Abstract
Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) 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 β2AR 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-βGal) or the β2AR (Adeno-β2AR). 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-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs 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 β2AR. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 408-414 |
| Number of pages | 7 |
| Journal | Circulation |
| Volume | 101 |
| Issue number | 4 |
| State | Published - Feb 1 2000 |
| Externally published | Yes |
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Keywords
- Gene therapy
- Heart failure
- Myocardium
- Receptors, adrenergic, β
- Signal transduction
- Ventricles
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart : Prospects for molecular ventricular assistance. / Shah, Ashish S.; Lilly, R. Eric; Kypson, Alan P.; Tai, Oliver; Hata, Jonathan A.; Pippen, Anne; Silvestry, Scott C.; Lefkowitz, Robert J.; Glower, Donald D.; Koch, Walter J.
In: Circulation, Vol. 101, No. 4, 01.02.2000, p. 408-414.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Intracoronary adenovirus-mediated delivery and overexpression of the β2-adrenergic receptor in the heart
T2 - Prospects for molecular ventricular assistance
AU - Shah, Ashish S.
AU - Lilly, R. Eric
AU - Kypson, Alan P.
AU - Tai, Oliver
AU - Hata, Jonathan A.
AU - Pippen, Anne
AU - Silvestry, Scott C.
AU - Lefkowitz, Robert J.
AU - Glower, Donald D.
AU - Koch, Walter J.
PY - 2000/2/1
Y1 - 2000/2/1
N2 - Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) 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 β2AR 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-βGal) or the β2AR (Adeno-β2AR). 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-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs 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 β2AR. 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.
AB - Background - Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of β2-adrenergic receptors (β2ARs) 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 β2AR 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-βGal) or the β2AR (Adeno-β2AR). 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-β2AR resulted in ≃10-fold overexpression in a chamber- specific manner. Delivery of Adeno-βGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of β2ARs 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 β2AR. 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.
KW - Gene therapy
KW - Heart failure
KW - Myocardium
KW - Receptors, adrenergic, β
KW - Signal transduction
KW - Ventricles
UR - http://www.scopus.com/inward/record.url?scp=17344389993&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=17344389993&partnerID=8YFLogxK
M3 - Article
C2 - 10653833
AN - SCOPUS:17344389993
VL - 101
SP - 408
EP - 414
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 4
ER -