Conventional approaches for the treatment of cardiac arrhythmias are limited to pharmacotherapy, ablation or implantable devices. Each of these strategies is effective in certain situations, but each is also associated with a number of untoward effects. With the limitations of currently available therapies, there is a need for new approaches to treat common cardiac arrhythmias. The central hypothesis of this proposal is that genetic manipulation of the cardiac substrate in a controlled, localized manner can effectively treat cardiac arrhythmias. As an initial attempt to investigate this theory, we will focus on the atrioventricular node, an anatomically well-defined region where functional changes are easily observed. Realizing the limitations of prior in vivo gene transfer strategies, this proposal seeks to investigate the central hypothesis in a systematic fashion by defining the variables important for vector delivery, by limiting the area of investigation to a specific intracardiac region, and by using conventional cellular techniques to investigate the mechanisms responsible for the observed phenotypic changes. To that end, the overall goal of this proposal will be to suppress AV nodal conduction in a controllable manner, sufficient to reduce the heart rate during atrial fibrillation but not to produce complete AV block. The specific aims to be addressed include: 1) To evaluate the effect of manipulating basic physiological variables on the efficiency of in vivo gene delivery to the AV node. 2) To evaluate the effect on AV nodal conduction of gene transfer-induced alterations in cellular levels of G proteins and potassium channels, and 3) To characterize the cellular mechanisms responsible for suppression of AV nodal conduction in states of gene transfer-induced protein overexpression. Successful completion of these aims will provide proof of principle that gene therapy strategies are viable options for the future treatment of common cardiac arrhythmias.