The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. However, the translation of animal data/models to humans is not straightforward. Even less so for SAN pacemaker cells than working myocar- dial cells given the big di↵erence in their main output (i.e. pacing rate) between human and laboratory animals. The development of a comprehensive model of the electrical activity of a human SAN pacemaker cell strictly based on and constrained by the available electrophysiological data will be presented. We started from the Severi-DiFrancesco rabbit SAN model, which integrates the two principal mecha- nisms that determine the beating rate: the ”membrane clock” and ”calcium clock”. Several current formulations were updated based on available measurements. A set of parameters, for which no specific data were available, were automatically opti- mized to reproduce the measured AP and calcium transient data. The model was then validated by assessing the e↵ects of several mutations a↵ecting heart rate and rate modulation. Moreover, two recent applications of the model will be presented: i) We used our SAN AP computational model to assess the e↵ects of the inclu- sion of the small conductance K+ current (ISK) on the biomarkers that describe the AP waveform and calcium transient; ii) We analysed the e↵ect of altered elec- trolyte levels (as systematically occurring in hemodialysis patients) on pacemaking to investigate the possible mechanisms of the bradycardic sudden cardiac deaths pointed out by two recent human studies using implantable loop recorders.
A. Fabbri, A. Loewe, R. Wilders, and S. Severi. Propagation of the primary pacemaker activity in the human heart: a computational approach. In European Medical and Biological Engineering Conference (EMBEC), vol. 65, pp. 201, 2017
The sinoatrial node (SAN) is the natural pacemaker of our heart. How this small tissue is able to drive a remarkably larger number of intrinsically quiescent atrial cells is still debated; a computational investigation of the underlying mechanisms can help to better understand the SAN’s ability to pace-and-drive the surrounding atrium. Aim of this work is to elucidate how the human SAN action potential can successfully be captured by and propagate into the surrounding atrial tissue. The Fabbri et al. and the Courtemanche et al. models were used to describe the human SAN and atrial cells, respectively. The behaviour of two coupled regions was investigated varying the interregional conductivity (σ) and relative size. Simulations showed that it requires at least an isopotential SAN region 2.85 times wider than the atrial one. A 1D strand of homogeneously coupled SAN and atrial elements was used to identify an interval for σ showing pace-and-drive behaviour (100 SAN vs 100 atrial elements) and to investigate the source-sink interplay (10, 50 or 100 SAN elements vs 100 atrial elements). The 1D strand showed pace-and-drive behaviour for 𝜎 = 0.08 − 36 S/m; a stronger source, with a higher number of SAN elements, led to a wider 𝜎 range that allowed pace-and-drive behaviour, whereas a stronger sink did not affect the behaviour of the tissue. This preliminary work shows the ability of a small human SAN region to pace-and-drive the surrounding atrial tissue. Further investigations are needed to explore different conductivity configurations, including spatial gradients.