Abstract 19535: Constitutive Expression of a Dominant Negative TGF-β Type-II Receptor in the Posterior Left Atrium Attenuates NADPH Oxidase and Mitochondrial Superoxide Production and Decreases Atrial Fibrosis (Resulting in Decreased AF)
Background: Oxidative stress is an important mechanism in the creation of AF substrate, especially in the setting of heart failure (HF). This is in part through reactive oxygen species (ROS) leading to activation of TGF-β signaling, which results in creation of atrial fibrosis. ROS are also an important downstream mediator of TGF-β signaling. We therefore hypothesized that in a canine model of HF induced by ventricular tachypacing, decreasing TGF-β signaling via atria-targeted dominant-negative type II TGF-β receptor expression will attenuate both oxidative stress and atrial fibrosis, thereby leading to decreased AF.
Methods: 17 dogs underwent injection + electroporation in the posterior left atrium (PLA) of either a plasmid expressing a dominant negative TGF-β type II receptor (pUBC-TGFβdnRII) (N=8) or control vector (p-UBC-LacZ) (N=7), followed by 3-4 weeks of right ventricular tachypacing (240 bpm). A terminal study was performed to assess for AF inducibility. Tissue was assayed for changes in fibrosis (Trichrome staining) and oxidative stress (superoxide quantification via lucigenin chemiluminescence).
Results: Downregulation of TGF-β signaling by TGFβdnRII significantly decreased fibrosis (Figure 1a, blue staining), attenuated NADPH- and mitochondrial-generated superoxide (Figure 1b) and significantly decreased AF duration (Figure 1c), as compared to control animals.
Conclusions: Targeted non-viral gene-therapy approaches aimed at reducing TGF-β signaling in the left atrium results in a decrease in AF substrate, in part through the reduction of oxidative stress and the development of fibrosis. Further optimization of this gene therapy approach may translate into effective AF therapies.
- Atrial fibrillation
- Gene therapy
- Heart failure
- Oxidative stress
- Mitochondrial energetics, heart failure, arrhythmias
- © 2012 by American Heart Association, Inc.