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Leonard Y. Lee
Shailen R. Patel
Charles A. Mack
O. Wayne Isom
Todd K. Rosengart
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Ann Thorac Surg 2000;69:14-23
© 2000 The Society of Thoracic Surgeons

Original Articles

Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 1211

Leonard Y. Lee, MDa,b, Shailen R. Patel, MDa,b, Neil R. Hackett, PhDb, Charles A. Mack, MDa,b, Dean R. Polce, BSa,b, Tarek El-Sawy, BSa,b, Rory Hachamovitch, PhDc,d, Pat Zanzonico, PhDc, Timothy A. Sanborn, MDd, Manish Parikh, PhDd, O. Wayne Isom, MDa, Ronald G. Crystal, MDb, Todd K. Rosengart, MDa

a Department of Cardiothoracic Surgery, The New York Hospital-Cornell Medical Center, New York, New York, USA
b Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center, New York, New York, USA
c Division of Nuclear Medicine, The New York Hospital-Cornell Medical Center, New York, New York, USA
d Division of Cardiology, The New York Hospital-Cornell Medical Center, New York, New York, USA

Address reprint requests to Dr Rosengart, Evanston Northwestern Healthcare, 2650 Ridge Ave, Evanston, IL 60201
e-mail: t-rosengart{at}nwu.edu

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

Background. Adenovirus (Ad) vector-mediated gene therapy strategies have emerged as promising modalities for the "biological revascularization" of tissues. We hypothesized that direct intramyocardial, as opposed to intracoronary, administration of an Ad vector coding for the vascular endothelial growth factor 121 cDNA (AdGVVEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic angiogenesis.

Methods. Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and enzyme-linked immunosorbent assay, after intramyocardial AdGVVEGF121.10 in the rat, and either intramyocardial or intracoronary (circumflex territory) vector in Yorkshire swine. Based on these results, we assessed the focal nature of the improved cardiac blood flow in a previously reported porcine myocardial ischemia model.

Results. Intramyocardial delivery of AdGVVEGF121.10 in the rat resulted in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks, with peak myocardial VEGF expression 24 to 72 h after vector delivery. After intramyocardial AdGVVEGF121.10 in the circumflex distribution of pigs, Ad vector genome and VEGF protein levels were more than 1,000-fold and more than 90-fold higher, respectively, in this distribution than in other myocardial regions. In comparison, intracoronary injection yielded maximum myocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days after intramyocardial AdGVVEGF121.10 demonstrated rapid circumflex reconstitution via collaterals localized to the region of vector administration.

Conclusions. These studies demonstrate that direct intramyocardial administration of AdGVVEGF121.10 results in focal genome and VEGF levels, including focal angiogenesis, sufficient to normalize blood flow to the ischemic myocardium, findings that are relevant to designing human trials of gene therapy-mediated cardiac angiogenesis.




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