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Abstract Atrial fibrillation (AF) is the most common human arrhythmia, forming thrombi mostly in the left atrial appendage (LAA). However, the relation between LAA morphology, blood patterns and clot formation is not yet fully understood. Furthermore, the impact of anatomical structures like the pulmonary veins (PVs) have not been thoroughly studied due to data acquisition difficulties. In-silico studies with flow simulations provide a detailed analysis of blood flow patterns under different boundary conditions, but a limited number of cases have been reported in the literature. To address these gaps, we investigated the influence of PVs on LA blood flow patterns and thrombus formation risk through computational fluid dynamics simulations conducted on a sizeable cohort of 130 patients, establishing the largest cohort of patient-specific LA fluid simulations reported to date. The investigation encompassed an in-depth analysis of several parameters, including pulmonary vein orientation (e.g., angles) and configuration (e.g., number), LAA and LA volumes as well as their ratio, flow, and mass-less particles. Our findings highlight the total number of particles within the LAA as a key parameter for distinguishing between the thrombus and non-thrombus groups. Moreover, the angles between the different PVs play an important role to determine the flow going inside the LAA and consequently the risk of thrombus formation. The alignment between the LAA and the main direction of the left superior pulmonary vein, or the position of the right pulmonary vein when it exhibits greater inclination, had an impact to distinguish the control group vs. the thrombus group. These insights shed light on the intricate relationship between PV configuration, LAA morphology, and thrombus formation, underscoring the importance of comprehensive blood flow pattern analyses.

IntroductionExtracting beat-by-beat information from electrocardiograms (ECGs) is crucial for various downstream diagnostic tasks that rely on ECG-based measurements. However, these measurements can be expensive and time-consuming to produce, especially for long-term recordings. Traditional ECG detection and delineation methods, relying on classical signal processing algorithms such as those based on wavelet transforms, produce high-quality delineations but struggle to generalise to diverse ECG patterns. Machine learning (ML) techniques based on deep learning algorithms have emerged as promising alternatives, capable of achieving similar performance without handcrafted features or thresholds. However, supervised ML techniques require large annotated datasets for training, and existing datasets for ECG detection/delineation are limited in size and the range of pathological conditions they represent.MethodsThis article addresses this challenge by introducing two key innovations. First, we develop a synthetic data generation scheme that probabilistically constructs unseen ECG traces from “pools” of fundamental segments extracted from existing databases. A set of rules guides the arrangement of these segments into coherent synthetic traces, while expert domain knowledge ensures the realism of the generated traces, increasing the input variability for training the model. Second, we propose two novel segmentation-based loss functions that encourage the accurate prediction of the number of independent ECG structures and promote tighter segmentation boundaries by focusing on a reduced number of samples.ResultsThe proposed approach achieves remarkable performance, with a F1-score of 99.38% and delineation errors of 2.19±17.73 ms and 4.45±18.32 ms for ECG segment onsets and offsets across the P, QRS, and T waves. These results, aggregated from three diverse freely available databases (QT, LU, and Zhejiang), surpass current state-of-the-art detection and delineation approaches.DiscussionNotably, the model demonstrated exceptional performance despite variations in lead configurations, sampling frequencies, and represented pathophysiology mechanisms, underscoring its robust generalisation capabilities. Real-world examples, featuring clinical data with various pathologies, illustrate the potential of our approach to streamline ECG analysis across different medical settings, fostered by releasing the codes as open source.

Cardiac arrhythmias cause depolarization waves to conduct unevenly on the myocardial surface, potentially delaying local components with respect to a previous beat when stimulated at faster frequencies. Despite the diagnostic value of localizing the distinct local electrocardiogram (EGM) components for identifying regions with decrement-evoked potentials (DEEPs), current software solutions do not perform automatic signal quantification. Electrophysiologists must manually measure distances on the EGM signals to assess the existence of DEEPs during pacing or extra-stimuli protocols. In this work, we present a deep learning (DL)-based algorithm to identify decrement in atrial components (measured in the coronary sinus) with respect to their ventricular counterparts from EGM signals, for disambiguating between accessory pathways (APs) and atrioventricular re-entrant tachycardias (AVRTs). Several U-Net and W-Net neural networks with different configurations were trained on a private dataset of signals from the coronary sinus (312 EGM recordings from 77 patients who underwent AP or AVRT ablation). A second, separate dataset was annotated for clinical validation, with clinical labels associated to EGM fragments in which decremental conduction was elucidated. To alleviate data scarcity, a synthetic data augmentation method was developed for generating EGM recordings. Moreover, two novel loss functions were developed to minimize false negatives and delineation errors. Finally, the addition of self-attention mechanisms and their effect on model performance was explored. The best performing model was a W-Net model with 6 levels, optimized solely with the Dice loss. The model obtained precisions of 91.28%, 77.78% and of 100.0%, and recalls of 94.86%, 95.25% and 100.0% for localizing local field, far field activations, and extra-stimuli, respectively. The clinical validation model demonstrated good overall agreement with respect to the evaluation of decremental properties. When compared to the criteria of electrophysiologists, the automatic exclusion step reached a sensitivity of 87.06% and a specificity of 97.03%. Out of the non-excluded signals, a sensitivity of 96.77% and a specificity of 95.24% was obtained for classifying them into decremental and non-decremental potentials. Current results show great promise while being, to the best of our knowledge, the first tool in the literature allowing the delineation of all local components present in an EGM recording. This is of capital importance at advancing processing for cardiac electrophysiological procedures and reducing intervention times, as many diagnosis procedures are performed by comparing segments or late potentials in subsequent cardiac cycles.

