Personalized Multi-Scale Modeling of the Atria: Heterogeneities, Fiber Architecture, Hemodialysis and Ablation Therapy

This book targets three fields of computational multi-scale cardiac modeling. First, advanced models of the cellular atrial electrophysiology and fiber orientation are introduced. Second, novel methods to create patient-specific models of the atria are described. Third, applications of personalized models in basic research and clinical practice are presented. The results mark an important step towards the patient-specific model-based atrial fibrillation diagnosis, understanding and treatment

Integrated Cardiac Electromechanics: Modeling and Personalization

Cardiac disease remains the leading cause of morbidity and mortality in the world. A variety of heart diagnosis techniques have been developed during the last century, and generally fall into two groups. The first group evaluates the electrical function of the heart using electrophysiological data such as electrocardiogram (ECG), while the second group aims to assess the mechanical function of the heart through medical imaging data. Nevertheless, the heart is an integrated electromechanical organ, where its cyclic pumping arises from the synergy of its electrical and mechanical function which requires first to be electrically excited in order to contract. At the same time, cardiac electrical function experiences feedback from mechanical contraction. This inter-dependent relationship determines that neither electrical function nor mechanical function alone can completely reflect the pathophysiological conditions of the heart. The aim of this thesis is working towards building an integrated framework for heart diagnosis through evaluation of electrical and mechanical functions simultaneously. The basic rational is to obtain quantitative interpretation of a subject-specific heart system by combining an electromechanical heart model and individual clinical measurements of the heart. To this end, we first develop a biologically-inspired mathematical model of the heart that provides a general, macroscopic description of cardiac electromechanics. The intrinsic electromechanical coupling arises from both excitation-induced contraction and deformation-induced mechano-electrical feedback. Then, as a first step towards a fully electromechanically integrated framework, we develop a model-based approach for investigating the effect of cardiac motion on noninvasive transmural imaging of cardiac electrophysiology. Specifically, we utilize the proposed heart model to obtain updated heart geometry through simulation, and further recover the electrical activities of the heart from body surface potential maps (BSPMs) by solving an optimization problem. Various simulations of the heart have been performed under healthy and abnormal conditions, which demonstrate the physiological plausibility of the proposed integrated electromechanical heart model. What\u27s more, this work presents the effect of cardiac motion to the solution of noninvasive estimation of cardiac electrophysiology and shows the importance of integrating cardiac electrical and mechanical functions for heart diagnosis. This thesis also paves the road for noninvasive evaluation of cardiac electromechanics

A new algorithm to diagnose atrial ectopic origin from multi lead ECG systems - insights from 3D virtual human atria and torso

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms

Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps

Non-invasive localization of continuous atrial ectopic beats remains a cornerstone for the treatment of atrial arrhythmias. The lack of accurate tools to guide electrophysiologists leads to an increase in the recurrence rate of ablation procedures. Existing approaches are based on the analysis of the P-waves main characteristics and the forward body surface potential maps (BSPMs) or on the inverse estimation of the electric activity of the heart from those BSPMs. These methods have not provided an efficient and systematic tool to localize ectopic triggers. In this work, we propose the use of machine learning techniques to spatially cluster and classify ectopic atrial foci into clearly differentiated atrial regions by using the body surface P-wave integral map (BSPiM) as a biomarker. Our simulated results show that ectopic foci with similar BSPiM naturally cluster into differentiated non-intersected atrial regions and that new patterns could be correctly classified with an accuracy of 97% when considering 2 clusters and 96% for 4 clusters. Our results also suggest that an increase in the number of clusters is feasible at the cost of decreasing accuracy.This work was partially supported by The "Programa Prometeu" from Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (www.edu.gva.es/fio/index_es.asp) Award Number: PROMETEU/2016/088 to JS; The "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016" from the Ministerio de Economia, Industria y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: DPI2016-75799-R to JS and The "Programa Estatal de Investigacion, Desarrollo e Innovacion Orientado a los Retos de la Sociedad" from the Ministerio de Economia y Competitividad of Spain, Agencia Estatal de Investigacion (www.mineco.gob.es) and the European Commission (European Regional Development Funds - ERDF -FEDER) (ec.europa.eu/regional_policy/es/funding/erdf/) Award Number: TIN2014-59932-JIN to AFA and RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ferrer Albero, A.; Godoy, EJ.; Lozano, M.; Martínez Mateu, L.; Alonso Atienza, F.; Saiz Rodríguez, FJ.; Sebastián Aguilar, R. (2017). Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps. PLoS ONE. 12(7):1-23. https://doi.org/10.1371/journal.pone.0181263S12312

Integrated whole-heart computational workflow for inverse potential mapping and personalized simulations

