Faculty Collaboration Database

Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance. Circulation 2000 Feb 01;101(4):408-14

Date

02/02/2000

Pubmed ID

10653833

DOI

10.1161/01.cir.101.4.408

Scopus ID

2-s2.0-17344389993 (requires institutional sign-in at Scopus site)   114 Citations

Abstract

BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) 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 beta(2)AR 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-betaGal) or the beta(2)AR (Adeno-beta(2)AR). 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-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), 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 beta(2)AR. 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.

Author List

Shah AS, Lilly RE, Kypson AP, Tai O, Hata JA, Pippen A, Silvestry SC, Lefkowitz RJ, Glower DD, Koch WJ

MESH terms used to index this publication - Major topics in bold

Adenoviridae
Animals
Cardiac Catheterization
Coronary Vessels
Genetic Therapy
Genetic Vectors
Heart Rate
Heart Ventricles
Humans
Immunohistochemistry
Isoproterenol
Male
Mice
Myocardial Contraction
Myocardium
Rabbits
Receptors, Adrenergic, beta-2
Systole
Ventricular Function, Left
beta-Galactosidase