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Data is structured in the format provided by Nanion SyncroPatch software. The folder structure is named after each compound tested, inside there is one folder per each of the three protocols used. Data is stored in JSON files containing the information of the experiment., Background and Objective: Assessment of drug cardiotoxicity is critical in the development of new compounds and modeling of drug-binding dynamics to hERG can improve early cardiotoxicity assessment. We previously developed a methodology to generate Markovian models reproducing preferential state-dependent binding properties, trapping dynamics and the onset of IKr block using simple voltage clamp protocols. Here, we test this methodology with real IKr blockers and investigate the impact of drug dynamics on action potential prolongation. Methods: Experiments were performed on HEK cells stably transfected with hERG and using the Nanion SyncroPatch 384i. Three protocols, P-80, P0 and P40, were applied to obtain the experimental data from the drugs and the Markovian models were generated using our pipeline. The corresponding static models were also generated and a modified version of the O´Hara-Rudy action potential model was used to simulate the action potential duration. Results: The experimental Hill plots and the onset of IKr block of ten compounds were obtained using our voltage clamp protocols and the models generated successfully mimicked these experimental data, unlike the CiPA dynamic models. Marked differences in APD prolongation were observed when drug effects were simulated using the dynamic models and the static models. Conclusions: These new dynamic models of ten well-known IKr blockers constitute a validation of our methodology to model dynamic drug–hERG channel interactions and highlight the importance of state-dependent binding, trapping dynamics and the time-course of IKr block to assess drug effects even at the steady-state.

This repository contains the code used to generate the male and female population of models and simulate the different pharmacokinetic scenarios in Llopis-Lorente et al. (2023). Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity

[ES] Hoy en día, el paradigma del "Internet de las cosas" no sólo se aplica en la vida cotidiana, sino también en la tecnología de automatización de la fábrica. La comunicación de los dispositivos juega un papel importante para el sistema global. Esto también significa una nueva forma de interacción en un entorno altamente automatizado para los seres humanos. Además de la interacción mediante interfaces de pantalla gráfica, también se puede comunicar información sencilla mediante señales acústicas, visuales o hápticas. Este tipo de interfaz de usuario puede percibirse subconscientemente sin que el empleado tenga que desviar su atención de su tarea real (="Calm Design ") En el ámbito de la labor se especificará un concepto de usuario uniforme que reúna los elementos individuales de esa interfaz de usuario. De este modo, se considerarán todos los aspectos del sistema tanto en el diseño físico como en el de los programas informáticos: Los componentes individuales de la interacción deben ser fácilmente instalados en el entorno y configurados por personas que no sean programadores. La interfaz de usuario del sistema de IoT (Internet of Things) debe ser lo suficientemente flexible como para ser diseñada por el usuario para satisfacer las necesidades individuales. En detalle, deben resolverse las siguientes tareas: - Diseño de un concepto de interfaces de usuario integradas en un contexto de fábrica - Adaptación y estandarización de los prototipos existentes y aplicación de los nuevos componentes de interacción - Diseño de una aplicación para la configuración de los componentes de interacción - Documentación de la obra, [EN] Nowadays, the paradigm of the "Internet of Things" is not only applied in everyday life, but also in the automation technology of the factory floor. The communication of the devices plays an important role for the overall system This also means a new form of interaction in a highly automated environment for humans. In addition to interaction via graphic screen interfaces, simple information can also be communicated by acoustic, visual or haptic sig-nals. This type of user interface can be perceived subconsciously without the employee having to turn his focus away from his actual task (="Calm Design") In the scope of the work, a uniform user concept is to be specified, which brings together the individual elements of such a user interface. Thereby all aspects of the system in the physical as well as in the software design shall be considered: The individual interaction components should be easily installed in the environment and configured by non-programmers. The user interface of the IoT system should be flexible enough to be de-signed by the user to meet individual requirements. In detail the following subtasks must be solved: Design of a concept for embedded user interfaces in a factory context Adaptation and standardization of existing prototypes and implementation of the new interaction components Design of an application for the configuration of the interaction components Documentation of the work

