Session SA3.2

Increasing the Effective Interstitial Resistivity Promotes the Escape of Premature Beats

ML Hubbard*, CS Henriquez

Duke University
Durham, NC, USA

Spontaneous electrical beats in diseased cardiac tissue require a heterogeneous substrate in order to evolve into dangerous, whole-heart arrhythmias. This substrate is often created by combined structural heterogeneities in both the intracellular and interstitial spaces of the heart. The objective of this study was to use microstructural computer models to determine how increasing the effective interstitial resistivity of a small region of poorly-coupled tissue can influence the escape of premature beats from the poorly-coupled region to surrounding well-coupled tissue.
We created a heterogeneous, microstructural model by introducing a 0.6 cm long central zone of poorly-coupled cells into a 1 cm long well-coupled fiber. Gap junctions were modeled as individual resistors (Rg), and the effective interstitial resistivity was incorporated into the monodomain fiber using an approximation that was based on bidomain simulations. The LRd model of guinea pig ventricular myocytes was used to represent membrane dynamics. Premature beats were generated in the central zone using an S1-S2 stimulus protocol, and the effect of increased effective interstitial resistivity on the escape of premature beats was tested for varying levels of coupling.
In the first test fiber, Rg of the central zone was set to 60 O-cm. Increasing the effective interstitial resistivity of the central zone from 0.5 to 2.5 kO-cm reduced the delay at the S1 transition between the well-coupled and poorly-coupled region by 70% and the delay at the S2 (Basic Cycle Length=220 ms) transition by 50%. In the second test fiber, Rg of the central zone was set to 70 O-cm. When the effective interstitial resistivity was set to 0.5 kO-cm, conduction block occurred at the S1 transition but did not occur at the S2 transition. When the effective interstitial resistivity was increased to 2.5 kO-cm, both S1 and S2 were able to conduct from the poorly-coupled region to the well-coupled region.
These results suggest the presence of two different mechanisms that reduce loading effects along the fiber and restore conduction at the transition between the poorly-coupled and well-coupled region. In one mechanism, the increase in effective interstitial resistivity increases the available sodium current and reduces the resistive loading effects along the fiber. In the second mechanism, the premature stimulus decreases the available sodium current yet also reduces loading effects along the fiber. Although these two mechanisms have competing modes of action, they both help premature beats to escape from poorly-coupled regions into well-coupled regions. The interplay between low intercellular coupling, reduced membrane excitability, and increased interstitial resistivity at the microscale level may enable complex activation patterns to develop from a small source of spontaneous electrical activity.

(Abstract Control Number: 123)