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.
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.
Catheter ablation is a curative therapeutic approach for atrial fibrillation (AF). Ablation of rotational sources based on basket catheter measurements has been proposed as a promising approach in patients with persistent AF to complement pulmonary vein isolation. However, clinically reported success rates are equivocal calling for a mechanistic investigation under controlled conditions. We present a computational framework to benchmark ablation strategies considering the whole cycle from excitation propagation to electrogram acquisition and processing to virtual therapy. Fibrillation was induced in a patient-specific 3D volumetric model of the left atrium, which was homogeneously remodelled to sustain reentry. The resulting extracellular potential field was sampled using models of grid catheters as well as realistically deformed basket catheters considering the specific atrial anatomy. Virtual electrograms were processed to compute phase singularity density maps to target rotor tips with up to three circular ablations. Stable rotors were successfully induced in different regions of the homogeneously remodelled atrium showing that rotors are not constrained to unique anatomical structures or locations. Phase singularity density maps correctly identified and located the rotors (deviation < 10 mm) based on catheter recordings only for sufficient resolution (inter-electrode distance = 3 mm) and proximity to the wall (< 10 mm). Targeting rotor sites with ablation did not stop reentries in the homogeneously remodelled atria independent from lesion size (1-7 mm radius), from linearly connecting lesions with anatomical obstacles, and from the number of rotors targeted sequentially (up to 3). Our results show that phase maps derived from intracardiac electrograms can be a powerful tool to map atrial activation patterns, yet they can also be misleading due to inaccurate localization of rotor tips depending on electrode resolution and distance to the wall. This should be considered to avoid ablating regions that are in fact free of rotor sources of AF. In our experience, ablation of rotor sites was not successful to stop fibrillation. Our comprehensive simulation framework provides the means to holistically benchmark ablation strategies in silico under consideration of all steps invol
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.
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.
End-stage chronic kidney disease (CKD) patients are facing a 30% rise for the risk of lethal cardiac events (LCE) compared to non-CKD patients. At the same time, these patients undergoing dialysis experience shifts in the potassium concentrations. The increased risk of LCE paired with the concentration changes suggest a connection between LCE and concentration disbalances. To prove this link, a continuous monitoring device for the ionic concentrations, e.g. the ECG, is needed. In this work, we want to answer if an optimised signal processing chain can improve the result quantify the influence of a disbalanced training dataset on the final estimation result. The study was performed on a dataset consisting of 12-lead ECGs recorded during dialysis sessions of 32 patients. We selected three features to find a mapping from ECG features to [K+]o: T-wave ascending slope, T-wave descending slope and T-wave amplitude. A polynomial model of 3rd order was used to reconstruct the concentrations from these features. We solved a regularised weighted least squares problem with a weighting matrix dependent on the frequency of each concentration in the dataset (frequent concentration weighted less). By doing so, we tried to generate a model being suitable for the whole range of the concentrations.With weighting, errors are increasing for the whole dataset. For the data partition with [K+]o<5 mmol/l, errors are increasing, for [K+]o≥5 mmol/l, errors are decreasing. However, and apart from the exact reconstruction results, we can conclude that a model being valid for all patients and not only the majority, needs to be learned with a more homogeneous dataset. This can be achieved by leaving out data points or by weighting the errors during the model fitting. With increasing weighting, we increase the performance on the part of the [K+]o that are less frequent which was desired in our case.
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.
Patients suffering from end stage of chronic kid- ney disease (CKD) often undergo haemodialysis to normalize the electrolyte concentrations. Moreover, cardiovascular disease (CVD) is the main cause of death in CKD patients. To study the connection between CKD and CVD, we investi- gated the effects of an electrolyte variation on cardiac signals (action potential and ECG) using a computational model. In a first step, simulations with the Himeno et al. ventricular cell model were performed on cellular level with different extra- cellular sodium ([Na+]o), calcium ([Ca2+]o) and potassium ([K+]o) concentrations as occurs in CKD patients. [Ca2+]o and [K+]o changes caused variations in different features describ- ing the morphology of the AP. Changes due to a [Na+]o varia- tion were not as prominent. Simulations with [Ca2+]o varia- tions were also carried out on ventricular ECG level and a 12-lead ECG was computed. Thus, a multiscale simulator from ion channel to ECG reproducing the calcium-dependent inactivation of ICaL was achieved. The results on cellular and ventricular level agree with results from literature. Moreover, we suggest novel features representing electrolyte changes that have not been described in literature. These results could be helpful for further studies aiming at the estimation of ionic concentrations based on ECG recordings.
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.
