title: Adenoviral beta-adrenergic receptor kinase inhibitor gene transfer improves exercise capacity, cardiac contractility, and systemic inflammation in a model of pressure overload hypertrophy.
abstract: OBJECTIVE
  We hypothesized that intracoronary adenoviral-mediated delivery of betaARKct would improve heart failure associated pathophysiologic abnormalities related to exercise capacity, cardiac contractility, systemic inflammation and volume overload.
  
  
  METHODS
  After aortic banding, a cohort of Sprague-Dawley rats was followed by echocardiography. When an absolute decline of 25% in fractional shortening was detected, animals were randomized to intracoronary delivery of Ad.ssARKct (n=14), Ad.beta-Gal (n=13), or followed without any other further intervention (n=18). Assessment of exercise tolerance and hemodynamic profile and measurement of markers of systemic inflammation and volume overload was performed at 7, 14, and 21 days after gene delivery. Data were analyzed using ANOVA.
  
  
  RESULTS
  Animals receiving Ad.ssARKct showed improved exercise tolerance compared to Ad.Gal-treated animals at 14 days (507+/-26 s vs. 408+/-19 s, P=0.01) and 21 days (526+/-55 s vs. 323+/-19 s, P<0.001) following injection. Animals receiving Ad.ssARKct demonstrated improved +dP/dtmax (mean+/-SD, 5,581+/-960 mmHg/s vs. 3,134+/-438 mmHg/s, P<0.01) and -dP/dtmax (mean+/-SD, -3,494+/-1,269 mmHg/s vs. -1,925+/-638 mmHg/s, P<0.01) compared to Ad.Gal-treated animals at 7 days. These differences were observed up to 21 days following injection. Serum levels of IL-1, IL-6, and TNF-alpha, as well as ANP were also decreased in animals receiving Ad.betaARKct.
  
  
  CONCLUSIONS
  Genetic modulation of heart failure using the betaARKct gene was associated with improved exercise capacity and cardiac function as well as amelioration in heart failure-associated profiles of systemic inflammation and volume overload.
authors.affiliation: Department of Cardiac Surgery, New York University, New York, NY, USA.
authors.forename: Dipin
authors.initials: D
authors.lastname: Gupta
authors.forename: Ezequiel J
authors.initials: EJ
authors.lastname: Molina
authors.forename: Jon
authors.initials: J
authors.lastname: Palma
authors.forename: John P
authors.initials: JP
authors.lastname: Gaughan
authors.forename: Walter
authors.initials: W
authors.lastname: Long
authors.forename: Mahender
authors.initials: M
authors.lastname: Macha
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology / Q000628:therapy; D006439:Hemodynamics / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D007249:Inflammation / Q000503:physiopathology / Q000628:therapy; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D045265:Natriuretic Peptides / Q000097:blood; D010455:Peptides / Q000235:genetics* / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D045265:Natriuretic Peptides; D010455:Peptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C445259:beta-adrenergic receptor kinase inhibitory peptide; D009320:Atrial Natriuretic Factor