title: Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium.
abstract: The parasympathetic (P) nervous system is thought to contribute significantly to focal atrial fibrillation (AF). Thus we hypothesized that P nerve fibers [and related muscarinic (M(2)) receptors] are preferentially located in the posterior left atrium (PLA) and that selective cholinergic blockade in the PLA can be successfully performed to alter vagal AF substrate. The PLA, pulmonary veins (PVs), and left atrial appendage (LAA) from six dogs were immunostained for sympathetic (S) nerves, P nerves, and M(2) receptors. Epicardial electrophysiological mapping was performed in seven additional dogs. The PLA was the most richly innervated, with nerve bundles containing P and S fibers (0.9 +/- 1, 3.2 +/- 2.5, and 0.17 +/- 0.3/cm(2) in the PV, PLA, and LAA, respectively, P < 0.001); nerve bundles were located in fibrofatty tissue as well as in surrounding myocardium. P fibers predominated over S fibers within bundles (P-to-S ratio = 4.4, 7.2, and 5.8 in PV, PLA, and LAA, respectively). M(2) distribution was also most pronounced in the PLA (17.8 +/- 8.3, 14.3 +/- 7.3, and 14.5 +/- 8 M(2)-stained cells/cm(2) in the PLA, PV, and LAA, respectively, P = 0.012). Left cervical vagal stimulation (VS) caused significant effective refractory period shortening in all regions, with easily inducible AF. Topical application of 1% tropicamide to the PLA significantly attenuated VS-induced effective refractory period shortening in the PLA, PV, and LAA and decreased AF inducibility by 92% (P < 0.001). We conclude that 1) P fibers and M(2) receptors are preferentially located in the PLA, suggesting an important role for this region in creation of vagal AF substrate and 2) targeted P blockade in the PLA is feasible and results in attenuation of vagal responses in the entire left atrium and, consequently, a change in AF substrate.
authors.affiliation: Division of Cardiology, Northwestern Memorial Hospital, 251 East Huron, Feinberg 8-542, Chicago, IL 60611, USA.
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Ulphani
authors.forename: Roger
authors.initials: R
authors.lastname: Villuendas
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.forename: Laura
authors.initials: L
authors.lastname: Harvey
authors.forename: Sarah
authors.initials: S
authors.lastname: Thordson
authors.forename: Firdous
authors.initials: F
authors.lastname: Inderyas
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Pablo
authors.initials: P
authors.lastname: Denes
authors.forename: Rodney
authors.initials: R
authors.lastname: Greene
authors.forename: Susan
authors.initials: S
authors.lastname: Crawford
authors.forename: Robert
authors.initials: R
authors.lastname: Decker
authors.forename: Alexander
authors.initials: A
authors.lastname: Morris
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Goldberger
authors.forename: Alan H
authors.initials: AH
authors.lastname: Kadish
mesh_terms: D000200:Action Potentials; D000818:Animals; D020517:Atrial Appendage / Q000294:innervation / Q000378:metabolism; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D004285:Dogs; D004558:Electric Stimulation; D005725:Ganglia, Autonomic / Q000378:metabolism / Q000503:physiopathology; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011667:Pulmonary Veins / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012107:Research Design; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D014331:Tropicamide / Q000494:pharmacology; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D014331:Tropicamide