Electrocardiogram Analysis Reveals Ionic Current Dysregulation Relevant for Atrial Fibrillation

Antiarrhythmic drug choice for atrial fibrillation (AF) neglects the individual ionic current profile of the patient, even though it determines drug safety and efficacy. We hypothesize that the electrocardiogram (ECG) might contain information critical for pharmacological treatment personalization. Thus, this study aims to identify the extent of atrial ionic information embedded in the ECG, using multi-scale modeling and simulation. A dataset of 1,000 simulated ECGs was computed using a population of human-based whole-atria models with 200 individual ionic profiles and 5 different torso-atria orientations. A regression neural network was built to predict key atrial ionic conductances based on P- and T$_a$ -wave biomarkers. The neural network predicted, with >80% precision, the density of seven ionic currents relevant for AF, namely, ultra-rapid (I$_{Kur}$ ), rapid (I$_{Kr}$ ), outward transient (I$_{to}$ ), inward rectifier K$^+$ (I$_{K1}$ ), L-type Ca$^{2+}$ (I$_{CaL}$ ), Na$^+$ /K$^+$ pump (I$_{NaK}$ ) and fast Na$^+$ (I$_{Na}$) currents. These ionic densities were identified through the P- (i.e., I$_{Na}$), Ta - (i.e., I$_{K1}$ , I$_{NaK}$) or both waves (i.e., I$_{Kur}$ , I$_{Kr}$ , I$_{to}$ , I$_{CaL}$), providing a non- invasive characterization of the atrial electrophysiology. This could improve patient stratification and cardiac safety and the efficacy of AF pharmacological treatment

Energy análisis of a residential building in the Project phase, proposals for improvement and feasibility study

[ES] El trabajo busca estudiar en detalle cómo se lleva a cabo un análisis energético en un estudio de arquitectura y como se toman las decisiones durante la fase de proyecto, adaptándose a las costumbres constructivas, las preferencias del promotor y buscando un necesario equilibro entre eficiencia energética y viabilidad. En concreto el objeto del estudio es analizar un proyecto de ejecución de un edificio de 17 viviendas en la ciudad de Valencia. Se divide esencialmente en tres fases. Siendo la primera de estas el análisis energético del proyecto básico, con el apoyo de herramientas BIM y software especializado. La segunda fase consistirá en la elaboración de una propuesta para la mejora del rendimiento energético del edificio hasta alcanzar un estado que, al menos, cumpla con la normativa vigente en materia de eficiencia. Por último, la tercera fase consistirá en estudiar la viabilidad del proyecto resultante desde el punto de vista técnico y económico.[CA] El treball busca estudiar detalladament com es du a terme una anàlisi energètica en un estudi d'arquitectura i com es prenen les decisions durant la fase de projecte, adaptant-se als costums constructius, les preferències del promotor i buscant un necessari equilibre entre eficiència energètica i viabilitat. En concret l'objecte de l'estudi és analitzar un projecte d'execució d'un edifici de 17 habitatges a la ciutat de València. Es divideix essencialment en tres fases. Sent la primera d'aquestes l'anàlisi energètica del projecte bàsic, amb el suport d'eines BIM i programari especialitzat. La segona fase consistirà en l'elaboració d'una proposta per a la millora del rendiment energètic de l'edifici fins aconseguir un estat que, almenys, complisca amb la normativa vigent en matèria d'eficiència. Finalment, la tercera fase consistirà a estudiar la viabilitat del projecte resultant des del punt de vista tècnic i econòmic.[EN] The project aims to study in detail how an energy analysis is carried out in an architecture firm and what is the decision process during the project phase, looking for a necessary balance between energy efficiency and viability. Specifically, the purpose of the study is to analyze an execution project of a 17-dwelling building in the city of Valencia. It is essentially divided into three phases. The first being the energy analysis of the basic project, supported by BIM tools and specialized software. The second phase will consist of the elaboration of a proposal for the improvement of the energy efficiency of the building until it reaches a state that, at least, complies with the current regulations on efficiency. Finally, the third phase will be to study the technical and economic viability of the resulting project.Navarro Dasí, A. (2023). Análisis energético de un edificio de viviendas en fase de proyecto, propuestas de mejora y estudio de la viabilidad. Universitat Politècnica de València. http://hdl.handle.net/10251/19632

