Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction.
BACKGROUND
Vascular endothelial growth factor (VEGF)-165 promotes cardiomyogenesis in chronic myocardial ischemia and nonreperfused myocardial infarction (MI). It is unknown whether this effect is present in reperfused MI. We sought to investigate the effect of VEGF-165 gene therapy on cardiomyogenesis after reperfused MI.


RESULTS
Twenty-four Yucatan minipigs underwent thoracotomy and a vascular clamp was placed in the left circumflex artery. Reperfusion was reestablished after 90 minutes, and VEGF-165 gene therapy or placebo was administered. A replication-deficient recombinant human adenovirus serotype 5 was used for gene transfer (Ad5-VEGF165). The same viral vector devoid of VEGF gene (Ad5-beta-galactosidase) was used as placebo. Two administration routes were tested, intramyocardial (IM) injection and circumflex intracoronary (IC) infusion. The pigs were assigned to one of the following groups: IM Ad5-VEGF165 (n = 6), IM Ad5-betaGal (n = 6), IC Ad5-VEGF165 (n = 6), and IC Ad5-betaGal (n = 6). All pigs received 5-bromo-2'-deoxyuridine (BrdU) 250 mg IV twice a week to label cells undergoing DNA replication. The hearts were explanted at 4 weeks. BrdU-labeled cardiomyocytes in the peri-infarct area were counted by a pathologist blinded to group assignment. The number of BrdU-labeled cardiomyocytes per million cells was 4-fold higher in the group receiving IM VEGF-165 (64 +/- 11.4) vs. IM placebo (16 +/- 10.6), P = 0.034. No difference in infarct size or ventricular function was observed between the groups.


CONCLUSIONS
IM VEGF-165 gene therapy promotes cardiomyogenesis in reperfused MI. However, no benefit in infarct size or cardiac function was observed at 4 weeks. The origin of these cells remains unknown and needs to be determined.
Guerrero
Mayra
M
Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan, USA. mguerre1@hfhs.org
Athota
Krishna
K
Moy
Jason
J
Mehta
Laxmi S
LS
Laguens
Ruben
R
Crottogini
Alberto
A
Borrelli
Michael
M
Corry
Peter
P
Schoenherr
Diane
D
Gentry
Ralph
R
Boura
Judith
J
Grines
Cindy L
CL
Raff
Gilbert L
GL
Shanley
Charles J
CJ
O'Neill
William W
WW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D019028:Magnetic Resonance Imaging, Cine; D024510:Muscle Development; D009203:Myocardial Infarction / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D015425:Myocardial Reperfusion; D013552:Swine; D013556:Swine, Miniature; D014161:Transduction, Genetic / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000627:therapeutic use*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A