Toward surgical angiogenesis using slow-released basic fibroblast growth factor.
OBJECTIVE
Therapeutic angiogenesis using basic fibroblast growth factor (bFGF) in coronary artery disease has been documented in a number of papers. However, the effectiveness is discrepant among documents. In this study, we evaluated the distribution of bFGF in the rat heart by different administration methods, and investigated the efficacy of slow-released administration of bFGF using biodegradable hydrogel microspheres (bFGF microspheres) in a pig infarction model toward an enhanced coronary bypass surgery.


METHODS
Heart failure due to myocardial infarction was induced in rats and pigs. In the rat study, free form of bFGF (central venous injection, intracoronary injection, and intramyocardial administration) and bFGF microspheres (intramyocardial administration) were given 4 weeks later. The remaining radioactivity of bFGF in the hearts was estimated 1, 24, and 72 h later. On the other hand, the pigs were randomized into two groups 4 weeks after myocardial infarction. While the control group (n=8) had gelatin hydrogel microspheres with saline, the FGF group (n=8) received bFGF microspheres in the left ventricular (LV) wall.


RESULTS
In the rat study, after intramyocardial administration of bFGF microspheres, more bFGF remained in the rat heart 72 h later compared with the other methods (P<0.0001). In the pig study, 4 weeks after the treatment, the FGF group had smaller LV diastolic diameter (48.7+/-5.3 vs. 56.7+/-5.2 mm, P<0.01) than the control group. LV end-systolic elastance was higher in the FGF group (2.96+/-1.2 vs. 1.06+/-0.3 mmHg/ml, P<0.01). In microscopic examinations, many neovessels were found in and around the scar tissue, and the vascular density in the FGF group was significantly higher (61.5+/-18.3 vs. 153.0+/-29.0/mm2, P<0.01). In addition, the infarcted LV walls were less expanded and more thickened in the FGF group.


CONCLUSIONS
Biodegradable hydrogel microspheres with bFGF improved LV function and inhibited LV remodeling by angiogenesis in pigs with chronic myocardial infarction. bFGF microspheres into ischemic myocardium may revascularize small ungraftable vessels and may potentially increase distal run-off when applied in coronary bypass surgery.
Sakakibara
Yutaka
Y
Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Tambara
Keiichi
K
Sakaguchi
Genichi
G
Lu
Fanglin
F
Yamamoto
Masaya
M
Nishimura
Kazunobu
K
Tabata
Yasuhiko
Y
Komeda
Masashi
M
D000818:Animals; D001673:Biodegradation, Environmental; D003097:Collateral Circulation; D017023:Coronary Angiography; D003692:Delayed-Action Preparations; D004452:Echocardiography; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D005782:Gels; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018919:Neovascularization, Physiologic; D011897:Random Allocation; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D013552:Swine; D017725:Ventricular Pressure
D003692:Delayed-Action Preparations; D005782:Gels; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D020097:Natriuretic Peptide, Brain