Modelado y simulación computacional de arritmias en tejidos formados por cardiomiocitos derivados de células pluripotenciales inducidas

[ES] Recientemente, los estudios de farmacología de seguridad han destacado la gran utilidad de las simulaciones por computador combinadas con experimentos in vitro con cardiomiocitos derivados de células madre pluripotentes inducidas (iPSC-CMs) para el diseño de fármacos y para el estudio de patologías cardíacas. Puesto que el acceso a células cardíacas humanas no es trivial, la experimentación con las iPSCs-CM nos abre un gran camino a la investigación. En el presente trabajo se pretende desarrollar un software para analizar, mediante simulación computacional, las causas de las arritmias reentrantes en tejidos formados por células iPSC-CMs y los efectos farmacológicos sobre éstas. Para ello, se van a emplear modelos de potencial de acción de iPSC-CMs y se van a modificar para simular el efecto farmacológico. Además, el alumno diseñará una plataforma de simulación para poder realizar las simulaciones y su análisis de manera automática.[EN] Recently, different pharmacological studies have highlighted the usefullness of computational simulation combined with in vitro experiments using cardiomyocites derived from induced pluripotent stem cells (iPSC-CM) to design drugs and to study cardiac pathologies. Because working with human cardiac myocytes is not easy, the use of iPSC-CM cells is a good alternative in research. In this work, the student will develop a software to analyze, using computational simulation, the causes of reentrant arrhythmias in tissues comprising iPSC-CM cells and also the pharmacologic effects in these cells. For this purpose, he will use action potential models adapted to iPSC-CM cells and will modify wuch models to simulate pharmacologic effects. Moreover, the student will design and develop a simulation platform useful to carry out the numerous simulations and their post-process analysis automatically.Dasí I Martínez, A. (2019). Modelado y simulación computacional de arritmias en tejidos formados por cardiomiocitos derivados de células pluripotenciales inducidas. http://hdl.handle.net/10251/124583TFG

Consideración del Remodelado Electromecánico en Insuficiencia Cardíaca en un Modelo 3D In-Silico de Miocardiopatía Dilatada

