Arrhythmias, end-stage coronary disease, and idiopathic or inherited cardiomyopathies are all examples of cardiac diseases with inadequate therapeutic options. Gene therapy was initially touted as the potential cure for all of these along with many other diseases. Unfortunately, the initial promise of gene therapy has never been fully realized. Some of the difficulties encountered while developing this new therapeutic include inadequate delivery of the transgene, immune reaction to the vector and/or the transgene, and an inability to sustain gene expression after delivery. This proposal focuses on the problem of transgene delivery, with a goal of developing new methods for efficient, safe and effective delivery of the transgene to all of the cells in the target region. The central hypothesis of this proposal is that a systematic exploration of the variables relevant to delivery, either global or local, will allow development of new tools for successful gene transfer. To explore this hypothesis, we will address three aims: 1) To achieve safe, homogeneous, global gene transfer to the heart by systematically evaluating the role of hemodynamic and physical variables on the efficiency of delivery; 2) To improve the precision of focal myocardial gene transfer by developing methods for anatomical and electrophysiological targeting of the injection; and 3) To improve the safety and efficiency of myocardial gene transfer by manipulation of the gene transfer vector. Successful completion of these aims will bring gene therapy one-step closer to realizing its potential as a cardiovascular therapeutic.