The treatment of outflow tract ventricular arrhythmias (OTVA) through radiofrequency ablation requires the precise identification of the site of origin (SOO). Pinpointing the SOO enhances the likelihood of a successful procedure, reducing intervention times and recurrence rates. Current clinical methods to identify the SOO are based on qualitative analysis of pre-operative electrocardiograms (ECG), heavily relying on physician’s expertise. Although computational models and machine learning (ML) approaches have been proposed to assist OTVA procedures, they either consume substantial time, lack interpretability or do not use clinical information. Here, we propose an alternative strategy for automatically predicting the ventricular origin of OTVA patients using ML. Our objective was to classify ventricular (left/right) origin in the outflow tracts (LVOT and RVOT, respectively), integrating ECG and clinical data from each patient. Extending beyond differentiating ventricle origin, we explored specific SOO characterization. Utilizing four databases, we also trained supervised learning models on the QRS complexes of the ECGs, clinical data, and their combinations. The best model achieved an accuracy of 89%, highlighting the significance of precordial leads V1-V4, especially in the R/S transition and initiation of the QRS complex in V2. Unsupervised analysis revealed that some origins tended to group closer than others, e.g., right coronary cusp (RCC) with a less sparse group than the aortic cusp origins, suggesting identifiable patterns for specific SOOs.

Segmentation of the left ventricle (LV) in echocardiography is an important task for the quantification of volume and mass in heart disease. Continuing advances in echocardiography have extended imaging capabilities into the 3D domain, subsequently overcoming the geometric assumptions associated with conventional 2D acquisitions. Nevertheless, the analysis of 3D echocardiography (3DE) poses several challenges associated with limited spatial resolution, poor contrast-to-noise ratio, complex noise characteristics, and image anisotropy. To develop automated methods for 3DE analysis, a sufficiently large, labeled dataset is typically required. However, ground truth segmentations have historically been difficult to obtain due to the high inter-observer variability associated with manual analysis. We address this lack of expert consensus by registering labels derived from higher-resolution subject-specific cardiac magnetic resonance (CMR) images, producing 536 annotated 3DE images from 143 human subjects (10 of which were excluded). This heterogeneous population consists of healthy controls and patients with cardiac disease, across a range of demographics. To demonstrate the utility of such a dataset, a state-of-the-art, self-configuring deep learning network for semantic segmentation was employed for automated 3DE analysis. Using the proposed dataset for training, the network produced measurement biases of −9 ± 16 ml, −1 ± 10 ml, −2 ± 5 %, and 5 ± 23 g, for end-diastolic volume, end-systolic volume, ejection fraction, and mass, respectively, outperforming an expert human observer in terms of accuracy as well as scan-rescan reproducibility. As part of the Cardiac Atlas Project, we present here a large, publicly available 3DE dataset with ground truth labels that leverage the higher resolution and contrast of CMR, to provide a new benchmark for automated 3DE analysis. Such an approach not only reduces the effect of observer-specific bias present in manual 3DE annotations, but also enables the development of analysis techniques which exhibit better agreement with CMR compared to conventional methods. This represents an important step for enabling more efficient and accurate diagnostic and prognostic information to be obtained from echocardiography.

RESUMEN Introducción y objetivos: El cierre de la orejuela izquierda (COI) puede ser una alternativa de tratamiento eficaz para prevenir eventos cardiovasculares en pacientes con fibrilación auricular, en especial en aquellos con alto riesgo de sangrado. Sin embargo, algunos de estos pacientes en los que se realiza COI desarrollan trombosis relacionada con el dispositivo (TRD). Este estudio presenta las características del flujo sanguíneo que son clave en la formación de TDR, a partir de simulaciones personalizadas para cada paciente. Métodos: Para crear las simulaciones personalizadas se incluyeron en el estudio pacientes intervenidos de COI entre 2014 y 2019 en un único centro, de quienes se disponía de imágenes de tomografía computarizada previas al procedimiento y de seguimiento, así como de control ecocardiográfico. Para el COI se utilizaron los dispositivos Amulet. Las simulaciones se analizaron de forma ciega al diagnóstico de TRD. Resultados: En total se estudiaron 6 pacientes, de los que la mitad presentaban TRD según las imágenes del seguimiento clínico. Tras analizar los resultados de las simulaciones, los índices hemodinámicos asociados con TRD fueron la presencia de flujo estancado, las recirculaciones de sangre a velocidades bajas (< 0,20 m/s) cerca de la superficie del dispositivo y las regiones con alta complejidad de flujo y baja tensión de cizallamiento en la pared. Conclusiones: Las simulaciones de flujo personalizadas en pacientes con COI predijeron correctamente el diagnóstico clínico de TRD en todos los casos analizados. Los resultados obtenidos demuestran el potencial de los modelos personalizados para recomendar configuraciones óptimas del dispositivo y minimizar el riesgo de TRD.

