Simulation models and artificial intelligence (AI) are largely used to address healthcare and biomedical engineering problems. Both approaches showed promising results in the analysis and optimization of healthcare processes. Therefore, the combination of simulation models and AI could provide a strategy to further boost the quality of health services. In this work, a systematic review of studies applying a hybrid simulation models and AI approach to address healthcare management challenges was carried out. Scopus, Web of Science, and PubMed databases were screened by independent reviewers. The main strategies to combine simulation and AI as well as the major healthcare application scenarios were identified and discussed. Moreover, tools and algorithms to implement the proposed approaches were described. Results showed that machine learning appears to be the most employed AI strategy in combination with simulation models, which mainly rely on agent-based and discrete-event systems. The scarcity and heterogeneity of the included studies suggested that a standardized framework to implement hybrid machine learning-simulation approaches in healthcare management is yet to be defined. Future efforts should aim to use these approaches to design novel intelligent in-silico models of healthcare processes and to provide effective translation to the clinics.
T. Gerach, and A. Loewe. Differential effects of mechano‐electric feedback mechanisms on whole‐heart activation, repolarization, and tension. In The Journal of Physiology, pp. 1-20, 2024
The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate.
We investigate the properties of static mechanical and dynamic electro-mechanical models for the deformation of the human heart. Numerically this is realized by a staggered scheme for the coupled partial/ordinary differential equation (PDE-ODE) system. First, we consider a static and purely mechanical benchmark configuration on a realistic geometry of the human ventricles. Using a penalty term for quasi-incompressibility, we test different parameters and mesh sizes and observe that this approach is not sufficient for lowest order conforming finite elements. Then, we compare the approaches of active stress and active strain for cardiac muscle contraction. Finally, we compare in a coupled anatomically realistic electro-mechanical model numerical Newmark damping with a visco-elastic model using Rayleigh damping. Nonphysiological oscillations can be better mitigated using viscosity.
Introduction: Photogrammetric surface scans provide a radiation-free option to assess and classify craniosynostosis. Due to the low prevalence of craniosynostosis and high patient restrictions, clinical data is rare. Synthetic data could support or even replace clinical data for the classification of craniosynostosis, but this has never been studied systematically. Methods: We test the combinations of three different synthetic data sources: a statistical shape model (SSM), a generative adversarial network (GAN), and image-based principal component analysis for a convolutional neural network (CNN)-based classification of craniosynostosis. The CNN is trained only on synthetic data, but validated and tested on clinical data. Results: The combination of a SSM and a GAN achieved an accuracy of more than 0.96 and a F1-score of more than 0.95 on the unseen test set. The difference to training on clinical data was smaller than 0.01. Including a second image modality improved classification performance for all data sources. Conclusion: Without a single clinical training sample, a CNN was able to classify head deformities as accurate as if it was trained on clinical data. Using multiple data sources was key for a good classification based on synthetic data alone. Synthetic data might play an important future role in the assessment of craniosynostosis.
L. Guo, and W. Nahm. Texture synthesis for generating realistic-looking bronchoscopic videos.. In International Journal of Computer Assisted Radiology and Surgery, vol. 18(12) , pp. 2287-2287, 2023
PURPOSE: Synthetic realistic-looking bronchoscopic videos are needed to develop and evaluate depth estimation methods as part of investigating vision-based bronchoscopic navigation system. To generate these synthetic videos under the circumstance where access to real bronchoscopic images/image sequences is limited, we need to create various realistic-looking image textures of the airway inner surface with large size using a small number of real bronchoscopic image texture patches. METHODS: A generative adversarial networks-based method is applied to create realistic-looking textures of the airway inner surface by learning from a limited number of small texture patches from real bronchoscopic images. By applying a purely convolutional architecture without any fully connected layers, this method allows the production of textures with arbitrary size. RESULTS: Authentic image textures of airway inner surface are created. An example of the synthesized textures and two frames of the thereby generated bronchoscopic video are shown. The necessity and sufficiency of the generated textures as image features for further depth estimation methods are demonstrated. CONCLUSIONS: The method can generate textures of the airway inner surface that meet the requirements for the texture itself and for the thereby generated bronchoscopic videos, including "realistic-looking," "long-term temporal consistency," "sufficient image features for depth estimation," and "large size and variety of synthesized textures." Besides, it also shows advantages with respect to the easy accessibility to required data source. A further validation of this approach is planned by utilizing the realistic-looking bronchoscopic videos with textures generated by this method as training and test data for some depth estimation networks.
A minimally-invasive manipulator characterized by hyper-redundant kinematics and embedded sensing modules is presented in this work. The bending angles (tilt and pan) of the robot tip are controlled through tendon-driven actuation; the transmission of the actuation forces to the tip is based on a Bowden-cable solution integrating some channels for optical fibers. The viability of the real-time measurement of the feedback control variables, through optoelectronic acquisition, is evaluated for automated bending of the flexible endoscope and trajectory tracking of the tip angles. Indeed, unlike conventional catheters and cannulae adopted in neurosurgery, the proposed robot can extend the actuation and control of snake-like kinematic chains with embedded sensing solutions, enabling real-time measurement, robust and accurate control of curvature, and tip bending of continuum robots for the manipulation of cannulae and microsurgical instruments in neurosurgical procedures. A prototype of the manipulator with a length of 43 mm and a diameter of 5.5 mm has been realized via 3D printing. Moreover, a multiple regression model has been estimated through a novel experimental setup to predict the tip angles from measured outputs of the optoelectronic modules. The sensing and control performance has also been evaluated during tasks involving tip rotations.
Digital twins of patients' hearts are a promising tool to assess arrhythmia vulnerability and to personalize therapy. However, the process of building personalized computational models can be challenging and requires a high level of human interaction. We propose a patient-specific Augmented Atria generation pipeline (AugmentA) as a highly automated framework which, starting from clinical geometrical data, provides ready-to-use atrial personalized computational models. AugmentA identifies and labels atrial orifices using only one reference point per atrium. If the user chooses to fit a statistical shape model to the input geometry, it is first rigidly aligned with the given mean shape before a non-rigid fitting procedure is applied. AugmentA automatically generates the fiber orientation and finds local conduction velocities by minimizing the error between the simulated and clinical local activation time (LAT) map. The pipeline was tested on a cohort of 29 patients on both segmented magnetic resonance images (MRI) and electroanatomical maps of the left atrium. Moreover, the pipeline was applied to a bi-atrial volumetric mesh derived from MRI. The pipeline robustly integrated fiber orientation and anatomical region annotations in 38.4 ± 5.7 s. In conclusion, AugmentA offers an automated and comprehensive pipeline delivering atrial digital twins from clinical data in procedural time.
Cardiovascular diseases account for 17 million deaths per year worldwide. Of these, 25% are categorized as sudden cardiac death, which can be related to ventricular tachycardia (VT). This type of arrhythmia can be caused by focal activation sources outside the sinus node. Catheter ablation of these foci is a curative treatment in order to inactivate the abnormal triggering activity. However, the localization procedure is usually time-consuming and requires an invasive procedure in the catheter lab. To facilitate and expedite the treatment, we present two novel localization support techniques based on convolutional neural networks (CNNs) that address these clinical needs. In contrast to existing methods, our approaches were designed to be independent of the patient-specific geometry and directly applicable to surface ECG signals, while also delivering a binary transmural position. Moreover, one of the method's outputs can be interpreted as several ranked solutions. The CNNs were trained on a dataset containing only simulated data and evaluated both on simulated test data and clinical data. On a novel large and open simulated dataset, the median test error was below 3 mm. The median localization error on the unseen clinical data ranged from 32 mm to 41 mm without optimizing the pre-processing and CNN to the clinical data. Interpreting the output of one of the approaches as ranked solutions, the best median error of the top-3 solutions decreased to 20 mm on the clinical data. The transmural position was correctly detected in up to 82% of all clinical cases. These results demonstrate a proof of principle to utilize CNNs to localize the activation source without the intrinsic need for patient-specific geometrical information. Furthermore, providing multiple solutions can assist physicians in identifying the true activation source amongst more than one possible location. With further optimization to clinical data, these methods have high potential to accelerate clinical interventions, replace certain steps within these procedures and consequently reduce procedural risk and improve VT patient outcomes.
