Neural substrate for atrial fibrillation: Implications for targeted parasympathetic blockade in the posterior left atrium

Rishi Arora, Joseph S. Ulphani, Roger Villuendas, Jason Ng, Laura Harvey, Sarah Thordson, Firdous Inderyas, Yi Lu, David Gordon, Pablo Denes, Rodney Greene, Susan Crawford, Robert Decker, Alexander Morris, Jeffrey Goldberger, Alan H. Kadish*

*Corresponding author for this work

Research output: Contribution to journalArticle

45 Scopus citations

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 (M2) 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/cm2 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 M2-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 M2 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.

Original languageEnglish (US)
Pages (from-to)H134-H144
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Autonomic
  • Immunohistochemistry
  • Nervous system

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Arora, R., Ulphani, J. S., Villuendas, R., Ng, J., Harvey, L., Thordson, S., Inderyas, F., Lu, Y., Gordon, D., Denes, P., Greene, R., Crawford, S., Decker, R., Morris, A., Goldberger, J., & Kadish, A. H. (2008). Neural substrate for atrial fibrillation: Implications for targeted parasympathetic blockade in the posterior left atrium. American Journal of Physiology - Heart and Circulatory Physiology, 294(1), H134-H144. https://doi.org/10.1152/ajpheart.00732.2007