ABSTRACT Introduction and objectives: Left atrial appendage occlusion (LAAO) can be an efficient treatment to prevent strokes in patients who suffer from atrial fibrillation, especially those at risk of bleeding. A non-negligible number of patients treated with LAAO develop device-related thrombosis (DRT) after device implantation. Our study aimed to identify the key blood flow characteristics leading to DRT using patient-specific flow simulations. Methods: Patients treated with LAAO between 2014 and 2019 at a single center with preoperative and follow-up computerized tomography images and ultrasound imaging (US) were used to create patient-specific flow simulations. Amulet LAAO devices were implanted in the study patients. Flow simulations were blindly assessed to discard the presence of DRT in the follow-up imaging. Results: A total of 6 patients were processed in this pivotal study, half of them with DRT at the follow-up according to the imaging analysis. After a comprehensive analysis of the simulations, the most relevant in silico indices associated with DRT were the presence of stagnant blood flow, recirculation with low flow velocities (< 0.20 m/s) next to the device surface, and regions with high flow complexity combined with low wall shear stress. Conclusions: Patient-specific flow simulations of LAAO were successfully used to predict blood flow patterns with different device configurations. The results show the potential of the present modelling and simulation approach to recommend optimal settings capable of minimizing the risk of DRT.

In order to determine the site of origin (SOO) in outflow tract ventricular arrhythmias (OTVAs) before an ablation procedure, several algorithms based on manual identification of electrocardiogram (ECG) features, have been developed. However, the reported accuracy decreases when tested with different datasets. Machine learning algorithms can automatize the process and improve generalization, but their performance is hampered by the lack of large enough OTVA databases. We propose the use of detailed electrophysiological simulations of OTVAs to train a machine learning classification model to predict the ventricular origin of the SOO of ectopic beats. We generated a synthetic database of 12-lead ECGs (2,496 signals) by running multiple simulations from the most typical OTVA SOO in 16 patient-specific geometries. Two types of input data were considered in the classification, raw and feature ECG signals. From the simulated raw 12-lead ECG, we analyzed the contribution of each lead in the predictions, keeping the best ones for the training process. For feature-based analysis, we used entropy-based methods to rank the obtained features. A cross-validation process was included to evaluate the machine learning model. Following, two clinical OTVA databases from different hospitals, including ECGs from 365 patients, were used as test-sets to assess the generalization of the proposed approach. The results show that V2 was the best lead for classification. Prediction of the SOO in OTVA, using both raw signals or features for classification, presented high accuracy values (>0.96). Generalization of the network trained on simulated data was good for both patient datasets (accuracy of 0.86 and 0.84, respectively) and presented better values than using exclusively real ECGs for classification (accuracy of 0.84 and 0.76 for each dataset). The use of simulated ECG data for training machine learning-based classification algorithms is critical to obtain good SOO predictions in OTVA compared to real data alone. The fast implementation and generalization of the proposed methodology may contribute towards its application to a clinical routine.

Abstract Detection and delineation are key steps for retrieving and structuring information of the electrocardiogram (ECG), being thus crucial for numerous tasks in clinical practice. Digital signal processing (DSP) algorithms are often considered state-of-the-art for this purpose but require laborious rule readaptation for adapting to unseen morphologies. This work explores the adaptation of the the U-Net, a deep learning (DL) network employed for image segmentation, to electrocardiographic data. The model was trained using PhysioNet’s QT database, a small dataset of 105 2-lead ambulatory recordings, while being independently tested for many architectural variations, comprising changes in the model’s capacity (depth, width) and inference strategy (single- and multi-lead) in a fivefold cross-validation manner. This work features several regularization techniques to alleviate data scarcity, such as semi-supervised pre-training with low-quality data labels, performing ECG-based data augmentation and applying in-built model regularizers. The best performing configuration reached precisions of 90.12%, 99.14% and 98.25% and recalls of 98.73%, 99.94% and 99.88% for the P, QRS and T waves, respectively, on par with DSP-based approaches. Despite being a data-hungry technique trained on a small dataset, a U-Net based approach demonstrates to be a viable alternative for this task.

