BPS2026 - Intercalated disc nanostructure regulates local ionic currents and cardiac conduction

The intercalated disc (ID) is a critical, structurally complex junctional complex essential for synchronized cardiac conduction. Previous computational models have often oversimplified ID geometry and ionic channel distribution, limiting the ability to capture the role of ID nanoscale heterogeneity. Here, we expand our finite element mesh framework to create a more physiologically realistic representation of the ID, incorporating spatially heterogeneous gap junctions and multiple ion and ionic current dynamics. We systematically quantify the influence of key structural and electrophysiological features on conduction by simulating tissue-level conduction for strong and reduced gap junctional. Further, we employ a multilayer perceptron (MLP) neural network to perform a gradient-based sensitivity analysis. This approach enables systematic quantification of the relative influence of geometric and nanostructural factors on ID and cleft dynamics and conduction velocity (CV). Our analysis reveals that gap junctional coupling, cleft geometry, and nanostructure heterogeneity are the dominant determinants of cleft potential, sodium current synchronization, and CV. We found that the influence of interplicate and plicate distance on conduction is context-dependent, either enhancing or slowing it depending on the strength of gap junctional coupling. Collectively, our findings highlight the regime-dependent roles of ID nanostructural and establish a quantitative framework that links nanoscale ID morphology to tissue-scale cardiac conduction.