Adenylylcyclase gene transfer increases function of the failing heart

A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.AC(VI)) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of G(alpha q). G(alpha q) mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5 x 10(10) viral particles of Ad.AC(VI) or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.AC(VI) increased LV ejection fraction (p < 0.01) and velocity of circumferential fiber shortening (p < 0.03). Detailed measurements in isolated hearts showed that AC(VI) gene transfer increased LV positive dP/dt (p = 0.02) and LV negative dP/dt (p = 0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.