Atrial fibrillation (AF) is one of the most commoncardiac diseases. However, a complete understanding of howto treat patients suffering from AF is still not achieved. Asthe isolation of the pulmonary veins in the left atrium (LA)is the standard treatment for AF, the role of the right atrium(RA) in AF is rarely considered. We investigated the impactof including the RA on arrhythmia vulnerability in silico. Wegenerated a dataset of five mono-atrial (LA) and five bi-atrialmodels with three different electrophysiological (EP) setupseach, regarding different states of AF-induced remodelling.For every model, a pacing protocol was run to induce reen-tries from a set of stimulation points. The average share ofinducing points across all EP setups was 0.0, 0.8 and 6.7 %for the mono-atrial scenario, 0.5, 27.3 and 37.9 % for the bi-atrial scenario. The increase in inducibility of LA stimula-tion points from mono- to bi-atrial scenario was 0.91 ± 2.03%,34.55 ± 14.9 % and 44.2 ± 14.9 %, respectively. In this study,the RA had a marked impact on the results of the vulnerabilityassessment that needs to be further investigated.
Atrial fibrillation (AF) is the most common sus- tained arrhythmia posing a significant burden to patients and leading to an increased risk of stroke and heart failure. Additional ablation of areas of arrhythmogenic substrate in the atrial body detected by either late gadolinium enhance- ment magnetic resonance imaging (LGE-MRI) or electro- anatomical mapping (EAM) may increase the success rate of restoring and maintaining sinus rhythm compared to the stan- dard treatment procedure of pulmonary vein isolation (PVI). To evaluate if LGE-MRI and EAM identify equivalent sub- strate as potential ablation targets, we divided the left atrium (LA) into six clinically important regions in ten patients. Then, we computed the correlation between both modalities by ana- lyzing the regional extents of identified pathological tissue. In this regional analysis, we observed no correlation between late gadolinium enhancement (LGE) and low voltage areas (LVA), neither in any region nor with regard to the entire atrial surface (−0.3 < 𝑟 < 0.3). Instead, the regional extents identified as pathological tissue varied significantly between both modali- ties. An increased extent of LVA compared to LGE was ob- served in the septal wall of the LA (𝑎 ̃sept.,LVA = 19.63 % and 𝑎 ̃sept.,LGE = 3.94 %, with 𝑎 ̃ = median of the extent of patho- logical tissue in the corresponding region). In contrast, in the inferior and lateral wall, the extent of LGE was higher than the extent of LVA for most geometries (𝑎 ̃inf.,LGE = 27.22% and 𝑎 ̃lat.,LGE = 32.70 % compared to 𝑎 ̃inf .,LVA = 9.21 % and 𝑎 ̃lat.,LVA = 6.69 %). Since both modalities provided dis- crepant results regarding the detection of arrhythmogenic sub- strate using clinically established thresholds, further investiga- tions regarding their constraints need to be performed in order to use these modalities for patient stratification and treatment planning.
The application of machine learning approachesin medical technology is gaining more and more attention.Due to the high restrictions for collecting intraoperative patientdata, synthetic data is increasingly used to support the trainingof artificial neural networks. We present a pipeline to createa statistical shape model (SSM) using 28 segmented clinicalliver CT scans. Our pipeline consists of four steps: data pre-processing, rigid alignment, template morphing, and statisti-cal modeling. We compared two different template morphingapproaches: Laplace-Beltrami-regularized projection (LBRP)and nonrigid iterative closest points translational (N-ICP-T)and evaluated both morphing approaches and their corre-sponding shape model performance using six metrics. LBRPachieved a smaller mean vertex-to-nearest-neighbor distances(2.486±0.897 mm) than N-ICP-T (5.559±2.413 mm). Gen-eralizationand specificity errors for LBRP were consistentlylower than those of N-ICP-T. The first principal componentsof the SSM showed realistic anatomical variations. The perfor-mance of the SSM was comparable to a state-of-the-art model.
Introduction: 3D surface scan-based diagnosis of craniosynostosis is a promising radiation-free alternative to traditional diagnosis using computed tomography. The cra- nial index (CI) and the cranial vault asymmetry index (CVAI) are well-established clinical parameters that are widely used. However, they also have the benefit of being easily adaptable for automatic diagnosis without the need of extensive prepro- cessing.Methods: We propose a multi-height-based classification ap- proach that uses CI and CVAI in different height layers and compare it to the initial approach using only one layer. We use ten-fold cross-validation and test seven different classi- fiers. The dataset of 504 patients consists of three types of craniosynostosis and a control group consisting of healthy and non-synostotic subjects.Results: The multi-height-based approach improved classifica- tion for all classifiers. The k-nearest neighbors classifier scored best with a mean accuracy of 89 % and a mean F1-score of 0.75.Conclusion: Taking height into account is beneficial for the classification. Based on accepted and widely used clinical pa- rameters, this might be a step towards an easy-to-understand and transparent classification approach for both physicians and patients.
Optical Coherence Tomography (OCT) is a stan- dard imaging procedure in ophthalmology. OCT Angiography is a promising extension, allowing for fast and non-invasive imaging of the retinal vasculature analyzing multiple OCT scans at the same place. Local variance is examined and highlighted. Despite its introduction in the clinic, unanswered questions remain when it comes to signal generation. Multi- phase fluids like intralipid, milk-water solutions and human blood cells were applied in phantom studies shedding light on some of the mechanisms. The use of hydrogel beads allows for the generation of alternative blood models for OCT and OCT Angiography. Beads were produced in Hannover, their size was measured and their long term stability was assessed. Then, beads were shipped to Karlsruhe, where OCT imaging resulted in first insights. The hydrogel acts as a diffusion barrier, which enables a clear distinction of bead and fluid when scattering particles were added. Further on, the scattering medium be- low the bead showed increased signal intensity. We conclude that the inside of the bead structure shows enhanced transmis- sion compared to the plasma substitute with dissolved TiO2 surrounding it. Beads were found clumped and deformed af- ter shipping, an issue to be addressed in further investigations. Nevertheless, hydrogel beads are promising as a blood model for OCT Angiography investigations, offering tunable optical parameters within the blood substitute solution.
Y. Gao, M. Weiß, and W. Nahm. Reduction of Uncertainty in Bolus Transit Time Measurement in Quantitative Fluorescence Angiography. In Current Directions in Biomedical Engineering, vol. 9(1) , pp. 619-622, 2023
During cerebral revascularization surgeries, blood flow values help surgeons to monitor the quality of the pro- cedure, e.g., to avoid cerebral hyperperfusion syndrome due to excessively enhanced perfusion. The state-of-the-art technique is the ultrasonic flow probe that has to be placed around the blood vessel. This causes contact between probe and vessel, which, in the worst case, leads to rupture. The recently devel- oped intraoperative indocyanine green (ICG) Quantitative Flu- orescence Angiography (QFA) is an alternative technique that overcomes this risk. However, it has been shown by the devel- oper that the calculated flow has deviations. After determining the bolus transit time as the most sensitive parameter in flow calculation, we propose a new two-step uncertainty reduction method for flow calculation. The first step is to generate more data in each measurement that results in functions of the pa- rameters. Noise can then be reduced in a second step. Two methods for this step are compared. The first method fits the model for each parameter function separately and calculates flow from models, while the second one fits multiple parame- ter functions together. The latter method is proven to perform best by in silico tests. Besides, this method reduces the de- viation of flow comparing to original QFA as expected. Our approach can be generally used in all QFA applications using two-point theory. Further development is possible if number of dimensions of the achieved parameter data are broadened that results in even more data for processing in the second step.