Multi-scale computational modeling of cardiac electrophysiology has fostered our understanding of the genesis of the ECG. While current models capture the relevant processes under physiological and many disease conditions with high fidelity, proper representation of the conditions in the extracellular milieu remains challenging. The recent human ventricular myocyte model by Himeno et al. is one of the first biophysical models which faithfully represents the dependence of the action potential (AP) duration on the extracellular calcium concentration ([Ca2+]o). Here, we present a heterogeneous formulation of the Himeno et al. cellular model and integrate it into a multi-scale framework to compute body surface ECGs. We propose three variants of the Himeno et al. model to account for transmural heterogeneity. The ionic current level parameter sets representing subendocardial, M, and subepicardial cell types were informed by the experimental data presented with the O’Hara-Rudy model and tuned to match AP level features such as repolarization stability. As shown in a previous work by Keller et al., an apico-basal gradient of IKs conductance is a likely mechanism causing concordant T-waves. Therefore, we increased the IKs conductance in the Himeno et al. model at the apex by a factor of 3.5 compared to the base to obtain an APD shortening of 12.5%. The model setup comprising transmural and apico-basal heterogeneity yielded a physiological ventricular ECG comparable to previous setups building on the ten Tusscher et al. cellular model. Our novel setup allows to study, for the first time, how realistic changes of the AP under hypo- and hypercalcaemic conditions translate to changes in the ECG. Resulting QT prolongation under hypocalcaemic conditions quantitatively matched human experimental data. In conclusion, the setup presented here provides a tool to study the effect of altered calcium levels in the extracellular milieu of the heart, as e. g. occurring during renal failure, across multiple spatial scales mechanistically.
Chronic kidney disease (CKD) affects more than 30 million patients in the European Union. CKD causes alterations in the extracellular plasma electrolyte concentrations, which affect cardiac electrophysiology. A total of 25% of all deaths of CKD patients are due to sudden cardiac death (SCD). Until recently, ventricular fibrillation was assumed to be the main reason. In a 2015 study, Wong et al. observed bradycardia and asystole as the predominant mechanisms of SCD in patients with CKD. This shows that the influence of electrolyte changes on the underlying mechanisms of pacemaking in the sinoatrial node (SAN) needs to be better understood. In this work, we have updated the computational model of the human SAN given by Fabbri et al. and investigated the CKD-induced change of [Ca2+]o (0.6-3mM), [K+]o (3-9mM) and [Na+]o (120-150mM) on pacemaking. [Ca2+]o had the most dominant effects on SAN function. Low [Ca2+]o caused severe bradycardia in the model (down to 17 bpm) for 0.6 mM. A critical concentration range of calcium in the subspace [Ca2+]sub was identified as the possible underlying mechanism for pacemaking. For increasing [Ca2+]o, the heart rate (HR) increased, resulting in 142 bpm for the highest calcium concentration. The effect of [K+]o variation was similar to the one for [Ca2+]o, but caused less pronounced change. The resultant changes due to variation of [Na+]o were relatively small. In this work, several potential mechanisms for SCD in CKD patients could be identified. The low HR for low [Ca2+]o is seen as a possible link to the observed bradycardia in CKD patients. The findings in this work could lead to a better surveillance of [Ca2+]o in hemodialysis patients, and therefore to a decrease in the SCD rate.
Atrial fibrillation (AF) ablation guided by basket catheter mapping has shown to be beneficial. Yet, the initial excitement is mitigated by a growing skepticism due to the difficulty in verifying the protocol in multicenter studies. Overall, the underlying assumptions of rotor ablation require further verification. The aim of this study was therefore to test such hypotheses by using computational modeling. The 3D left atrial geometry of an AF patient was segmented from a pre-operative MR scan. Atrial activation was simulated on the 3D anatomy using the monodomain approach and a variant of the Courtemanche action potential model. Ablated tissue was assigned zero conductivity. Reentry was successfully initialized by applying a single suitably delayed extra stimulus. Unipolar electrograms were computed at the simulated electrode positions. The final dataset was generated by varying location of reentry and catheter position within the LA. The effect of inter-electrode distance and distance to the atrial wall was studied in relation to the ability to recover rotor trajectory, as computed by a novel algorithm described here. The effect of rotor ablation was also assessed.
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, 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
Atrial fibrillation (AF) is the most common type of arrhythmia encountered in clinical practice but its maintaining mechanisms remain elusive. Over the last years, various theories have been proposed to target AF mechanisms. Recently, there has been an increasing interest in understanding how spiral waves and rotors sustain AF and how they might be therapeutic targets for catheter-based ablation. Phase mapping has recently been used as a robust method to characterize the spatiotemporal variability of electrical activities. In this study, we propose an independent approach for basket catheter electrogram (EGM) processing to detect rotors in AF. An improved version of the sinusoidal recomposition method for the local activation timings (LATs) has been developed and 3D phase maps have been reconstructed. An algorithm able to detect stable and meandering rotors on the left atrium (LA) surface was then developed. This workflow has been validated on synthetic EGMs and in silico showing excellent results. On in vivo data, we found 4.0±3.4 and 4.6±5.0 localized and meandering rotors with a persistence in time: 303.2 ±58.2ms and 302.3±52.0ms respectively.
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.