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.