Modelling the sinoatrial node across the scales: the role of heterogeneity in pacemaking and atrial driving

During a human being’s life, the heart beats on average 2 to 3 billion times. At each cycle, the primary pacemaker of the heart – the sinoatrial node – automatically depolarizes and excites the atria. The stimulus then travels along the cardiac conduction system and spreads to the ventricles, determining contraction. Why the sinoatrial node is able to show spontaneous and rhythmic electrical activity, as well as how it manages to drive the surrounding tissue, is still in-completely understood. The contribution of neural control to the physiology and pathology of the sinoatrial node is even less known. All this limits the chances of preventing and treating diseases originating from the disruption of these mechanisms, as it happens during aging. In this dissertation, the sub-cellular, cellular, tissue and organism levels of cardiac pacemaking are investigated using computational models and heart rate variability analysis. In particular, the aim of this work is that of providing quantitative information about the role of heterogeneity in sinoatrial node functioning. In summary, the main results show that heterogeneity I) regulates the relative contribution of ion channels and intracellular calcium handling to the beating rate; II) increases the robustness of the sinoatrial node in originating the heartbeat and propagating it to the atrium, in both physiological and pathological conditions and III) vagal nerve stimulation stabilizes spectral heart rate variability metrics and promotes heart rate reduction and variability after myocardial infarction in pigs. In conclusion, this PhD dissertation represent a step forward in the comprehension of fundamental aspects of cardiac pacemaking.