Historically, heterogeneity of the myocardium has been strongly associated with arrhythmogenic behavior, both in experimental studies and in clinical data. Several groups have examined how isolated microstructural heterogeneities affect local tissue conduction, but less well-understood is how the aggregate behavior of numerous micro-heterogeneities affects macroscopic conduction. The objective of this work was therefore to construct paired experimental and computational studies to explore the mechanisms of conduction in heterogeneous tissues. Regular patterns of acellular ‘obstacles’ were created in in vitro and in silico monolayers of excitable cells. A simplified excitable cell line and our previously described mathematical model of this cell line were utilized. Increasing the width of the obstacles relative to the surroundings strands of excitable tissue resulted in significant macroscopic conduction slowing and anisotropy of the activation wavefront. Tortuous conduction around obstacles was shown to be insufficient to explain the observed macroscale behavior. However, on the microscale, sites of tissue expansion and convergence were shown to slow and speed local conduction, respectively. When taken in aggregate, these microscale behaviors were shown to be a key determinant of macroscopic conduction. In addition, under diseased conditions that involve reduced excitability, alteration of these microscale behaviors led to reversal of changes in wavefront curvature, and created a substrate that may be more susceptible to wave break and reentry.

This is joint work with Huda Asfour, Nenad Bursac and Craig Henriquez. This work was supported in part by NIH grants R01HL093711 to CH; R21HL126193, R01HL126524, and R01HL132389 to NB; and support from the Duke Medical Scientist Training Program training grant (T32GM007171) to TG.