Purpose While the standard setting during radiofrequency catheter ablation (RFCA) consists of applying low power for long times, a new setting based on high power and short duration (HPSD) has recently been suggested as safer and more effective. Our aim was to compare the electrical and thermal performance of standard vs. HPSD settings, especially to assess the effect of the catheter orientation. Methods A 3D computational model was built based on a coupled electric-thermal-flow problem. Standard (20 W–45 s and 30 W–30 s) and HPSD settings (70 W–7 s and 90 W–4 s) were compared. Since the model only included a cardiac tissue fragment, the power values were adjusted to 80% of the clinical values (15, 23, 53 and 69 W). Three catheter-tissue orientations were considered (90°, 45° and 0°). Thermal lesions were assessed by the Arrhenius equation. Safety was assessed by checking the occurrence of steam pops (100 °C in tissue) and thrombus formation (80 °C in blood). Results The computed thermal lesions were in close agreement with the experimental data in the literature, in particular with in vivo studies. HPSD created shallower and wider lesions than standard settings, especially with the catheter at 45°. Steam pops occurred earlier with HPSD, regardless of catheter orientation. Conclusion HPSD seems to be more effective in cases that need shallow and extensive lesions, especially when the catheter is at 0° or at 45°, as used in pulmonary vein isolation.

The use of multi-site datasets in neuroimaging provides neuroscientists with more statistical power to perform their analyses. However, it has been shown that the imaging-site introduces variability in the data that cannot be attributed to biological sources. In this work, we show that functional connectivity matrices derived from resting-state multi-site data contain a significant imaging-site bias. To this aim, we exploited the fact that functional connectivity matrices belong to the manifold of symmetric positive-definite (SPD) matrices, making it possible to operate on them with Riemannian geometry. We hereby propose a geometry-aware harmonization approach, Rigid Log-Euclidean Translation, that accounts for this site bias. Moreover, we adapted other Riemannian-geometric methods designed for other domain adaptation tasks and compared them to our proposal. Based on our results, Rigid Log-Euclidean Translation of multi-site functional connectivity matrices seems to be among the studied methods the most suitable in a clinical setting. This represents an advance with respect to previous functional connectivity data harmonization approaches, which do not respect the geometric constraints imposed by the underlying structure of the manifold. In particular, when applying our proposed method to data from the ADHD-200 dataset, a multi-site dataset built for the study of attention-deficit/hyperactivity disorder, we obtained results that display a remarkable correlation with established pathophysiological findings and, therefore, represent a substantial improvement when compared to the non-harmonization analysis. Thus, we present evidence supporting that harmonization should be extended to other functional neuroimaging datasets and provide a simple geometric method to address it.

Background: Optic neuritis (ON) is one of the first manifestations of multiple sclerosis, a disabling disease with rising prevalence. Detecting optic nerve lesions could be a relevant diagnostic marker in patients with multiple sclerosis. Objectives: We aim to create an automated, interpretable method for optic nerve lesion detection from MRI scans. Materials and Methods: We present a 3D convolutional neural network (CNN) model that learns to detect optic nerve lesions based on T2-weighted fat-saturated MRI scans. We validated our system on two different datasets (N = 107 and 62) and interpreted the behaviour of the model using saliency maps. Results: The model showed good performance (68.11% balanced accuracy) that generalizes to unseen data (64.11%). The developed network focuses its attention to the areas that correspond to lesions in the optic nerve. Conclusions: The method shows robustness and, when using only a single imaging sequence, its performance is not far from diagnosis by trained radiologists with the same constraint. Given its speed and performance, the developed methodology could serve as a first step to develop methods that could be translated into a clinical setting.

The use of machine learning (ML) approaches to target clinical problems is called to revolutionize clinical decision-making in cardiology. The success of these tools is dependent on the understanding of the intrinsic processes being used during the conventional pathway by which clinicians make decisions. In a parallelism with this pathway, ML can have an impact at four levels: for data acquisition, predominantly by extracting standardized, high-quality information with the smallest possible learning curve; for feature extraction, by discharging healthcare practitioners from performing tedious measurements on raw data; for interpretation, by digesting complex, heterogeneous data in order to augment the understanding of the patient status; and for decision support, by leveraging the previous steps to predict clinical outcomes, response to treatment or to recommend a specific intervention. This paper discusses the state-of-the-art, as well as the current clinical status and challenges associated with the two later tasks of interpretation and decision support, together with the challenges related to the learning process, the auditability/traceability, the system infrastructure and the integration within clinical processes in cardiovascular imaging.

The human brain develops from a smooth cortical surface in early stages of fetal life to a convoluted one postnatally, creating an organized ensemble of folds. Abnormal folding patterns are linked to neurodevelopmental disorders. However, the complex multi-scale interactions involved in cortical folding are not fully known yet. Computational models of brain development have contributed to better understand the process of cortical folding, but still leave several questions unanswered. A major limitation of the existing models is that they have basically been applied to synthetic examples or simplified brain anatomies. However, the integration of patient-specific longitudinal imaging data is key for improving the realism of simulations. In this work we present a complete computational pipeline to build and validate patient-specific mechanical models of brain development. Starting from the processing of fetal brain magnetic resonance images (MRI), personalised finite-element 3D meshes were generated, in which biomechanical models were run to simulate brain development. Several metrics were then employed to compare simulation results with neonatal images from the same subjects, on a common reference space. We applied the computational pipeline to a cohort of 29 subjects where fetal and neonatal MRI were available, including controls and ventriculomegaly cases. The neonatal brain simulations had several sulcal patterns similar to the ones observed in neonatal MRI data. However, the pipeline also revealed some limitations of the evaluated mechanical model and the importance of including patient-specific cortical thickness as well as regional and anisotropic growth to obtain more realistic and personalised brain development models. Statement of Significance: Computational modelling has emerged as a powerful tool to study the complex process of brain development during gestation. However, most of the studies performed so far have been carried out in synthetic or two-dimensional geometries due to the difficulties involved in processing real fetal data. Moreover, as there is no correspondence between meshes, comparing them or assessing whether they are realistic or not is not a trivial task. In this work we present a complete computational pipeline to build and validate patient-specific mechanical models of brain development, mainly based on open-source tools.

