Modeling the Heart as a Communication System

Electrical communication between cardiomyocytes can be perturbed during arrhythmia, but these perturbations are not captured by conventional electrocardiographic metrics. We developed a theoretical framework to quantify electrical communication using information theory metrics in 2-dimensional cell lattice models of cardiac excitation propagation. The time series generated by each cell was coarse-grained to 1 when excited or 0 when resting. The Shannon entropy for each cell was calculated from the time series during four clinically important heart rhythms: normal heartbeat, anatomical reentry, spiral reentry, and multiple reentry. We also used mutual information to perform spatial profiling of communication during these cardiac arrhythmias. We found that information sharing between cells was spatially heterogeneous. In addition, cardiac arrhythmia significantly impacted information sharing within the heart. Entropy localized the path of the drifting core of spiral reentry, which could be an optimal target of therapeutic ablation. We conclude that information theory metrics can quantitatively assess electrical communication among cardiomyocytes. The traditional concept of the heart as a functional syncytium sharing electrical information cannot predict altered entropy and information sharing during complex arrhythmia. Information theory metrics may find clinical application in the identification of rhythm-specific treatments which are currently unmet by traditional electrocardiographic techniques.Comment: 26 pages (including Appendix), 6 figures, 8 videos (not uploaded due to size limitation

Pathophysiology of atrial fibrillation: From initiation to maintenance

Atrial fibrillation (AF) is the most common arrhythmia in adults; it affects approximately 0.8 million patients in Japan alone. Yet despite many years of basic and clinical research, the exact mechanisms underlying the initiation and maintenance of AF remain poorly understood. In this review article, we summarize recent high‐resolution optical mapping studies in isolated sheep hearts, which have provided new insights into the dynamics and mechanisms of AF. We focus on 3 models of AF. First, we discuss results from experiments on AF induced by atrial stretch that revealed the presence of spatio‐temporally organized waves emerging from the posterior wall of the left atrium. In the presence of adreno‐cholinergic stimulation and stretch, AF was governed by evolving interactions between reentry and spontaneous focal discharges. Next, we outline the results obtained from a persistent AF model (average AF duration: 21.3 day) induced by intermittent rapid atrial pacing. By using simultaneous optical mapping of epicardial and endocardial activation patterns, we demonstrated that AF in this model was maintained by 3‐dimensional scroll waves with I‐shaped filaments anchored to junctions between thin and thick myocardium. Numerical simulation results predicted that wall thickness‐dependent activation of stretch‐activated channels and the filament tension dynamics were sufficient to explain the specific localization of the I‐shaped filament. In a final set of studies discussed herein, we investigated AF in sheep with tachypacing‐induced heart failure and found that micro‐reentry in the left atria was a major mechanism of AF maintenance, although focal discharges at the pulmonary vein area also played a role. Large fibrotic patches in failing hearts may serve as potential anchoring sites for micro‐reentry in this model. Thus, the 3 different experimental results in isolated sheep hearts presented here clearly suggest that self‐sustained rotors do exist in the atria and that such rotors are in fact the high frequency sources that determine the complex patterns of activation that characterize AF.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142071/1/joa3129.pd

Computer-Aided Clinical Decision Support Systems for Atrial Fibrillation

Clinical decision support systems (clinical DSSs) are widely used today for various clinical applications such as diagnosis, treatment, and recovery. Clinical DSS aims to enhance the end‐to‐end therapy management for the doctors, and also helps to provide improved experience for patients during each phase of the therapy. The goal of this chapter is to provide an insight into the clinical DSS associated with the highly prevalent heart rhythm disorder, atrial fibrillation (AF). The use of clinical DSS in AF management is ubiquitous, starting from detection of AF through sophisticated electrophysiology treatment procedures, all the way to monitoring the patient\u27s health during follow‐ups. Most of the software associated with AF DSS are developed based on signal processing, image processing, and artificial intelligence techniques. The chapter begins with a brief description of DSS in general and then introduces DSS that are used for various clinical applications. The chapter continues with a background on AF and some relevant mechanisms. Finally, a couple of clinical DSS used today in regard with AF are discussed, along with some proposed methods for potential implementation of clinical DSS for detection of AF, prediction of an AF treatment outcome, and localization of AF targets during a treatment procedure

