Emergent Electrical Activity, Tissue Heterogeneity, and Robustness in a Calcium Feedback Regulatory Model of the Sinoatrial Node

The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN activity emerges at an early point in life and maintains a steady rhythm for the lifetime of the organism. The ion channel composition and currents of SAN cells can be influenced by a variety of factors. Therefore, the emergent activity and long-term stability imply some form of dynamical feedback control of SAN activity. We adapt a recent feedback model - previously utilized to describedion conductances in neurons - to a model of SAN cells and tissue. The model describes a minimal regulatory mechanism of ion channel conductances via feedback between intracellular calcium and an intrinsic target calcium level. By coupling a SAN cell to the calcium feedback model, we show that spontaneous electrical activity emerges from quiescence and is maintained at steady-state. In a 2D SAN tissue, spatial variability in intracellular calcium targets lead to significant, self-organized heterogeneous ion channel expression and calcium transients throughout the tissue. Further, multiple pacemaking regions appear, which interact and lead to time-varying cycle length, demonstrating that variability in heart rate is an emergent property of the feedback model. Finally, we demonstrate that the SAN tissue is robust to the silencing of leading cells or ion channel knockouts. Thus, the calcium feedback model can reproduce and explain many fundamental emergent properties of activity in the SAN that have been observed experimentally based on a minimal description of intracellular calcium and ion channel regulatory networks. Key Points SummaryO_LIThe robust function of the sinoatrial node (SAN) is reproduced in an intracellular calcium feedback model governing ion channel conductances C_LIO_LIThe feedback model predicts the emergence and long-term maintenance of spontaneous oscillatory electrical activity C_LIO_LIIntegrating the feedback model into a 2D SAN tissue leads to emergent spatial heterogeneity, multiple pacemaking regions, and variable cycle length C_LIO_LISAN cells and tissue with feedback are robust to cell injury and channel knock-outs C_LI