Background. Atrial fibrillation (AF) is considered the most common human arrhythmia. In nonvalvular AF, around 99% of thrombi are formed in the left atrial appendage (LAA). Nevertheless, there is not a consensus in the community about the relevant factors to stratify the AF population according to thrombogenic risk. Objective. To demonstrate the need for combining left atrial morphological and haemodynamics indices to improve the thrombogenic risk assessment in nonvalvular AF patients. Methods. A cohort of 71 nonvalvular AF patients was analysed. Statistical analysis, regression models, and random forests were used to analyse the differences between morphological and haemodynamics parameters, extracted from computational simulations built on 3D rotational angiography images, between patients with and without transient ischemic attack (TIA) or cerebrovascular accident (CVA). Results. The analysis showed that models composed of both morphological and haemodynamic factors were better predictors of TIA/CVA compared with models based on either morphological or haemodynamic factors separately. Maximum ostium diameter, length of the centreline, blood flow velocity within the LAA, oscillatory shear index, and time average wall shear stress parameters were found to be key risk factors for TIA/CVA prediction. In addition, TIA/CVA patients presented more flow stagnation within the LAA. Conclusion. Thrombus formation in the LAA is the result of multiple factors. Analyses based only on morphological or haemodynamic parameters are not precise enough to predict such a phenomenon, as demonstrated in our results; a better patient stratification can be obtained by jointly analysing morphological and haemodynamic features.

Patient-specific computational fluid dynamics (CFD) simulations can provide invaluable insight into the interaction of left atrial appendage (LAA) morphology, hemodynamics, and the formation of thrombi in atrial fibrillation (AF) patients. Nonetheless, CFD solvers are notoriously time-consuming and computationally demanding, which has sparked an ever-growing body of literature aiming to develop surrogate models of fluid simulations based on neural networks. The present study aims at developing a deep learning (DL) framework capable of predicting the endothelial cell activation potential (ECAP), an in-silico index linked to the risk of thrombosis, typically derived from CFD simulations, solely from the patient-specific LAA morphology. To this end, a set of popular DL approaches were evaluated, including fully connected networks (FCN), convolutional neural networks (CNN), and geometric deep learning. While the latter directly operated over non-Euclidean domains, the FCN and CNN approaches required previous registration or 2D mapping of the input LAA mesh. First, the superior performance of the graph-based DL model was demonstrated in a dataset consisting of 256 synthetic and real LAA, where CFD simulations with simplified boundary conditions were run. Subsequently, the adaptability of the geometric DL model was further proven in a more realistic dataset of 114 cases, which included the complete patient-specific LA and CFD simulations with more complex boundary conditions. The resulting DL framework successfully predicted the overall distribution of the ECAP in both datasets, based solely on anatomical features, while reducing computational times by orders of magnitude compared to conventional CFD solvers.

Purpose: Although experimental data have suggested that temporary occlusion of the coronary sinus (CS) can facilitate the creation of transmural lesions across the atrial wall (AW) during mitral isthmus radiofrequency (RF) ablation, no computer modeling study has yet been made on the effect of the blood flow inside the epicardial vessels and its stoppage by an occlusion balloon. Methods: Computer simulations using constant power were conducted to study these phenomena by two methods: (1) by setting blood velocity in the CS to zero, which mimics a distal occlusion; and (2) by including a balloon filled with air in the model just below the ablation site, which mimics a proximal occlusion. Results: For short ablations (15 s) and perpendicular electrode/tissue orientation, lesion size was smaller with proximal occlusion compared to distal or no occlusion, regardless of the AW-CS distance (from 0.5 mm to 3.4 mm). For other angulations (0 and 45°) lesion size was almost the same in all cases. For longer ablations (60 s), the internal CS blood flow (no occlusion) considerably reduced lesion size, while stoppage combined with the proximal presence of a balloon produced the largest lesions. This performance was similar for different catheter angulations (0, 45 and 90°). Balloon length (from 10 to 40 mm) was found to be an irrelevant parameter when proximal occlusion was modeled. Conclusions: Using an air-filled balloon to occlude CS facilitates mitral isthmus ablation in long ablations, while proximal occlusion could impede transmural lesions in the case of short ablations (15 s).

