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J Thorac Cardiovasc Surg 1998;115:168-177
© 1998 Mosby, Inc.
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Department of Cardiothoracic Surgery,a Division of Pulmonary and Critical Care Medicine,b Division of Nuclear Medicine,c and Division of Cardiology,d The New York Hospital–Cornell Medical Center, New York, N.Y., and GenVec, Inc.,e Rockville, Md. These studies were supported, in part, by The Jeffry M. and Barbara Picower Foundation, Palm Beach, Florida; by GenVec, Inc., Rockville, Maryland; the Will Rogers Memorial Fund, White Plains, New York; The New York Heart Association, Grant-in-Aid 94066; and GCRC Grant RR00102.
Read at the Seventy-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, D.C., May 4-7, 1997.
Received for publication May 9, 1997. Accepted for publication Sept. 15, 1997. Revisions requested July 15, 1997; revisions received Sept. 2, 1997. Address for reprints: The New York Hospital–Cornell Medical Center, New York, NY 10021.
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 VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) 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) with99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10 8 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 AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 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.
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