In Silico Investigation of the Compensatory Effect of the Autonomic Nervous System in Haemodialysis Patients at Tissue Level

The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for the rhythmic initiation of each heartbeat through the spontaneous activity of specialised pacemaker cells. Its automaticity arises from a tightly regulated interplay between membrane ionic currents and intracellular calcium cycling, and is highly susceptible to changes in the extracellular milieu. Electrolyte imbalances are common in patients with chronic kidney disease undergoing haemodialysis (HD), a population with a markedly increased incidence of sudden cardiac death (SCD), which is frequently preceded by sinus bradycardia and asystole. Previous single-cell in silico investigations demonstrated that hypocalcaemia slows the beating rate; this effect can be transiently offset by sympathetic stimulation, whereas abrupt withdrawal of sympathetic tone can abolish automaticity.To determine whether these mechanisms are preserved at the tissue level, we implemented a discrete intercellular coupling framework in openCARP. A calibrated population of models generated from the extended Severi DiFrancesco model was embedded in a two-dimensional patch of SAN tissue. Subsequently, hypocalcaemia and graded autonomic modulation were simulated over a wide range of coupling resistances.Our results demonstrate that intercellular coupling and cellular heterogeneity prevent sinus arrest at the tissue level, even under severe hypocalcaemia and sympathetic withdrawal. Although sympathetic stimulation reduced the cycle length and increased the proportion of spontaneously depolarising cells, it was not essential to maintain global tissue automaticity, in contrast to single-cell predictions. These findings indicate that tissue-level interactions mitigate the deleterious effects of hypocalcaemia predicted in isolated cells, suggesting that the mechanism underlying HD patients SCD episodes needs to be further investigated by considering the interaction between the SAN and the surrounding atria.