Computational models of cardiac electrophysiology are promising tools for reducing the rates of non-response patients suitable for cardiac resynchronization therapy (CRT) by optimizing electrode placement. The majority of computational models in the literature are mesh-based, primarily using the finite element method (FEM). The generation of patient-specific cardiac meshes has traditionally been a tedious task requiring manual intervention and hindering the modeling of a large number of cases. Meshless models can be a valid alternative due to their mesh quality independence. The organization of challenges such as the CRT-EPiggy19, providing unique experimental data as open access, enables benchmarking analysis of different cardiac computational modeling solutions with quantitative metrics. We present a benchmark analysis of a meshless-based method with finite-element methods for the prediction of cardiac electrical patterns in CRT, based on a subset of the CRT-EPiggy19 dataset. A data assimilation strategy was designed to personalize the most relevant parameters of the electrophysiological simulations and identify the optimal CRT lead configuration. The simulation results obtained with the meshless model were equivalent to FEM, with the most relevant aspect for accurate CRT predictions being the parameter personalization strategy (e.g., regional conduction velocity distribution, including the Purkinje system and CRT lead distribution).

Cardiovascular magnetic resonance (CMR) radiomics is a novel technique for advanced cardiac image phenotyping by analyzing multiple quantifiers of shape and tissue texture. In this paper, we assess, in the largest sample published to date, the performance of CMR radiomics models for identifying changes in cardiac structure and tissue texture due to cardiovascular risk factors. We evaluated five risk factor groups from the first 5,065 UK Biobank participants: hypertension (n = 1,394), diabetes (n = 243), high cholesterol (n = 779), current smoker (n = 320), and previous smoker (n = 1,394). Each group was randomly matched with an equal number of healthy comparators (without known cardiovascular disease or risk factors). Radiomics analysis was applied to short axis images of the left and right ventricles at end-diastole and end-systole, yielding a total of 684 features per study. Sequential forward feature selection in combination with machine learning (ML) algorithms (support vector machine, random forest, and logistic regression) were used to build radiomics signatures for each specific risk group. We evaluated the degree of separation achieved by the identified radiomics signatures using area under curve (AUC), receiver operating characteristic (ROC), and statistical testing. Logistic regression with L1-regularization was the optimal ML model. Compared to conventional imaging indices, radiomics signatures improved the discrimination of risk factor vs. healthy subgroups as assessed by AUC [diabetes: 0.80 vs. 0.70, hypertension: 0.72 vs. 0.69, high cholesterol: 0.71 vs. 0.65, current smoker: 0.68 vs. 0.65, previous smoker: 0.63 vs. 0.60]. Furthermore, we considered clinical interpretation of risk-specific radiomics signatures. For hypertensive individuals and previous smokers, the surface area to volume ratio was smaller in the risk factor vs. healthy subjects; perhaps reflecting a pattern of global concentric hypertrophy in these conditions. In the diabetes subgroup, the most discriminatory radiomics feature was the median intensity of the myocardium at end-systole, which suggests a global alteration at the myocardial tissue level. This study confirms the feasibility and potential of CMR radiomics for deeper image phenotyping of cardiovascular health and disease. We demonstrate such analysis may have utility beyond conventional CMR metrics for improved detection and understanding of the early effects of cardiovascular risk factors on cardiac structure and tissue.

Background. Voltage mapping allows identifying the arrhythmogenic substrate during scar-related ventricular arrhythmia (VA) ablation procedures. Slow conducting channels (SCCs), defined by the presence of electrogram (EGM) signals with delayed components (EGM-DC), are responsible for sustaining VAs and constitute potential ablation targets. However, voltage mapping, as it is currently performed, is time-consuming, requiring a manual analysis of all EGMs to detect SCCs, and its accuracy is limited by electric far-field. We sought to evaluate an algorithm that automatically identifies EGM-DC, classifies mapping points, and creates new voltage maps, named “Slow Conducting Channel Maps” (SCC-Maps). Methods. Retrospective analysis of electroanatomic maps (EAM) from 20 patients (10 ischemic, 10 with arrhythmogenic right ventricular dysplasia/cardiomyopathy) was performed. EAM voltage maps were acquired during sinus rhythm and used for ablation. Preprocedural contrast-enhanced cardiac magnetic resonance (Ce-CMR) imaging was available for the ischemic population. Three mapping modalities were analysed: (i) EAM voltage maps using standard (EAM standard) or manual (EAM screening) thresholds for defining core and border zones; (ii) SCC-Maps derived from the use of the novel SCC-Mapping algorithm that automatically identify EGM-DCs measuring the voltage of the local component; and (iii) Ce-CMR maps (when available). The ability of each mapping modality in identifying SCCs and their agreement was evaluated. Results. SCC-Maps and EAM screening identified a greater number of SCC entrances than EAM standard (3.45 ± 1.61 and 2.95 ± 2.31, resp., vs. 1.05 ± 1.10; p

