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J Thorac Cardiovasc Surg 2005;130:1364
© 2005 The American Association for Thoracic Surgery

Evolving Technology

Efficient myocyte gene delivery with complete cardiac surgical isolation in situ

Charles R. Bridges, MD, ScD a , * , Kapil Gopal, MD a , David E. Holt, BVSc b , Charles Yarnall, BS a , Steven Cole, VMD b , Rochelle B. Anderson, DVM b , Xiaoqing Yin, MD a , Anthony Nelson, BS a , Benjamin W. Kozyak, BS a , Zhonglin Wang, MD a , James Lesniewski, MD a , Leonard T. Su, MD a , Danielle M. Thesier, BS a , Hari Sundar, BE a , Hansell H. Stedman, MD a

a Departments of Surgery of the University of Pennsylvania Health System, Philadelphia, Pa.
b Veterinary Hospital of the University of Pennsylvania, Philadelphia, Pa.

Received for publication January 3, 2005; revisions received May 2, 2005; accepted for publication July 5, 2005.

* Address for reprints: Charles R. Bridges, MD, ScD, Department of Surgery, the University of Pennsylvania Health System, 4 Silverstein, Hospital of the University of Pennsylvania, Philadelphia, Pa., 19104. (Email: cbridges{at}pahosp.com).

BACKGROUND: Previously, we used cardiopulmonary bypass with incomplete cardiac isolation and antegrade administration of vector for global cardiac gene delivery. Here we present a translatable cardiac surgical procedure that allows for complete surgical isolation of the heart in situ with retrograde (through the coronary venous circulation) administration of both vector and endothelial permeabilizing agents to increase myocyte transduction efficiency.

METHODS: In 6 adult dogs the heart was completely isolated with tourniquets placed around both vena cavae and cannulas and all pulmonary veins. On cardiopulmonary bypass, the aorta and pulmonary artery were crossclamped, and the heart was isolated. Crystalloid cardioplegia at 4°C containing 1013 particles of adenovirus encoding LacZ and 15 µg of vascular endothelial growth factor was infused retrograde into the coronary sinus and recirculated for a total of 30 minutes. The dogs were then weaned from cardiopulmonary bypass and allowed to recover. With a catheter, 3 control dogs underwent retrograde infusion of the same cocktail without cardiac isolation or cardiopulmonary bypass.

RESULTS: ß-Galactosidase activities in the cardiopulmonary bypass group were several orders of magnitude higher in both the right and left ventricles when compared with those in the control group (P < .05). X-gal staining from the cardiopulmonary bypass group showed unequivocal evidence of myocyte gene expression globally in a significant proportion of cardiac myocytes. No myocyte gene expression was observed in the control group.

CONCLUSION: A novel cardiac surgical technique has been developed. This approach with cardiac isolation and retrograde delivery of vector through the coronary sinus results in efficient myocyte transduction in an adult large animal in vivo.

Abbreviations and Acronyms AAV = adeno-associated virus; CPB = cardiopulmonary bypass; VEGF = vascular endothelial growth factor




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