Microheterogeneity-induced conduction slowing and wavefront collisions govern macroscopic conduction behavior: A computational and experimental study
Microheterogeneity-induced conduction slowing and wavefront collisions govern macroscopic conduction behavior: A computational and experimental study
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DOI：
10.1371/journal.pcbi.1006276
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发表时间：
2018-07-01
影响因子：
4.3
通讯作者：
Henriquez, Craig S.
中科院分区：
文献类型：
--
作者：
Gokhale, Tanmay A.;Asfour, Huda;Henriquez, Craig S.
心律失常的发生与包括纤维化在内的组织异质性有关。然而，微观结构异质性对可兴奋组织传导的影响仍然知之甚少。在这项研究中，我们研究了脱细胞微异质性如何影响正常和降低兴奋性条件下的宏观传导，利用一个新的平台配对体外和硅研究来检查传导机制。在先前描述的工程可激发Ex293细胞系的汇合单层中创建了规则的非导电微障碍物。增加障碍尺寸与障碍内链宽度的相对比例，导致传导速度显著减慢，达到23.6%，波前曲率各向异性（波前形状的空间变化指标）显著增加。体积电导率和路径弯曲度的变化不足以解释这些观察到的宏观变化。相反，包括微尺度分支导致的局部传导减慢和波前合并导致的传导加速在内的微尺度行为被证明有助于宏观现象。由于空间不均匀的微观慢化和加速效应，降低激发性的条件导致传导进一步减慢和波前曲率各向异性的逆转。这个独特的实验和计算平台为微观异质性对宏观传导的影响提供了关键的机制见解，与纤维化心脏病的设置有关。
The incidence of cardiac arrhythmias is known to be associated with tissue heterogeneities including fibrosis. However, the impact of microscopic structural heterogeneities on conduction in excitable tissues remains poorly understood. In this study, we investigated how acellular microheterogeneities affect macroscopic conduction under conditions of normal and reduced excitability by utilizing a novel platform of paired in vitro and in silico studies to examine the mechanisms of conduction. Regular patterns of nonconductive micro-obstacles were created in confluent monolayers of the previously described engineered-excitable Ex293 cell line. Increasing the relative ratio of obstacle size to intra-obstacle strand width resulted in significant conduction slowing up to 23.6% and a significant increase in wavefront curvature anisotropy, a measure of spatial variation in wavefront shape. Changes in bulk electrical conductivity and in path tortuosity were insufficient to explain these observed macroscopic changes. Rather, microscale behaviors including local conduction slowing due to microscale branching, and conduction acceleration due to wavefront merging were shown to contribute to macroscopic phenomena. Conditions of reduced excitability led to further conduction slowing and a reversal of wavefront curvature anisotropy due to spatially nonuniform effects on microscopic slowing and acceleration. This unique experimental and computation platform provided critical mechanistic insights in the impact of microscopic heterogeneities on macroscopic conduction, pertinent to settings of fibrotic heart disease.