[ES] Las arritmias cardíacas son una de las causas más importantes de mortalidad en los países desarrollados. Se ha demostrado que los defectos genéticos y el sexo de las personas son importantes en la susceptibilidad a las arritmias y en la eficacia y seguridad de las terapias farmacológicas. A pesar de que las arritmias cardíacas afectan tanto a hombres como a mujeres, existen diferencias entre las distintas patologías. Por ejemplo, es bien conocida en la modulación del riesgo de arritmias malignas el efecto de las hormonas sexuales en pacientes con el síndrome de QT largo (SQTL). En este trabajo se analizará la influencia del sexo en el riesgo de producirse arritmias cardíacas en ausencia y en presencia de ciertas hormonas, en el SQTL y en el efecto de fármacos. Se empleará el modelo de Tomek et al. como línea base, que es un modelo de potencial de acción ventricular de base humana. A este modelo se le aplicarán las modificaciones necesarias para simular el sexo, las hormonas, varios tipos de SQTL y determinados fármacos. Con los 105 modelos generados se elaborarán poblaciones de 809 individuos para cada caso y se representarán los resultados obtenidos mediante histogramas de los APD90 y de sus incrementos para cada una de las poblaciones del estudio. Los resultados muestran que la duración de los potenciales de acción es mayor en mujeres que en hombres. Además, las hormonas sexuales en hombres (testosterona) acortan el APD90, mientras que ocurre lo contrario para el caso de las mujeres, ya que la duración de APD90 aumentará de menor a mayor prolongación en la fase folicular temprana, lútea o folicular tardía respectivamente. Cada una de las tres fases del ciclo menstrual se originan en combinación de diferentes concentraciones de estradiol y progesterona. El estudio muestra una prolongación del APD en presencia de SQTL1, SQTL2 y SQTL3, obteniéndose mayores prolongaciones de APD para SQTL2 y SQTL3 y teniendo el SQTL3 la mayor variabilidad de incrementos de APD90.

[ES] Las enfermedades cardiovasculares siguen siendo la principal causa de muerte en Europa. Las arritmias cardíacas son una causa importante de muerte súbita, pero sus mecanismos son complejos. Esto denota la importancia de su estudio y prevención. La investigación sobre electrofisiología cardíaca ha demostrado que las anomalías eléctricas causadas por mutaciones que afectan a canales cardíacos pueden desencadenar arritmias. Sorprendentemente, se ha descubierto una gran variedad de fármacos proarrítmicos, incluidos aquellos que usamos para prevenirlas. Las indicaciones de uso de fármacos actuales intentaron solucionar este problema diseñando una prueba para identificar aquellos fármacos que podían ser peligrosos basado en el bloqueo de un solo canal iónico. El estudio de las interacciones fármaco-canal ha revelado la existencia no sólo de compuestos que bloquean múltiples canales, sino también una gran complejidad en esas interacciones. Esto podría explicar por qué algunos medicamentos pueden mostrar efectos muy diferentes en la misma enfermedad. Existen dos desafíos importantes con respecto a los efectos de los fármacos en la electrofisiología cardíaca. Por un lado, las empresas y entidades reguladoras están buscando una herramienta de alto rendimiento que mejore la detección del potencial proarrítmico durante el desarrollo de fármacos. Por otro lado, los pacientes con anomalías eléctricas a menudo requieren tratamientos personalizados más seguros. Las simulaciones computacionales contienen un poder sin precedentes para abordar fenómenos biofísicos complejos. Deberían ser de utilidad a la hora de determinar las características que definen tanto los efectos beneficiosos como no deseados de los fármacos mediante la reproducción de datos experimentales y clínicos. En esta tesis doctoral, se han utilizado modelos computacionales y simulaciones para dar respuesta a estos dos desafíos. El estudio de los efectos de los fármacos sobre la actividad cardíaca se dividió en e, [CA] Les malalties cardiovasculars continuen sent la principal causa de mort a Europa. Les arrítmies cardíaques són una causa important de mort sobtada, però els seus mecanismes són complexos. Això denota la importància del seu estudi i prevenció. La investigació sobre electrofisiologia cardíaca ha demostrat que les anomalies elèctriques que afecten a canals cardiacs poden desencadenar arrítmies. Sorprenentment, s'ha descobert una gran varietat de fàrmacs proarrítmics, inclosos aquells que utilitzem per a previndre-les. Les indicacions d'ús de fàrmacs actuals van intentar solucionar aquest problema dissenyant una prova per a identificar aquells fàrmacs que podien ser perillosos basada en el bloqueig d'un sol canal iònic. L'estudi de les interaccions fàrmac-canal ha revelat l'existència no sols de compostos que bloquegen múltiples canals, sinó també una gran complexitat en aquestes interaccions. Això podria explicar per què alguns medicaments poden mostrar efectes molt diferents en la mateixa malaltia. Existeixen dos desafiaments importants respecte als efectes dels fàrmacs en la electrofisiologia cardíaca. D'una banda, les empreses i entitats reguladores estan buscant una eina d'alt rendiment que millore la detecció del potencial proarrítmic durant el desenvolupament de fàrmacs. D'altra banda, els pacients amb anomalies elèctriques sovint requereixen tractaments personalitzats més segurs. Les simulacions computacionals contenen un poder sense precedents per a abordar fenòmens biofísics complexos. Haurien de ser d'utilitat a l'hora de determinar les característiques que defineixen tant els efectes beneficiosos com no desitjats dels fàrmacs mitjançant la reproducció de dades experimentals i clíniques. En aquesta tesi doctoral, s'han utilitzat models computacionals i simulacions per a donar resposta a aquests dos desafiaments. L'estudi dels efectes dels fàrmacs sobre l'activitat cardíaca es va dividir en l'estudi de la seva seguretat i la seva eficacia. Per a donar res, [EN] Cardiovascular disease remains the main cause of death in Europe. Cardiac arrhythmias are an important cause of sudden death, but their mechanisms are complex. This denotes the importance of their study and prevention. Research on cardiac electrophysiology has shown that electrical abnormalities caused by mutations in cardiac channels can trigger arrhythmias. Surprisingly, a wide variety of drugs have also shown proarrhythmic potential, including those that we use to prevent arrhythmia. Current guidelines designed a test to identify dangerous drugs by assessing their blocking power on a single ion channel to address this situation. Study of drug-channel interactions has revealed not only compounds that block multiple channels but also a great complexity in those interactions. This could explain why similar drugs can show vastly different effects in some diseases. There are two important challenges regarding the effects of drugs on cardiac electrophysiology. On the one hand, companies and regulators are in search of a high throughput tool that improves proarrhythmic potential detection during drug development. On the other hand, patients with electrical abnormalities often require safer personalized treatments owing to their condition. Computer simulations provide an unprecedented power to tackle complex biophysical phenomena. They should prove useful determining the characteristics that define the drugs' beneficial and unwanted effects by reproducing experimental and clinical observations. In this PhD thesis, we used computational models and simulations to address the two abovementioned challenges. We split the study of drug effects on the cardiac activity into the study of their safety and efficacy, respectively. For the former, we took a wider approach and generated a new easy-to-use biomarker for proarrhythmic potential classification using cardiac cell and tissue human action potential models. We integrated multiple channel block through IC50s and therapeut

