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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.01105

Acetylcholine delays atrial activation to facilitate atrial fibrillation

 Jason D. Bayer1, 2*,  Sébastien P. Krul3,  Bastiaan J. Boukens4,  Caroline H. Roney5, Antoine H. Driessen3, Wouter R. Berger3*, Nicoline W. van den Berg3, Edward J. Vigmond1, 2,  Ruben Coronel1, 3 and  Joris R. de Groot3
  • 1Institut de rythmologie et modélisation cardiaque (IHU-Liryc), France
  • 2UMR5251 Institut de mathématiques de Bordeaux (IMB), France
  • 3Academic Medical Center (AMC), Netherlands
  • 4Department of Medical Biology, Academic Medical Center, Netherlands
  • 5King's College London, United Kingdom

Background
Acetylcholine (ACh) shortens action potential duration (APD) in human atria. APD shortening facilitates atrial fibrillation (AF) by reducing the wavelength for reentry. However, the influence of ACh on electrical conduction in human atria and its contribution to AF are unclear, particularly when combined with impaired conduction from interstitial fibrosis.

Objective
Investigate the effect of ACh effect on human atrial conduction and its role in AF with computational, experimental, and clinical approaches.

Methods
S1S2 pacing (S1=600ms and S2=variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify ACh effects on APD, maximum upstroke velocity (Vmax), and resting membrane potential (RMP); a LAA monolayer to quantify ACh conduction effects; and 3) a left atrium (LA) to determine ACh arrhythmogenicity. Heterogeneous ACh and interstitial fibrosis were applied to the monolayer and LA models. To corroborate the simulations, APD and RMP from isolated human atrial myocytes were recorded before and after 0.1 µM ACh. At the tissue level, LAAs from AF patients were optically mapped ex vivo using Di-4-ANEPPS. The difference in total activation time (AT) was determined between AT initially recorded with S1 pacing, and AT recorded during subsequent S1 pacing without (n=6) or with (n=7) 100 µM ACh.

Results
In LAA myocyte simulations, S1 pacing with 0.1 µM ACh shortened APD by 41 ms, hyperpolarized RMP by 7 mV, and increased Vmax by 27 mV/ms. In human atrial myocytes, 0.1 µM ACh shortened APD by 48 ms, hyperpolarized RMP by 3 mV, and increased Vmax by 6 mV/ms. In LAA monolayer simulations, S1 pacing with ACh hyperpolarized RMP to delay total AT by 32 ms without and 35ms with fibrosis. This led to unidirectional conduction block and sustained reentry in fibrotic LA with heterogeneous ACh during S2 pacing. In AF patient LAAs, S1 pacing with ACh increased total AT from 39.3±26 ms to 71.4±31.2 ms (P=0.036) compared to no change without ACh (56.7±29.3 ms to 50.0±21.9 ms, P=0.140).

Conclusions:In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.

Keywords: atrial fibrillation (AF), Acetycholine, conduction, Fibrosis, computational modeling

Received: 09 Oct 2018; Accepted: 09 Aug 2019.

Edited by:

Zhilin Qu, University of California, Los Angeles, United States

Reviewed by:

Wayne R. Giles, University of Calgary, Canada
Thao P. Nguyen, UCLA David Geffen School of Medicine, United States
Oleg Aslanidi, King's College London, United Kingdom  

Copyright: © 2019 Bayer, Krul, Boukens, Roney, Driessen, Berger, van den Berg, Vigmond, Coronel and de Groot. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Jason D. Bayer, Institut de rythmologie et modélisation cardiaque (IHU-Liryc), Pessac, 33604, Aquitaine, France, jason.bayer@ihu-liryc.fr
MD. Wouter R. Berger, Academic Medical Center (AMC), Amsterdam, 1105, Noord-Holland, Netherlands, w.r.berger@amc.uva.nl