Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation
BackgroundAcetylcholine (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, particularl...
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Frontiers Media S.A.
2019-09-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.01105/full |
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doaj-d87b55a12d60489698faa16ffc931e9b |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jason D. Bayer Jason D. Bayer Bastiaan J. Boukens Sébastien P. J. Krul Caroline H. Roney Antoine H. G. Driessen Wouter R. Berger Wouter R. Berger Nicoline W. E. van den Berg Arie O. Verkerk Arie O. Verkerk Edward J. Vigmond Edward J. Vigmond Ruben Coronel Ruben Coronel Joris R. de Groot |
spellingShingle |
Jason D. Bayer Jason D. Bayer Bastiaan J. Boukens Sébastien P. J. Krul Caroline H. Roney Antoine H. G. Driessen Wouter R. Berger Wouter R. Berger Nicoline W. E. van den Berg Arie O. Verkerk Arie O. Verkerk Edward J. Vigmond Edward J. Vigmond Ruben Coronel Ruben Coronel Joris R. de Groot Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation Frontiers in Physiology atria fibrillation acetylcholine conduction fibrosis computational modeling |
author_facet |
Jason D. Bayer Jason D. Bayer Bastiaan J. Boukens Sébastien P. J. Krul Caroline H. Roney Antoine H. G. Driessen Wouter R. Berger Wouter R. Berger Nicoline W. E. van den Berg Arie O. Verkerk Arie O. Verkerk Edward J. Vigmond Edward J. Vigmond Ruben Coronel Ruben Coronel Joris R. de Groot |
author_sort |
Jason D. Bayer |
title |
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation |
title_short |
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation |
title_full |
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation |
title_fullStr |
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation |
title_full_unstemmed |
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation |
title_sort |
acetylcholine delays atrial activation to facilitate atrial fibrillation |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2019-09-01 |
description |
BackgroundAcetylcholine (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.ObjectiveTo investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches.MethodsS1S2 pacing (S1 = 600 ms and S2 = variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify the effects of ACh on APD, maximum upstroke velocity (Vmax), and resting membrane potential (RMP); a monolayer of LAA myocytes to quantify the effects of ACh on conduction; and 3) an intact left atrium (LA) to determine the effects of ACh on 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.ResultsIn 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 35 ms 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).ConclusionIn fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry. |
topic |
atria fibrillation acetylcholine conduction fibrosis computational modeling |
url |
https://www.frontiersin.org/article/10.3389/fphys.2019.01105/full |
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doaj-d87b55a12d60489698faa16ffc931e9b2020-11-25T02:26:27ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-09-011010.3389/fphys.2019.01105429803Acetylcholine Delays Atrial Activation to Facilitate Atrial FibrillationJason D. Bayer0Jason D. Bayer1Bastiaan J. Boukens2Sébastien P. J. Krul3Caroline H. Roney4Antoine H. G. Driessen5Wouter R. Berger6Wouter R. Berger7Nicoline W. E. van den Berg8Arie O. Verkerk9Arie O. Verkerk10Edward J. Vigmond11Edward J. Vigmond12Ruben Coronel13Ruben Coronel14Joris R. de Groot15Electrophysiology and Heart Modeling Institute (IHU-LIRYC), Bordeaux University Foundation, Bordeaux, FranceInstitute of Mathematics of Bordeaux (U5251), University of Bordeaux, Bordeaux, FranceDepartment of Medical Biology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Cardiology, Academic Medical Center, Amsterdam, NetherlandsDivision of Imaging Sciences and Bioengineering, King’s College London, London, United KingdomDepartment of Cardiology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Cardiology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Cardiology, Heart Center, OLVG, Amsterdam, NetherlandsDepartment of Cardiology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Medical Biology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Experimental Cardiology, Academic Medical Center, Amsterdam, NetherlandsElectrophysiology and Heart Modeling Institute (IHU-LIRYC), Bordeaux University Foundation, Bordeaux, FranceInstitute of Mathematics of Bordeaux (U5251), University of Bordeaux, Bordeaux, FranceElectrophysiology and Heart Modeling Institute (IHU-LIRYC), Bordeaux University Foundation, Bordeaux, FranceDepartment of Experimental Cardiology, Academic Medical Center, Amsterdam, NetherlandsDepartment of Cardiology, Academic Medical Center, Amsterdam, NetherlandsBackgroundAcetylcholine (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.ObjectiveTo investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches.MethodsS1S2 pacing (S1 = 600 ms and S2 = variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify the effects of ACh on APD, maximum upstroke velocity (Vmax), and resting membrane potential (RMP); a monolayer of LAA myocytes to quantify the effects of ACh on conduction; and 3) an intact left atrium (LA) to determine the effects of ACh on 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.ResultsIn 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 35 ms 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).ConclusionIn fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.https://www.frontiersin.org/article/10.3389/fphys.2019.01105/fullatriafibrillationacetylcholineconductionfibrosiscomputational modeling |