title: Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is commonly associated with congestive heart failure (CHF). The autonomic nervous system is involved in the pathogenesis of both AF and CHF. We examined the role of autonomic remodeling in contributing to AF substrate in CHF.
  
  
  RESULTS
  Electrophysiological mapping was performed in the pulmonary veins and left atrium in 38 rapid ventricular-paced dogs (CHF group) and 39 control dogs under the following conditions: vagal stimulation, isoproterenol infusion, β-adrenergic blockade, acetylcholinesterase (AChE) inhibition (physostigmine), parasympathetic blockade, and double autonomic blockade. Explanted atria were examined for nerve density/distribution, muscarinic receptor and β-adrenergic receptor densities, and AChE activity. In CHF dogs, there was an increase in nerve bundle size, parasympathetic fibers/bundle, and density of sympathetic fibrils and cardiac ganglia, all preferentially in the posterior left atrium/pulmonary veins. Sympathetic hyperinnervation was accompanied by increases in β(1)-adrenergic receptor R density and in sympathetic effect on effective refractory periods and activation direction. β-Adrenergic blockade slowed AF dominant frequency. Parasympathetic remodeling was more complex, resulting in increased AChE activity, unchanged muscarinic receptor density, unchanged parasympathetic effect on activation direction and decreased effect of vagal stimulation on effective refractory period (restored by AChE inhibition). Parasympathetic blockade markedly decreased AF duration.
  
  
  CONCLUSIONS
  In this heart failure model, autonomic and electrophysiological remodeling occurs, involving the posterior left atrium and pulmonary veins. Despite synaptic compensation, parasympathetic hyperinnervation contributes significantly to AF maintenance. Parasympathetic and/or sympathetic signaling may be possible therapeutic targets for AF in CHF.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University-Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ng
authors.forename: Roger
authors.initials: R
authors.lastname: Villuendas
authors.forename: Ivan
authors.initials: I
authors.lastname: Cokic
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Schliamser
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Hemanth
authors.initials: H
authors.lastname: Koduri
authors.forename: Brandon
authors.initials: B
authors.lastname: Benefield
authors.forename: Julia
authors.initials: J
authors.lastname: Simon
authors.forename: S N Prasanna
authors.initials: SN
authors.lastname: Murthy
authors.forename: Jon W
authors.initials: JW
authors.lastname: Lomasney
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Wasserstrom
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Goldberger
authors.forename: Gary L
authors.initials: GL
authors.lastname: Aistrup
authors.forename: Rishi
authors.initials: R
authors.lastname: Arora
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology*; D001341:Autonomic Nervous System / Q000503:physiopathology*; D018780:Body Surface Potential Mapping / Q000379:methods*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D011667:Pulmonary Veins / Q000294:innervation / Q000503:physiopathology*