Abstract 92: Cardiac Bridging Integrator 1 Gene Transfer Improves Left Ventricular Lusitropy in Mice With Continuous Infusion of Isoproterenol

Background: Cardiac bridging integrator 1(cBIN1) is a membrane scaffolding protein, which organizes t-tubule dyad microdomains critical for normal calcium transient development. BIN1 is transcriptionally reduced in heart failure, and reduced BIN1 diminishes calcium transients, limiting excitation-contraction coupling and impairing contractility. Furthermore, cBIN1-microdomains organize with acute β-adrenergic activation. It remains unclear whether over-expression of cBIN1 improves myocardial function in mice with chronic sympathetic overdrive. Methods: Adult male C57BL/6 mice received retro-orbital injections of adeno-associate virus 9 (AAV9) transducing either control GFP, sBIN1 (small BIN1), BIN1+13, BIN1+17, or cBIN1 (BIN1+13+17). Three weeks after virus injection, mice were subjected to subcutaneous implantation of micro osmotic pumps continuously releasing isoproterenol at 30mg /kg/day for four weeks. Left ventricular (LV) geometry and function were evaluated by echocardiography before and weekly after isoproterenol infusion. Results: In the control GFP group, isoproterenol infusion significantly increased LV mass and relative wall thickness (RWT), consistent with concentric hypertrophy. Over-expression of any of the four BIN1 isoforms attenuated left ventricular hypertrophy (n=5 per group). However, only cBIN1 over-expressing mice became more efficient. Their hearts had improved left ventricular relaxation, and were able to preserve ejection fraction yet with increased end systolic and diastolic volumes. As a result of improved relaxation, cBIN1 over-expression increased stroke volume and cardiac output without their hearts becoming hyperdynamic. Thus cBIN1 conveys a general BIN1 protection against isoproterenol induced hypertrophy together with a cBIN1 specific improvement in lusitropy. Conclusions: In mice with chronic sympathetic overdrive, over-expression of cBIN1 increases LV compliance, preserves heart lusitropy, and improves cardiac function. This athletic heart like phenotype induced by cBin1 gene therapy indicates that exogenous cBIN1 can reverse the diastolic dysfunction associated with sympathetic overdrive and heart failure progression.