L. Guo, and W. Nahm. A cGAN-based network for depth estimation from bronchoscopic images.. In International Journal of Computer Assisted Radiology and Surgery, 2023
PURPOSE: Depth estimation is the basis of 3D reconstruction of airway structure from 2D bronchoscopic scenes, which can be further used to develop a vision-based bronchoscopic navigation system. This work aims to improve the performance of depth estimation directly from bronchoscopic images by training a depth estimation network on both synthetic and real datasets. METHODS: We propose a cGAN-based network Bronchoscopic-Depth-GAN (BronchoDep-GAN) to estimate depth from bronchoscopic images by translating bronchoscopic images into depth maps. The network is trained in a supervised way learning from synthetic textured bronchoscopic image-depth pairs and virtual bronchoscopic image-depth pairs, and simultaneously, also in an unsupervised way learning from unpaired real bronchoscopic images and depth maps to adapt the model to real bronchoscopic scenes. RESULTS: Our method is tested on both synthetic data and real data. However, the tests on real data are only qualitative, as no ground truth is available. The results show that our network obtains better accuracy in all cases in estimating depth from bronchoscopic images compared to the well-known cGANs pix2pix. CONCLUSIONS: Including virtual and real bronchoscopic images in the training phase of the depth estimation networks can improve depth estimation's performance on both synthetic and real scenes. Further validation of this work is planned on 3D clinical phantoms. Based on the depth estimation results obtained in this work, the accuracy of locating bronchoscopes with corresponding pre-operative CTs will also be evaluated in comparison with the current clinical status.
Mechanistic cardiac electrophysiology models allow for personalized simulations of the electrical activity in the heart and the ensuing electrocardiogram (ECG) on the body surface. As such, synthetic signals possess known ground truth labels of the underlying disease and can be employed for validation of machine learning ECG analysis tools in addition to clinical signals. Recently, synthetic ECGs were used to enrich sparse clinical data or even replace them completely during training leading to improved performance on real-world clinical test data. We thus generated a novel synthetic database comprising a total of 16,900 12 lead ECGs based on electrophysiological simulations equally distributed into healthy control and 7 pathology classes. The pathological case of myocardial infraction had 6 sub-classes. A comparison of extracted features between the virtual cohort and a publicly available clinical ECG database demonstrated that the synthetic signals represent clinical ECGs for healthy and pathological subpopulations with high fidelity. The ECG database is split into training, validation, and test folds for development and objective assessment of novel machine learning algorithms.
AIMS: Electro-anatomical voltage, conduction velocity (CV) mapping, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) have been correlated with atrial cardiomyopathy (ACM). However, the comparability between these modalities remains unclear. This study aims to (i) compare pathological substrate extent and location between current modalities, (ii) establish spatial histograms in a cohort, (iii) develop a new estimated optimized image intensity threshold (EOIIT) for LGE-MRI identifying patients with ACM, (iv) predict rhythm outcome after pulmonary vein isolation (PVI) for persistent atrial fibrillation (AF). METHODS AND RESULTS: Thirty-six ablation-naive persistent AF patients underwent LGE-MRI and high-definition electro-anatomical mapping in sinus rhythm. Late gadolinium enhancement areas were classified using the UTAH, image intensity ratio (IIR >1.20), and new EOIIT method for comparison to low-voltage substrate (LVS) and slow conduction areas <0.2 m/s. Receiver operating characteristic analysis was used to determine LGE thresholds optimally matching LVS. Atrial cardiomyopathy was defined as LVS extent ≥5% of the left atrium (LA) surface at <0.5 mV. The degree and distribution of detected pathological substrate (percentage of individual LA surface are) varied significantly (P < 0.001) across the mapping modalities: 10% (interquartile range 0-14%) of the LA displayed LVS <0.5 mV vs. 7% (0-12%) slow conduction areas <0.2 m/s vs. 15% (8-23%) LGE with the UTAH method vs. 13% (2-23%) using IIR >1.20, with most discrepancies on the posterior LA. Optimized image intensity thresholds and each patient's mean blood pool intensity correlated linearly (R2 = 0.89, P < 0.001). Concordance between LGE-MRI-based and LVS-based ACM diagnosis improved with the novel EOIIT applied at the anterior LA [83% sensitivity, 79% specificity, area under the curve (AUC): 0.89] in comparison to the UTAH method (67% sensitivity, 75% specificity, AUC: 0.81) and IIR >1.20 (75% sensitivity, 62% specificity, AUC: 0.67). CONCLUSION: Discordances in detected pathological substrate exist between LVS, CV, and LGE-MRI in the LA, irrespective of the LGE detection method. The new EOIIT method improves concordance of LGE-MRI-based ACM diagnosis with LVS in ablation-naive AF patients but discrepancy remains particularly on the posterior wall. All methods may enable the prediction of rhythm outcomes after PVI in patients with persistent AF.
A. Jadidi, and A. Loewe. Omnipolar Voltage: A Novel Modality for Rhythm-Independent Identification of the Atrial Low-Voltage Substrate During AF?. In JACC Clinical Electrophysiology, vol. 9(8 Pt 2) , pp. 1513-1513, 2023
Purpose: To evaluate the impact of lens opacity on the reliability of optical coherence tomog- raphy angiography metrics and to find a vessel caliber threshold that is reproducible in cataract patients.Methods: A prospective cohort study of 31 patients, examining one eye per patient, by applying 33mm macular optical coherence tomography angiography before (18.94±12.22days) and 3 months (111 ± 23.45 days) after uncomplicated cataract surgery. We extracted superficial (SVC) and deep vascular plexuses (DVC) for further analysis and evaluated changes in image contrast, vessel metrics (perfusion density, flow deficit and vessel-diameter index) and foveal avascular area (FAZ). Results: After surgery, the blood flow signal in smaller capillaries was enhanced as image contrast improved. Signal strength correlated to average lens density defined by objective measurement in Scheimpflug images (Pearson’s r: –.40, p: .027) and to flow deficit (r1⁄4 –.70, p<.001). Perfusion density correlated to the signal strength index (r1⁄4.70, p<.001). Vessel metrics and FAZ area, except for FAZ area in DVC, were significantly different after cataract surgery, but the mean change was approximately 3–6%. A stepwise approach in extracting vessels according to their pixel caliber showed a threshold of > 6 pixels caliber ($20–30 mm) was comparable before and after lens removal.Conclusion: In patients with cataract, OCTA vessel metrics should be interpreted with caution. In addition to signal strength, contrast and pixel properties can serve as supplementary quality met- rics to improve the interpretation of OCTA metrics. Vessels with $20–30 mm in caliber seem to be reproducible.
INTRODUCTION: Improved sinus rhythm (SR) maintenance rates have been achieved in patients with persistent atrial fibrillation (AF) undergoing pulmonary vein isolation plus additional ablation of low voltage substrate (LVS) during SR. However, voltage mapping during SR may be hindered in persistent and long-persistent AF patients by immediate AF recurrence after electrical cardioversion. We assess correlations between LVS extent and location during SR and AF, aiming to identify regional voltage thresholds for rhythm-independent delineation/detection of LVS areas. (1) Identification of voltage dissimilarities between mapping in SR and AF. (2) Identification of regional voltage thresholds that improve cross-rhythm substrate detection. (3) Comparison of LVS between SR and native versus induced AF. METHODS: Forty-one ablation-naive persistent AF patients underwent high-definition (1 mm electrodes; >1200 left atrial (LA) mapping sites per rhythm) voltage mapping in SR and AF. Global and regional voltage thresholds in AF were identified which best match LVS < 0.5 mV and <1.0 mV in SR. Additionally, the correlation between SR-LVS with induced versus native AF-LVS was assessed. RESULTS: Substantial voltage differences (median: 0.52, interquartile range: 0.33-0.69, maximum: 1.19 mV) with a predominance of the posterior/inferior LA wall exist between the rhythms. An AF threshold of 0.34 mV for the entire left atrium provides an accuracy, sensitivity and specificity of 69%, 67%, and 69% to identify SR-LVS < 0.5 mV, respectively. Lower thresholds for the posterior wall (0.27 mV) and inferior wall (0.3 mV) result in higher spatial concordance to SR-LVS (4% and 7% increase). Concordance with SR-LVS was higher for induced AF compared to native AF (area under the curve[AUC]: 0.80 vs. 0.73). AF-LVS < 0.5 mV corresponds to SR-LVS < 0.97 mV (AUC: 0.73). CONCLUSION: Although the proposed region-specific voltage thresholds during AF improve the consistency of LVS identification as determined during SR, the concordance in LVS between SR and AF remains moderate, with larger LVS detection during AF. Voltage-based substrate ablation should preferentially be performed during SR to limit the amount of ablated atrial myocardium.
