Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure.
BACKGROUND
We tested the hypothesis that intracoronary delivery of an adenovirus encoding adenylyl cyclase type VI (Ad.AC(VI)) would be associated with increased left ventricular (LV) function in pigs with congestive heart failure.


RESULTS
Pigs (52+/-6 kg; n=16) underwent placement of pacemakers, LV pressure transducers, and left atrial and aortic catheters. Physiological and echocardiographic studies were obtained from conscious animals 13 days later, and pacing was initiated (220 bpm). Seven days later, measures of LV function were reduced, documenting severe LV dysfunction and dilation. Pigs then received intracoronary Ad.AC(VI) (1.4x10(12) vp; n=7) or saline (PBS; n=9) (randomized, blinded), with concomitant infusion of nitroprusside (50 microg/min, 6.4 minutes) to increase gene transfer. Pacing was continued for 14 days, and final studies were obtained. The a priori key end point was change in LV dP/dt during isoproterenol infusion (pre-Ad.AC(VI) value minus value after 21 days of pacing). Pigs receiving Ad.AC(VI) showed a smaller decrease in both LV +dP/dt (P=0.0014) and LV -dP/dt (P=0.0008). Serial echocardiography showed that Ad.AC(VI) treatment was associated with increased LV function and reduced LV dilation and that end-systolic wall stress was reduced. AC-stimulated cAMP production was increased 1.7-fold in LV samples from Ad.AC(VI)-treated pigs (P=0.006), and B-type natriuretic peptide was reduced (0.035). Gene transfer was confirmed by polymerase chain reaction.


CONCLUSIONS
AC(VI) gene transfer increases LV function and attenuates deleterious LV remodeling in congestive heart failure.
Lai
N Chin
NC
Department of Medicine, University of California, San Diego, USA.
Roth
David M
DM
Gao
Mei Hua
MH
Tang
Tong
T
Dalton
Nancy
N
Lai
Yin Yin
YY
Spellman
Matthew
M
Clopton
Paul
P
Hammond
H Kirk
HK
D000256:Adenoviridae / Q000235:genetics*; D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D005822:Genetic Vectors; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000097:blood; D016133:Polymerase Chain Reaction; D013552:Swine; D014463:Ultrasonography; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D020097:Natriuretic Peptide, Brain; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6