A variety of experimental myocardial molecular alterations have suggested that genetic therapies may impact on cardiac disease (24,34,35). Vascular growth factor genes may serve in the treatment of coronary artery disease or ischemic cardiomyopathy (29,45,46). States of left ventricular dysfunction or heart failure (HF) can be ameliorated with exogenous genes which alter the native #-adrenergic receptor (AR) system or which improve myocardial calcium handling(24,34,37). However, in order to utilize such genetic strategies to treat cardiac disease, safe and efficient methods for cardiac gene delivery must be developed. Importantly, to achieve alterations of heart function or structure, efficient gene delivery methods must be developed to transfect a majority of themyocardium. In this proposal, we investigate myocardial gene transfer in adult swine models employing cardiac surgery. The primary components of modem cardiac surgery include cardiopulmonary bypass (CPB), cardioplegic arrest and crossclamping of the ascending aorta. These steps may facilitate safer gene delivery since they result in an interruption of the coronary Circulation and an isolation of the coronary circulation from the systemic circulation, making """"""""cardioselective"""""""" gene transfer possible.The central hypothesis is that global myocardial transgene expression and secondary functional changes can be achieve in adult swine utilizing adenoviral delivery during simulated cardiac surgery.
The specific aims are: 1. Achieve safe and efficient myocardial gene transfer in adult pigs utilizing adenoviral and advanced generation vectors, delivered during simulated cardiac surgery. 2. Characterize post-cardiac surgery left ventricular dysfunction in adult pigs :and :reverse the dysfunction with betaAR based gene therapy delivered during the surgery. 3. Employ functional transgenes to achieve positive inotropic effects in a swine pacing heart failure model. i. Study inotropic effects of transgenes in cultured LV myocytes from failing pig hearts. ii. Deliver functional transgenes to failing pig hearts during simulated cardiac surgery and evaluate effect on LV performance. These studies will help to develop safer and more efficient methods for gene delivery which can be coupled to cardiac surgery. As our knowledge advances, gene therapy may supplement established surgical treatments.