Machine learning (ML) methods for the analysis of electrocardiography (ECG) data are gaining importance, substantially supported by the release of large public datasets. However, these current datasets miss important derived descriptors such as ECG features that have been devised in the past hundred years and still form the basis of most automatic ECG analysis algorithms and are critical for cardiologists' decision processes. ECG features are available from sophisticated commercial software but are not accessible to the general public. To alleviate this issue, we add ECG features from two leading commercial algorithms and an open-source implementation supplemented by a set of automatic diagnostic statements from a commercial ECG analysis software in preprocessed format. This allows the comparison of ML models trained on clinically versus automatically generated label sets. We provide an extensive technical validation of features and diagnostic statements for ML applications. We believe this release crucially enhances the usability of the PTB-XL dataset as a reference dataset for ML methods in the context of ECG data.
Clonogenic assays are routinely used to evaluate the response of cancer cells to external radiation fields, assess their radioresistance and radiosensitivity, estimate the performance of radiotherapy. However, classic clonogenic tests focus on the number of colonies forming on a substrate upon exposure to ionizing radiation, and disregard other important characteristics of cells such their ability to generate structures with a certain shape. The radioresistance and radiosensitivity of cancer cells may depend less on the number of cells in a colony and more on the way cells interact to form complex networks. In this study, we have examined whether the topology of 2D cancer-cell graphs is influenced by ionizing radiation. We subjected different cancer cell lines, i.e. H4 epithelial neuroglioma cells, H460 lung cancer cells, PC3 bone metastasis of grade IV of prostate cancer and T24 urinary bladder cancer cells, cultured on planar surfaces, to increasing photon radiation levels up to 6 Gy. Fluorescence images of samples were then processed to determine the topological parameters of the cell-graphs developing over time. We found that the larger the dose, the less uniform the distribution of cells on the substrate—evidenced by high values of small-world coefficient (cc), high values of clustering coefficient (cc), and small values of characteristic path length (cpl). For all considered cell lines, 𝑠𝑤>1 for doses higher or equal to 4 Gy, while the sensitivity to the dose varied for different cell lines: T24 cells seem more distinctly affected by the radiation, followed by the H4, H460 and PC3 cells. Results of the work reinforce the view that the characteristics of cancer cells and their response to radiotherapy can be determined by examining their collective behavior—encoded in a few topological parameters—as an alternative to classical clonogenic assays.
Purpose Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of extranodal non-Hodgkin lym- phoma. To predict the overall survival (OS) in advance is of utmost importance as it has the potential to aid clinical decision-making. Though radiomics-based machine learning (ML) has demonstrated the promising performance in PCNSL, it demands large amounts of manual feature extraction efforts from magnetic resonance images beforehand. deep learning (DL) overcomes this limitation.Methods In this paper, we tailored the 3D ResNet to predict the OS of patients with PCNSL. To overcome the limitation of data sparsity, we introduced data augmentation and transfer learning, and we evaluated the results using r stratified k-fold cross-validation. To explain the results of our model, gradient-weighted class activation mapping was applied.Results We obtained the best performance (the standard error) on post-contrast T1-weighted (T1Gd)—area under curve = 0.81(0.03), accuracy = 0.87(0.07), precision = 0.88(0.07), recall = 0.88(0.07) and F1-score = 0.87(0.07), while compared with ML-based models on clinical data and radiomics data, respectively, further confirming the stability of our model. Also, we observed that PCNSL is a whole-brain disease and in the cases where the OS is less than 1 year, it is more difficult to distinguish the tumor boundary from the normal part of the brain, which is consistent with the clinical outcome. Conclusions All these findings indicate that T1Gd can improve prognosis predictions of patients with PCNSL. To the best of our knowledge, this is the first time to use DL to explain model patterns in OS classification of patients with PCNSL. Future work would involve collecting more data of patients with PCNSL, or additional retrospective studies on different patient populations with rare diseases, to further promote the clinical role of our model.
T. Gerach, S. Schuler, A. Wachter, and A. Loewe. The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model. In Cardiovascular Engineering and Technology, vol. 14(2) , pp. 296-314, 2023
PURPOSE: Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected. METHODS: In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation. RESULTS: We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. CONCLUSION: This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment.
A. Loewe, A. Luik, R. Sassi, and P. Laguna. Together we are strong! Collaboration between clinicians and engineers as an enabler for better diagnosis and therapy of atrial arrhythmias.. In Medical & Biological Engineering & Computing, vol. 61(4) , pp. 875-875, 2023
Background and Objective: Planning the optimal ablation strategy for the treatment of complex atrial tachycardia (CAT) is a time consuming task and is error-prone. Recently, directed network mapping, a technology based on graph theory, proved to efficiently identify CAT based solely on data of clinical interventions. Briefly, a directed network was used to model the atrial electrical propagation and reentrant activities were identified by looking for closed-loop paths in the network. In this study, we propose a recommender system, built as an optimization problem, able to suggest the optimal ablation strategy for the treatment of CAT.Methods: The optimization problem modeled the optimal ablation strategy as that one interrupting all reentrant mechanisms while minimizing the ablated atrial surface. The problem was designed on top of directed network mapping. Considering the exponential complexity of finding the optimal solution of the problem, we introduced a heuristic algorithm with polynomial complexity. The proposed algorithm was applied to the data of i) 6 simulated scenarios including both left and right atrial flutter; and ii) 10 subjects that underwent a clinical routine.Results: The recommender system suggested the optimal strategy in 4 out of 6 simulated scenarios. On clinical data, the recommended ablation lines were found satisfactory on 67% of the cases according to the clinician’s opinion, while they were correctly located in 89%. The algorithm made use of only data collected during mapping and was able to process them nearly real-time.Conclusions: The first recommender system for the identification of the optimal ablation lines for CAT, based solely on the data collected during the intervention, is presented. The study may open up interesting scenarios for the application of graph theory for the treatment of CAT.
Primary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of patients do not respond to HD–MTX-based chemotherapy (15–25%) or experience relapse (25–50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (p-value < 10−12). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice.
AIMS: The long-term success rate of ablation therapy is still sub-optimal in patients with persistent atrial fibrillation (AF), mostly due to arrhythmia recurrence originating from arrhythmogenic sites outside the pulmonary veins. Computational modelling provides a framework to integrate and augment clinical data, potentially enabling the patient-specific identification of AF mechanisms and of the optimal ablation sites. We developed a technology to tailor ablations in anatomical and functional digital atrial twins of patients with persistent AF aiming to identify the most successful ablation strategy. METHODS AND RESULTS: Twenty-nine patient-specific computational models integrating clinical information from tomographic imaging and electro-anatomical activation time and voltage maps were generated. Areas sustaining AF were identified by a personalized induction protocol at multiple locations. State-of-the-art anatomical and substrate ablation strategies were compared with our proposed Personalized Ablation Lines (PersonAL) plan, which consists of iteratively targeting emergent high dominant frequency (HDF) regions, to identify the optimal ablation strategy. Localized ablations were connected to the closest non-conductive barrier to prevent recurrence of AF or atrial tachycardia. The first application of the HDF strategy had a success of >98% and isolated only 5-6% of the left atrial myocardium. In contrast, conventional ablation strategies targeting anatomical or structural substrate resulted in isolation of up to 20% of left atrial myocardium. After a second iteration of the HDF strategy, no further arrhythmia episode could be induced in any of the patient-specific models. CONCLUSION: The novel PersonAL in silico technology allows to unveil all AF-perpetuating areas and personalize ablation by leveraging atrial digital twins.
The bidomain model and the finite element method are an established standard to mathematically describe cardiac electrophysiology, but are both suboptimal choices for fast and large-scale simulations due to high computational costs. We investigate to what extent simplified approaches for propagation models (monodomain, reaction-Eikonal and Eikonal) and forward calculation (boundary element and infinite volume conductor) deliver markedly accelerated, yet physiologically accurate simulation results in atrial electrophysiology. <i>Methods:</i> We compared action potential durations, local activation times (LATs), and electrocardiograms (ECGs) for sinus rhythm simulations on healthy and fibrotically infiltrated atrial models. <i>Results:</i> All simplified model solutions yielded LATs and P waves in accurate accordance with the bidomain results. Only for the Eikonal model with pre-computed action potential templates shifted in time to derive transmembrane voltages, repolarization behavior notably deviated from the bidomain results. ECGs calculated with the boundary element method were characterized by correlation coefficients <inline-formula><tex-math notation="LaTeX">$>$</tex-math></inline-formula>0.9 compared to the finite element method. The infinite volume conductor method led to lower correlation coefficients caused predominantly by systematic overestimations of P wave amplitudes in the precordial leads. <i>Conclusion:</i> Our results demonstrate that the Eikonal model yields accurate LATs and combined with the boundary element method precise ECGs compared to markedly more expensive full bidomain simulations. However, for an accurate representation of atrial repolarization dynamics, diffusion terms must be accounted for in simplified models. <i>Significance:</i> Simulations of atrial LATs and ECGs can be notably accelerated to clinically feasible time frames at high accuracy by resorting to the Eikonal and boundary element methods.
