The Heart Failure Rabbit Core (Core C) will develop and manage rabbits with an arrhythmogenic form of nonischemic heart failure from which myocytes will be isolated for use at UC Davis, Rush University and UC San Diego in 3 of the 4 PPG projects. The rabbits used will have heart failure (HF) induced by combined pressure and volume overload. The core will be responsible for the preparation and functional monitoring of HF rabbits during the evolution of dysfunction (under the direction of Dr. S.M. Pogwizd at UAB). The core will also perform in vivo drug studies to assess the potential antiarrhythmic effects of inhibiting CaMKII in the failing heart. HF rabbits will be shipped directly to UC Davis and Rush University projects for functional, imaging and biochemical analysis, and tissue will be shipped to UC San Diego for biochemical analysis. The procedures carried out are specialized, but the personnel involved are expert in their respective roles and this should run smoothly and efficiently in making the best use of the myocytes available. As an alternative that could increase the availability of HF rabbit myocytes to investigators of Projects 1 and 2, approaches are being developed to isolate HF rabbit atrial and ventricular myocytes in Birmingham and shipping myocytes by same-day delivery to Davis and Chicago (in a shorter time frame than that used successfully in Altschuld et al. Circulation 1995). As a complement to mouse studies (as part of Core B), rabbit studies offer a number of advantages. First, the electrophysiological and Ca handling properties in rabbit ventricle are very similar to that in human. Second, we have already developed and extensively characterized this rabbit model of heart failure that we have validated. Indeed, the HF rabbits manifest both severely depressed LV contractile function and spontaneously-occurring ventricular arrhythmias. Rabbit myocytes are also well suited for the measurements to be made, including: voltage clamp, fluorescence imaging, biochemical and molecular studies, and in vitro adenoviral gene transfer. The services provided by this core are essential to the successful completion of the science in Projects l-IV, enabling the elucidation of mechanistic roles of 1P3R and CaMKII in ECC arrhythmogenesis, hypertrophy and HF.

RELEVANCE (See instructions): HF affects over 5 million Americans and leads to premature death. Developing new therapies to treat HF and prevent sudden death requires studies in experimental models of heart failure. This core will create such an experimental HF model in rabbits that will be used by investigators studying the role of altered calcium handling in HF as part of this Program Project Grant.