(Circulation. 2001;103:1311.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
In Vivo Ventricular Gene Delivery of a ß-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction
From the Departments of General and Thoracic Surgery (A.S.S., D.C.W., S.E., A.P.K., R.E.L., D.D.G., W.J.K.) and Medicine and Biochemistry (K.W., R.J.K.) and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC.
Correspondence to Walter J. Koch, PhD, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo ß-adrenergic receptor kinase (ßARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI).
Methods and Results—Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x1011 viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of ßARK1 (Adeno-ßARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-ßARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the ßARKct. Baseline in vivo LV systolic performance was improved in Adeno-ßARKct–treated animals compared with their individual pre–gene delivery values and compared with EV-treated rabbits. Total ß-AR density and ßARK1 levels were unchanged between treatment groups; however, ß-AR–stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-ßARKct–treated rabbits compared with EV-treated animals.
Conclusions—In vivo delivery of Adeno-ßARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of ßARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of ßARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.
Key Words: gene therapy • receptors • heart failure • signal transduction
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