Intracoronary Delivery of Adenovirus Encoding Adenylyl Cyclase VI Increases Left Ventricular Function and cAMP-Generating Capacity

Abstract

Background—We tested the hypothesis that intracoronary injection of a recombinant adenovirus encoding adenylyl cyclase type VI (AC_VI) would increase cardiac function in pigs. Methods and Results—Left ventricular (LV) dP/dt and cardiac output in response to isoproterenol and NKH477 stimulation were assessed in normal pigs before and 12 days after intracoronary delivery of histamine followed by intracoronary delivery of an adenovirus encoding lacZ (control) or AC_VI (1.4×10¹² vp). Animals that had received AC_VI gene transfer showed increases in peak LV dP/dt (average increase of 1267±807 mm Hg/s; P=0.0002) and cardiac output (average increase of 39±20 mL · kg⁻¹ · min⁻¹; PVI gene transfer showed increased AC_VI protein content (P=0.0007) and stimulated cAMP production (P=0.0006), confirming transgene expression and function; basal LV AC activity was unchanged. Increased cAMP-generating capacity persisted for at least 18 weeks (PConclusions—Intracoronary injection of a recombinant adenovirus encoding AC provides enduring increases in cardiac function.