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.

Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology

“…Second, the presence of the intracellular Ca 2+ handling system, which was composed of the sarcoplasmic reticulum and the Ca 2+ SERCA pump, stops this automaticity and leads to a steady-state with a resting membrane potential of –46 mV, which is in accordance with experimentally reported values [ 9 , 38 , 53 , 61 ]. Human sinus node cells, which also exhibit automaticity, showed a diastolic depolarization rate (DDR100) of around 76 mV/s and a cycle length of around 828 ms [ 66 , 67 , 68 ]. The myofibroblast model with only the L-type Ca 2+ channel had a DDR100 of 62.60 mV/s and a cycle length of 799.9 ms, which could potentially trigger ectopic activity [ 69 ].…”

TheopenCARPSimulation Environment for Cardiac Electrophysiology

“…Such four chamber models account for anisotropic tissue properties and discrete conduction pathways in all chambers, the specialized cardiac conduction system comprising sinus node [30,31], atrio-ventricular node [32] and the His-Purkinje system [33]. Pathologies altering conduction velocities or pathways such as ischemia [34], infarct scars and surrounding transitional tissue [35], or various types of fibrotic lesions [36][37][38] are considered at increasing levels of physiological [39] and structural detail [40][41][42][43].…”

The Cardiac Pacemaker Story—Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity

“…One year later, the Lakatta group (Bogdanov et al, 2001) further analyzed the spontaneous Ca 2+ releases (local Ca 2+ releases, LCR, Figure 4) in isolated rabbit sinoatrial cells. Their findings indicate that the pre-AP releases are locally propagating Ca 2+ waves, resulting from ryanodine-sensitive Ca 2+ -induced Noble andNoble, 1984 mammalian DiFrancesco andNoble, 1985 no/yes no yes no Rasmusson et al, 1990 bullfrog Fischmeister and Vassort, 1981 yes/yes yes no no Wilders et al, 1991 rabbit Noble and Noble, 1984 yes/yes no yes no Demir et al, 1994 rabbit DiFrancesco and Noble, 1985 yes/yes yes yes no Dokos et al, 1996 mammalian Matsuoka and Hilgemann, 1992 yes/yes no yes no Zhang et al, 2000rabbit Demir et al, 1994 no/no no yes yes Kurata et al, 2002rabbit Dokos et al, 1996 yes/yes yes yes yes Garny et al, 2003rabbit Zhang et al, 2000 (Kurata et al, 2002;Garny et al, 2003;Maltsev and Lakatta, 2009;Yaniv et al, 2011;Severi et al, 2012), mouse (Kharche et al, 2011), and the human Loewe-Lutz-Fabbri-Severi (LLFS) model (Loewe et al, 2019a;Loewe et al, 2019b).…”

“…Indeed, it has been shown that computational models of SNCs of different species (mouse, rabbit, human) react markedly different to changes of e.g. extracellular Ca 2+ concentration (Loewe et al, 2019b). Given the potential relevance of this alteration regarding sudden bradycardic death in dialysis patients (Loewe et al, 2019a), species-dependent investigations are desirable.…”

“…proposed the Loewe-Lutz-Fabbri-Severi model (LLFS) (Loewe et al, 2019b) as an extension of the Fabbri et al model which considers, among other improvements, the dynamics and transients of the intracellular sodium and potassium concentrations in contrast to the previously fixed concentrations, thus further constraining the model physiologically by requiring homeostasis across time spans of minutes (Loewe et al, 2019a). In the LLFS model, the response to complete I f block (CL +25.9%) was in accordance with the available experimental human data [+26% reported by Verkerk et al (2007)] (Verkerk et al, 2007).…”