[CA] La insuficiència cardíaca (IC) és un terme ampli que inclou nombroses lesions, malalties i altres anomalies cardíaques que generen una disfunció general del miocardi. Es caracteritza per un rendiment cardíac reduït que afavoreix un subministrament insuficient d'oxigen a l organisme. Per aquesta raó, la IC és una de les principals causes de mortalitat a nivell mundial. En aquest treball pretenem desenvolupar un model 3D detallat d un cor virtual amb IC a partir d una cardiomiopatia dilatada (DCM) no isquèmica. Per complir aquest propòsit, es considerarà el corresponent remodelat ventricular associat a HF i, concretament, a DCM. En aquest sentit, entre els diversos canvis observats en pacients amb DCM, destaquem (1) un augment del volum de les cavitats cardíaques, afectant principalment el ventricle esquerre (LV), acompanyat per una disminució del gruix de la paret; (2) el remodelat electromecànic, tenint en compte la disminució del rendiment electrofisiològic i la contractilitat muscular; (3) reorganització de fibres: el cor perd la seva el·lipticitat i es torna més esfèric; i (4) canvis en la matriu extracel·lular (fibrosi). A més, la DCM es caracteritza per una major rigidesa del cor (produïda principalment per fibrosi) així com per la reducció de la tensió longitudinal, circumferència i radial. Tots aquests canvis donen lloc a una disminució de la funció sistòlica i, conseqüentment, de la fracció d ejecció (EF). Un cop construïm el model HF a través dels punts 1-3, el compararem amb el model de referència i el validarem mitjançant les dades de ressonància magnètica de Sunnybrook Cardiac Data (SCD) de lliure disposició. La introducció de fibrosi es tindrà en compte un cop assolits tots els altres objectius.[EN] Heart failure (HF) is a broad term which encompasses numerous injuries, diseases and other cardiac abnormalities that yield to an overall dysfunction of the myocardium. It is characterized by a poor beating performance which promotes insufficient oxygen supply to the body. Therefore, HF is one of the leading causes of mortality worldwide. In this work, we aim to develop a detailed 3D-model of a failing virtual heart on the basis of a non-ischemic dilated cardiomyopathy (DCM). For that purpose, the corresponding ventricular remodelling associated with HF and, specifically, with DCM will be considered. In this sense, among the several changes observed in DCM patients compared with controls, we highlight (1) an increased cavity volume, mainly affecting the left ventricle (LV), accompanied by a decreased wall thickness; (2) electromechanical remodelling, considering both, decreased electrophysiological performance and muscle contractility; (3) fibre reorganization: the heart loses its ellipticity and becomes more spherical; and (4) changes in the extracellular matrix (fibrosis). Furthermore, DCM is characterized by increased stiffness of the heart (mainly produced by fibrosis) as well as by the reduction in the longitudinal, circumferential and radial strain. All these changes yield to a decreased systolic function and consequent lower ejection fraction (EF). Once we build the HF model through points 1-3, we will compare it to the healthy reference model and validate it using cine MRI data from the publicly available Sunnybrook Cardiac Data (SCD). The introduction of fibrosis will be considered once all other goals are achieved.Dasí I Martínez, A. (2020). Consideración del Remodelado Electromecánico en Insuficiencia Cardíaca en un Modelo 3D In-Silico de Miocardiopatía Dilatada. Universitat Politècnica de València. http://hdl.handle.net/10251/161181TFG

Escola catalana

Este artículo forma parte de la monografía 'Editar avui' (Editar hoy)Se relata la experiencia llevada a cabo en la escuela Gavina de Valencia, donde se decidió editar poemarios con el objetivo de aprender poesía y disfrutar leyéndola y escribiéndola. Se comentan algunos números según la motivación que los originó .CataluñaES

In-silico drug trials for precision medicine in atrial fibrillation: from ionic mechanisms to electrocardiogram-based predictions in structurally-healthy human atria

Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were conducted using a population of human structurally-healthy atria models to 1) identify key ionic current properties determining AF inducibility, maintenance and pharmacological cardioversion, and 2) compare the prognostic value for predicting individual AF cardioversion of ionic current properties and electrocardiogram (ECG) metrics. In the population of structurally-healthy atria, 477 AF episodes were induced in ionic current profiles with both steep action potential duration (APD) restitution (eliciting APD alternans), and high excitability (enabling propagation at fast rates that transformed alternans into discordant). High excitability also favored 211 sustained AF episodes, so its decrease, through prolonged refractoriness, explained pharmacological cardioversion. In-silico trials over 200 AF episodes, 100 ionic profiles and 10 antiarrhythmic compounds were consistent with previous clinical trials, and identified optimal treatments for individual electrophysiological properties of the atria. Algorithms trained on 211 simulated AF episodes exhibited >70% accuracy in predictions of cardioversion for individual treatments using either ionic current profiles or ECG metrics. In structurally-healthy atria, AF inducibility and sustainability are enabled by discordant alternans, under high excitability and steep restitution conditions. Successful pharmacological cardioversion is predicted with 70% accuracy from either ionic or ECG properties, and it is optimal for treatments maximizing refractoriness (thus reducing excitability) for the given ionic current profile of the atria

Table1_In-silico drug trials for precision medicine in atrial fibrillation: From ionic mechanisms to electrocardiogram-based predictions in structurally-healthy human atria.DOCX

