Heterogeneity and Intercellular Coupling Prevent Sinus Arrest in Rabbit Sinoatrial Node Model

Abstract

The sinoatrial node (SAN) is the primary pacemaker of the heart, initiating each regular heartbeat through the spontaneous activity of specialized pacemaker cells. Its automaticity is governed by a tightly regulated interplay between ionic membrane currents and intracellular calcium cycling and is highly sensitive 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 hypocalcemia slows the beating rate; this effect can be 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. Therefore, a calibrated population of models generated from the extended Severi DiFrancesco model was embedded in a two-dimensional patch. Subsequently, hypocalcemia and graded autonomic modulation were simulated over a wide range of coupling resistances. Our results demonstrate that intercellular coupling and cellular heterogeneity can prevent sinus arrest at the tissue level, even under severe hypocalcemia and sympathetic withdrawal. Although sympathetic stimulation reduced the cycle length and increased the proportion of spontaneously depolarizing cells, it was not essential to maintain global tissue automaticity, in contrast to single-cell predictions. These findings indicate that tissue-level interactions and cell-to-cell heterogeneity mitigate the deleterious effects of hypocalcemia predicted in isolated cells, suggesting that the mechanism underlying HD patients SCDs needs to be further investigated by considering the interaction between the SAN and the surrounding atria.