A. Loewe, and A. Jadidi. Atrial arrhythmogenic substrate assessment: Is seeing always knowing?. In Journal of Cardiovascular Electrophysiology, vol. 34(2) , pp. 313-314, 2023
Background: Progressive atrial fibrotic remodeling has been reported to be associated with atrial cardiomyopathy (ACM) and the transition from paroxysmal to persistent atrial fibrillation (AF). We sought to identify the anatomical/structural and electrophysiological factors involved in atrial remodeling that promote AF persistency.Methods: Consecutive patients with paroxysmal (n = 134) or persistent (n = 136) AF who presented for their first AF ablation procedure were included. Patients underwent left atrial (LA) high-definition mapping (1,835 ± 421 sites/map) during sinus rhythm (SR) and were randomized to training and validation sets for model development and evaluation. A total of 62 parameters from both electro-anatomical mapping and non-invasive baseline data were extracted encompassing four main categories: (1) LA size, (2) extent of low-voltage-substrate (LVS), (3) LA voltages and (4) bi-atrial conduction time as identified by the duration of amplified P-wave (APWD) in a digital 12-lead-ECG. Least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to identify the factors that are most relevant to AF persistency in each category alone and all categories combined. The performance of the developed models for diagnosis of AF persistency was validated regarding discrimination, calibration and clinical usefulness. In addition, HATCH score and C2HEST score were also evaluated for their performance in identification of AF persistency.Results: In training and validation sets, APWD (threshold 151 ms), LA volume (LAV, threshold 94 mL), bipolar LVS area < 1.0 mV (threshold 4.55 cm2) and LA global mean voltage (GMV, threshold 1.66 mV) were identified as best determinants for AF persistency in the respective category. Moreover, APWD (AUC 0.851 and 0.801) and LA volume (AUC 0.788 and 0.741) achieved better discrimination between AF types than LVS extent (AUC 0.783 and 0.682) and GMV (AUC 0.751 and 0.707). The integrated model (combining APWD and LAV) yielded the best discrimination performance between AF types (AUC 0.876 in training set and 0.830 in validation set). In contrast, HATCH score and C2HEST score only achieved AUC < 0.60 in identifying individuals with persistent AF in current study.Conclusion: Among 62 electro-anatomical parameters, we identified APWD, LA volume, LVS extent, and mean LA voltage as the four determinant electrophysiological and structural factors that are most relevant for AF persistency. Notably, the combination of APWD with LA volume enabled discrimination between paroxysmal and persistent AF with high accuracy, emphasizing their importance as underlying substrate of persistent AF.
The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.
Life-threatening cardiac arrhythmias require immediate defibrillation. For state-of-the-art shock treatments, a high field strength is required to achieve a sufficient success rate for terminating the complex spiral wave (rotor) dynamics underlying cardiac fibrillation. However, such high energy shocks have many adverse side effects due to the large electric currents applied. In this study, we show, using 2D simulations based on the Fenton-Karma model, that also pulses of relatively low energy may terminate the chaotic activity if applied at the right moment in time. In our simplified model for defibrillation, complex spiral waves are terminated by local perturbations corresponding to conductance heterogeneities acting as virtual electrodes in the presence of an external electric field. We demonstrate that time series of the success rate for low energy shocks exhibit pronounced peaks which correspond to short intervals in time during which perturbations aiming at terminating the chaotic fibrillation state are (much) more successful. Thus, the low energy shock regime, although yielding very low temporal average success rates, exhibits moments in time for which success rates are significantly higher than the average value shown in dose-response curves. This feature might be exploited in future defibrillation protocols for achieving high termination success rates with low or medium pulse energies.
L. Scherer, M. Kuss, and W. Nahm. Review of Artificial Intelligence-Based Signal Processing in Dialysis: Challenges for Machine-Embedded and Complementary Applications.. In Advances in kidney disease and health, vol. 30(1) , pp. 40-40, 2023
Artificial intelligence technology is trending in nearly every medical area. It offers the possibility for improving analytics, therapy outcome, and user experience during therapy. In dialysis, the application of artificial intelligence as a therapy-individualization tool is led more by start-ups than consolidated players, and innovation in dialysis seems comparably stagnant. Factors such as technical requirements or regulatory processes are important and necessary but can slow down the implementation of artificial intelligence due to missing data infrastructure and undefined approval processes. Current research focuses mainly on analyzing health records or wearable technology to add to existing health data. It barely uses signal data from treatment devices to apply artificial intelligence models. This article, therefore, discusses requirements for signal processing through artificial intelligence in health care and compares these with the status quo in dialysis therapy. It offers solutions for given barriers to speed up innovation with sensor data, opening access to existing and untapped sources, and shows the unique advantage of signal processing in dialysis compared to other health care domains. This research shows that even though the combination of different data is vital for improving patients' therapy, adding signal-based treatment data from dialysis devices to the picture can benefit the understanding of treatment dynamics, improving and individualizing therapy.
Objective: Diagnosis of craniosynostosis using photogrammetric 3D surface scans is a promising radiation-free alternative to traditional computed tomography. We propose a 3D surface scan to 2D distance map conversion enabling the usage of the first convolutional neural networks (CNNs)-based classification of craniosynostosis. Benefits of using 2D images include preserving patient anonymity, enabling data augmentation during training, and a strong under-sampling of the 3D surface with good classification performance.Methods: The proposed distance maps sample 2D images from 3D surface scans using a coordinate transformation, ray casting, and distance extraction. We introduce a CNNbased classification pipeline and compare our classifier to alternative approaches on a dataset of 496 patients. We investigate into low-resolution sampling, data augmentation, and attribution mapping.Results: Resnet18 outperformed alternative classifiers on our dataset with an F1-score of 0.964 and an accuracy of 98.4 %. Data augmentation on 2D distance maps increased performance for all classifiers. Under-sampling allowed 256-fold computation reduction during ray casting while retaining an F1-score of 0.92. Attribution maps showed high amplitudes on the frontal head.Conclusion: We demonstrated a versatile mapping approach to extract a 2D distance map from the 3D head geometry increasing classification performance, enabling data augmentation during training on 2D distance maps, and the usage of CNNs. We found that low-resolution images were sufficient for a good classification performance.Significance: Photogrammetric surface scans are a suitable craniosynostosis diagnosis tool for clinical practice. Domain transfer to computed tomography seems likely and can further contribute to reducing ionizing radiation exposure for infants.
BACKGROUND: Electrical impedance measurements have become an accepted tool for monitoring intracardiac radio frequency ablation. Recently, the long-established generator impedance was joined by novel local impedance measurement capabilities with all electrical circuit terminals being accommodated within the catheter. OBJECTIVE: This work aims at in silico quantification of distinct influencing factors that have remained challenges due to the lack of ground truth knowledge and the superposition of effects in clinical settings. METHODS: We introduced a highly detailed in silico model of two local impedance enabled catheters, namely IntellaNav MiFi™ OI and IntellaNav Stablepoint™, embedded in a series of clinically relevant environments. Assigning material and frequency specific conductivities and subsequently calculating the spread of the electrical field with the finite element method yielded in silico local impedances. The in silico model was validated by comparison to in vitro measurements of standardized sodium chloride solutions. We then investigated the effect of the withdrawal of the catheter into the transseptal sheath, catheter-tissue interaction, insertion of the catheter into pulmonary veins, and catheter irrigation. RESULTS: All simulated setups were in line with in vitro experiments and in human measurements and gave detailed insight into determinants of local impedance changes as well as the relation between values measured with two different devices. CONCLUSION: The in silico environment proved to be capable of resembling clinical scenarios and quantifying local impedance changes. SIGNIFICANCE: The tool can assists the interpretation of measurements in humans and has the potential to support future catheter development.
