title: Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure.
abstract: 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.
authors.affiliation: Department of Medicine, University of California, San Diego, USA.
authors.forename: N Chin
authors.initials: NC
authors.lastname: Lai
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Gao
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: Nancy
authors.initials: N
authors.lastname: Dalton
authors.forename: Yin Yin
authors.initials: YY
authors.lastname: Lai
authors.forename: Matthew
authors.initials: M
authors.lastname: Spellman
authors.forename: Paul
authors.initials: P
authors.lastname: Clopton
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
mesh_terms: 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
chemical_list: D020097:Natriuretic Peptide, Brain; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6