Beta-adrenergic gene transfer and myocardial function: Heart failure (HF), a condition resulting from a variety of cardiac diseases, is a major cause of morbidity and mortality in this nation. It is well documented that a characteristic of chronic HF is the marked impairment of the beta-adrenergic receptor (beta-AR) system which contributes to the dysfunction of the heart. Adding to its importance, is the fact that drugs which act by altering beta-AR signal transduction are at the forefront of conventional HF therapeutic strategies. Alternative therapeutic strategies for improving myocardial performance are of significant interest and increasing beta-AR signaling properties represents a potential novel intervention to improve cardiac function. This proposal capitalizing on the recent discoveries that cardiac-overexpression of either beta-ARs or an inhibitor of beta-AR desensitization in transgenic mice causes marked improvement of in vivo cardiac contractility, is formulated to learn whether these transgenes will render a similar effect if delivered exogenously to adult myocardium. In addition, gene transfer of beta-AR transgenes will increase the understanding of the role of this critical signaling system in normal and compromised heart function. The Central Hypothesis is that efficient gene transfer to adult myocardium of DNA's encoding specific beta-AR-signaling components will alter cardiac function. To test this hypothesis, a model of gene transfer to the adult rabbit heart consisting of percutaneous coronary artery catherterization and adenovirus injection will be utilized. The associated Specific Aims are: (1) To optimize intra-coronary adenovirus delivery to the rabbit heart of transgenes consisting of various beta-AR signaling components and to study the biochemical consequences of altered adrenergic signaling. (2) T determine the in vivo physiologic effects of the delivered beta-AR transgenes and cardiac responses to beta-agonists in treated rabbit myocardium. (3) To test the validity of using beta-AR gene transfer to improve heart function during disease states by applying it to an experimental model of rabbit HF.
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