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Published on: February 26, 2013
Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation
Jason D Bayer1,2, Bastiaan J Boukens3, Sébastien P J Krul4
1Electrophysiology and Heart Modeling Institute (IHU-LIRYC), Bordeaux University Foundation, Bordeaux, France.
Insights
Acetylcholine (ACh) shortens action potential duration and slows conduction in fibrotic atria, promoting reentry and facilitating atrial fibrillation (AF). This study clarifies ACh's role in AF development, especially with fibrosis.
Area of Science:
- Cardiovascular Electrophysiology
- Computational Biology
- Medical Research
Background:
- Acetylcholine (ACh) shortens action potential duration (APD) in human atria, a known factor in atrial fibrillation (AF) development.
- The precise role of ACh in atrial electrical conduction, particularly alongside interstitial fibrosis, remains incompletely understood.
Purpose of the Study:
- To investigate the multifaceted effects of ACh on human atrial conduction and its contribution to AF.
- To utilize computational modeling, experimental data, and clinical observations to elucidate these mechanisms.
Main Methods:
- Computational models of human atrial myocytes, monolayers, and intact atria were used to simulate ACh effects on APD, conduction velocity, and arrhythmogenicity.
- Experiments included recording APD and resting membrane potential (RMP) in isolated human atrial myocytes and optical mapping of atrial appendages from AF patients.
- Simulations incorporated heterogeneous ACh levels and interstitial fibrosis to mimic clinical conditions.
Main Results:
- ACh significantly shortened APD, hyperpolarized RMP, and increased maximum upstroke velocity in both simulated and isolated human atrial myocytes.
- In simulated fibrotic atria, ACh induced unidirectional conduction block and sustained reentry.
- Optical mapping of AF patient atria showed ACh significantly increased total activation time, indicating slowed conduction.
Conclusions:
- ACh plays a crucial role in facilitating AF in fibrotic atria with heterogeneous parasympathetic activation.
- By shortening APD and slowing conduction, ACh promotes unidirectional block and reentry, key mechanisms in AF.
- These findings highlight the pro-arrhythmic potential of ACh in specific atrial conditions.
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:
To investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches.
Methods:
S1S2 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 (V ), 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.
Results:
In LAA myocyte simulations, S1 pacing with 0.1 μM ACh shortened APD by 41 ms, hyperpolarized RMP by 7 mV, and increased V by 27 mV/ms. In human atrial myocytes, 0.1 μM ACh shortened APD by 48 ms, hyperpolarized RMP by 3 mV, and increased V 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).
Conclusion:
In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.
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