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 wil...

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Bibliographic Details
Published inHuman gene therapy Vol. 17; no. 10; p. 1043
Main Authors Rebolledo, Brian, Lai, N Chin, Gao, Mei Hua, Takahashi, Toshiyuki, Roth, David M, Baird, Stephen M, Hammond, H Kirk
Format Journal Article
LanguageEnglish
Published United States 01.10.2006
Subjects
Adenoviridae - genetics
Adenylyl Cyclases - genetics
Animals
Cardiomyopathy, Dilated - chemically induced
Cardiomyopathy, Dilated - physiopathology
Cardiomyopathy, Dilated - therapy
Echocardiography
Exercise Test
Gene Transfer Techniques
Genetic Therapy - methods
Genetic Vectors - therapeutic use
Heart - physiopathology
Heart Function Tests
Injections, Intra-Arterial
Mice
Mice, Transgenic
Myocardium - ultrastructure
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Summary: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.
ISSN:1043-0342
DOI:10.1089/hum.2006.17.1043