Y. Lutz. Influence of electrolyte change on sinus node function. A new player regarding sudden cardiac death in patients with chronic kidney disease?. Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT). Masterarbeit. 2016
Chronic kidney disease (CKD) affects more than 30 million patients in the European Union . 25 % of all deaths in this population are due to sudden cardiac death (SCD) [1 5]. Until recently, ventricular fibrillation was assumed to be the main reason. In a 2015 study, Wong et al. showed that bradycardia and asystole are the predominant mecha- nisms of SCD in patients with CKD . This shows that the underlying mechanisms in the pacemaking of the sinoatrial node (SAN) need to be further analyzed. In this work, a computational model of the human SAN by Fabbri et al.  is used to investigate the CKD-induced electrolyte changes on SAN cell electrophysiology. The original model does not show a stable output for low [Ca2+]o. Furthermore, the model lacks a variable formu- lation of [Na+]i. Since low [Ca2+]o occur in heamodialysis patients and variable [Na+]i is required if the electrolyte concentrations change, a model adaption was performed. A simplex-downhill algorithm and the evaluation of several AP markers was used to adapt the dynamics of the L-type calcium current ICaL.The achieved action potential (AP) shape for the model optimization yielded good accor- dance with the AP shape of the original model. Additionally, the adapted model resulted in physiological excitation of APs down to 0.6mM of [Ca2+]o. The unoptimized model exhibited a critical concentration of ≈1.18 mM. A critical concentration range of calcium in the subspace [Ca2+]sub was identified as possible underlying mechanisms for pacemak- ing. Besides the model adaptation, the main part of this work was the evaluation of the impact of electrolyte changes on the model. Therefore, a wide range of maximal and minimal extracellular electrolyte concentrations in HD patients were determined. [Ca2+]o had the most dominant effects in the original and adapted model. Low [Ca2+]o led to a significant increase in cycle length (CL). The longest achieved CL in the original Fabbri et al. model was 2918 ms, which correlated with a +358 % increase compared to reference CL of 814ms. The related low heart rate of 21bpm can be seen as a possible link to the observed bradycardia in HD patients. For increasing calcium concentration the CL declined, resulting in 383 ms for the highest calcium concentration in the original model. The process of extracellular potassium variation was similar to the one for calcium but resulted in less pronounced maximum and minimum values. The resultant changes in the variation of [Na+]o were relatively small. Variable [Na+]i showed compensating effects compared to the original model.In summary, the adaptations in the Fabbri et al. model led to a more stable output for low [Ca2+]o and to the more realistic assumption of variable [Na+]i. In this work, it showed that the variation of [Ca2+]o had dominating effect on the model electrophysiology. In this context, a critical range of [Ca2+]sub was identified as possible mechanism that af- fects pacemaking. The L-type calcium current ICaL was identified as the main pacemaker current, while the influence of the funny current If or the Na+-Ca2+ exchanger INaCa were relatively small in the critical calcium concentration range.