Nerve Sprouting and Sympathetic Hyperinnervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Right Atrial Pacing

Abstract

Background —Long-term rapid atrial pacing may result in atrial fibrillation (AF) in dogs. Whether there is histological evidence for neural remodeling is unclear. Method and Results —We performed rapid right atrial pacing in 6 dogs for 111±76 days to induce sustained AF. Tissues from 6 healthy dogs were used as controls. Immunocytochemical staining of cardiac nerves was performed using anti–growth-associated protein 43 (GAP43) and anti–tyrosine hydroxylase (TH) antibodies. In dogs with AF, the density of GAP43-positive and TH-positive nerves in the right atrium was 470±406 and 231±126 per mm 2 , respectively, which was significantly ( P <0.001) higher than the nerve density in control tissues (25±32 and 88±40 per mm 2 , respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317±36 and 155±85 per mm 2 , respectively, and was significantly ( P <0.001) higher than the nerve density in control tissues (9±13 and 30±7 per mm 2 , respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119±61 and 91±40 per mm 2 , respectively, which was significantly ( P <0.001) higher than the nerve density in control tissues (10±15 and 38±39 per mm 2 , respectively). Furthermore, in dogs with AF, the right atrium had a significantly higher nerve density than the left atrium. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves within each sampling site. Conclusions —Significant nerve sprouting and sympathetic hyperinnervation are present in a canine model of sustained AF produced by prolonged right atrial pacing. The magnitude of nerve sprouting and hyperinnervation was higher in the right atrium than in the left atrium.