Improvement of myocardial contractility in a porcine model of chronic ischemia using a combined transmyocardial revascularization and gene therapy approach.
OBJECTIVE
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 CO 2 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 CO 2 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 CO 2 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-alpha-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 CO 2 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.
Horvath
Keith A
KA
Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. horvathka@mail.nih.gov
Lu
Chia Yang J
CY
Robert
Emmanuel
E
Pierce
Glenn F
GF
Greene
Rodney
R
Sosnowski
Barbara A
BA
Doukas
John
J
D000256:Adenoviridae; D000818:Animals; D001160:Arterioles / Q000254:growth & development; D002626:Chemistry, Pharmaceutical; D002908:Chronic Disease; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004452:Echocardiography; D005080:Exercise Test; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D007150:Immunohistochemistry; D053685:Laser Therapy / Q000379:methods*; D019028:Magnetic Resonance Imaging, Cine; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D018919:Neovascularization, Physiologic; D011897:Random Allocation; D013552:Swine; D016896:Treatment Outcome; D016277:Ventricular Function, Left
D016222:Fibroblast Growth Factor 2