In silico model suggests that interdigitation promotes robust activation of atrial cells by pacemaker cells

Abstract

AbstractThe heartbeat is initiated by electrical pulses generated by a specialized patch of cells called the sinoatrial node (SAN), located on top of the right upper chamber, and then passed on to the atrium. Cardiac arrhythmias may arise if these electrical pulses fail to propagate toward the atrial cells. This computational modeling study asks how the morphology of the interface between sinoatrial (pacemaker) cells and atrial cells can influence the robustness of pulse propagation. Due to its strong negative potential, the atrium may suppress the pacemaker activity of the SAN if the electrical coupling between atrial cells is too strong. If the electrical coupling is too weak, however, the pacemaker cells cannot activate the atrial cells due to a source-sink mismatch. The SAN and atrium are connected through interdigitating structures, which are believed to contribute to the robustness of action potentials and potentially solve this trade-off. Here we investigate this interdigitation hypothesis using a hybrid model, integrating the cellular Potts model (CPM) for cellular morphology and partial-differential equations-based electrophysiological models for pulse propagation. Systematic examination of interdigitation patterns revealed that a symmetric geometry with medium-sized protrusions can prevent exit blocks. We conclude that interdigitation of SAN cells and atrial cells can promote robust propagation of action potentials toward the atrial tissue but only if the protrusions are of sufficient size and synchronicity of the action potential wave is maintained due to symmetry. This study not only highlights essential design principles forin vitromodels of cardiac arrhythmias, but also provides insights into the occurrence of exit blocksin vivo.Author summaryOur hearts beat automatically and robustly. This autonomous heartbeat is initiated by electrical pulses generated by a specialized patch of cells called the sinoatrial node, located on top of the right upper chamber. These pulses can be interpreted as electrical signals that allow the heart muscle to contract. The heart muscle cells surrounding the sinoatrial node tend to hinder this spontaneous activation because of a mismatch in electrical properties. Therefore, the pacemaker cells must be sufficiently electrically insulated from their surroundings. However, full insulation of the pacemaker cells would hinder propagation of the activation pulse toward the rest of the heart. A common hypothesis is that the sinoatrial node is fully insulated, except for some specialized pathways. We have studied the arrangement of different cell types within these pathways with the central question: how should the sinoatrial node and atrium be connected to ensure robust propagation of the electrical pulse? We implemented a computational model inspired byin vitroexperimental setups and found several relevant mechanisms. For example, we found that a folding-finger-like structure between the cell types can dramatically improve the robustness of action potentials propagating in such a tissue, provided that the folds do not become too small. This study may help improve design ofin vitromodels of sinoatrial node diseases.