Approximating the fast dynamics of depolarization waves in the human heart described by the monodomain model is numerically challenging. Splitting methods for the PDE-ODE coupling enable the computation with very fine space and time discretizations. Here, we compare different splitting approaches regarding convergence, accuracy, and efficiency. Simulations were performed for a benchmark problem with the Beeler-Reuter cell model on a truncated ellipsoid approximating the left ventricle including a localized stimulation. For this configuration, we provide a reference solution for the transmembrane potential. We found a semi-implicit approach with state variable interpolation to be the most efficient scheme. The results are transferred to a more physiological setup using a bi-ventricular domain with a complex external stimulation pattern to evaluate the accuracy of the activation time for different resolutions in space and time.
Sinus node (SN) pacemaking is based on a coupling between surface membrane ion-channels and intracellular Ca2+-handling. The fundamental role of the inward Na+/Ca2+ exchanger (NCX) is firmly established. However, little is known about the reverse mode exchange. A simulation study attributed important role to reverse NCX activity, however experimental evidence is still missing. Whole-cell and perforated patch-clamp experiments were performed on rabbit SN cells supplemented with fluorescent Ca2+-tracking. We established 2 and 8 mM pipette NaCl groups to suppress and enable reverse NCX. NCX was assessed by specific block with 1 μM ORM-10962. Mechanistic simulations were performed by Maltsev–Lakatta minimal computational SN model. Active reverse NCX resulted in larger Ca2+-transient amplitude with larger SR Ca2+-content. Spontaneous action potential (AP) frequency increased with 8 mM NaCl. When reverse NCX was facilitated by 1 μM strophantin the Ca2+i and spontaneous rate increased. ORM-10962 applied prior to strophantin prevented Ca2+i and AP cycle change. Computational simulations indicated gradually increasing reverse NCX current, Ca2+i and heart rate with increasing Na+i. Our results provide further evidence for the role of reverse NCX in SN pacemaking. The reverse NCX activity may provide additional Ca2+-influx that could increase SR Ca2+-content, which consequently leads to enhanced pacemaking activity.
A. Amsaleg, J. Sánchez, R. Mikut, and A. Loewe. Characterization of the pace-and-drive capacity of the human sinoatrial node: A 3D in silico study.. In Biophysical journal, vol. 121(22) , pp. 4247-4259, 2022
The sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically ("pacing") and excites the surrounding non-automatic cardiac cells ("drive") to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEPs). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA) at varying rates induced by gradual If block. Additionally, we investigated the influence of the SEPs by varying their number, length, and width. SEPs created a transition zone of transmembrane voltage and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized transmembrane voltage (-66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted toward the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46 ± 1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared with a larger distance from the LPS to the areas where SEPs were located (7.17± 0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace and drive in silico.
Interatrial conduction block refers to a disturbance in the propagation of electrical impulses in the conduction pathways between the right and the left atrium. It is a risk factor for atrial fibrillation, stroke, and premature death. Clin- ical diagnostic criteria comprise an increased P wave dura- tion and biphasic P waves in lead II, III and aVF due to ret- rograde activation of the left atrium. Machine learning algo- rithms could improve the diagnosis but require a large-scale, well-controlled and balanced dataset. In silico electrocardio- gram (ECG) signals, optimally obtained from a statistical shape model to cover anatomical variability, carry the poten- tial to produce an extensive database meeting the requirements for successful machine learning application. We generated the first in silico dataset including interatrial conduction block of 9,800simulated ECG signals based on a bi-atrial statistical shape model. Automated feature analysis was performed to evaluate P wave morphology, duration and P wave terminal force in lead V1. Increased P wave duration and P wave ter- minal force in lead V1 were found for models with interatrial conduction block compared to healthy models. A wide vari- ability of P wave morphology was detected for models with in- teratrial conduction block. Contrary to previous assumptions, our results suggest that a biphasic P wave morphology seems to be neither necessary nor sufficient for the diagnosis of in- teratrial conduction block. The presented dataset is ready for a classification with machine learning algorithms and can be easily extended.
Atrial fibrillation is responsible for a significant and steadily rising burden. Simultaneously, the treatment options for atrial fibrillation are far from optimal. Personalized simulations of cardiac electrophysiology could assist clinicians in the risk stratification and therapy planning for atrial fibrillation. However, the use of personalized simulations in clinics is currently not possible due to either too high computational costs or non-sufficient accuracy. Eikonal simulations come with low computational costs but cannot replicate the influence of cardiac tissue geometry on the conduction velocity of the wave propagation. Consequently, they currently lack the required accuracy to be applied in clinics. Biophysically detailed simulations on the other hand are accurate but associated with too high computational costs. To tackle this issue, a regression model is created based on biophysically detailed bidomain simulation data. This regression formula calculates the conduction velocity dependent on the thickness and curvature of the heart wall. Afterwards the formula was implemented into the eikonal model with the goal to increase the accuracy of the eikonal model without losing its advantage of computational efficiency. The results of the modified eikonal simulations demonstrate that (i) the local activation times become significantly closer to those of the biophysically detailed bidomain simulations, (ii) the advantage of the eikonal model of a low sensitivity to the resolution of the mesh was reduced further, and (iii) the unrealistic occurrence of endo-epicardial dissociation in simulations was remedied. The results suggest that the accuracy of the eikonal model was significantly increased. At the same time, the additional computational costs caused by the implementation of the regression formula are neglectable. In conclusion, a successful step towards a more accurate and fast computational model of cardiac electrophysiology was achieved.
Craniosynostosis is a congenital disease character-ized by the premature closure of one or multiple sutures of theinfant’s skull. For diagnosis, 3D photogrammetric scans are aradiation-free alternative to computed tomography. However,data is only sparsely available and the role of data augmentation for the classification of craniosynostosis has not yet beenanalyzed.In this work, we use a 2D distance map representation ofthe infants’ heads with a convolutional-neural-network-basedclassifier and employ a generative adversarial network (GAN)for data augmentation. We simulate two data scarcity scenar-ios with 15 % and 10 % training data and test the influence ofdifferent degrees of added synthetic data and balancing under-represented classes. We used total accuracy and F1-score as ametric to evaluate the final classifiers.For 15 % training data, the GAN-augmented dataset showedan increased F1-score up to 0.1 and classification accuracy upto 3 %. For 10 % training data, both metrics decreased. We present a deep convolutional GAN capable of creatingsynthetic data for the classification of craniosynostosis. Us-ing a moderate amount of synthetic data using a GAN showedslightly better performance, but had little effect overall. Thesimulated scarcity scenario of 10 % training data may havelimited the model’s ability to learn the underlying data distribution.
Conduction velocity (CV) slowing is associated with atrial fibrillation (AF) and reentrant ventricular tachycardia (VT). Clinical electroanatomical mapping systems used to localize AF or VT sources as ablation targets remain limited by the number of measuring electrodes and signal processing methods to generate high-density local activation time (LAT) and CV maps of heterogeneous atrial or trabeculated ventricular endocardium. The morphology and amplitude of bipolar electrograms depend on the direction of propagating electrical wavefront, making identification of low-amplitude signal sources commonly associated with fibrotic area difficulty. In comparison, unipolar electrograms are not sensitive to wavefront direction, but measurements are susceptible to distal activity. This study proposes a method for local CV calculation from optical mapping measurements, termed the circle method (CM). The local CV is obtained as a weighted sum of CV values calculated along different chords spanning a circle of predefined radius centered at a CV measurement location. As a distinct maximum in LAT differences is along the chord normal to the propagating wavefront, the method is adaptive to the propagating wavefront direction changes, suitable for electrical conductivity characterization of heterogeneous myocardium. In numerical simulations, CM was validated characterizing modeled ablated areas as zones of distinct CV slowing. Experimentally, CM was used to characterize lesions created by radiofrequency ablation (RFA) on isolated hearts of rats, guinea pig, and explanted human hearts. To infer the depth of RFA-created lesions, excitation light bands of different penetration depths were used, and a beat-to-beat CV difference analysis was performed to identify CV alternans. Despite being limited to laboratory research, studies based on CM with optical mapping may lead to new translational insights into better-guided ablation therapies.
