Abstract 13928: Targeted Atrial Inhibition of Galphaq Signaling With Inhibitory Peptides Attenuates Fibrosis and Inducibility of Atrial Fibrillation in a Canine Heart Failure Model

Introduction: Endothelial dysfunction, a hallmark of heart failure (HF), is closely associated with atrial fibrillation (AF). However, the precise role of endothelial dysfunction in creating an atrial arrhythmogenic substrate is unknown. Endothelin-1 (ET-1) and its downstream Gα _q signaling are significantly upregulated in the atria of patients with HF. We therefore hypothesized that ET-1-Gα _q signaling contributes to adverse structural remodeling in the atria in the setting of HF.

Hypothesis: Inhibition of atrial ET-1-Gα _q signaling with Gα _q inhibitory peptides (Gα _q -ct) will attenuate the development of atrial fibrosis and AF inducibility in a HF model.

Methods: Plasmids expressing Gα _q -ct were injected and electroporated in the left atria of 4 dogs. LacZ or scrambled plasmids were used in 8 control dogs. HF was induced by ventricular tachypacing (VTP) at 240 bpm for 3 weeks. At terminal EP study, left atrial conduction vectors were recorded with high-density mapping and AF inducibility assessed. Left atrial fibrosis was quantified by Masson Trichrome.

Results: All animals developed clinical HF (prolonged capillary refill time, ascites, reduced activity level) and LV systolic dysfunction by echocardiogram (LVEF 17.5±8.3% in Gα _q -ct, 13.7±3.1% in controls, p=0.55). Conduction inhomogeneity was reduced in Gα _q -ct animals (example of posterior left atrium recordings in Fig. A). AF was less inducible in Gα _q -ct than control animals (4.8% of pacing attempts Vs 17.8%, p<0.001, Fig. B) and AF episodes were shorter (5.6±0.9 sec Vs 63.8±11.9 sec). Left atrial fibrosis was significantly attenuated in Gα _q -ct animals Vs controls (Fig. C).

Conclusions: Gα _q signaling contributes to atrial fibrosis and subsequent AF susceptibility in VTP-induced HF, thereby highlighting an important role for ET-1 signaling in HF-related atrial remodeling. Future optimization of gene therapy targeting ET-1 signaling may lead to novel, mechanism-guided treatments for AF in the context of HF.