[EN] Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation¿namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M¿using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters¿ value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor¿s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor¿s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor¿s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor¿s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhyth

[ES] La evaluación de la cardiotoxicidad es clave en el desarrollo de nuevos compuestos y se suele realizar analizando el grado de bloqueo que provocan en los canales de potasio relacionados con el gen humano ether-à-go-go (hERG). El objetivo de este trabajo es desarrollar un clasificador que determine la preferencia de un fármaco para unirse a un estado determinado del canal. Se ha creado un conjunto de 2600, divididos en 13 clases, bloqueadores virtuales con diferentes afinidades y cinéticas por los estados conformacionales del canal. Se realizaron simulaciones utilizando tres protocolos de estimulación que aumentan la probabilidad del canal de ocupar ciertos estados. Para cada simulación se han tomado tres medidas: IC50, la constante de recuperación de la corriente de potasio IKr y una estimación del tiempo necesario para alcanzar el estado estacionario. Por lo tanto, se obtuvieron 9 variables por cada fármaco estudiado. Se desarrolló, entrenó y evaluó un clasificador en dos pasos. En primer lugar, se usaron máquinas de soporte vectorial sobre las IC50 para separar las 13 clases en tres grupos con 4, 5 y 4 clases respectivamente. En segundo lugar, se usaron redes neuronales en cada grupo para terminar de clasificar los bloqueadores. Los tres clasificadores obtuvieron una precisión global en los grupos de test del 90.83, 88.66 y 89.16% respectivamente.