Aims Atrial flutter (AFlut) is a common re-entrant atrial tachycardia driven by self-sustainable mechanisms that cause excitations to propagate along pathways different from sinus rhythm. Intra-cardiac electrophysiological mapping and catheter ablation are often performed without detailed prior knowledge of the mechanism perpetuating AFlut, likely prolonging the procedure time of these invasive interventions. We sought to discriminate the AFlut location [cavotricuspid isthmus-dependent (CTI), peri-mitral, and other left atrium (LA) AFlut classes] with a machine learning-based algorithm using only the non-invasive signals from the 12-lead electrocardiogram (ECG). Methods and results Hybrid 12-lead ECG dataset of 1769 signals was used (1424 in silico ECGs, and 345 clinical ECGs from 115 patients—three different ECG segments over time were extracted from each patient corresponding to single AFlut cycles). Seventy-seven features were extracted. A decision tree classifier with a hold-out classification approach was trained, validated, and tested on the dataset randomly split after selecting the most informative features. The clinical test set comprised 38 patients (114 clinical ECGs). The classifier yielded 76.3% accuracy on the clinical test set with a sensitivity of 89.7%, 75.0%, and 64.1% and a positive predictive value of 71.4%, 75.0%, and 86.2% for CTI, peri-mitral, and other LA class, respectively. Considering majority vote of the three segments taken from each patient, the CTI class was correctly classified at 92%. Conclusion Our results show that a machine learning classifier relying only on non-invasive signals can potentially identify the location of AFlut mechanisms. This method could aid in planning and tailoring patient-specific AFlut treatments.
L. Krames, P. Suppa, and W. Nahm. Does the 3D Feature Descriptor Impact The Registration Accuracy in Laparoscopic Liver Surgery?. In Current Directions in Biomedical Engineering, vol. 8(1) , pp. 46-49, 2022
In laparoscopic liver surgery (LLS) image-guidednavigation systems could support the surgeon by providingsubsurface information such as the positions of tumors andvessels. For this purpose, one option is to perform a registra-tion of preoperative 3D data and 3D surface patches recon-structed from laparoscopic images. Part of an automatic 3Dregistration pipeline is the feature description, which takes intoaccount various geometric and spatial information. Since thereis no leading feature descriptor in the field of LLS, two featuredescriptors are compared in this paper: The Fast Point FeatureHistogram (FPFH) and Triple Orthogonal Local Depth Images(TOLDI). To evaluate their performance, three perturbationswere induced: varying surface patch sizes, spatial displace-ment, and Gaussian deformation. Registration was performedusing the RANSAC algorithm. FPFH outperformed TOLDIfor small surface patches and in case of Gaussian deformationsin terms of registration accuracy. In contrast, TOLDI showedlower registration errors for patches with spatial displacement.While developing a 3D-3D registration pipeline, the choice ofthe feature descriptor is of importance, consequently a carefulchoice suitable for the application in LLS is necessary.
Background: Craniosynostosis is a condition caused by the premature fusion of skull sutures, leading to irregular growth patterns of the head. Three-dimensional photogrammetry is a radiation-free alternative to the diagnosis using computed tomography. While statistical shape models have been proposed to quantify head shape, no shape-model-based classification approach has been presented yet. Methods: We present a classification pipeline that enables an automated diagnosis of three types of craniosynostosis. The pipeline is based on a statistical shape model built from photogrammetric surface scans. We made the model and pathology-specific submodels publicly available, making it the first publicly available craniosynostosis-related head model, as well as the first focusing on infants younger than 1.5 years. To the best of our knowledge, we performed the largest classification study for craniosynostosis to date. Results: Our classification approach yields an accuracy of 97.8 %, comparable to other state-of-the-art methods using both computed tomography scans and stereophotogrammetry. Regarding the statistical shape model, we demonstrate that our model performs similar to other statistical shape models of the human head. Conclusion: We present a state-of-the-art shape-model-based classification approach for a radiation-free diagnosis of craniosynostosis. Our publicly available shape model enables the assessment of craniosynostosis on realistic and synthetic data.
Objective: To investigate cardiac activation maps estimated using electrocardiographic imaging and to find methods reducing line-of-block (LoB) artifacts, while preserving real LoBs. Methods: Body surface potentials were computed for 137 simulated ventricular excitations. Subsequently, the inverse problem was solved to obtain extracellular potentials (EP) and transmembrane voltages (TMV). From these, activation times (AT) were estimated using four methods and compared to the ground truth. This process was evaluated with two cardiac mesh resolutions. Factors contributing to LoB artifacts were identified by analyzing the impact of spatial and temporal smoothing on the morphology of source signals. Results: AT estimation using a spatiotemporal derivative performed better than using a temporal derivative. Compared to deflection-based AT estimation, correlation-based methods were less prone to LoB artifacts but performed worse in identifying real LoBs. Temporal smoothing could eliminate artifacts for TMVs but not for EPs, which could be linked to their temporal morphology. TMVs led to more accurate ATs on the septum than EPs. Mesh resolution had a negligible effect on inverse reconstructions, but small distances were important for cross-correlation-based estimation of AT delays. Conclusion: LoB artifacts are mainly caused by the inherent spatial smoothing effect of the inverse reconstruction. Among the configurations evaluated, only deflection-based AT estimation in combination with TMVs and strong temporal smoothing can prevent LoB artifacts, while preserving real LoBs. Significance: Regions of slow conduction are of considerable clinical interest and LoB artifacts observed in non-invasive ATs can lead to misinterpretations. We addressed this problem by identifying factors causing such artifacts and methods to reduce them.
J. Sánchez, and A. Loewe. A Review of Healthy and Fibrotic Myocardium Microstructure Modeling and Corresponding Intracardiac Electrograms. In Frontiers in Physiology, vol. 13, 2022
Computational simulations of cardiac electrophysiology provide detailed information on the depolarization phenomena at different spatial and temporal scales. With the development of new hardware and software, in silico experiments have gained more importance in cardiac electrophysiology research. For plane waves in healthy tissue, in vivo and in silico electrograms at the surface of the tissue demonstrate symmetric morphology and high peak-to-peak amplitude. Simulations provided insight into the factors that alter the morphology and amplitude of the electrograms. The situation is more complex in remodeled tissue with fibrotic infiltrations. Clinically, different changes including fractionation of the signal, extended duration and reduced amplitude have been described. In silico, numerous approaches have been proposed to represent the pathological changes on different spatial and functional scales. Different modeling approaches can reproduce distinct subsets of the clinically observed electrogram phenomena. This review provides an overview of how different modeling approaches to incorporate fibrotic and structural remodeling affect the electrogram and highlights open challenges to be addressed in future research.
Cardiac resynchronization therapy is a valuable tool to restore left ventricular function in patients experiencing dyssynchronous ventricular activation. However, the non-responder rate is still as high as 40%. Recent studies suggest that left ventricular torsion or specifically the lack thereof might be a good predictor for the response of cardiac resynchronization therapy. Since left ventricular torsion is governed by the muscle fiber orientation and the heterogeneous electromechanical activation of the myocardium, understanding the relation between these components and the ability to measure them is vital. To analyze if locally altered electromechanical activation in heart failure patients affects left ventricular torsion, we conducted a simulation study on 27 personalized left ventricular models. Electroanatomical maps and late gadolinium enhanced magnetic resonance imaging data informed our in-silico model cohort. The angle of rotation was evaluated in every material point of the model and averaged values were used to classify the rotation as clockwise or counterclockwise in each segment and sector of the left ventricle. 88% of the patient models (n = 24) were classified as a wringing rotation and 12% (n = 3) as a rigid-body-type rotation. Comparison to classification based on in vivo rotational NOGA XP maps showed no correlation. Thus, isolated changes of the electromechanical activation sequence in the left ventricle are not sufficient to reproduce the rotation pattern changes observed in vivo and suggest that further patho-mechanisms are involved.
