Abstract 18444: Constitutive Expression of a Dominant Negative TGF-β Type II Receptor in the Posterior Left Atrium Interrupts Heart Failure Induced Conduction Changes, with a Resulting Decrease in Atrial Fibrillation

Abstract

Introduction: Fibrosis is thought to be a key contributor to the conduction slowing and heterogeneity seen in the heart failure (HF) atrium, providing a substrate for atrial fibrillation (AF). Hypothesis: Since the TGF-β pathway contributes to the creation of atrial fibrosis, we hypothesized that decreasing TGF-β signaling in the HF posterior left atrium (PLA) by expressing a dominant-negative TGF-β type II receptor (TGF-β-II-DN) will, by attenuating formation of fibrosis, decrease conduction slowing and in-homogeneity and thereby decrease AF. Methods: 17 dogs underwent injection+electroporation in the PLA of either an HA-tagged plasmid expressing TGF-β-II-DN (pUBc-TGFβdnRII) (Group A, N=8) or control vector (pUBc-LacZ) (Group B, N=7), followed by 3-4 weeks of right ventricular tachypacing (240 bpm) to induce HF. The following were assessed both at baseline and the terminal study: left atrial effective refractory periods (ERPs), high density activation maps of the PLA, and the number of AF episodes >30s by burst pacing. Total activation time and a conduction in-homogeneity index were determined from the activation maps. Tissue was assayed for gene expression and fibrosis (Trichrome staining). Results: RT-PCR and western blotting showed robust gene expression in the PLA. Group A developed significantly less fibrosis as a percentage of the PLA than group B (41.6±5.6 vs. 56.4±4.5%, p=0.05). ERP increases after ventricular tachypacing were equal in both groups (32 vs. 34.5 ms, p=NS). Ventricular tachypacing significantly increased the PLA activation time in Group B (from 22.8±2.9 to 43.3±8.6 ms, p<0.002), but not in Group A (from 25.3±5.2 to 28.7±11.3, p=0.6). The in-homogeneity index was also significantly increased in Group B (from 1.9±0.9 to 4.4±1.9, p=0.05) but not in Group A (p=0.12). This was accompanied by a lower number of sustained AF episodes in Group A compared to Group B (0.33±0.21 vs. 3±1.1, p<0.05). Conclusions: Targeted non-viral gene-therapy aimed at reducing TGF-β signaling - and consequent development of fibrosis - in the PLA interrupts the development of conduction slowing and in-homogeneity in the HF atrium, with a significant decrease in AF. Further optimization of this gene therapy approach may translate into effective AF therapies.