Abstract 14878: AAV6-betaARKct Cardiac Gene Therapy Rescues Failing Myocardium in a Clinically Relevant Large Animal Heart Failure Model
Background: Failing myocardium is characterized by marked upregulation of G protein-coupled receptor kinase 2 contributing to dysfunctional beta-adrenergic receptor (betaAR) signalling and cardiac dysfunction. The GRK2-inhibitor peptide betaARKct could rescue disparate small animal heart failure models. This study was designed to evaluate long-term betaARKct expression in a clinically relevant large animal heart failure model with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6).
Methods and Results: A porcine model of left ventricular myocardial infarction was used. Two weeks after left circumflex myocardial infarction we measured baseline cardiac function (hemodynamics, echocardiography) and delivered AAV6-betaARKct or AAV6-Luciferase as control by retrograde injection into the anterior interventricular vein. 6 weeks later, cardiac function was assessed and hearts were harvested for further analyses. Robust and long-term betaARKct expression was found after AAV6 mediated delivery. Interestingly, AVV6-betaARKct gene transfer significantly improved left ventricular hemodynamics (dp/dtmax in mmHg/s: sham 1390+/−100, betaARKct 1262+/−100 vs. Luciferase 1012+/−160, p<0,05) and ejection fraction (EF in %: sham 72+/−8, betaARKct 54+/−7 vs. Luciferase 47+/−8, p<0,05), whereas in AAV6-Luciferase treated control animals a decline in cardiac function was observed. The neurohormonal axis was virtually normalized in AAV-betaARKct treated animals, represented by reductions in plasma norepinephrine levels whereas AAV6-Luciferase treated animals revealed further increases in plasma norepinephrine levels (sham 589+/−300, betaARKct 658+/−360 vs. Luciferase 855+/−390).
Conclusions: Myocardial AAV6-betaARKct gene therapy in a clinically relevant large animal heart failure model resulted in sustained improvement of global cardiac function and normalization of the neurohormonal signalling axis.
- © 2010 by American Heart Association, Inc.