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J Thorac Cardiovasc Surg 2005;129:1071-1077
© 2005 The American Association for Thoracic Surgery

Evolving Technology

Improvement of myocardial contractility in a porcine model of chronic ischemia using a combined transmyocardial revascularization and gene therapy approach

^a Northwestern University, Feinberg School of Medicine, Chicago, Ill.
^b Selective Genetics Inc, San Diego, Calif.

The research presented here was funded in part by the American Heart Association grant 0030271N. Adenoviral vector for FGF2 and matrix was provided by Selective Genetics Inc, San Diego, Calif.

Received for publication July 21, 2004; revisions received October 14, 2004; accepted for publication October 27, 2004.

^_* Address for reprints: Keith A. Horvath, MD, Chief, Cardiothoracic Surgery Branch, National Heart, Lung, and Blood Institute, NIH, Building 10, Room 8C103, 10 Center Dr, MSC 1754, Bethesda, MD 20892. (E-mail: horvathka{at}mail.nih.gov).

OBJECTIVES: The purpose of this study was to investigate whether a novel fibroblast growth factor-2 gene formulation, providing a localized and sustained availability of the adenoviral vector from a collagen-based matrix, in combination with CO₂ transmyocardial laser revascularization would lead to an enhanced angiogenic response and improved myocardial function.

METHODS: Fibroblast growth factor-2 gene was delivered by means of an adenoviral vector (adenoviral fibroblast growth factor-2) formulated in a collagen-based matrix. The ischemic areas of 33 animals were then treated. Group 1 was treated with CO₂ transmyocardial laser revascularization; group 2 was treated with intramyocardial injections of adenoviral fibroblast growth factor-2 in a collagen-based matrix; group 3 had a combination treatment of matrix adenoviral fibroblast growth factor-2 and CO₂ transmyocardial laser revascularization; and group 4 received injections with saline-formulated adenoviral fibroblast growth factor-2. Baseline left ventricular function was assessed by echocardiography and cine magnetic resonance imaging. Studies were repeated 6 weeks after treatment. Vascular development was assessed using anti--actin immunohistochemistry.

RESULTS: Matrix adenoviral fibroblast growth factor-2 + transmyocardial laser revascularization-treated areas had a 105% increase in arteriolar development versus either treatment alone (P < .05) and a 390% increase compared with saline-formulated adenoviral fibroblast growth factor-2 treatment alone (P < .05). Contractility was significantly improved in matrix adenoviral fibroblast growth factor-2 + transmyocardial laser revascularization-treated areas as measured by myocardial wall thickening. This functional improvement was confirmed by cine magnetic resonance imaging, in which a 90% increase in the contractility of the treated segments was demonstrated after matrix adenoviral fibroblast growth factor-2 + transmyocardial laser revascularation. The other treatments provided significantly less restoration of myocardial function.

CONCLUSIONS: The increase in angiogenesis as a result of matrix adenoviral fibroblast growth factor-2 gene therapy in combination with CO₂ transmyocardial laser revascularization is greater than that seen in either therapy alone. A concomitant improvement in myocardial function was seen as a result of this angiogenic response.

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