Adenylylcyclase gene transfer increases function of the failing heart.
A persistent question in cardiovascular gene transfer concerns whether an exogenously delivered gene can increase function of the failing heart. Here we test the hypothesis that intracoronary delivery of adenovirus encoding adenylylcyclase type VI (Ad.ACVI) in the setting of active heart failure will increase function of the failing heart. As a model of heart failure, we used transgenic mice with dilated and poorly functioning hearts resulting from cardiac-directed expression of Galphaq.Galphaq mice with equivalent pretreatment impairment in left ventricular (LV) function (echocardiography) received 2.5x1010 viral particles of Ad.ACVI or Ad.EGFP (enhanced green fluorescent protein), or saline, by indirect intracoronary delivery. Serial echocardiograms obtained before and 14 days after gene transfer showed that Ad.ACVI increased LV ejection fraction (p<0.01) and velocity of circumferential fiber shortening (p<0.03). Detailed measurements in isolated hearts showed that ACVI gene transfer increased LV positive dP/dt (p=0.02) and LV negative dP/dt (p=0.01). Gene transfer was confirmed by polymerase chain reaction. These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart.
Rebolledo
Brian
B
San Diego Veterans Healthcare System, and Department of Medicine, University of California, San Diego 92093, USA.
Lai
N Chin
NC
Gao
Mei Hua
MH
Takahashi
Toshiyuki
T
Roth
David M
DM
Baird
Stephen M
SM
Hammond
H Kirk
HK
D000256:Adenoviridae / Q000235:genetics*; D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D004452:Echocardiography; D005080:Exercise Test; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D006321:Heart / Q000503:physiopathology; D006334:Heart Function Tests; D007269:Injections, Intra-Arterial; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000648:ultrastructure
D000262:Adenylyl Cyclases