Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction

Mayra Guerrero, Krishna Athota, Jason Moy, Laxmi S. Mehta, Ruben Laguens, Alberto Crottogini, Michael Borrelli, Peter Corry, Diane Schoenherr, Ralph Gentry, Judith Boura, Cindy L. Grines, Gilbert L. Raff, Charles J. Shanley, William W. O'Neill

Research output: Contribution to journalArticle

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Abstract

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. Methods and 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-β-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-βGal (n = 6), IC Ad5-VEGF165 (n = 6), and IC Ad5-βGal (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.

Original languageEnglish (US)
Pages (from-to)242-251
Number of pages10
JournalJournal of Interventional Cardiology
Volume21
Issue number3
DOIs
StatePublished - Jun 1 2008
Externally publishedYes

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Genetic Therapy
Myocardial Infarction
Deoxyuridine
Placebos
Cardiac Myocytes
Swine
Galactosidases
Miniature Swine
Human Adenoviruses
Ventricular Function
Bromodeoxyuridine
Thoracotomy
DNA Replication
Vascular Endothelial Growth Factor A
Genes
Reperfusion
Myocardial Ischemia
Blood Vessels
Arteries
human VEGFA protein

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Cite this

Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction. / Guerrero, Mayra; Athota, Krishna; Moy, Jason; Mehta, Laxmi S.; Laguens, Ruben; Crottogini, Alberto; Borrelli, Michael; Corry, Peter; Schoenherr, Diane; Gentry, Ralph; Boura, Judith; Grines, Cindy L.; Raff, Gilbert L.; Shanley, Charles J.; O'Neill, William W.

In: Journal of Interventional Cardiology, Vol. 21, No. 3, 01.06.2008, p. 242-251.

Research output: Contribution to journalArticle

Guerrero, M, Athota, K, Moy, J, Mehta, LS, Laguens, R, Crottogini, A, Borrelli, M, Corry, P, Schoenherr, D, Gentry, R, Boura, J, Grines, CL, Raff, GL, Shanley, CJ & O'Neill, WW 2008, 'Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction', Journal of Interventional Cardiology, vol. 21, no. 3, pp. 242-251. https://doi.org/10.1111/j.1540-8183.2008.00358.x
Guerrero, Mayra ; Athota, Krishna ; Moy, Jason ; Mehta, Laxmi S. ; Laguens, Ruben ; Crottogini, Alberto ; Borrelli, Michael ; Corry, Peter ; Schoenherr, Diane ; Gentry, Ralph ; Boura, Judith ; Grines, Cindy L. ; Raff, Gilbert L. ; Shanley, Charles J. ; O'Neill, William W. / Vascular endothelial growth factor-165 gene therapy promotes cardiomyogenesis in reperfused myocardial infarction. In: Journal of Interventional Cardiology. 2008 ; Vol. 21, No. 3. pp. 242-251.
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abstract = "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. Methods and 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-β-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-βGal (n = 6), IC Ad5-VEGF165 (n = 6), and IC Ad5-βGal (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.",
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AU - Laguens, Ruben

AU - Crottogini, Alberto

AU - Borrelli, Michael

AU - Corry, Peter

AU - Schoenherr, Diane

AU - Gentry, Ralph

AU - Boura, Judith

AU - Grines, Cindy L.

AU - Raff, Gilbert L.

AU - Shanley, Charles J.

AU - O'Neill, William W.

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N2 - 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. Methods and 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-β-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-βGal (n = 6), IC Ad5-VEGF165 (n = 6), and IC Ad5-βGal (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.

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