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

Characterization of Cardiac Electrogram Signals During Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in United States. The most popular treatment for AF is a percutaneous procedure called catheter ablation. Current AF ablation procedures unfortunately have a poor success rate, primarily because the mechanisms involved in AF are incompletely understood even today. Intra-atrial electrograms have previously been shown to provide information on the mechanisms of AF. This thesis focuses on two such mechanisms – AF-sustaining sites known as sustained rotational activities (RotAs), and atrial tissue with unique electrical properties known as myocardial scars. Catheter ablation procedures today construct the 3D electroanatomic map of the left atrium (LA) by maneuvering a conventional Multipolar Diagnostic Catheter (MPDC) along the LA endocardial surface. These procedures are limited to pulmonary vein isolation and other linear ablation performed on various regions of the left atrium (such as roof and mitral isthmus) where the regions are decided based on the atrial anatomy. However, it remains unclear how to utilize the information provided by the MPDC to analyze and characterize the RotAs and scars. Previous electrogram characterization studies mainly use a single bipole rather than MPDCs to characterize the electrograms based on features such as cycle length or dominant frequency from the time or frequency domain. In this thesis we developed novel techniques for investigating the above mentioned mechanisms using signal analysis, mathematical modeling, numerical simulation and clinical experiments, all utilizing MPDC recordings. First, the variations in the total conduction delay (TCD) from MPDC electrograms as the MPDC moves towards a RotA source was investigated. Second, the maximum peak-to-peak amplitudes of MPDC electrograms recorded during AF and NSR were analyzed. This thesis provides insights into methods of characterization of cardiac electrograms and the findings of this thesis could address the current challenges in AF ablation

Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias

[EN] Atrial tachyarrhythmias present a high prevalence in the developed world, and several studies predict that in the coming decades it will be increased. Micro or macro-reentrant mechanisms of the electrical wavefronts that govern the mechanical behavior of the heart are one of the main responsibles for the maintenance of these arrhythmias. Atrial flutter is maintained by a macro-reentry around an anatomical or functional obstacle located in the atria. In the case of atrial fibrillation, the hypothesis which describes high frequency rotors as dominant sources of the fibrillation and responsible for the maintenance of the arrhythmia, has been gaining relevance in the last years. However, the therapies that target high frequency sources have a limited efficacy with current techniques. Radiofrequency ablation allows the destruction of parts of the cardiac tissue resulting in the interruption of the reentrant circuit in case of macro-reentries or the isolation of micro-reentrant circuits. The non-invasive location of reentrant circuits would increment the efficacy of these therapies and would shorten surgery interventions. In parallel, pharmacological therapies modify ionic expressions associated to the excitability and electrical refractoriness of the cardiac tissue with the objective of hindering the maintenance of reentrant behaviors. These therapies require a deep knowledge of the ionic mechanisms underlying the reentrant behavior and its properties in order to be effective. The research in these mechanisms allows the evaluation of new targets for the treatment and thus may improve the efficacy in atrial fibrillation termination. In this thesis, mathematical modeling is used to go forward in the minimization of the limitations associated to these treatments. Body surface potential mapping has been evaluated, both clinically and by means of mathematical simulations for the diagnosis and location of macro-reentrant circuits. The analysis of phase maps obtained from multiple lead electrocardiographic recordings distributed in the whole torso allowed the discrimination between different reentrant circuits. It is the reason why this technique is presented as a tool for the non-invasive location of macro and micro-reentrant circuits. A population of mathematical models designed in this thesis based on the action potentials recordings of atrial cardiomyocites from 149 patients, allowed the evaluation of the ionic mechanisms defining the properties of reentrant behaviors. This study has allowed us defining the blockade of ICaL as a target for the pharmacological treatment. The blockade of this current is associated with the increase of the movement in the core of the rotor which easies the collision of the rotor with other wavefronts or anatomical obstacles promoting the extinction of the reentry. The variability observed between patients modeled in our population has allowed showing and explaining the mechanisms promoting divergent results of a single treatment. This is why the introduction of populations of models will allow the prevention of side effects associated to inter-subject variability and to go forward in the development of individualized therapies. These works are built through a simulation platform of cardiac electrophysiology based in Graphic Processing Units (GPUs) and developed in this thesis. The platform allows the simulation of cellular models, tissues and organs with a realistic geometry and shows features comparable to that of the platforms used by the most relevant electrophysiology research groups at the moment.[ES] Las taquiarritmias auriculares tienen una alta prevalencia en el mundo desarrollado, además diversos estudios poblacionales indican que en las próximas décadas ésta se verá incrementada. Los mecanismos de micro o macro-reentrada de los frentes de onda eléctricos que rigen el comportamiento mecánico del corazón, se presentan como una de las principales causas del mantenimiento de estas arritmias. El flutter auricular es mantenido por un macro-reentrada alrededor de un obstáculo anatómico o funcional en las aurículas, mientras que en el caso de la fibrilación auricular la hipótesis que define a los rotores de alta frecuencia como elementos dominantes y responsables del mantenimiento de la arritmia se ha ido imponiendo al resto en los últimos años. Sin embargo, las terapias que tienen como objetivo finalizar o aislar estas reentradas tienen todavía una eficacia limitada. La ablación por radiofrecuencia permite eliminar zonas del tejido cardiaco resultando en la interrupción del circuito de reentrada en el caso de macro-reentradas o el aislamiento de comportamientos micro-reentrantes. La localización no invasiva de los circuitos reentrantes incrementaría la eficacia de estas terapias y reduciría la duración de las intervenciones quirúrgicas. Por otro lado, las terapias farmacológicas alteran las expresiones iónicas asociadas a la excitabilidad y la refractoriedad del tejido con el fin de dificultar el mantenimiento de comportamientos reentrantes. Este tipo de terapias exigen incrementar el conocimiento de los mecanismos subyacentes que explican el proceso de reentrada y sus propiedades, la investigación de estos mecanismos permite definir las dianas terapéuticas que mejoran la eficacia en la extinción de estos comportamientos. En esta tesis el modelado matemático se utiliza para dar un paso importante en la minimización de las limitaciones asociadas a estos tratamientos. La cartografía eléctrica de superficie ha sido testada, clínicamente y con simulaciones matemática,s como técnica de diagnóstico y localización de circuitos macro-reentrantes. El análisis de mapas de fase obtenidos a partir de los registros multicanal de derivaciones electrocardiográficas distribuidas en la superficie del torso permite diferenciar distintos circuitos de reentrada. Es por ello que esta técnica de registro y análisis se presenta como una herramienta para la localización no invasiva de circuitos macro y micro-reentrantes. Una población de modelos matemáticos, diseñada en esta tesis a partir de los registros de los potenciales de acción de 149 pacientes, ha permitido evaluar los mecanismos iónicos que definen las propiedades asociadas a los procesos de reentrada. Esto ha permitido apuntar al bloqueo de la corriente ICaL como diana terapéutica. Ésta se asocia al incremento del movimiento del núcleo que facilita el impacto del rotor con otros frentes de onda u obstáculos extinguiéndose así el comportamiento reentrante. La variabilidad entre pacientes reflejada en la población de modelos ha permitido además mostrar los mecanismos por los cuales un mismo tratamiento puede mostrar efectos divergentes, así el uso de poblaciones de modelos matemáticos permitirá prevenir efectos secundarios asociados a la variabilidad entre pacientes y profundizar en el desarrollo de terapias individualizadas. Estos trabajos se cimientan sobre una plataforma de simulación de electrofisiología cardiaca de basado en Unidades de Procesado Gráfico (GPUs) y desarrollada en esta tesis. La plataforma permite la simulación de modelos celulares cardiacos así como de tejidos u órganos con geometría realista, mostrando unas prestaciones comparables con las de las utilizadas por los grupos de investigación más potentes en el campo de la electrofisiología.[CA] Les taquiarítmies auriculars tenen una alta prevalença en el món desenvolupat, a més diversos estudis poblacionals indiquen que en les pròximes dècades aquesta es veurà incrementada. Els mecanismes de micro o macro-reentrada dels fronts d'ona elèctrics que regeixen el comportament mecànic del cor, es presenten com una de les principals causes del manteniment d'aquestes arítmies. El flutter auricular és mantingut per una macro-reentrada al voltant d'un obstacle anatòmic o funcional en les aurícules, mentre que en el cas de la fibril·lació auricular la hipòtesi que defineix als rotors d'alta freqüència com a elements dominants i responsables del manteniment de l'arítmia s'ha anat imposant a la resta en els últims anys. No obstant això, les teràpies que tenen com a objectiu finalitzar o aïllar aquestes reentrades tenen encara una eficàcia limitada. L'ablació per radiofreqüència permet eliminar zones del teixit cardíac resultant en la interrupció del circuit de reentrada en el cas de macro-reentrades o l'aïllament de comportaments micro-reentrants. La localització no invasiva dels circuits reentrants incrementaria l'eficàcia d'aquestes teràpies i reduiria la durada de les intervencions quirúrgiques. D'altra banda, les teràpies farmacològiques alteren les expressions iòniques associades a la excitabilitat i la refractaritat del teixit amb la finalitat de dificultar el manteniment de comportaments reentrants. Aquest tipus de teràpies exigeixen incrementar el coneixement dels mecanismes subjacents que expliquen el procés de reentrada i les seues propietats, la recerca d'aquests mecanismes permet definir les dianes terapèutiques que milloren l'eficàcia en l'extinció d'aquests comportaments. En aquesta tesi el modelatge matemàtic s'utilitza per a fer un pas important en la minimització de les limitacions associades a aquests tractaments. La cartografia elèctrica de superfície ha sigut testada, clínicament i amb simulacions matemàtiques com a tècnica de diagnòstic i localització de circuits macro-reentrants. L'anàlisi de mapes de fase obtinguts a partir dels registres multicanal de derivacions electrocardiogràfiques distribuïdes en la superfície del tors permet diferenciar diferents circuits de reentrada. És per açò que aquesta tècnica de registre i anàlisi es presenta com una eina per a la localització no invasiva de circuits macro i micro-reentrants. Una població de models matemàtics, dissenyada en aquesta tesi a partir dels registres dels potencials d'acció de 149 pacients, ha permès avaluar els mecanismes iònics que defineixen les propietats associades als processos de reentrada. Açò ha permès apuntar al bloqueig del corrent ICaL com a diana terapèutica. Aquesta s'associa a l'increment del moviment del nucli que facilita l'impacte del rotor amb altres fronts d'ona o obstacles extingint-se així el comportament reentrant. La variabilitat entre pacients reflectida en la població de models ha permès a més mostrar els mecanismes pels quals un mateix tractament pot mostrar efectes divergents, així l'ús de poblacions de models matemàtics permetrà prevenir efectes secundaris associats a la variabilitat entre pacients i aprofundir en el desenvolupament de teràpies individualitzades. Aquests treballs es fonamenten sobre una plataforma de simulació de electrofisiologia cardíaca basat en Unitats de Processament Gràfic (GPUs) i desenvolupada en aquesta tesi. La plataforma permet la simulació de models cel·lulars cardíacs així com de teixits o òrgans amb geometria realista, mostrant unes prestacions comparables amb les de les utilitzades per els grups de recerca més importants en aquesta área.Liberos Mascarell, A. (2016). Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166TESI