Background: Integration of whole-heart activation simulations and inverse potential mapping (IPM) could benefit the guidance and planning of electrophysiological procedures. Routine clinical application requires a fast and adaptable workflow. These requirements limit clinical translation of existing simulation models. This study proposes a comprehensive finite element model (FEM) based whole-heart computational workflow suitable for IPM and simulations. Methods: Three volunteers and eight patients with premature ventricular contractions underwent body surface potential (BSP) acquisition followed by a cardiac MRI (CMR) scan. The cardiac volumes were segmented from the CMR images using custom written software. The feasibility to integrate tissue-characteristics was assessed by generating meshes with virtual edema and scar. Isochronal activation maps were constructed by identifying the fastest route through the cardiac volume using the Möller-Trumbore and Floyd-Warshall algorithms. IPM's were reconstructed from the BSP's. Results: Whole-heart computational meshes were generated within seconds. The first point of atrial activation on IPM was located near the crista terminalis of the superior vena cave into the right atrium. The IPM demonstrated the ventricular epicardial breakthrough at the attachment of the moderator band with the right ventricular free wall. Simulations of sinus rhythm were successfully performed. The conduction through the virtual edema and scar meshes demonstrated delayed activation or a complete conductional block respectively. Conclusion: The proposed FEM based whole-heart computational workflow offers an integrated platform for cardiac electrical assessment using simulations and IPM. This workflow can incorporate patient-specific electrical parameters, perform whole-heart cardiac activation simulations and accurately reconstruct cardiac activation sequences from BSP's

Bayesian Active Learning for Personalization and Uncertainty Quantification in Cardiac Electrophysiological Model

Cardiacvascular disease is the top death causing disease worldwide. In recent years, high-fidelity personalized models of the heart have shown an increasing capability to supplement clinical cardiology for improved patient-specific diagnosis, prediction, and treatment planning. In addition, they have shown promise to improve scientific understanding of a variety of disease mechanisms. However, model personalization by estimating the patient-specific tissue properties that are in the form of parameters of a physiological model is challenging. This is because tissue properties, in general, cannot be directly measured and they need to be estimated from measurements that are indirectly related to them through a physiological model. Moreover, these unknown tissue properties are heterogeneous and spatially varying throughout the heart volume presenting a difficulty of high-dimensional (HD) estimation from indirect and limited measurement data. The challenge in model personalization, therefore, summarizes to solving an ill-posed inverse problem where the unknown parameters are HD and the forward model is complex with a non-linear and computationally expensive physiological model. In this dissertation, we address the above challenge with following contributions. First, to address the concern of a complex forward model, we propose the surrogate modeling of the complex target function containing the forward model – an objective function in deterministic estimation or a posterior probability density function in probabilistic estimation – by actively selecting a set of training samples and a Bayesian update of the prior over the target function. The efficient and accurate surrogate of the expensive target function obtained in this manner is then utilized to accelerate either deterministic or probabilistic parameter estimation. Next, within the framework of Bayesian active learning we enable active surrogate learning over a HD parameter space with two novel approaches: 1) a multi-scale optimization that can adaptively allocate higher resolution to heterogeneous tissue regions and lower resolution to homogeneous tissue regions; and 2) a generative model from low-dimensional (LD) latent code to HD tissue properties. Both of these approaches are independently developed and tested within a parameter optimization framework. Furthermore, we devise a novel method that utilizes the surrogate pdf learned on an estimated LD parameter space to improve the proposal distribution of Metropolis Hastings for an accelerated sampling of the exact posterior pdf. We evaluate the presented methods on estimating local tissue excitability of a cardiac electrophysiological model in both synthetic data experiments and real data experiments. Results demonstrate that the presented methods are able to improve the accuracy and efficiency in patient-specific model parameter estimation in comparison to the existing approaches used for model personalization

Personalized noninvasive imaging of volumetric cardiac electrophysiology

Three-dimensionally distributed electrical functioning is the trigger of mechanical contraction of the heart. Disturbance of this electrical flow is known to predispose to mechanical catastrophe but, due to its amenability to certain intervention techniques, a detailed understanding of subject-specific cardiac electrophysiological conditions is of great medical interest. In current clinical practice, body surface potential recording is the standard tool for diagnosing cardiac electrical dysfunctions. However, successful treatments normally require invasive catheter mapping for a more detailed observation of these dysfunctions. In this dissertation, we take a system approach to pursue personalized noninvasive imaging of volumetric cardiac electrophysiology. Under the guidance of existing scientific knowledge of the cardiac electrophysiological system, we extract the subject specific cardiac electrical information from noninvasive body surface potential mapping and tomographic imaging data of individual subjects. In this way, a priori knowledge of system physiology leads the physiologically meaningful interpretation of personal data; at the same time, subject-specific information contained in the data identifies parameters in individual systems that differ from prior knowledge. Based on this perspective, we develop a physiological model-constrained statistical framework for the quantitative reconstruction of the electrical dynamics and inherent electrophysiological property of each individual cardiac system. To accomplish this, we first develop a coupled meshfree-BE (boundary element) modeling approach to represent existing physiological knowledge of the cardiac electrophysiological system on personalized heart-torso structures. Through a state space system approach and sequential data assimilation techniques, we then develop statistical model-data coupling algorithms for quantitative reconstruction of volumetric transmembrane potential dynamics and tissue property of 3D myocardium from body surface potential recoding of individual subjects. We also introduce a data integration component to build personalized cardiac electrophysiology by fusing tomographic image and BSP sequence of the same subject. In addition, we develop a computational reduction strategy that improves the efficiency and stability of the framework. Phantom experiments and real-data human studies are performed for validating each of the framework’s major components. These experiments demonstrate the potential of our framework in providing quantitative understanding of volumetric cardiac electrophysiology for individual subjects and in identifying latent threats in individual’s heart. This may aid in personalized diagnose, treatment planning, and fundamentally, prevention of fatal cardiac arrhythmia