C. Nagel, M. Schaufelberger, O. Dössel, and A. Loewe. A Bi-atrial Statistical Shape Model as a Basis to Classify Left Atrial Enlargement from Simulated and Clinical 12-Lead ECGs. In Statistical Atlases and Computational Models of the Heart. Multi-Disease, Multi-View, and Multi-Center Right Ventricular Segmentation in Cardiac MRI Challenge, vol. 13131, pp. 38-47, 2022
Left atrial enlargement (LAE) is one of the risk factors for atrial fibrillation (AF). A non-invasive and automated detection of LAE with the 12-lead electrocardiogram (ECG) could therefore contribute to an improved AF risk stratification and an early detection of new-onset AF incidents. However, one major challenge when applying machine learning techniques to identify and classify cardiac diseases usually lies in the lack of large, reliably labeled and balanced clinical datasets. We therefore examined if the extension of clinical training data by simulated ECGs derived from a novel bi-atrial shape model could improve the automated detection of LAE based on P waves of the 12-lead ECG. We derived 95 volumetric geometries from the bi-atrial statistical shape model with continuously increasing left atrial volumes in the range of 30 ml to 65 ml. Electrophysiological simulations with 10 different conduction velocity settings and 2 different torso models were conducted. Extracting the P waves of the 12-lead ECG thus yielded a synthetic dataset of 1,900 signals. Besides the simulated data, 7,168 healthy and 309 LAE ECGs from a public clinical ECG database were available for training and testing of an LSTM network to identify LAE. The class imbalance of the training data could be reduced from 1:23 to 1:6 when adding simulated data to the training set. The accuracy evaluated on the test dataset comprising a subset of the clinical ECG recordings improved from 0.91 to 0.95 if simulated ECGs were included as an additional input for the training of the classifier. Our results suggest that using a bi-atrial statistical shape model as a basis for ECG simulations can help to overcome the drawbacks of clinical ECG recordings and can thus lead to an improved performance of machine learning classifiers to detect LAE based on the 12-lead ECG.
This reprint showcases a selection of bleeding-edge articles about medical image processing and segmentation workflows based on artificial intelligence algorithms. The proposed papers are applied to multiple and different anatomical districts and clinical scenarios.
Die Vorteile der Datennutzung im Gesundheitswesen sind mittler- weile so offensichtlich, dass es fahrlässig wäre, diese nicht umzu- setzen. Der vorliegende IMPULS will Anstoß für eine sichere und souveräne Nutzung von Gesundheitsdaten geben. Dazu werden Chancen, Hemmnisse sowie Diskussionspunkte und Handlungs- felder aufgezeigt und in Bezug gesetzt zu aktuellen Gesetzesvor- haben in diesem Bereich. Das Papier richtet sich vor allem an politische Entscheidungsträgerinnen und Entscheidungsträger und soll Wege aufzeigen, wie der Datenschatz zum Wohle der Patientinnen und Patienten gehoben werden kann.Aufbauend auf einer Bestandsaufnahme des heutigen Gesund- heitssystems und einer Analyse der bestehenden Hürden und Hindernisse haben wir Handlungsfelder identifiziert, in denen die zuständigen Akteure aktiv werden müssen:Die Datenfreigabe ist die alles entscheidende Grundlage für die Datennutzung. In einem dermaßen komplexen System wie dem Gesundheitswesen reicht eine binäre Entweder-oder-Entscheidung nicht aus; ein abgestuftes, differenziertes Einwilligungsverfahren ist nötig, um einen souveränen Umgang mit den Gesundheitsdaten jeder und jedes Einzelnen zu ermöglichen. Es gibt heute Möglich- keiten, die feingranulare Einwilligung zur Nutzung der Daten so zu gestalten, dass sie relativ schnell und gut informiert durchgeführt werden kann, zum Beispiel mithilfe des Mobiltelefons.Nur Daten mit einer hinreichenden Datenqualität sind für die Nutzung sowohl in der medizinischen Versorgung als auch in Forschung und Entwicklung verwendbar. Daher sind einheitliche Standards und Formate dringend nötig.Alle öffentlichen und privaten Akteure, die Gesundheitsdaten erheben, sollten durch die Datenbereitstellung an gemeinsamen Gesundheitsdatenräumen beteiligt sein. Dabei braucht es neben einer möglichst weitreichenden Veröffentlichung von Daten auch klare Regelungen zum Schutz von geistigem Eigentum und damit der Wettbewerbsfähigkeit der Beteiligten. Zudem müssen neben staatlichen Forschungseinrichtungen wie der Universitäts- medizin auch Unternehmen der Pharma- und der Medizintechnik- branche Zugriff auf die Daten erhalten, damit die Ergebnisse der Forschung bei den Millionen von Patientinnen und Patienten auch tatsächlich ankommen.Die Datenweitergabe sollte im Sinne der Sicherheit soweit möglich in anonymisierter und aggregierter Form erfolgen;gleichzeitig sollten angesichts des potenziellen medizinischen Mehrwerts unter bestimmten Umständen auch eine Nutzung pseudonymisierter und personalisierter Daten möglich sein. Einrichtungen und Unternehmen, die Gesundheitsdaten für die allgemeine Nutzung zur Verfügung stellen, sollten auch einen besseren Zugang zu solchen Daten erhalten. Die Publikation datenbasierter Forschungsergebnisse sollte die Regel sein.Für den Bereich Infrastruktur und Datensicherheit ist darauf zu achten, dass Datengewinnung, Datenbereitstellung und Datenfreigabe konsequent getrennt, also in unterschiedlichen Einrichtungen angesiedelt werden, um Datenmissbrauch so gut wie möglich zu verhindern. Eine schnellere, robuste und sichere Infrastruktur für Gesundheitsdaten ist hierfür Grund- voraussetzung; bei deren Erarbeitung müssen alle Beteiligten konsequent eingebunden werden, auch im Hinblick auf gute Benutzerschnittstellen.Die Datennutzung sollte im Sinne einer Value-based Healthcare erfolgen und den Fokus zudem auch auf präventive Angebote und den Ausbau von telemedizinischen Leistungen legen. Dazu braucht es neue Metriken zur umfassenden Bewertung von Gesundheit und zur Integration neuer Leistungen in die Ver- sorgung.Die digitale Gesundheitskompetenz muss durch Aus- und Weiter- bildung auf allen Ebenen – von den Patientinnen und Patienten über die Ärzteschaft und das Pflegepersonal bis hin zu Presse und anderen Medien – besser werden. Wir benötigen dringend mehr und exzellent ausgebildete IT-Expertinnen und -Experten für den Gesundheitsbereich, zum Beispiel Medical Data Scientists.Die öffentliche Meinungsbildung über das Thema Datennutzung im Gesundheitswesen sollte neben den berechtigten Datenschutz- anliegen auch die Vorteile berücksichtigen und einen öffentlichen Diskurs über Datenschutzmöglichkeiten und den Mehrwert der Datennutzung anregen.Zur Innovationsförderung auf Basis von Datennutzung braucht es einheitliche Rahmenbedingungen auf nationaler und europäischer Ebene, um Rechtssicherheit zu schaffen. Gleich- zeitig müssen datengetriebene Ansätze und neue Diagnose- und Therapiemöglichkeiten, zum Beispiel durch KI, in der Zulassung gleichwertig mit klassischen Verfahren berücksichtigt werdenDigitalisierung und Datennutzung erlauben durch Auto- matisierung und Personalisierung ein nachhaltiges und zu- kunftsfähiges Gesundheitswesen, welches das Patientenwohl ins Zentrum stellt und Gesundheit ganzheitlich betrachtet.
M. Houillon, J. Klar, T. Stary, and A. Loewe. Automated Software Metadata Conversion and Publication Based on CodeMeta. In E-Science-Tage 2023: Empower Your Research – Preserve Your Data, heiBOOKS, pp. 228-234, 2023
J. Steyer, L. P. M. Diaz, L. A. Unger, and A. Loewe. Simulated Excitation Patterns in the Atria and Their Corresponding Electrograms. In Functional Imaging and Modeling of the Heart, Springer Nature Switzerland, Cham, pp. 204-212, 2023
UNLABELLED: Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir: (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44231-022-00021-4.
A. Loewe, G. Luongo, and J. Sánchez. Machine Learning for Clinical Electrophysiology. In Innovative Treatment Strategies for Clinical Electrophysiology, Springer Nature Singapore, Singapore, pp. 93-109, 2022