Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disorder and a major cause of stroke. Unfortunately, current therapies for AF are suboptimal, largely because the molecular mechanisms underlying AF are poorly understood. Since the autonomic nervous system is thought to increase vulnerability to AF, we used a rapid atrial pacing (RAP) canine model to investigate the anatomic and electrophysiological characteristics of autonomic remodeling in different regions of the left atrium. RAP led to marked hypertrophy of parent nerve bundles in the posterior left atrium (PLA), resulting in a global increase in parasympathetic and sympathetic innervation throughout the left atrium. Parasympathetic fibers were more heterogeneously distributed in the PLA when compared with other left atrial regions; this led to greater fractionation and disorganization of AF electrograms in the PLA. Computational modeling revealed that heterogeneously distributed parasympathetic activity exacerbates sympathetic substrate for wave break and reentry. We further discovered that levels of nerve growth factor (NGF) were greatest in the left atrial appendage (LAA), where AF was most organized. Preferential NGF release by the LAA-likely a direct function of frequency and regularity of atrial stimulation-may have important implications for creation of a vulnerable AF substrate.