Bayer Jason D, Boukens Bastiaan J, Krul Sébastien P J, Roney Caroline H, Driessen Antoine H G, Berger Wouter R, van den Berg Nicoline W E, Verkerk Arie O, Vigmond Edward J, Coronel Ruben, de Groot Joris R
Electrophysiology and Heart Modeling Institute (IHU-LIRYC), Bordeaux University Foundation, Bordeaux, France.
Institute of Mathematics of Bordeaux (U5251), University of Bordeaux, Bordeaux, France.
Front Physiol. 2019 Sep 4;10:1105. doi: 10.3389/fphys.2019.01105. eCollection 2019.
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.
To investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches.
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 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 ( = 6) or with ( = 7) 100 μM ACh.
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 ( = 0.036) compared to no change without ACh (56.7 ± 29.3 ms to 50.0 ± 21.9 ms, = 0.140).
In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.
乙酰胆碱（ACh）可缩短人心房动作电位时程（APD）。APD缩短通过减少折返波长促进心房颤动（AF）。然而，ACh对人心房电传导的影响及其对AF的作用尚不清楚，尤其是与间质纤维化导致的传导受损相结合时。
采用计算、实验和临床方法研究ACh对人心房传导的影响及其在AF中的作用。
将S1S2起搏（S1 = 600 ms，S2 = 可变周期长度）应用于以下人心房颤动计算机模型：左心耳（LAA）心肌细胞，以量化ACh对APD、最大除极速度（V ）和静息膜电位（RMP）的影响；单层LAA心肌细胞，以量化ACh对传导的影响；完整左心房（LA），以确定ACh对致心律失常性的影响。将异质性ACh和间质纤维化应用于单层和LA模型。为了证实模拟结果，在0.1 μM ACh处理前后记录分离的人心房肌细胞的APD和RMP。在组织水平，使用Di-4-ANEPPS对AF患者的LAA进行光学标测。测定最初在S1起搏时记录的总激活时间（AT）与随后在无（ = 6）或有（ = 7）100 μM ACh的S1起搏期间记录的AT之间的差异。
在LAA心肌细胞模拟中，0.1 μM ACh的S1起搏使APD缩短41 ms，RMP超极化7 mV，V 增加27 mV/ms。在人心房肌细胞中，0.1 μM ACh使APD缩短48 ms，RMP超极化3 mV，V 增加6 mV/ms。在LAA单层模拟中，ACh的S1起搏使RMP超极化，在无纤维化时总AT延迟32 ms，有纤维化时延迟35 ms。这导致在S2起搏期间，异质性ACh的纤维化LA中出现单向传导阻滞和持续折返。在AF患者的LAA中，与无ACh时无变化（56.7 ± 29.3 ms至50.0 ± 21.9 ms； = 0.140）相比，ACh的S1起搏使总AT从39.3 ± 26 ms增加到71.4 ± 31.2 ms（ = 0.036）。
在具有异质性副交感神经激活的纤维化心房中，ACh通过缩短APD和减慢传导促进单向传导阻滞和折返，从而促进AF。
