BS-400-37 TARGETED ATRIAL EXPRESSION OF NGF SHRNA ATTENUATES NEW PARASYMPATHETIC AND SYMPATHETIC NERVE SPROUTING AND RESULTING DEVELOPMENT OF PERSISTENT ATRIAL FIBRILLATION IN A CANINE MODEL - A NOVEL GENE THERAPY APPROACH TO ATRIAL FIBRILLATION

Abstract

The autonomic nervous system plays an important role in development of atrial fibrillation (AF). We previously showed marked autonomic remodeling in a canine rapid atrial pacing (RAP) model of persistent AF. Nerve growth factor (NGF), a neurotrophin essential for the growth and survival of peripheral neurons, was upregulated in fibrillating atria. However, the role of NGF in the development of autonomic remodeling in AF remains to be demonstrated. To prevent autonomic remodeling and development of persistent AF in a canine RAP model of AF. NGF shRNA was injected in the atria of 8 dogs followed by electroporation to facilitate atrial gene delivery. The animals were then subjected to RAP for up to 12 weeks. Time to AF onset was determined. At the terminal EP study, episodes of AF were recorded with high-density mapping in the posterior left atrium (PLA), left atrial free wall (LAFW) and left atrial appendage (LAA) for offline analysis of AF characteristics. Tissue of each atrial region was harvested and used for immunohistochemistry with markers for parasympathetic (acetylcholinesterase, brown) or sympathetic nerves (dopamine beta-hydroxylase, blue). After initiation of RAP, control animals developed persistent atrial fibrillation (>8 hours) after a median of 14 days. In contrast, NGF shRNA animals never developed this burden of AF over the duration of the study. Residual AF recorded at time of terminal EP study was slower (lower dominant frequency; PLA: 10.5±0.8Hz Vs 11.0±0.7Hz; LAFW: 9.7±0.8Hz Vs 10.4±0.7Hz; LAA: 8.8±0.5Hz Vs 9.9±0.5Hz; two-way ANOVA p<0.001), less fractionated (longer fractionation interval; PLA: 80.4±8.1ms Vs 68.1±5.2ms; LAFW: 79.3±9.3ms Vs 70.9±3.1ms; LAA: 87.9±7.8ms Vs 80.3±2.0ms; two-way ANOVA p<0.001) and more organized (higher organization index and lower Shannon's entropy). Tissue analysis showed that RAP induced hypertrophy of nerve bundles was significantly attenuated in dogs receiving NGF shRNA. This decrease in bundle size was accompanied by a significant decrease in parasympathetic and sympathetic fibers in the atrial myocardium. Targeted inhibition of atrial autonomic remodeling by NGF shRNA prevents development of persistent AF. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.