A New Efficient Method for Detecting Phase Singularity in Cardiac Fibrillation

BACKGROUND: The point of phase singularity (PS) is considered to represent a spiral wave core or a rotor in cardiac fibrillation. Computational efficiency is important for detection of PS in clinical electrophysiology. We developed a novel algorithm for highly efficient and robust detection of PS. METHODS: In contrast to the conventional method, which calculates PS based on the line integral of the phase around a PS point equal to ±2π (the Iyer-Gray method), the proposed algorithm (the location-centric method) looks for the phase discontinuity point at which PS actually occurs. We tested the efficiency and robustness of these two methods in a two-dimensional mathematical model of atrial fibrillation (AF), with and without remodeling of ionic currents. RESULTS: 1. There was a significant association, in terms of the Hausdorff distance (3.30 ± 0.0 mm), between the PS points measured using the Iyer-Gray and location-centric methods, with almost identical PS trajectories generated by the two methods. 2. For the condition of electrical remodeling of AF (0.3 × ICaL), the PS points calculated by the two methods were satisfactorily co-localized (with the Hausdorff distance of 1.64 ± 0.09 mm). 3. The proposed location-centric method was substantially more efficient than the Iyer-Gray method, with a 28.6-fold and 28.2-fold shorter run times for the control and remodeling scenarios, respectively. CONCLUSION: We propose a new location-centric method for calculating PS, which is robust and more efficient compared with the conventionally used method.ope

Spatiotemporal Control of Human Cardiac Tissue Through Optogenetics

Cardiac arrhythmias are caused by disordered propagation of electrical activity. Progress in understanding and controlling arrhythmias requires novel methods to characterize and control the spatiotemporal propagation of electrical activity. We used patterned illumination of cardiomyocytes derived from optogenetic human induced pluripotent stem cells to create dynamic conduction blocks, and to test spatially extended control schemes. Using this model, we demonstrated the ability to initiate, circumscribe, relocate, and terminate pathologic spiral waves that drive many arrhythmias. When cells were derived from patients with long QT syndrome, longer action potential durations made spiral waves more resistant to termination. This work lays the foundation for personalized models of cardiac injury and disease, and the development of tailored approaches to the management of arrhythmias