Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcemia, i.e. a decrease of the extra-cellular calcium concentration [Ca2+]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 [Ca2+]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 [Ca2+]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.
Each heartbeat is initiated by cyclic spontaneous depolarization of cardiomyocytes in the sinus node forming the primary natural pacemaker. In patients with end-stage renal disease undergoing hemodialysis, it was recently shown that the heart rate drops to very low values before they suffer from sudden cardiac death with an unexplained high incidence. We hypothesize that the electrolyte changes commonly occurring in these patients affect sinus node beating rate and could be responsible for severe bradycardia. To test this hypothesis, we extended the Fabbri et al. computational model of human sinus node cells to account for the dynamic intracellular balance of ion concentrations. Using this model, we systematically tested the effect of altered extracellular potassium, calcium, and sodium concentrations. Although sodium changes had negligible (0.15 bpm/mM) and potassium changes mild effects (8 bpm/mM), calcium changes markedly affected the beating rate (46 bpm/mM ionized calcium without autonomic control). This pronounced bradycardic effect of hypocalcemia was mediated primarily by I attenuation due to reduced driving force, particularly during late depolarization. This, in turn, caused secondary reduction of calcium concentration in the intracellular compartments and subsequent attenuation of inward I and reduction of intracellular sodium. Our in silico findings are complemented and substantiated by an empirical database study comprising 22,501 pairs of blood samples and in vivo heart rate measurements in hemodialysis patients and healthy individuals. A reduction of extracellular calcium was correlated with a decrease of heartrate by 9.9 bpm/mM total serum calcium (p < 0.001) with intact autonomic control in the cross-sectional population. In conclusion, we present mechanistic in silico and empirical in vivo data supporting the so far neglected but experimentally testable and potentially important mechanism of hypocalcemia-induced bradycardia and asystole, potentially responsible for the highly increased and so far unexplained risk of sudden cardiac death in the hemodialysis patient population.
Conference Contributions (10)
A. Fabbri, A. Loewe, R. Wilders, and S. Severi. Propagation of the primary pacemaker activity in the human heart: a computational approach. In European Medical and Biological Engineering Conference (EMBEC), vol. 65, pp. 201, 2017
The sinoatrial node (SAN) is the natural pacemaker of our heart. How this small tissue is able to drive a remarkably larger number of intrinsically quiescent atrial cells is still debated; a computational investigation of the underlying mechanisms can help to better understand the SAN’s ability to pace-and-drive the surrounding atrium. Aim of this work is to elucidate how the human SAN action potential can successfully be captured by and propagate into the surrounding atrial tissue. The Fabbri et al. and the Courtemanche et al. models were used to describe the human SAN and atrial cells, respectively. The behaviour of two coupled regions was investigated varying the interregional conductivity (σ) and relative size. Simulations showed that it requires at least an isopotential SAN region 2.85 times wider than the atrial one. A 1D strand of homogeneously coupled SAN and atrial elements was used to identify an interval for σ showing pace-and-drive behaviour (100 SAN vs 100 atrial elements) and to investigate the source-sink interplay (10, 50 or 100 SAN elements vs 100 atrial elements). The 1D strand showed pace-and-drive behaviour for 𝜎 = 0.08 − 36 S/m; a stronger source, with a higher number of SAN elements, led to a wider 𝜎 range that allowed pace-and-drive behaviour, whereas a stronger sink did not affect the behaviour of the tissue. This preliminary work shows the ability of a small human SAN region to pace-and-drive the surrounding atrial tissue. Further investigations are needed to explore different conductivity configurations, including spatial gradients.
A. Loewe, Y. Lutz, A. Fabbri, and S. Severi. Sinus Bradycardia Due to Electrolyte Changes as a Potential Pathomechanism of Sudden Cardiac Death in Hemodialysis Patients. In Biophysical Journal, vol. 116(3 suppl1) , pp. 231A, 2019
A. Loewe, Y. Lutz, N. Nagy, A. Fabbri, C. Schweda, A. Varro, and S. Severi. Inter-Species Differences in the Response of Sinus Node Cellular Pacemaking to Changes of Extracellular Calcium. In 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), pp. 1875-1878, 2019
Changes of serum and extracellular ion concentrations occur regularly in patients with chronic kidney disease (CKD). Recently, hypocalcaemia, 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.
