Sinoatrial Node Cell Response to Isoprenaline Stimulation and Hypocalcemia

Aims: The purpose of this study is to assess the effects of autonomic modulation and hypocalcemia on the pace-making rate in a human sinoatrial node (SAN) cell model. The clinical relevance is to bring a better understanding of the increased risk of sudden cardiac death in chronic kidney disease patients who regularly undergo hemodialysis. Methods: The Fabbri et al. (2017) SAN model was used to compute the gradual response on isoprenaline concentration ([$\text{ISO}$]) between 0 and $1.5\ \mu\mathrm{M}$ with extracellular calcium concentrations ($[\text{Ca}^{+2}]_{o}$) in the range from 1.2 to 2.2 mM. The pacing capacity of the model was evaluated by assessing the pacing rate (in beats per minute (BPM)). Results: Low $[\text{Ca}^{+2}]_{\mathrm{o}}$ led to decreased pacing rate: at $[\text{Ca}^{+2}]_{\mathrm{o}}=1.4mM$, the rate without extra autonomous stimulation was only 50 BPM compared to the 74 BPM at the default $[\text{Ca}^{+2}]_{\mathrm{o}}=1.8mM$ This effect was counteracted by autonomous modulation. The [$\text{ISO}$] necessary to restore the baseline pacing rate was $0.5 \mu \mathrm{M}$ and $1\mu \mathrm{M}$ when $[\text{Ca}^{+2}]_{\mathrm{o}}$ was reduced to 1.6 mM and 1.4 mM, respectively. Conclusions: Isoprenaline stimulation can conserve the pacing capacity during hypocalcemia. However, extremely high [$\text{ISO}$] may lead to saturation and a non-linear response, which the current model does not take into account.