Inter-Species Differences in the Response of Sinus Node Cellular Pacemaking to Changes of Extracellular Calcium

Abstract

Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extracellular calcium concentration [Ca 2+ ]o, has been suggested as potential pathomechanism contributing to the unexplained high rate of sudden cardiac death (SCD) in CKD patients. In particular, there is a hypothesis that hypocalcaemia could slow down natural pacemaking in the human sinus node to fatal degrees. Here, we address the question whether there are inter-species differences in the response of cellular sinus node pacemaking to changes of [Ca 2+ ]o. Towards this end, we employ computational models of mouse, rabbit and human sinus node cells. The Fabbri et al. human model was updated to consider changes of intracellular ion concentrations. We identified crucial inter-species differences in the response of cellular pacemaking in the sinus node to changes of [Ca 2+ ]o with little changes of cycle length in mouse and rabbit models (<83 ms) in contrast to a pronounced bradycardic effect in the human model (up to >1000 ms). Our results suggest that experiments with human sinus node cells are required to investigate the potential mechanism of hypocalcaemia-induced bradycardic SCD in CKD patients and small animal models are not well suited.

Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

“…Development of hypocalcemia and hypercalcemia have been documented in several pathologic states, and both conditions have been associated with increased pro-arrhythmic risk [ 52 ]. Our simulations show that increasing [Ca 2+ ] o enhances SAM automaticity ( Figure 10 ), in agreement with recent computational work that also has suggested that this effect is even more pronounced in humans vs. small mammals [ 53 , 54 ]. Our results further demonstrate that increasing [Ca 2+ ] o increased SAM susceptibility to irregularities induced by combined NKA and NCX block ( Figure 10 ), confirming recent experimental observations reporting that hypercalcemia not only increases FR but can also increase the propensity of SAN dysfunction in mice [ 55 ].…”

Hypocalcemia-Induced Slowing of Human Sinus Node Pacemaking

“…Therefore, experimental validation of our in silico-derived hypothesis is desirable. However, such experiments would need to be performed using human sinus node cells because of crucial interspecies differences in the response of sinus node cells to changes of [Ca 2þ ] o (11). We could show that rabbit experimental data matches well with rabbit model predictions of the effect of hypocalcemia both qualitatively and quantitatively, but the effect is less pronounced by a factor of z10 compared to human sinus node cells (11).…”

“…However, such experiments would need to be performed using human sinus node cells because of crucial interspecies differences in the response of sinus node cells to changes of [Ca 2þ ] o (11). We could show that rabbit experimental data matches well with rabbit model predictions of the effect of hypocalcemia both qualitatively and quantitatively, but the effect is less pronounced by a factor of z10 compared to human sinus node cells (11). Considering that the bradycardic effect of hypocalcemia observed here was mainly due to changes in late DD (beyond 100 ms), the interspecies differences are scarcely surprising, given that this phase is not present in species with high baseline heart rate as is typical for common laboratory animals.…”

“…However, when modeling the effects of altered extracellular concentrations like those occurring in ESRD patients, this assumption is not valid anymore because intracellular concentrations will respond to changes of the extracellular milieu. Therefore, we extended the original model as described in detail in (11). In brief, we considered the dynamic balance of intracellular K þ and Na þ concentrations as governed by their influx and efflux.…”

“…Given the vastly different beating rates of commonly used laboratory animals (mouse: 500 bpm, rabbit: 300 bpm) and humans (60 bpm), it cannot be assumed that the delicate balance of competing effects on pacemaking can be transferred from animal models to humans in general and in particular during late DD, which only exists at comparatively low beating rates as typical for humans. Indeed, a computational interspecies analysis revealed fundamental differences regarding the response to extracellular ion concentration changes between human and animal (rabbit, mouse) models with a markedly higher effect in humans (11).…”