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J Thorac Cardiovasc Surg 1996;111:246-252
© 1996 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

CARDIAC GENE TRANSFER BY INTRACORONARY INFUSION OF ADENOVIRUS VECTOR—MEDIATED REPORTER GENE IN THE TRANSPLANTED MOUSE HEART

Los Angeles, Calif.

From the Division of Cardiothoracic Surgery, University of California at Los Angeles Medical Center, Los Angeles, Calif.

Address for reprints: Hillel Laks, MD, Division of Cardiothoracic Surgery, UCLA Medical Center, Center for the Health Sciences, Room 62-182A, 10833 LeConte Ave., Los Angeles, CA 90024.

Abstract

This study introduces a model for intracoronary gene transfer in murine cardiac isografts using adenovirus vectors. This approach may offer an opportunity to modulate alloreactivity after cardiac transplantation. Donor hearts were infected via the coronary arteries with a volume of 10 ⁹plaque-forming units per milliliter of a recombinant adenovirus containing theß-galactosidase–encoding gene (Ad.CMVLacZ). In a control group, 200µl of normal saline solution was infused. The grafts were stored in 4º C cold saline solution for 15 minutes, then transplanted heterotopically into syngeneic hosts (B10.BR). The grafts were harvested at 3, 7, 15, or 30 days (n= 5 for each group) after transplantation, andß-galactosidase activity was assessed by histochemical staining (X-gal). All grafts were functioning when harvested. X-gal staining pattern was nonuniform with positive staining appearing in epicardial, myocardial, and endocardial cells, as well as in the vessel walls. The cells permissive to infection consisted predominantly of myocardial cells. The mean total numbers ofß-gal–positive staining cells per slice were 68.7 ± 27.3 in the 3-day group, 330.4 ± 53.8 in the 7-day group, 151.3 ± 48.0 in the 15-day group, and 39.9 ± 10.8 in the 30-day group, thus peaking in the 7-day group (p< 0.05). Control isografts (n= 5), retrieved at day 30, revealed no staining activity. In conclusion, our model demonstrates that intracoronary gene transfer to the transplanted murine cardiac grafts is feasible at the time of harvest. Adenovirus-mediated gene transfer produces widespread gene expression which, though perhaps transient, does not adversely affect myocardial structure or function. This technology may allow modification of graft immunogenicity in the future through the production of therapeutic proteins sufficient to modulate local immune responses. (J THORACCARDIOVASCSURG1996;111:246-52)

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