Korean J Physiol Pharmacol.  2016 Jan;20(1):111-117. 10.4196/kjpp.2016.20.1.111.

Inducibility of human atrial fibrillation in an in silico model reflecting local acetylcholine distribution and concentration

• Hwang M
• Lee HS
• Pak HN
• Shim EB

• KMID: 2150480
• DOI: http://doi.org/10.4196/kjpp.2016.20.1.111

Abstract

Vagal nerve activity has been known to play a crucial role in the induction and maintenance of atrial fibrillation (AF). However, it is unclear how the distribution and concentration of local acetylcholine (ACh) promotes AF. In this study, we investigated the effect of the spatial distribution and concentration of ACh on fibrillation patterns in an in silico human atrial model. A human atrial action potential model with an ACh-dependent K+ current (I(KAch)) was used to examine the effect of vagal activation. A simulation of cardiac wave dynamics was performed in a realistic 3D model of the atrium. A model of the ganglionated plexus (GP) and nerve was developed based on the "octopus hypothesis". The pattern of cardiac wave dynamics was examined by applying vagal activation to the GP areas or randomly. AF inducibility in the octopus hypothesis-based GP and nerve model was tested. The effect of the ACh concentration level was also examined. In the single cell simulation, an increase in the ACh concentration shortened APD90 and increased the maximal slope of the restitution curve. In the 3D simulation, a random distribution of vagal activation promoted wavebreaks while ACh secretion limited to the GP areas did not induce a noticeable change in wave dynamics. The octopus hypothesis-based model of the GP and nerve exhibited AF inducibility at higher ACh concentrations. In conclusion, a 3D in silico model of the GP and parasympathetic nerve based on the octopus model exhibited higher AF inducibility with higher ACh concentrations.

Keyword

Atrial fibrillation; Autonomic nervous system; Simulation; Vagal activation

MeSH Terms

Acetylcholine*
Action Potentials
Atrial Fibrillation*
Autonomic Nervous System
Computer Simulation*
Ganglion Cysts
Humans*
Octopodiformes
Acetylcholine

Figure

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  Fig. 1 Ramp pacing protocol.Initially, pacing was applied 8 times with a 1,000 ms cycle length. The cycle length was then decreased by 50 ms until it reached 250 ms. Afterwards, the cycle length was decreased by 10 ms until an alternan was observed.

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  Fig. 2 Three dimensional model of LA and ACh distribution.(A) Random distribution of ACh. (B) ACh distributions in GP areas only. (C) ACh distribution based on the octopus hypothesis [8].

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  Fig. 3 Action potential curves of ionic currents obtained from the baseline model identical to Courtemanche et al. [5] model.

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  Fig. 4 Action potential and restitution curves.(A) Action potential curves exhibiting APD90 shortening with increasing ACh concentrations. (B) APD90 shortening with decreasing cycle length. (C) Action potential restitution curves for various ACh concentrations.

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  Fig. 5 The pattern of wave dynamics in a 3D model in which ACh is distributed randomly for ACh concentrations (µM) of 0 (A), 0.001 (B), 0.05 (C), and 0.1 (D).Voltage maps are shown on both the anterior and posterior sides as well as on action potential curves at a spatial location.

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  Fig. 6 The pattern of wave dynamics in a 3D model in which ACh is present only in GP areas for ACh concentrations (µM) of 0.001 (A), 0.05 (B), and 0.1 (C).Voltage maps are shown on both the anterior and posterior sides as well as on action potential curves at a spatial location.

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  Fig. 7 The pattern of wave dynamics pattern in an octopus hypothesis-based model of GP and nerve for ACh concentrations (µM) of 0.03 (A) and 0.3 (B).Voltage maps are shown on both the anterior and posterior sides as well as on action potential curves at a spatial location.

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