Microheterogeneity-induced conduction slowing and wavefront collisions govern macroscopic conduction behavior: A computational and experimental study

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 non-uniform 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.