Abstract Background Cardiovascular magnetic resonance (CMR) imaging has been used to visualise post-ablation atrial scar (PAAS), generally employing a three-dimensional (3D) late gadolinium enhancement (LGE) technique. However the reproducibility of PAAS imaging has not been determined. This cross-over study is the first to investigate the reproducibility of the technique, crucial for both future research design and clinical implementation. Methods Forty subjects undergoing first time ablation for atrial fibrillation (AF) had detailed CMR assessment of PAAS. Following baseline pre-ablation scan, two scans (separated by 48 h) were performed at three months post-ablation. Each scan session included 3D LGE acquisition at 10, 20 and 30 min post administration of gadolinium-based contrast agent (GBCA). Subjects were allocated at second scan post-ablation to identical imaging parameters (‘Repro’, n = 10), 3 T scanner (‘3 T’, n = 10), half-slice thickness (‘Half-slice’, n = 10) or half GBCA dose (‘Half-gad’, n = 10). PAAS was compared to baseline scar and then reproducibility was assessed for two measures of thresholded scar (% left atrial (LA) occupied by PAAS (%LA PAAS) and Pulmonary Vein Encirclement (PVE)), and then four measures of non-thresholded scar (point-by-point assessment of PAAS, four normalisation methods). Thresholded measures of PAAS were evaluated against procedural outcome (AF recurrence). Results A total of 271 3D acquisitions (out of maximum 280, 96.7%) were acquired. At 20 and 30 min, inter-scan reproducibility was good to excellent (coefficient of variation at 20 min and 30 min: %LA PAAS 0.41 and 0.20; PVE 0.13 and 0.04 respectively for ‘Repro’ group). Changes in imaging parameters, especially reduced GBCA dose, reduced inter-scan reproducibility, but for most measures remained good to excellent (ICC for %LA PAAS 0.454–0.825, PVE 0.618–0.809 at 30 min). For non-thresholded scar, highest reproducibility was observed using blood pool z-score normalisation technique: inter-scan ICC 0.759 (absolute agreement, ‘Repro’ group). There was no significant relationship between indices of PAAS and AF recurrence. Conclusion PAAS imaging is a reproducible finding. Imaging should be performed at least 20 min post-GBCA injection, and a blood pool z-score should be considered for normalisation of signal intensities. The clinical implications of these findings remain to be established in the absence of a simple correlation with arrhythmia outcome. Trial registration United Kingdom National Research Ethics Service 08/H0802/68 – 30th September 2008.

Atrial fibrillation (AF) is nowadays the most common human arrhythmia and it is considered a marker of an increased risk of embolic stroke. It is known that 99% of AF-related thrombi are generated in the left atrial appendage (LAA), an anatomical structure located within the left atrium (LA). Left atrial appendage occlusion (LAAO) has become a good alternative for nonvalvular AF patients with contraindications to anticoagulants. However, there is a non-negligible number of device-related thrombus (DRT) events, created next to the device surface. In silico fluid simulations can be a powerful tool to better understand the relation between LA anatomy, haemodynamics, and the process of thrombus formation. Despite the increasing literature in LA fluid modelling, a consensus has not been reached yet in the community on the optimal modelling choices and boundary conditions for generating realistic simulations. In this line, we have performed a sensitivity analysis of several boundary conditions scenarios, varying inlet/outlet and LA wall movement configurations, using patient-specific imaging data of six LAAO patients (three of them with DRT at follow-up). Mesh and cardiac cycle convergence were also analysed. The boundary conditions scenario that better predicted DRT cases had echocardiography-based velocities at the mitral valve outlet, a generic pressure wave from an AF patient at the pulmonary vein inlets, and a dynamic mesh approach for LA wall deformation, emphasizing the need for patient-specific data for realistic simulations. The obtained promising results need to be further validated with larger cohorts, ideally with ground truth data, but they already offer unique insights on thrombogenic risk in the left atria.

Electro-anatomical maps (EAMs) are commonly acquired in clinical routine for guiding ablation therapies. They provide voltage and activation time information on a 3-D anatomical mesh representation, making them useful for analyzing the electrical activation patterns in specific pathologies. However, the variability between the different acquisitions and anatomies hampers the comparison between different maps. This paper presents two contributions for the analysis of electrical patterns in EAM data from biventricular surfaces of cardiac chambers. The first contribution is an integrated automatic 2-D disk representation (2-D bull's eye plot) of the left ventricle (LV) and right ventricle (RV) obtained with a quasi-conformal mapping from the 3-D EAM meshes, that allows an analysis of cardiac resynchronization therapy (CRT) lead positioning, interpretation of global (total activation time), and local indices (local activation time (LAT), surrogates of conduction velocity, inter-ventricular, and transmural delays) that characterize changes in the electrical activation pattern. The second contribution is a set of indices derived from the electrical activation: speed maps, computed from LAT values, to study the electrical wave propagation, and histograms of isochrones to analyze regional electrical heterogeneities in the ventricles. We have applied the proposed methods to look for the underlying physiological mechanisms of left bundle branch block (LBBB) and CRT, with the goal of optimizing the therapy by improving CRT response. To better illustrate the benefits of the proposed tools, we created a set of synthetically generated and fully controlled activation patterns, where the proposed representation and indices were validated. Then, the proposed analysis tools are used to analyze EAM data from an experimental swine model of induced LBBB with an implanted CRT device. We have analyzed and compared the electrical activation patterns at baseline, LBBB, and CRT stages in four animals: two without any structural disease and two with an induced infarction. By relating the CRT lead location with electrical dyssynchrony, we evaluated current hypotheses about lead placement in CRT and showed that optimal pacing sites should target the RV lead close to the apex and the LV one distant from it.

