(Circulation. 2000;101:408.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Intracoronary Adenovirus-Mediated Delivery and Overexpression of the ß2-Adrenergic Receptor in the Heart
Prospects for Molecular Ventricular Assistance
From the Departments of General and Thoracic Surgery (A.S.S., R.E.L., A.P.K., O.T., J.A.H., S.C.S., D.D.G, W.J.K.), Pharmacology and Cancer Biology (W.J.K.), Medicine and Biochemistry (A.P., R.J.L.), and The Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC.
Correspondence to Walter J. Koch, PhD, Laboratory of Molecular Cardiovascular Biology, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of ß2-adrenergic receptors (ß2ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human ß2AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery.
Methods and Results—Rabbits underwent
percutaneous subselective
catheterization of either the left or right
coronary artery and infusion of adenoviral vectors containing
either a marker transgene (Adeno-ßGal) or the ß2AR
(Adeno-ß2AR). Ventricular function was
assessed before catheterization and 3 to 6 days after
gene delivery. Both left circumflex– and right coronary
artery–mediated delivery of Adeno-ß2AR resulted in
10-fold overexpression in a chamber-specific manner. Delivery of
Adeno-ßGal did not alter in vivo left ventricular (LV)
systolic function, whereas overexpression of
ß2ARs in the LV improved global LV
contractility, as measured by dP/dtmax, at
baseline and in response to isoproterenol at both 3 and 6 days after
gene delivery.
Conclusions—Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the ß2AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.
Key Words: gene therapy • myocardium • receptors, adrenergic, ß • ventricles • heart failure • signal transduction
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