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 _αqq. G _αq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5 × 10¹⁰ 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 AC_VI increases function of the failing heart.