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Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation
Georg Gussak, … , Yohannes Shiferaw, Rishi Arora
Georg Gussak, … , Yohannes Shiferaw, Rishi Arora
Published September 10, 2019
Citation Information: JCI Insight. 2019;4(20):e130532. https://doi.org/10.1172/jci.insight.130532.
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Research Article Cardiology

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation

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Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder and a major cause of stroke. Unfortunately, current therapies for AF are suboptimal, largely because the molecular mechanisms underlying AF are poorly understood. Since the autonomic nervous system is thought to increase vulnerability to AF, we used a rapid atrial pacing (RAP) canine model to investigate the anatomic and electrophysiological characteristics of autonomic remodeling in different regions of the left atrium. RAP led to marked hypertrophy of parent nerve bundles in the posterior left atrium (PLA), resulting in a global increase in parasympathetic and sympathetic innervation throughout the left atrium. Parasympathetic fibers were more heterogeneously distributed in the PLA when compared with other left atrial regions; this led to greater fractionation and disorganization of AF electrograms in the PLA. Computational modeling revealed that heterogeneously distributed parasympathetic activity exacerbates sympathetic substrate for wave break and reentry. We further discovered that levels of nerve growth factor (NGF) were greatest in the left atrial appendage (LAA), where AF was most organized. Preferential NGF release by the LAA — likely a direct function of frequency and regularity of atrial stimulation — may have important implications for creation of a vulnerable AF substrate.

Authors

Georg Gussak, Anna Pfenniger, Lisa Wren, Mehul Gilani, Wenwei Zhang, Shin Yoo, David A. Johnson, Amy Burrell, Brandon Benefield, Gabriel Knight, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, Gary Aistrup, J. Andrew Wasserstrom, Yohannes Shiferaw, Rishi Arora

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Figure 5

Response to atropine is more homogeneous in the left atrial appendage (LAA), whereas propranolol does not induce a differential response.

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Response to atropine is more homogeneous in the left atrial appendage (L...
(A) Effect of atropine or dual blockade on mean dominant frequency (DF), organization index (OI), fractionation interval (FI), Shannon’s entropy (ShEn), and recurrence cycle length (CLR) in the posterior left atrium (PLA) and left atrial appendage (LAA). n = 10 for baseline and atropine, n = 4 for dual blockade. Data is shown as scatterplot with mean ± SEM from mixed linear model. (B) Representative example of high-density electrode recordings of DF (left panels) and OI (right panels) in the PLA (top) and LAA (bottom) at baseline and after atropine. The change induced by atropine is shown as a Δ map. (C) SD of change induced by atropine in parameters shown in A for the PLA, left atrial free wall (LAFW), and LAA is shown as scatterplot with mean ± SEM. n = 10 in all groups. ANOVA significance indicated in graphs. (D) Representative examples of high-density electrode recordings of DF (right) and OI (left) in the PLA (top) and LAA (bottom) after atropine and dual blockade. The change induced by propranolol is shown as a Δ map. (E) SD of change induced by propranolol in parameters shown in A for the PLA and LAA is shown as scatterplot with mean ± SEM. n = 4 in all groups. ANOVA significance indicated in graphs. *P < 0.05; **P< 0.01; ***P < 0.001 for pairwise comparison with Holm-Sidak method.

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