Adenoviral beta-adrenergic receptor kinase inhibitor gene transfer improves exercise capacity, cardiac contractility, and systemic inflammation in a model of pressure overload hypertrophy.
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.
Gupta
Dipin
D
Department of Cardiac Surgery, New York University, New York, NY, USA.
Molina
Ezequiel J
EJ
Palma
Jon
J
Gaughan
John P
JP
Long
Walter
W
Macha
Mahender
M
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
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