Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart

Abstract

Objectives: Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF ₁₂₁ complementary deoxyribonucleic acid (Ad_GVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function. Methods: Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with^99mTc-labeled sestamibi and by echocardiography during rest and stress. Ad_GVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10⁸ pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed. Results: SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in Ad_GVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in Ad _GVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with Ad_GVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in Ad_GVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in Ad_GVVEGF121.10 animals. Conclusions: An Ad vector expressing the VEGF₁₂₁ cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible. (J Thorac Cardiovasc Surg 1998;115:168–77)