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 (1.4ϫ10 12 vp). Animals that had received AC VI gene transfer showed increases in peak LV dP/dt (average increase of 1267Ϯ807 mm Hg/s; Pϭ0.0002) and cardiac output (average increase of 39Ϯ20 mL ⅐ kg Ϫ1 ⅐ min Ϫ1 ; PϽ0.0001); control animals showed no changes. Increased LV dP/dt was evident 6 days after gene transfer and persisted for at least 57 days. Basal heart rate, blood pressure, and LV dP/dt were unchanged, despite changes in cardiac responsiveness to catecholamine stimulation. Twenty-three hour ECG recordings showed no change in mean heart rate or ectopic beats and no arrhythmias. LV homogenates from animals receiving AC VI gene transfer showed increased AC VI protein content (Pϭ0.0007) and stimulated cAMP production (Pϭ0.0006), confirming transgene expression and function; basal LV AC activity was unchanged. Increased cAMP-generating capacity persisted for at least 18 weeks (PϽ0.0002). Conclusions-Intracoronary injection of a recombinant adenovirus encoding AC provides enduring increases in cardiac function.

Cardiac gene therapy in large animals: bridge from bench to bedside

“…There are two predominant isoforms of AC in the heart (type 5 and type 6), however the beneficial effect of AC overexpression appears to be limited to AC6. Adenovirus encoding AC6 was injected into coronary arteries of naive 75 and pacing-induced heart failure pigs, 27 and resulted in increased left ventricular contractility. In addition, left ventricular local gene transfer of AC6 has been shown to have the potential to create biological pacemaker after atrioventricular node ablation.…”

Intracoronary Adenovirus Encoding Adenylyl Cyclase VI Increases Left Ventricular Function in Heart Failure

“…1,5 Seven days after the initiation of LV pacing, animals underwent echocardiographic and hemodynamic studies and then received Ad.AC VI or saline by intracoronary injection as previously described. 5 A 5F multipurpose coronary catheter (A1, end hole only) was advanced 1 cm into the ostium in the proximal portion of each of the 3 coronary arteries: left anterior descending, left circumflex, and right coronary artery. Intracoronary sodium nitroprusside (Gensia Sicor Pharmaceuticals) was infused (50 g/min) continuously beginning 3 minutes before and persisting 2.3 minutes after vector or saline delivery was completed via a separate portal in the manifold.…”

“…3,4 We then showed that global left ventricular (LV) function and responsiveness can be changed by gene transfer of AC VI in a manner that can be applied clinically: intracoronary delivery. 5 …”

Gene Therapy for Heart Failure

“…24) Another alternative therapeutic approach is to increase the expression of adenylyl cyclase type VI(AC VI ). Lai et al 25) have demonstrated that intracoronary delivery …”