Abstract 3983: AAV9 Mediated G-protein Receptor Inhibition by Beta-adrenoreceptor Kinase Carboxyl-terminus Ameliorates Cardiac Function in a Pig Model of Chronic Heart Failure
Chronic heart failure is accompanied by a desensitization of the beta-adrenoreceptor pathway despite increased levels of endogenous catecholamines. This is due to an activation of the beta adrenoreceptor kinase (βARK) in these conditions. Inhibition of βARK by overexpression of its c-terminal peptide βARKct has been shown to improve myocardial function in various rodent models. We therefore wanted to test, if adeno-associated viral vector mediated gene therapy of βARKct is able to preserve myocardial function in a preclinical pig model of chronic heart failure.
Methods: Pigs underwent left anterior descending artery (LAD) occlusion for 90 min and reperfusion, to induce chronic heart failure. 14 days later hemodynamic measurements were performed to verify left ventricular dysfunction. Pigs were then randomized into 3 groups:
beta-blocker treatment (n=5). Gene transfer was performed as a single retrograde infusion of AAV9 constructs into the coronary vein (AIV) at day 14.
Global and regional myocardial function were determined again at day 56 of the study. Pigs were then sacrificed and infarct size was measured using TTC staining. Tissue was harvested for further analysis.
Results: All animals did show a decrease in left ventricular ejection fraction and an increase in LVEDP at day 14 post ischemia/reperfusion. Overexpression of βARKct and treatment with beta-blockers did improve left ventricular ejection fraction in a comparable manner compared to control at day 56 (LVEF: 27±2% control vs. 42±3% βARKct vs. 42±1% β-blocker, p<0.05 control vs. βARKct and β-blocker). LVEDP however, was predominantly improved by βARKct gene transfer (LVEDP: 18±1 mmHg control vs. 12±1 mmHg βARKct vs. 16±0,5 mmHg β-blocker, p<0.05 control vs. βARKct). In addition, subendocardial segment shortening as measure for regional myocardial function was significantly improved in the βARKct group (27±6 % control vs. 86±5% βARKct vs. 101±30%, p<0.05 βARKct vs. control).
Conclusions: AAV9-mediated cardiac gene therapy with βARKct ameliorates global and regional myocardial function in a preclinical pig model of chronic heart failure in a manner at least similar to standard medical treatment.