Atrial fibrillation (AF) inducibility, sustainability and response to pharmacological treatment of individual patients are expected to be determined by their ionic current properties, especially in structurally-healthy atria. Mechanisms underlying AF and optimal cardioversion are however still unclear. In this study, in-silico drug trials were conducted using a population of human structurally-healthy atria models to 1) identify key ionic current properties determining AF inducibility, maintenance and pharmacological cardioversion, and 2) compare the prognostic value for predicting individual AF cardioversion of ionic current properties and electrocardiogram (ECG) metrics. In the population of structurally-healthy atria, 477 AF episodes were induced in ionic current profiles with both steep action potential duration (APD) restitution (eliciting APD alternans), and high excitability (enabling propagation at fast rates that transformed alternans into discordant). High excitability also favored 211 sustained AF episodes, so its decrease, through prolonged refractoriness, explained pharmacological cardioversion. In-silico trials over 200 AF episodes, 100 ionic profiles and 10 antiarrhythmic compounds were consistent with previous clinical trials, and identified optimal treatments for individual electrophysiological properties of the atria. Algorithms trained on 211 simulated AF episodes exhibited >70% accuracy in predictions of cardioversion for individual treatments using either ionic current profiles or ECG metrics. In structurally-healthy atria, AF inducibility and sustainability are enabled by discordant alternans, under high excitability and steep restitution conditions. Successful pharmacological cardioversion is predicted with 70% accuracy from either ionic or ECG properties, and it is optimal for treatments maximizing refractoriness (thus reducing excitability) for the given ionic current profile of the atria.</p

Analysis of the response of human iPSC-derived cardiomyocyte tissue to I CaL block. A combined in vitro and in silico approach

[EN] The high incidence of cardiac arrythmias underlines the need for the assessment of pharmacological therapies. In this field of drug efficacy, as in the field of drug safety highlighted by the Comprehensive in Vitro Proarrhythmia Assay initiative, new pillars for research have become crucial: firstly, the integration of in-silico experiments, and secondly the evaluation of fully integrated biological systems, such as human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). In this study, we therefore aimed to combine in-vitro experiments and in-silico simulations to evaluate the antiarrhythmic effect of L-type calcium current (I-CaL) block in hiPSC-CMs. For this, hiPSC-CM preparations were cultured and an equivalent virtual tissue was modeled. Re-entry patterns of electrical activation were induced and several biomarkers were obtained before and after I-CaL block. The virtual hiPSC-CM simulations were also reproduced using a tissue composed of adult ventricular cardiomyocytes (hAdultV-CMs). The analysis of phases, currents and safety factor for propagation showed an increased size of the re-entry core when I-CaL was blocked as a result of depressed cellular excitability. The bigger wavefront curvature yielded reductions of 12.2%, 6.9%, and 4.2% in the frequency of the re-entry for hiPSC-CM cultures, virtual hiPSC-CM, and hAdultV-CM tissues, respectively. Furthermore, I-CaL block led to a 47.8% shortening of the vulnerable window for re-entry in the virtual hiPSC-CM tissue and to re-entry vanishment in hAdultV-CM tissue. The consistent behavior between in-vitro and in-silico hiPSC-CMs and between in-silico hiPSC-CMs and hAdultV-CMs evidences that virtual hiPSC-CM tissues are suitable for assessing cardiac efficacy, as done in the present study through the analysis of I-CaL block.This work was supported by the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2017-2020" of the Ministerio de Ciencia e Innovacion y Universidades (PID2019-104356RB-C41/AEI/10.13039/501100011033) , also by the Direccion General de Politica Cientifica de la Generalitat Valenciana (PROMETEO 2020/043) , by the European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 101016496, and by the Agencia Estatal de Investigacion [RYC2018-024346-I].Dasí, A.; Hernández-Romero, I.; Gómez, JF.; Climent, AM.; Ferrero De Loma-Osorio, JM.; Trenor Gomis, BA. (2021). Analysis of the response of human iPSC-derived cardiomyocyte tissue to I CaL block. A combined in vitro and in silico approach. Computers in Biology and Medicine. 137:1-10. https://doi.org/10.1016/j.compbiomed.2021.104796S11013