05 versus 1.17 +/- 0.06; p = NS), Collateral filling of t he occluded circumflex artery improved in five of six VEGF-treated pigs (me an change in Rentrop score, +1.5). We conclude that direct intramyocardial transfection phVEGF165 is safe and capable of producing sufficient VEGF pro tein to enhance collateral formation and myocardial perfusion. This approac h may offer an alternative therapy for patients with intractable myocardial ischemia not amenable to PTCA or CABG.