OBJECTIVEVectors commonly used for therapeutic angiogenesis such as adenovirus and plasmid had their own limitations. Adenovirus-associated virus (AAV) is a relatively new but probably more ideal vector as it is safe and efficient. We will study the efficiency of recombinant AAV-2 mediated vascular endothelial growth factor165 gene transfer in inducing angiogenesis and arteriogenesis, in improving blood flow and myocardium function in a porcine chronic myocardial ischemic model.

METHODSChinese experimental minipigs underwent placement of a left circumflex artery aneroid constrictor. Five weeks later, electrocardiogram, coronary angiography and magnetic resonance imaging were performed to confirm occlusion of LCX or ischemia of myocardium in LCX territory. Coronary blood flow, myocardium perfusion and left ventricular wall function were also evaluated. Then the animals were randomized to treatment with rAAV2-VEGF(165) (1 x 10(12) virus genome) or administration of PBS, both by direct myocardial injection. Three and six months after therapy, the animals were evaluated with regard to expression of VEGF(165) Capillary density and arteriole density of the ischemic myocardium, coronary angiography, myocardial perfusion and left ventricular function were also assessed six months after therapy.

RESULTSFive weeks after aneroid occluder implantation, all the animals demonstrated complete or nearly complete occlusion of LCX and perfusion deficiency in LCX territory. Three months after therapy, expression of VEGF(165) mRNA and protein were higher in the VEGF than control group. The difference between the two groups diminished after six months. There was significant increase in capillary density (1404.06 +/- 250.48/mm(2) vs 976.88 +/- 344.79/mm(2), P < 0.05) and arteriole density (167.81 +/- 36.29/mm(2) vs 116.56 +/- 34.48/mm(2), P < 0.05) in VEGF group compared with control. Comparison of myocardial perfusion demonstrated marked differences between the two groups with significant improvement in animals treated with rAAV2-VEGF(165). No significant improvement in left ventricular function was seen in either the VEGF or control group.

CONCLUSIONSTransmyocardial delivery of rAAV2-VEGF(165) resulted in VEGF gene expression for at least three months and stimulated angiogenesis and arteriogenesis in porcine model of chronic myocardial ischemia. Myocardial perfusion was also improved after VEGF gene delivery.