Variance of Peptidic Nerve Innervation in a Canine Model of Atrial Fibrillation Produced by Prolonged Atrial Pacing

BACKGROUND: Long-term rapid atrial pacing may result in nerve sprouting and sympathetic hyperinnervation in atrial fibrillation (AF) in dogs. Whether peptidic nerve is involved in neural remodeling is unclear. METHOD AND RESULTS: We performed rapid left atrial pacing in six dogs to induce sustained AF. Tissues from six healthy dogs were used as controls. Nerve was identified by immunocytochemical techniques. The degree of nerve innervation was quantified by measuring the amount of staining area for each antibody and the heterogeneity of nerve distribution was qualitatively studied. In dogs with AF, the density of growth-associated protein 43 (GAP43) immunopositivenerve fibers in the left atrium (LA), atrial septum (AS), and right atrium (RA) was significantly (19,454.31 +/- 1,592.81 microm(2)/mm(2) vs 1,673.41 +/- 142.62 microm(2)/mm(2)P < 0.001, 3,931.26 +/- 361.78 microm(2)/mm(2) vs 1,614.20 +/- 140. 41 microm(2)/mm(2) P < 0.05 and 2,324.15 +/- 1,123.77 microm(2)/mm(2) vs 1,620.47 +/- 189.05 microm(2)/mm(2) P < 0.05, respectively) higher than the nerve density in control tissues. The density of (neuropeptide Y) NPY-positive nerves in the, AS, and RA was (13,547.62 +/- 2,983.37 microm(2)/mm(2) vs 703.72 +/- 287.52 microm(2)/mm(2) P < 0.01, 2,689.22 +/- 340.93 microm(2)/mm(2) vs 651.7 +/- 283.02 microm(2)/mm(2) P < 0.01 and 1,574.70 +/- 424.37 microm(2)/mm(2) vs 580.42 +/- 188.12 microm(2)/mm(2) P < 0.001, respectively) higher than the nerve density in control tissues. At the same time, vasoactive intestinal polypeptide (VIP) positive nerve innervation shrank in dogs with AF. The density of VIP positive in LA, AS, and RA was statistically lower than the nerve density in control tissues, respectively. (110.48 +/- 45.63microm(2)/mm(2) vs 1679.32 +/- 1020.34microm(2)/mm(2) P < 0.01, 265.92 +/- 52.51 microm(2)/mm(2) vs 2602.68 +/- 1257.16microm(2)/mm(2) P < 0.001 and 609.56 +/- 139.75microm(2)/mm(2) vs 2771.68 +/- 779.08microm(2)/mm(2) P < 0.01, respectively). CONCLUSIONS: Combined with VIP-ergic nerve denervation, significant nerve sprouting and NPY-ergic nerve hyperinnervation are present in a canine model of sustained AF produced by prolonged atrial pacing.