Computational modeling of human sinoatrial node: what simulations tell us about pacemaking

The Sinoatrial node (SAN) is the primary pacemaker in physiological conditions. SAN tissue is characterized by auto-ryhthmicity, i.e. it does not need external stimuli to initiate its electrical activity. The auto-rhythmic behavior is due to the spontaneous slow depolarization during the diastolic phase. Understanding the biophysical mechanisms at the base of diastolic depolarization is crucial to modulate the heart rate (HR). In turn, HR modulation is fundamental to treat cardiac arrhythmias, so that atria and ventricles can fill and pump the blood properly. The overall aim of the thesis is the investigation of the underlying mechanisms responsible for the pacemaking in human. To this end, a human computational model of the action potential (AP) of the SAN was developed. Pacemaking modulation at single cell level, effects of ion channel mutations on the beating rate and propagation of the electrical trigger from SAN to atrial tissue are the faced topics The human single cell SAN model was developed starting from the rabbit SAN by Severi et al.; the parent model was updated with experimental data and automatic optimization to match the AP features reported in literature. A sensitivity analysis was performed to identify the most influencing parameters. The investigation of pacemaking modulation was carried out through the simulation of current blockade and mimicking the stimulation of the autonomic nervous system. The model was validated comparing the simulated electrophysiological effects due to ion channel mutations on beating rate with clinical data of symptomatic subjects carriers of the mutation. More insights on pacemaking mechanisms were obtained thanks to the inclusion of calcium-activated potassium currents, which link changes in the intracellular calcium to the membrane. Finally, the propagation of the AP from the SAN to the atrial tissue and the source-sink interplay was investigated employing a mono-dimensional strand composed by SAN and atrial models.