Autonomic remodeling in the left atrium and pulmonary veins in heart failure creation of a dynamic substrate for atrial fibrillation

Jason Ng, Roger Villuendas, Ivan Cokic, Jorge E. Schliamser, David Gordon, Hemanth Koduri, Brandon Benefield, Julia Simon, S. N Prasanna Murthy, Jon W. Lomasney, J. Andrew Wasserstrom, Jeffrey Goldberger, Gary L. Aistrup, Rishi Arora

Research output: Contribution to journalArticle

72 Citations (Scopus)

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. Methods and 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 β1-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.

Original languageEnglish (US)
Pages (from-to)388-396
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume4
Issue number3
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

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Pulmonary Veins
Heart Atria
Atrial Fibrillation
Heart Failure
Acetylcholinesterase
Muscarinic Receptors
Dogs
Adrenergic Agents
Adrenergic Receptors
Physostigmine
Autonomic Nervous System
Isoproterenol
Ganglia
Maintenance
Control Groups

Keywords

  • Atrial fibrillation
  • Autonomic nervous system
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Autonomic remodeling in the left atrium and pulmonary veins in heart failure creation of a dynamic substrate for atrial fibrillation. / Ng, Jason; Villuendas, Roger; Cokic, Ivan; Schliamser, Jorge E.; Gordon, David; Koduri, Hemanth; Benefield, Brandon; Simon, Julia; Murthy, S. N Prasanna; Lomasney, Jon W.; Wasserstrom, J. Andrew; Goldberger, Jeffrey; Aistrup, Gary L.; Arora, Rishi.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 4, No. 3, 01.06.2011, p. 388-396.

Research output: Contribution to journalArticle

Ng, J, Villuendas, R, Cokic, I, Schliamser, JE, Gordon, D, Koduri, H, Benefield, B, Simon, J, Murthy, SNP, Lomasney, JW, Wasserstrom, JA, Goldberger, J, Aistrup, GL & Arora, R 2011, 'Autonomic remodeling in the left atrium and pulmonary veins in heart failure creation of a dynamic substrate for atrial fibrillation', Circulation: Arrhythmia and Electrophysiology, vol. 4, no. 3, pp. 388-396. https://doi.org/10.1161/CIRCEP.110.959650
Ng, Jason ; Villuendas, Roger ; Cokic, Ivan ; Schliamser, Jorge E. ; Gordon, David ; Koduri, Hemanth ; Benefield, Brandon ; Simon, Julia ; Murthy, S. N Prasanna ; Lomasney, Jon W. ; Wasserstrom, J. Andrew ; Goldberger, Jeffrey ; Aistrup, Gary L. ; Arora, Rishi. / Autonomic remodeling in the left atrium and pulmonary veins in heart failure creation of a dynamic substrate for atrial fibrillation. In: Circulation: Arrhythmia and Electrophysiology. 2011 ; Vol. 4, No. 3. pp. 388-396.
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AU - Ng, Jason

AU - Villuendas, Roger

AU - Cokic, Ivan

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AU - Gordon, David

AU - Koduri, Hemanth

AU - Benefield, Brandon

AU - Simon, Julia

AU - Murthy, S. N Prasanna

AU - Lomasney, Jon W.

AU - Wasserstrom, J. Andrew

AU - Goldberger, Jeffrey

AU - Aistrup, Gary L.

AU - Arora, Rishi

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N2 - 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. Methods and 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 β1-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.

AB - 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. Methods and 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 β1-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.

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