Abstract:

Regular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANCs). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus we investigated the effects of hypocalcaemia and sympathetic stimulation on the SANC beating rate (BR). The β-adrenergic receptor (β-AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca]) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) for a sufficient period of time to allow transient oscillations to equilibrate and reach a limit cycle. The β-AR cell response of the extended models was validated against new Langendorff-perfused rabbit heart experiments and literature data. The extended models revealed that decreased [Ca] necessitated an exponential-like increase in [ISO] to restore the basal BR. Specifically at 1.2 mM [Ca], the Severi and Fabbri models required 28.0 and 9.6 nM [ISO], respectively, to restore the initial BR. Further reduction in [Ca] to 0.6 mM required 170.0 and 43.6 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca] resulted in a loss of automaticity within seconds. These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the β-AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients. KEY POINTS: We extended the sinoatrial node cell (SANC) models of Severi et al. (rabbit) and Fabbri et al. (human) using the β-adrenergic receptor (β-AR) signalling cascade Behar et al. described. Simulations were conducted across various extracellular calcium ([Ca]) (0.6-1.8 mM) and isoprenaline concentrations [ISO] (0-1000 nM) to reflect conditions in haemodialysis (HD) patients. An exponential-like increase in [ISO] compensated for hypocalcaemia-induced bradycardia in both models, whereas interspecies differences increased the sensitivity of the extended Fabbri model towards hypocalcaemia and increased sympathetic tone. The extended models may help to further understand the pathomechanisms of several cardiovascular diseases affecting pacemaking, such as the high occurrence of sudden cardiac death (SCD) in chronic kidney disease (CKD) patients.

Abstract:

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.

Abstract:

Atrial flutter (AFL) is a common heart rhythm disorder, which is characterised by regularly propagating electrical signals and self-sustained electrophysiological mechanisms. Since AFl mechanisms are usually discriminated from invasive intra-cardiac signals, enabling a non-invasive categorisation of driving mechanisms prior to the invasive procedure, would greatly benefit the ablation strategy. In the present work, various image and video classifi- cation approaches are implemented and evaluated, in order to discriminate distinguishable electrophysiological mechanisms sustaining AFl. Therefore, the cardiac excitation of 20 different AFl scenarios, was simulated on eight volumetric bi-atrial anatomies. Solving the forward problem of electrocardiography, the body surface potential maps (BSPMs) were calculated and projected onto eight triangulated torso meshes. Given by the implementation of 124 atrial rotations within the different torso models, the provided database comprising 153,760 simulations, was completed. Finally, with further processing the generated 12-lead electrocardiograms (ECGs) and spatially down- sampling the obtained BSPMs, a consistent ground truth for AFl perpetuation mechanisms, was established. In the first part of this work, the resulting recurrence plots (RPs) and distance plots (DPs) were discriminated via the atlas and K-nearest-neighbour (KNN) classification approach as well as referring to two residual convolutional neural networks (CNNs). Moreover, for each approach the ascription into 20 AFl mechanisms and five macro groups was performed independently. Hit rates of 21% considering the assignment into 20 AFl scenarios and 40% corresponding to the macro groups, were achieved. Focused on the classification of the BSPM video sequences, the second part of this work contained the assignments based on a three-dimensional residual network (ResNet). This resulted in average accuracy values of 57%, in cases of 20 AFl mechanisms and 67% considering the simplified macro groups ascription task. Thus, the BSPM-based categorisation has been shown an effective method to discriminate distinguishable AFl electrophysiological mechanisms in a non-invasive in silico study. It is outlined that this could help to delineate the ablation strategy, reduce resources to conduct invasive cardiac mapping and time.