In heart failure, impairment of the bAR system contributes to the dysfunction. Cardiac transplantation is an accepted treatment for severe heart failure; however, myocardial dysfunction is also a problem following this surgical procedure. Increasing bAR signaling properties represents a potential novel therapeutic intervention to improve cardiac function after transplantation and to expand the donor pool. This proposal, capitalizing on the investigator s recent discoveries that cardiac-overexpression of either b2-ARs or inhibitors of bAR desensitization in transgenic mice causes marked improvement of in vivo LV contractility, is formulated to investigate whether these genetic manipulations will render a similar effect if delivered exogenously to donor hearts prior to transplantation, using an adenoviral vector. Direct access to the donor heart prior to surgery provides a unique opportunity for such gene transfer experiments. The central hypothesis to be tested is that alteration in myocardial bAR signaling exists in the transplanted heart, and correcting these alterations will result in improved performance of the graft. To test this hypothesis, a surgical rat heterotopic transplant model and an intra-coronary adenoviral gene delivery system will be utilized.
Specific aims are: 1) To optimize adenoviral mediated gene delivery to the transplanted myocardium and to characterize the level of dysfunction of bAR signaling in the transplanted rat heart. 2) To determine the physiological functional effects of delivered bAR-based adenoviral genes to the transplanted rat heart. 3) To determine whether alterations in bAR signaling play a role in causing the cellular injury and physiologic dysfunction associated with acute graft rejection.
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