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.
BACKGROUND: The prevalence of atrial fibrillation is increased in patients with end-stage renal disease. Previous studies suggested that extracellular electrolyte alterations caused by hemodialysis (HD) therapy could be proarrhythmic. METHODS: Multiscale models were used for a consequent analysis of the effects of extracellular ion concentration changes on atrial electrophysiology. Simulations were based on measured electrolyte concentrations from patients with end-stage renal disease. RESULTS: Simulated conduction velocity and effective refractory period are decreased at the end of an HD session, with potassium having the strongest influence. P-wave is prolonged in patients undergoing HD therapy in the simulation as in measurements. CONCLUSIONS: Electrolyte concentration alterations impact atrial electrophysiology from the action potential level to the P-wave and can be proarrhythmic, especially because of induced hypokalemia. Analysis of blood electrolytes enables patient-specific electrophysiology modeling. We are providing a tool to investigate atrial arrhythmias associated with HD therapy, which, in the future, can be used to prevent such complications.
Background: Patients with end-stage renal disease show an increased prevalence of atrial fibrillation. A combined simulation and electrocardio- gram analysis study revealed a correlation between the changes in plasma electrolytes and intra-atrial conduction velocity related to hemodialysis (HD) session. A recognized limitation of the study is that simulations were performed on single-cell level. We present a computer study to investigate the influence of HD-related electrolyte modifications on atrial electrophys- iology in a volumetric environment.Methods: Based on the Courtemanche-Ramirez-Nattel model and its parameterization for different atrial tissues, we studied action potential, effective refractory period, conduction velocity (CV) restitution, and wave length restitution for common atrial myocardium (CAM) and fast conducting Crista Terminalis (CT). We used isotropic, homogeneous tissue patches. External stimuli were applied with 184 different pacing rates (PRs) from 330 to 1250 milliseconds.Results: The effect of temporary HD- related electrolyte changes on the action potential morphology and effective refractory period showed results consistent with the previous single-cell study. Action potential morphology was not significantly altered both in CAM and CT, but resting potential decreased from ␣82.6 to ␣88.2 mV for CAM and from ␣81.7 to ␣87.3 mV for CT. Effective refractory period decreased from 32 (pre-HD) to 308 milliseconds (end-HD). At a PR of 832 milliseconds, CV dropped by ␣6.3% for both types of tissue (CAM: 741 694 mm/s; CT: 746 699 mm/s). Wave length increased slightly with higher PR, but rapidly fell off below a PR of 450 milliseconds. Wave length was ␣30 mm shorter in the end-HD condition.Conclusions: Conduction velocity decrease and consequent wave length shortening increases vulnerability for atrial fibrillation onset, especially in conjunction with structural dilation often present in atria of end-stage renaldisease patients. Temporary HD-caused electrical remodeling has equal effects on regular and fast-conducting tissue. Although there is no biophysical model for fast interatrial condition pathways (eg, Bachmann dundle) available, the HD influence on them should also be similar and therefore slow down interatrial conduction significantly. It has been suggested that constantly repeating alteration of atrial electrophysiology may lead to a longer lasting electrical atrial remodeling; future studies should therefore investigate the long-term HD effects.