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J Thorac Cardiovasc Surg 2000;120:581-588
© 2000 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Adenovirus-mediated genetic manipulation of the myocardial ß-adrenergic signaling system in transplanted hearts

From the Departments of General and Thoracic Surgery^a and Medicine^b and the Howard Hughes Medical Institute,^c Duke University Medical Center, Durham, NC.

This work was supported by National Institute of Health grants HL-59533 and HL-56205 to W.J.K. R.J.L. is an investigator of the Howard Hughes Medical Institute.

Address for reprints: Walter J. Koch, PhD, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710 (E-mail: koch0002{at}mc.duke.edu ).

Objectives: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the ß-adrenergic receptor–signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of ß-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation.
Methods: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human ß₂-adrenergic receptor, a peptide inhibitor of ß-adrenergic receptor densensitization, or the marker transgene ß-galactosidase.
Results: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of ß-galactosidase was observed, and ß₂-adrenergic receptor density was elevated 10-fold in grafts that received adeno-ß₂-adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-ß₂-adrenergic receptor or adeno-ß-adrenergic receptor densensitization compared with control grafts that received adeno-ß-galactosidase.
Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of ß-adrenergic receptor signaling either by increasing ß₂-adrenergic receptor density or blocking endogenous receptor desensitization improves graft function acutely in this allograft model.

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