Intercalated disk structure, tissue heterogeneity and ion channel distribution modulate conduction and local calcium...

The intercalated disk (ID) is the specialized cellular structure that connects cardiomyocytes. Electrogenic proteins are known to be preferentially located at the ID, such as the voltage-gated sodium channel (NaV1.5), inward-rectifying potassium channel (Kir2.1), sodium-potassium ATPase (NKA) and the L-type calcium channel (CaV1.2). Experimental evidence shows that modifying ID properties alters conduction, and that perturbed ID structures are found in patients with cardiac arrhythmias. In our previous work, we have shown that chamber-specific ID structures and changes in intermembrane distance lead to changes in tissue-level conduction velocity. Here, we expand our model to include the dynamics of multiple ions within the extracellular cleft as well as representations of multiple ionic currents and gap junctions (GJs) within the ID. First, we observe that ionic fluxes at the cleft critically alter local ionic currents: Na⁺ depletion in the cleft leads to a compensatory influx of Ca²⁺, which in turn drives a significant increase in ID calcium current. Furthermore, we find that concentrated Na⁺ channel or GJ clusters lead to slowed conduction at the tissue level. Finally, tissue-scale heterogeneities in ID structure lead to conduction block or spatially heterogeneous conduction velocity, suggesting a newly identified mechanism for cardiac re-entry. Our results show that local ion channel clustering can regulate cardiac conduction. Moreover, the interplay between ion channel localization and ion concentration dynamics suggests a novel mechanism to enhance robustness of local calcium currents within the ID. KEY POINTS: Intercalated disk and extracellular cleft structure have been previously shown to modulate cardiac conduction and regulate local sodium currents. In this study, we find that cleft sodium depletion drives cleft calcium influx within the extracellular cleft space and increases local intercalated disk calcium current. Enhanced sodium channel or gap junction clustering tends to slow conduction. Tissue heterogeneity in intercalated disk disruption and channel clustering can lead to localized conduction block.