Mechanism of a Novel Stable Compensatory Cardiac Hypertrophy Model

During development and maturation growth is a necessity; however, in the adult excess myocardial growth (cardiac hypertrophy) is a risk factor for arrhythmogenesis and for heart failure. In this proposal we will test a paradigm shift. We now show data supporting the idea that enhanced myocardial Ca2+-entry can instigate a safe, stable cardiac hypertrophic phenotype resulting in improved cardiac function. The key mechanistic insight to date is that selective manipulation of the L-type Ca2+ channel complex, specifically deletion of Rad-GTPase provides a finely graded increased sarcolemmal Ca2+-entry. Moreover, Rad deletion provides cardioprotection in response to chronic pressure overload hypertrophy and against heart failure remodeling in remote myocardium after myocardial infarction. To dissect the basis for Rad-ablation cardioprotection we propose two Specific Aims: 1) To evaluate the mechanistic link between Rad, T-tubule structure, and Ca2+-homeostasis; and, 2) To evaluate Rad-deletion as a potential therapeutic target for heart failure remodeling. A major premise of this proposal is that selective finely graded increase of LTCC activity would improve contractility thus obviating the reflexive hyper-ƒÒ-AR signaling in HF. Our proposed studies have the potential to establish a proof-of-principle that Rad-LTCC signaling treats the disease rather than the symptoms of HF. .