The effect of complex intramural microstructure caused by structural remodeling on the stability of atrial fibrillation: Insights from a three-dimensional multi-layer modeling study

Background
Recent researches have suggested that the complex three-dimensional structures caused by structural remodeling play a key role in atrial fibrillation (AF) substrates. Here we aimed to investigate this hypothesis using a multi-layer model representing intramural microstructural features.
Methods
The proposed multi-layer model was composed of the endocardium, connection wall, and epicardium. In the connection wall, intramural fibrosis was simulated using fibrotic patches randomly scattered in the myocardial tissue of fibrotic layers, while endo-epicardial dissociation was simulated using myocardial patches randomly scattered in the fibrotic tissue of isolation layers. Multiple simulation groups were generated to quantitatively analyze the effects of endo-epicardial dissociation and intramural fibrosis on AF stability, including a stochastic group, interrelated groups, fibrosis-degree-controlled groups, and dissociation-degree-controlled groups.
Results
1. Stable intramural re-entries were observed to move along complete re-entrant circuits inside the transmural wall in four of 65 simulations in the stochastic group. 2. About 21 of 23 stable simulations in the stochastic group were distributed in the areas with high endo-epicardial dissociation and intramural fibrosis. 3. The difference between fibrosis-degree-controlled groups and dissociation-degree-controlled groups suggested that some distributions of connection areas may affect AF episodes despite low intramural fibrosis and endo-epicardial dissociation. 4. The overview of tracking phase singularities revealed that endo-epicardial dissociation played a visible role in AF substrates.
Conclusion
The complex intramural microstructure is positively correlated with critical components of AF maintenance mechanisms. The occurrence of intramural re-entry further indicates the complexity of AF wave-dynamics.

研究背景
已有研究表明，由结构重构引发的复杂三维结构在心房颤动（atrial fibrillation, AF）基质中发挥关键作用。本研究旨在通过构建表征壁内微结构特征的多层模型，对这一假说展开验证。

研究方法
本研究提出的多层模型由心内膜（endocardium）、连接壁以及心外膜（epicardium）构成。在连接壁中，研究人员通过在纤维化层的心肌组织内随机散布纤维化灶，模拟壁内纤维化（intramural fibrosis）；同时通过在隔离层的纤维化组织内随机散布心肌灶，模拟心内膜-心外膜分离（endo-epicardial dissociation）。为定量分析心内膜-心外膜分离与壁内纤维化对心房颤动稳定性的影响，本研究设置了多组仿真实验，包括随机组（stochastic group）、关联组（interrelated groups）、纤维化程度控制组（fibrosis-degree-controlled groups）以及分离程度控制组（dissociation-degree-controlled groups）。

研究结果
1. 在随机组的65次仿真实验中，有4次观察到稳定的壁内折返（intramural re-entries）沿跨壁完整折返环路移动。
2. 随机组中23个稳定仿真结果里，约21个分布于心内膜-心外膜分离与壁内纤维化程度均较高的区域。
3. 纤维化程度控制组与分离程度控制组的对比结果表明，即便壁内纤维化与心内膜-心外膜分离程度较低，连接区域的部分分布特征仍可能影响心房颤动发作。
4. 对相位奇点（phase singularities）的追踪分析显示，心内膜-心外膜分离在心房颤动基质中发挥了显著作用。

研究结论
复杂的壁内微结构与心房颤动维持机制的关键组分呈正相关。壁内折返的出现进一步表明心房颤动波动力学（wave-dynamics）的复杂性。