Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery banding.
BACKGROUND
Increased right ventricular (RV) afterload results in RV hypertrophy and dysfunction, as well as increased levels of intracellular beta-adrenergic receptor kinase (betaARK1). We hypothesize that gene transfer of a betaARK1 inhibitor (betaARKct) may improve RV performance, morbidity, and mortality early after pulmonary artery (PA) banding.


METHODS
Rabbits underwent PA banding 3 days after right coronary artery injection of an adenovirus containing the gene encoding the betaARKct peptide (n = 14), beta-galactosidase (n = 10), or an empty adenovirus (n = 19). After banding, hemodynamic instability and maximal rate of increase in right ventricular pressure (RV dP/dt(max)) were documented. For 7 days after banding, animals were monitored for mortality, activity, and appetite.


RESULTS
When compared with controls, animals receiving the betaARKct transgene showed improvement in survival at 7 days (92.8% +/- 7% vs 48.3% +/- 9%, p = 0.01), less lethargy, a trend toward greater RV dP/dt(max) (NS), and increased hemodynamic stability at the time of banding (78% vs 41%, p = 0.03).


CONCLUSIONS
Selective RV expression of betaARKct improves survival and morbidity after PA banding. This represents a novel therapeutic modality for clinical situations involving increased RV afterload.
Emani
S M
SM
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Shah
A S
AS
White
D C
DC
Glower
D D
DD
Koch
W J
WJ
D000818:Animals; D002352:Carrier Proteins / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D006352:Heart Ventricles; D010455:Peptides; D011651:Pulmonary Artery; D011817:Rabbits; D011994:Recombinant Proteins; D015996:Survival Rate; D019076:Transgenes; D018497:Ventricular Dysfunction, Right / Q000401:mortality / Q000473:pathology / Q000628:therapy*
D002352:Carrier Proteins; D010455:Peptides; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide