Diseases caused by alterations of ionic concentrations are frequently observed challenges and play an important role in clinical practice. The clinically established method for the diagnosis of electrolyte concentration imbalance is blood tests. A rapid and non-invasive point-of-care method is yet needed. The electrocardiogram (ECG) could meet this need and becomes an established diagnostic tool allowing home monitoring of the electrolyte concentration also by wearable devices. In this review, we present the current state of potassium and calcium concentration monitoring using the ECG and summarize results from previous work. Selected clinical studies are presented, supporting or questioning the use of the ECG for the monitoring of electrolyte concentration imbalances. Differences in the findings from automatic monitoring studies are discussed, and current studies utilizing machine learning are presented demonstrating the potential of the deep learning approach. Furthermore, we demonstrate the potential of computational modeling approaches to gain insight into the mechanisms of relevant clinical findings and as a tool to obtain synthetic data for methodical improvements in monitoring approaches.
A. Loewe. Ein digitales Herz. In Spektrum der Wissenschaft, vol. 20(10) , pp. 44-48, 2020
Identification of atrial sites that perpetuate atrial fibrillation (AF), and ablation thereof terminates AF, is challenging. We hypothesized that specific electrogram (EGM) characteristics identify AF-termination sites (AFTS). Twenty-one patients in whom low-voltage-guided ablation after pulmonary vein isolation terminated clinical persistent AF were included. Patients were included if short RF-delivery for <8sec at a given atrial site was associated with acute termination of clinical persistent AF. EGM-characteristics at 21 AFTS, 105 targeted sites without termination and 105 non-targeted control sites were analyzed. Alteration of EGM-characteristics by local fibrosis was evaluated in a three-dimensional high resolution (100 µm)-computational AF model. AFTS demonstrated lower EGM-voltage, higher EGM-cycle-length-coverage, shorter AF-cycle-length and higher pattern consistency than control sites (0.49 ± 0.39 mV vs. 0.83 ± 0.76 mV, p < 0.0001; 79 ± 16% vs. 59 ± 22%, p = 0.0022; 173 ± 49 ms vs. 198 ± 34 ms, p = 0.047; 80% vs. 30%, p < 0.01). Among targeted sites, AFTS had higher EGM-cycle-length coverage, shorter local AF-cycle-length and higher pattern consistency than targeted sites without AF-termination (79 ± 16% vs. 63 ± 23%, p = 0.02; 173 ± 49 ms vs. 210 ± 44 ms, p = 0.002; 80% vs. 40%, p = 0.01). Low voltage (0.52 ± 0.3 mV) fractionated EGMs (79 ± 24 ms) with delayed components in sinus rhythm ('atrial late potentials', respectively 'ALP') were observed at 71% of AFTS. EGMs recorded from fibrotic areas in computational models demonstrated comparable EGM-characteristics both in simulated AF and sinus rhythm. AFTS may therefore be identified by locally consistent, fractionated low-voltage EGMs with high cycle-length-coverage and rapid activity in AF, with low-voltage, fractionated EGMs with delayed components/ 'atrial late potentials' (ALP) persisting in sinus rhythm.
The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called "funny current". However, parallel investigations increasingly emphasized the importance of the Ca-homeostasis and Na/Ca exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na/Ca exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca handling render the design and interpretation of these experiments challenging.
OBJECTIVE: Atrial flutter (AFl) is a common arrhythmia that can be categorized according to different self-sustained electrophysiological mechanisms. The non-invasive discrimination of such mechanisms would greatly benefit ablative methods for AFl therapy as the driving mechanisms would be described prior to the invasive procedure, helping to guide ablation. In the present work, we sought to implement recurrence quantification analysis (RQA) on 12-lead ECG signals from a computational framework to discriminate different electrophysiological mechanisms sustaining AFl. METHODS: 20 different AFl mechanisms were generated in 8 atrial models and were propagated into 8 torso models via forward solution, resulting in 1,256 sets of 12-lead ECG signals. Principal component analysis was applied on the 12-lead ECGs, and six RQA-based features were extracted from the most significant principal component scores in two different approaches: individual component RQA and spatial reduced RQA. RESULTS: In both approaches, RQA-based features were significantly sensitive to the dynamic structures underlying different AFl mechanisms. Hit rate as high as 67.7% was achieved when discriminating the 20 AFl mechanisms. RQA-based features estimated for a clinical sample suggested high agreement with the results found in the computational framework. CONCLUSION: RQA has been shown an effective method to distinguish different AFl electrophysiological mechanisms in a non-invasive computational framework. A clinical 12-lead ECG used as proof of concept showed the value of both the simulations and the methods. SIGNIFICANCE: The non-invasive discrimination of AFl mechanisms helps to delineate the ablation strategy, reducing time and resources required to conduct invasive cardiac mapping and ablation procedures.
S. Pollnow, G. Schwaderlapp, A. Loewe, and O. Dössel. Monitoring the dynamics of acute radiofrequency ablation lesion formation in thin-walled atria – a simultaneous optical and electrical mapping study. In Biomedical Engineering / Biomedizinische Technik, vol. 65(3) , pp. 327-341, 2020
Background Radiofrequency ablation (RFA) is a common approach to treat cardiac arrhythmias. During this intervention, numerous strategies are applied to indirectly estimate lesion formation. However, the assessment of the spatial extent of these acute injuries needs to be improved in order to create well-defined and durable ablation lesions. Methods We investigated the electrophysiological characteristics of rat atrial myocardium during an ex vivo RFA procedure with fluorescence-optical and electrical mapping. By analyzing optical data, the temporal growth of punctiform ablation lesions was reconstructed after stepwise RFA sequences. Unipolar electrograms (EGMs) were simultaneously recorded by a multielectrode array (MEA) before and after each RFA sequence. Based on the optical results, we searched for electrical features to delineate these lesions from healthy myocardium. Results Several unipolar EGM parameters were monotonically decreasing when distances between the electrode and lesion boundary were smaller than 2 mm. The negative component of the unipolar EGM [negative peak amplitude (Aneg)] vanished for distances lesser than 0.4 mm to the lesion boundary. Median peak-to-peak amplitude (Vpp) was decreased by 75% compared to baseline. Conclusion Aneg and Vpp are excellent parameters to discriminate the growing lesion area from healthy myocardium. The experimental setup opens new opportunities to investigate EGM characteristics of more complex ablation lesions.
Von wandernden Ionen über das Zellgewebe bis hin zur Aufzeichnung eines EKG: Die Softwaresimulation des menschlichen Herzens ermöglicht maßgeschneiderte Therapien. Am Karlsruher Institut für Technologie (KIT) haben Forscher ein Computermodell des menschlichen Herzens entwickelt. Die Wissenschaftler sind mittlerweile sogar schon so weit, dass sie das Modell auf die individuellen Eigenschaften eines einzelnen Patienten maßschneidern können. Diese Simulation hat einen erheblichen Nutzen für die medizinische Praxis.
OBJECTIVE: Unipolar intracardiac electrograms (uEGMs) measured inside the atria during electro-anatomic mapping contain diagnostic information about cardiac excitation and tissue properties. The ventricular far field (VFF) caused by ventricular depolarization compromises these signals. Current signal processing techniques require several seconds of local uEGMs to remove the VFF component and thus prolong the clinical mapping procedure. We developed an approach to remove the VFF component using data obtained during initial anatomy acquisition. METHODS: We developed two models which can approximate the spatio-temporal distribution of the VFF component based on acquired EGM data: Polynomial fit, and dipole fit. Both were benchmarked based on simulated cardiac excitation in two models of the human heart and applied to clinical data. RESULTS: VFF data acquired in one atrium were used to estimate model parameters. Under realistic noise conditions, a dipole model approximated the VFF with a median deviation of 0.029mV, yielding a median VFF attenuation of 142. In a different setup, only VFF data acquired at distances of more than 5mm to the atrial endocardium were used to estimate the model parameters. The VFF component was then extrapolated for a layer of 5mm thickness lining the endocardial tissue. A median deviation of 0.082mV (median VFF attenuation of 49x) was achieved under realistic noise conditions. CONCLUSION: It is feasible to model the VFF component in a personalized way and effectively remove it from uEGMs. SIGNIFICANCE: Application of our novel, simple and computationally inexpensive methods allows immediate diagnostic assessment of uEGM data without prolonging data acquisition.
Background and Purpose: The exact mechanism of spontaneous pacemaking is not fully understood. Recent results suggest tight cooperation between intracellular Ca handling and sarcolemmal ion channels. An important player of this crosstalk is the Na/Ca exchanger (NCX), however, direct pharmacological evidence was unavailable so far because of the lack of a selective inhibitor. We investigated the role of the NCX current in pacemaking and analyzed the functional consequences of the I-NCX coupling by applying the novel selective NCX inhibitor ORM-10962 on the sinus node (SAN). Experimental Approach: Currents were measured by patch-clamp, Ca-transients were monitored by fluorescent optical method in rabbit SAN cells. Action potentials (AP) were recorded from rabbit SAN tissue preparations. Mechanistic computational data were obtained using the Yaniv . SAN model. Key Results: ORM-10962 (ORM) marginally reduced the SAN pacemaking cycle length with a marked increase in the diastolic Ca level as well as the transient amplitude. The bradycardic effect of NCX inhibition was augmented when the funny-current (I) was previously inhibited and , the effect of I was augmented when the Ca handling was suppressed. Conclusion and Implications: We confirmed the contribution of the NCX current to cardiac pacemaking using a novel NCX inhibitor. Our experimental and modeling data support a close cooperation between I and NCX providing an important functional consequence: these currents together establish a strong depolarization capacity providing important safety factor for stable pacemaking. Thus, after individual inhibition of I or NCX, excessive bradycardia or instability cannot be expected because each of these currents may compensate for the reduction of the other providing safe and rhythmic SAN pacemaking.
Introduction: Multi-scale computational models of cardiac electrophysiology are used to investigate complex phenomena such as cardiac arrhythmias, its therapies and the testing of drugs or medical devices. While a couple of software solutions exist, none fully meets the needs of the community. In particular, newcomers to the field often have to go through a very steep learning curve which could be facilitated by dedicated user interfaces, documentation, and training material. Outcome: openCARP is an open cardiac electrophysiology simulator, released to the community to advance the computational cardiology field by making state-of-the-art simulations accessible. It aims to achieve this by supporting self-driven learning. To this end, an online platform is available containing educational video tutorials, user and developer-oriented documentation, detailed examples, and a question-and-answer system. The software is written in C++. We provide binary packages, a Docker container, and a CMake-based compilation workflow, making the installation process simple. The software can fully scale from desktop to high-performance computers. Nightly tests are run to ensure the consistency of the simulator based on predefined reference solutions, keeping a high standard of quality for all its components. openCARP interoperates with different input/output standard data formats. Additionally, sustainability is achieved through automated continuous integration to generate not only software packages, but also documentation and content for the community platform. Furthermore, carputils provides a user-friendly environment to create complex, multi-scale simulations that are shareable and reproducible. Conclusion: In conclusion, openCARP is a tailored software solution for the scientific community in the cardiac electrophysiology field and contributes to increasing use and reproducibility of in-silico experiments.
This work uses a highly detailed computational model of human atria to investigate the effect of spatial gradient and smoothing of atrial wall thickness on inducibility and maintenance of atrial fibrillation (AF) episodes. An atrial model with homogeneous thickness (HO) was used as baseline for the generation of different atrial models including either a low (LG) or high thickness gradient between left/right atrial free wall and the other regions. Since the model with high spatial gradient presented non-natural sharp edges between regions, either 1 (HG1) or 2 (HG2) Laplacian smoothing iterations were applied. Arrhythmic episodes were initiated using a rapid pacing protocol and long-living rotors were detected and tracked over time. Thresholds optimised with receiver operating characteristic analysis were used to define high gradient/curvature regions. Greater spatial gradients increased the atrial model inducibility and unveiled additional regions vulnerable to maintain AF drivers. In the models with heterogeneous wall thickness (LG, HG2 and HG1), 73.5 ± 8.7% of the long living rotors were found in areas within 1.5 mm from nodes with high thickness gradient, and 85.0 ± 3.4% in areas around high endocardial curvature. These findings promote wall thickness gradient and endocardial curvature as measures of AF vulnerability.
A variety of biophysical and phenomenological active tension models has been proposed during the last decade that show physiological behaviour on a cellular level. However, applying these models in a whole heart finite element simulation framework yields either unphysiological values of stress and strain or an insufficient deformation pattern compared to magnetic resonance imaging data. In this study, we evaluate how introducing an orthotropic active stress tensor affects the deformation pattern by conducting a sensitivity analysis regarding the active tension at resting length Tref and three orthotropic activation parameters (Kss, Ksn and Knn). Deformation of left ventricular contraction is evaluated on a truncated ellipsoid using four features: wall thickening (WT), longitudinal shortening (LS), torsion (Θ) and ejection fraction (EF). We show that EF, WT and LS are positively correlated with the parameters Tref and Knn while Kss reduces all of the four observed features. Introducing shear stress to the model has little to no effect on EF, WT and LS, although it reduces torsion by up to 3◦. We find that added stress in the normal direction can support healthy deformation patterns. However, the twisting motion, which has been shown to be important for cardiac function, reduces by up to 20◦.
Over the last decades, computational models have been applied in in-silico simulations of the heart biomechan- ics. These models depend on input parameters. In particular, four parameters are needed for the constitutive law of Guc- cione et al., a model describing the stress-strain relation of the heart tissue. In the literature, we could find a wide range of values for these parameters. In this work, we propose an optimization framework which identifies the parameters of a constitutive law. This framework is based on experimental measurements conducted by Klotz et al.. They provide an end-diastolic pressure-volume relation- ship. We applied the proposed framework on one heart model and identified the following elastic parameters to optimally match the Klotz curve: 𝐶 = 313 Pa, 𝑏𝑓 = 17.8, 𝑏𝑡 = 7.1 and 𝑏𝑓𝑡 = 12.4. In general, this approach allows to identify optimized param- eters for a constitutive law, for a patient-specific heart geome- try. The use of optimized parameters will lead to physiological simulation results of the heart biomechanics and is therefore an important step towards applying computational models in clinical practice.
Atrial flutter (AFl) is a common heart rhythm disor- der driven by different self-sustaining electrophysiological atrial mechanisms. In the present work, we sought to dis- criminate which mechanism is sustaining the arrhythmia in an individual patient using non-invasive 12-lead elec- trocardiogram (ECG) signals. Specifically, we analyse the influence of atrial and torso geometries for the success of such discrimination. 2,512 ECG were simulated and 151 features were extracted from the signals. Three clas- sification scenarios were investigated: random set clas- sification; leave-one-atrium-out (LOAO); and leave-one- torso-out (LOTO). A radial basis neural network classifier achieved test accuracies of 89.84%, 88.98%, and 59.82% for the random set classification, LOTO, and LOAO, re- spectively. The most discriminative single feature was the F-wave duration (74% test accuracy). Our results show that a machine learning approach can potentially identify a high number of different AFl mechanisms using the 12- lead ECG. More than the 8 atrial models used in this work should be included during training due to the significant influence that the atrial geometry has on the ECG signals and thus on the resulting classification. This non-invasive classification can help to identify the optimal ablation strategy, reducing time and resources required to conduct invasive cardiac mapping and ablation procedures.
Atrial fibrillation (AF) is an irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. In the present work, we sought to characterize and discriminate whether simulated single stable rotors are located in the pulmonary veins (PVs) or not, only by using non-invasive signals (i.e., the 12-lead ECG). Several features have been extracted from the signals, such as Hjort descriptors, recurrence quantification analysis (RQA), and principal component analysis. All the extracted features have shown significant discriminatory power, with particular emphasis to the RQA parameters. A decision tree classifier achieved 98.48% accuracy, 83.33% sensitivity, and 100% specificity on simulated data. Clinical relevance— This study might guide ablation proce- dures, suggesting doctors to proceed directly in some patients with a pulmonary veins isolation, and avoiding the prior use of an invasive atrial mapping system.
Atrial fibrillation (AF) is the most frequent irregular heart rhythm due to disorganized atrial electrical activity, often sustained by rotational drivers called rotors. The non-invasive localization of AF drivers can lead to improved personalized ablation strategy, suggesting pulmonary vein (PV) isolation or more complex extra- PV ablation procedures in case the driver is on other atrial regions. We used a Machine Learning approach to characterize and discriminate simulated single stable rotors (1R) location: PVs, left atrium (LA) excluding the PVs, and right atrium (RA), utilizing solely non-invasive signals (i.e., the 12-lead ECG). 1R episodes sustaining AF were simulated. 128 features were extracted from the signals. Greedy forward algorithm was implemented to select the best feature set which was fed to a decision tree classifier with hold-out cross-validation technique. All tested features showed significant discriminatory power, especially those based on recurrence quantification analysis (up to 80.9% accuracy with single feature classification). The decision tree classifier achieved 89.4% test accuracy with 18 features on simulated data, with sensitivities of 93.0%, 82.4%, and 83.3% for RA, LA, and PV classes, respectively. Our results show that a machine learning approach can potentially identify the location of 1R sustaining AF using the 12-lead ECG.
Numerical simulations are increasingly often in- volved in developing new and improving existing medical therapies. While the models involved in those simulations are designed to resemble a specific phenomenon realistically, the results of the interplay of those models are often not suffi- ciently validated. We created a plugin for a cardiac simula- tion framework to validate the simulation results using clinical MRI data. The MRI data were used to create a static whole- heart mesh as well as slices from the left ventricular short axis, providing the motion over time. The static heart was a starting point for a simulation of the heart’s motion. From the simula- tion result, we created slices and compared them to the clinical MRI slices using two different metrics: the area of the slices and the point distances. The comparison showed global simi- larities in the deformation of simulated and clinical data, but also indicated points for potential improvements. Performing this comparison with more clinical data could lead to person- alized modeling of elastomechanics of the heart.
C. Nagel, N. Pilia, A. Loewe, and O. Dössel. Quantification of Interpatient 12-lead ECG Variabilities within a Healthy Cohort. In Current Directions in Biomedical Engineering, vol. 6(3) , pp. 493-496, 2020
The morphology of the electrocardiogram (ECG) varies among different healthy subjects due to anatomical and structural reasons, such as for example the shape of the heart geometry or the position and size of surrounding organs in the torso. Knowledge about these ECG morphology changes could be used to parameterize electrophysiological simula- tions of the human heart. In this work, we detected the boundaries of ECG waveforms, i.e. the P-wave, the QRS-complex and the T-wave, in 12- lead ECGs from 918 healthy subjects in the Physionet Com- puting in Cardiology Challenge 2020 Database with the IBT openECG toolbox. Subsequently, we obtained the onset, the peak and the offset of each P-wave, QRS-complex and T-wave in the signal. In this way, the duration of the P-wave, the QRS- complex and the T-wave, the PQ-, RR- and the QT-interval as well as the amplitudes of the P-wave, the Q-, R- and S- peak and the T-wave in each lead were extracted from the 918 healthy ECGs. Their statistical distributions and correlation between each other were assessed. The highest variabilities among the 918 healthy subject were found for the RR interval and the amplitudes of the QRS- complex. The highest correlation was observed for feature pairs that represent the same feature in different leads. Es- pecially the R-peak amplitudes showed a strong correlation across different leads. The calculated feature distributions can be used to optimize the parameters of populations of cardiac electrophysiological models. In this way, realistic in-silico generated surface ECGs can be simulated in large scale and could be used as input data for machine learning algorithms for a classification of cardio- vascular diseases.
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.