A. Loewe, Y. Lutz, A. Fabbri, and S. Severi. Severe sinus bradycardia due to electrolyte changes as a pathomechanism of sudden cardiac death in chronic kidney disease patients undergoing hemodialysis. In Heart Rhythm, vol. 15(5S) , pp. S354-S355, 2018
Background: For chronic kidney disease patients undergoing maintenance hemodialysis (HD), the risk to die from sudden cardiac death (SCD) is 14x higher compared to patients with a history of cardiovascular disease and normal kidney function. Traditional SCD risk factors cannot explain this high rate. Two recent human studies using implantable loop recorders surprisingly point towards bradycardia and asystole as the prevailing arrhythmias causing SCD in HD patients. This suggests a decisive role of the sinus node. Objective: To identify the effect of altered electrolyte levels (as systematically occurring in HD patients) on pacemaking in a computational model of human sinus node cells. Methods: We enhanced the Fabbri et al. model of human sinus node cells to account for the dynamic intracellular balance of all considered electrolytes. The model was exposed to clinically relevant extracellular electrolyte concentrations of potassium, sodium, and calcium to study their effect on spontaneous beating rate and underlying pacemaking mechanisms. The level of sympathetic stimulation was kept constant. Results: The beating rate showed a monotonic relationship with altered electrolyte concentrations starting from a baseline value of 72.5bpm. It increased with sodium (70.8-73.8bpm for [Na+]o from 120-150mM), with potassium (70.7-81.9bpm for [K+]o from 3-9mM), and most pronouncedly with calcium (33.5- 133.8bpm for [Ca2+]o from 0.8-3mM). The severe bradycardia under hypocalcemic conditions was due to hyperpolarized maximum diastolic potential and slower diastolic depolarization driven by attenuation of ICaT and INCX, the latter due to depletion of intracellular calcium. Conclusion: Our human computational study suggests that hypocalcemia causes a pronounced decrease of cellular sinus node pacing rate, which may be a relevant mechanism in HD patients. While increased sympathetic tone will likely compensate the lower basal beating rate, patients developing severe hypocalcaemia are at high risk to experience severe bradycardia and die from SCD during a sudden loss of sympathetic tone.
The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. However, the translation of animal data/models to humans is not straightforward. Even less so for SAN pacemaker cells than working myocar- dial cells given the big di↵erence in their main output (i.e. pacing rate) between human and laboratory animals. The development of a comprehensive model of the electrical activity of a human SAN pacemaker cell strictly based on and constrained by the available electrophysiological data will be presented. We started from the Severi-DiFrancesco rabbit SAN model, which integrates the two principal mecha- nisms that determine the beating rate: the ”membrane clock” and ”calcium clock”. Several current formulations were updated based on available measurements. A set of parameters, for which no specific data were available, were automatically opti- mized to reproduce the measured AP and calcium transient data. The model was then validated by assessing the e↵ects of several mutations a↵ecting heart rate and rate modulation. Moreover, two recent applications of the model will be presented: i) We used our SAN AP computational model to assess the e↵ects of the inclu- sion of the small conductance K+ current (ISK) on the biomarkers that describe the AP waveform and calcium transient; ii) We analysed the e↵ect of altered elec- trolyte levels (as systematically occurring in hemodialysis patients) on pacemaking to investigate the possible mechanisms of the bradycardic sudden cardiac deaths pointed out by two recent human studies using implantable loop recorders.
A. Loewe, Y. Lutz, A. Fabbri, S. Severi, G. Seemann, and D. Dössel. Influence of Electrolyte Concentration Changes on Sinus Node Function - A new Player Regarding Sudden Cardiac Death in Patients with Chronic Kidney Disease?. In Gordon Research Conference on Cardiac Arrhythmia Mechanisms, 2017