According to clinical studies, around one third of patients with atrial fibrillation (AF) will suffer a stroke during their lifetime. Between 70 and 90% of these strokes are caused by thrombus formed in the left atrial appendage. In patients with contraindications to oral anticoagulants, a left atrial appendage occluder (LAAO) is often implanted to prevent blood flow entering in the LAA. A limited range of LAAO devices is available, with different designs and sizes. Together with the heterogeneity of LAA morphology, these factors make LAAO success dependent on clinician's experience. A sub-optimal LAAO implantation can generate thrombi outside the device, eventually leading to stroke if not treated. The aim of this study was to develop clinician-friendly tools based on biophysical models to optimize LAAO device therapies. A web-based 3D interactive virtual implantation platform, so-called VIDAA, was created to select the most appropriate LAAO configurations (type of device, size, landing zone) for a given patient-specific LAA morphology. An initial LAAO configuration is proposed in VIDAA, automatically computed from LAA shape features (centreline, diameters). The most promising LAAO settings and LAA geometries were exported from VIDAA to build volumetric meshes and run Computational Fluid Dynamics (CFD) simulations to assess blood flow patterns after implantation. Risk of thrombus formation was estimated from the simulated hemodynamics with an index combining information from blood flow velocity and complexity. The combination of the VIDAA platform with in silico indices allowed to identify the LAAO configurations associated to a lower risk of thrombus formation; device positioning was key to the creation of regions with turbulent flows after implantation. Our results demonstrate the potential for optimizing LAAO therapy settings during pre-implant planning based on modeling tools and contribute to reduce the risk of thrombus formation after treatment.

Experimental studies on isolated cardiomyocytes from different animal species and human hearts have demonstrated that there are regional differences in the Ca2+ release, Ca2+ decay and sarcomere deformation. Local deformation heterogeneities can occur due to a combination of factors: regional/local differences in Ca2+ release and/or re-uptake, intra-cellular material properties, sarcomere proteins and distribution of the intracellular organelles. To investigate the possible causes of these heterogeneities, we developed a two-dimensional finite-element electromechanical model of a cardiomyocyte that takes into account the experimentally measured local deformation and cytosolic [Ca2+] to locally define the different variables of the constitutive equations describing the electro/mechanical behaviour of the cell. Then, the model was individualised to three different rat cardiac cells. The local [Ca2+] transients were used to define the [Ca2+]-dependent activation functions. The cell-specific local Young's moduli were estimated by solving an inverse problem, minimizing the error between the measured and simulated local deformations along the longitudinal axis of the cell. We found that heterogeneities in the deformation during contraction were determined mainly by the local elasticity rather than the local amount of Ca2+, while in the relaxation phase deformation was mainly influenced by Ca2+ re-uptake. Our electromechanical model was able to successfully estimate the local elasticity along the longitudinal direction in three different cells. In conclusion, our proposed model seems to be a good approximation to assess the heterogeneous intracellular mechanical properties to help in the understanding of the underlying mechanisms of cardiomyocyte dysfunction.

The specialised conducting tissues present in the ventricles are responsible for the fast distribution of the electrical impulse from the atrio-ventricular node to regions in the subendocardial myocardium. Characterisation of anatomical features of the specialised conducting tissues in the ventricles is highly challenging, in particular its most distal section, which is connected to the working myocardium via Purkinje-myocardial junctions. The goal of this work is to characterise the architecture of the distal section of the Purkinje network by differentiating Purkinje cells from surrounding tissue, performing a segmentation of Purkinje fibres at cellular scale, and mathematically describing its morphology and interconnections. Purkinje cells from rabbit hearts were visualised by confocal microscopy using wheat germ agglutinin labelling. A total of 16 3D stacks including labeled Purkinje cells were collected, and semi-automatically segmented. State-of-the-art graph metrics were applied to estimate regional and global features of the Purkinje network complexity. Two types of cell types, tubular and star-like, were characterised from 3D segmentations. The analysis of 3D imaging data confirms the previously suggested presence of two types of Purkinje-myocardium connections, a 2D interconnection sheet and a funnel one, in which the narrow side of a Purkinje fibre connect progressively to muscle fibres. The complex network analysis of interconnected Purkinje cells showed no small-world connectivity or assortativity properties. These results might help building more realistic computational PK systems at high resolution levels including different cell configurations and shapes. Better knowledge on the organisation of the network might help in understanding the effects that several treatments such as radio-frequency ablation might have when the PK system is disrupted locally.

Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.