A robust wavelet-based approach for dominant frequency analysis of atrial fibrillation in body surface signals

This is an author-created, un-copyedited versíon of an article published in Physiological Measurement. IOP Publishing Ltd is not responsíble for any errors or omissíons in this versíon of the manuscript or any versíon derived from it. The Versíon of Record is available online at https://doi.org/10.1088/1361-6579/ab97c1.[EN] Objective: Atrial dominant frequency (DF) maps undergoing atrial fibrillation (AF) presented good spatial correlation with those obtained with the non-invasive body surface potential mapping (BSPM). In this study, a robust BSPM-DF calculation method based on wavelet analysis is proposed. Approach: Continuous wavelet transform along 40 scales in the pseudo-frequency range of 3¿30 Hz is performed in each BSPM signal using a Gaussian mother wavelet. DFs are estimated from the intervals between the peaks, representing the activation times, in the maximum energy scale. The results are compared with the traditionally widely applied Welch periodogram and the robustness was tested on different protocols: increasing levels of white Gaussian noise, artificial DF harmonics presence and reduction in the number of leads. A total of 11 AF simulations and 12 AF patients are considered in the analysis. For each patient, intracardiac electrograms were acquired in 15 locations from both atria. The accuracy of both methods was assessed by calculating the absolute errors of the highest DFBSPM (HDFBSPM) with respect to the atrial HDF, either simulated or intracardially measured, and assumed correct if ¿1 Hz. The spatial distribution of the errors between torso DFs and atrial HDFs were compared with atria driving mechanism locations. Torso HDF regions, defined as portions of the maps with |DF ¿ HDFBSPM| ¿ 0.5 Hz were identified and the percentage of the torso occuping these regions was compared between methods. The robustness of both methods to white Gaussian noise, ventricular influence and harmonics, and to lower spatial resolution BSPM lead layouts was analyzed: computer AF models (567 leads vs 256 leads down to 16 leads) and patient data (67 leads vs 32 and 16 leads). Main results: The proposed method allowed an improvement in non-invasive estimation of the atria HDF. For the models the median relative errors were 7.14% for the wavelet-based algorithm vs 60.00% for the Welch method; in patients, the errors were 10.03% vs 12.66%, respectively. The wavelet method outperformed the Welch approach in correct estimations of atrial HDFs in models (81.82% vs 45.45%, respectively) and patients (66.67% vs 41.67%). A low positive BSPM-DF map correlation was seen between the techniques (0.47 for models and 0.63 for patients), highlighting the overall differences in DF distributions. The wavelet-based algorithm was more robust to white Gaussian noise, residual ventricular activity and harmonics, and presented more consistent results in lead layouts with low spatial resolution. Significance: Estimation of atrial HDFs using BSPM is improved by the proposed wavelet-based algorithm, helping to increase the non-invasive diagnostic ability in AF.This study was supported in part by grants from Sao Paulo Research Foundation (2017/19775-3), Instituto de Salud Carlos III FEDER (Fondo Europeo de Desarrollo Regional PI17/01106) and Generalitat Valenciana Grants (AICO/2018/267).Marques, V.; Rodrigo Bort, M.; Guillem Sánchez, MS.; Salinet, J. (2020). A robust wavelet-based approach for dominant frequency analysis of atrial fibrillation in body surface signals. Physiological Measurement. 41(7):1-14. https://doi.org/10.1088/1361-6579/ab97c1S11441

Numerical simulation of electrocardiograms for full cardiac cycles in healthy and pathological conditions

This work is dedicated to the simulation of full cycles of the electrical activity of the heart and the corresponding body surface potential. The model is based on a realistic torso and heart anatomy, including ventricles and atria. One of the specificities of our approach is to model the atria as a surface, which is the kind of data typically provided by medical imaging for thin volumes. The bidomain equations are considered in their usual formulation in the ventricles, and in a surface formulation on the atria. Two ionic models are used: the Courtemanche-Ramirez-Nattel model on the atria, and the "Minimal model for human Ventricular action potentials" (MV) by Bueno-Orovio, Cherry and Fenton in the ventricles. The heart is weakly coupled to the torso by a Robin boundary condition based on a resistor- capacitor transmission condition. Various ECGs are simulated in healthy and pathological conditions (left and right bundle branch blocks, Bachmann's bundle block, Wolff-Parkinson-White syndrome). To assess the numerical ECGs, we use several qualitative and quantitative criteria found in the medical literature. Our simulator can also be used to generate the signals measured by a vest of electrodes. This capability is illustrated at the end of the article