[EN] The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak

[EN] Drug-induced torsade de pointes (TdP) is a life-threatening ventricular arrhythmia responsible for the withdrawal of many drugs from the market. Although currently used TdP risk-assessment methods are effective, they are expensive and prone to produce false positives. In recent years, in silico cardiac simulations have proven to be a valuable tool for the prediction of drug effects. The objective of this work is to evaluate different biomarkers of drug-induced proarrhythmic risk and to develop an in silico risk classifier. Cellular simulations were performed using a modified version of the O'Hara et al. ventricular action potential model and existing pharmacological data (IC50 and effective free therapeutic plasma concentration, EFTPC) for 109 drugs of known torsadogenic risk (51 positive). For each compound, four biomarkers were tested: T-x (drug concentration leading to a 10% prolongation of the action potential over the EFTPC), T-qNet (net charge carried by ionic currents when exposed to 10 times the EFTPC with respect to the net charge in control), T-triang (triangulation for a drug concentration of 10 times the EFTPC over triangulation in control), and T-EAD (drug concentration originating early afterdepolarizations over EFTPC). Receiver operating characteristic (ROC) curves were built for each biomarker to evaluate their individual predictive quality. At the optimal cutoff point, accuracies for T-x, T-qNet, T-triang, and T-EAD were 89.9, 91.7, 90.8, and 78.9% respectively. The resulting accuracy of the hERG IC50 test (current biomarker) was 78.9%. When combining T-x, T-qNet and T-triang into a classifier based on decision trees, the prediction improves, achieving an accuracy of 94.5%. The sensitivity analysis revealed that most of the effects on the action potential are mainly due to changes in I-Kr, I-CaL, I-NaL and I-Ks. In fact, considering that drugs affect only these four currents, TdP risk classification can be as accurate as when considering effect

Every sheet in described files contains a table of numbers (doubles), resulting from the transformation of a three-dimensional matrix. To do so, the first three columns of each table contain the Coordinates x, y and z or z' of the original matrix respectively (no units). They range from -3 to 1.5. Coordinates were calculated as the logarithm of the ratio of a drug concentration (C) over the concentration that is required to inhibit a 50% of a given ion channel current (Half inhibitory concentration or IC50). They represent the block effect of such drug on four main currents which control the Action Potential shape and duration, namely, the rapid component of the potassium delayed rectifier current (IKr), the slow component of the potassium delayed rectifier current (IKs), the late sodium current (INaL) and the calcium type L current (ICaL). The following formulae can be used to deduce mentioned Coordinates: x = log_10(C/(IC_50 (I_Kr))) ; y = log_10(C/(IC_50 (I_CaL ) )); z = log_10(C/(IC_50 (I_CaL)); and z' = log_10(C/(IC_50 (I_NaL)). These are indeed part of the Hill equation (Hill coefficient set to 1), where G is the channel’s resulting conductance and G0 is the channel’s control conductance: G_[x || y || z || z'] = G_0·1/(1+C/(IC_(50, [x || y || z || z'] ) )) = G_0·1/(1+10^([x || y || z || z']) ). Conductances of the four main currents are thus translated into cardiac cellular or tissue models to study the effect of a wide range of drug concentrations. The following parameters were obtained and summarized in currently described files. Detailed methods of the performed simulations, as well as biomarker calculations, can be consulted in [1]., This repository contains the Matlab functions used in [1] and six Excel files named “Tx matrix KrKsCaL.xlsx”, “Tx matix KrNaLCaL.xlsx”, “TqNet matrix KrKsCaL.xlsx”, “TqNet matrix KrNaLCaL.xlsx”, "Ttirang matrix KrKsCaL.xlsx" and “Ttirang matrix KrNaLCaL.xlsx”. These files contain the value of three arrhythmogenic indices proposed in [1] (Tx, TqNet and Ttriang) resulting from simulations of drug effects on the action potential. The simulations were performed in a modified version of the O’Hara-Rudy model (ORd) [2] of human endocardial ventricular cells (492.536 simulations). References: [1]. Llopis J., Gomis-Tena J., Cano J., Romero L., Saiz J., Trenor B. In-Silico Classifiers for Assessment of Drug Proarrhythmicity. 2020 (Currently under revision) [2]. O’Hara, T.; Virág, L.; Varró, A.; Rudy, Y. Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Comput. Biol. 2011, 7 (5), e1002061.

[EN] Atrial fibrillation (AF) is the most common cardiac arrhythmia characterized by disorganized electrical activations of the upper chambers of the heart, leading to uncoordinated contraction and compromising the pumping action of the organ. AF risk factors include cardiovascular pathologies, endocrine disorders, advanced age, obesity, smoking and heritability. Genetic mutations affecting gene encoding for ion channel protein structures are in fact considered as cause of fibrillatory events in individuals who do not present any other co-morbidities. In this work, two genetic mutations found in literature and affecting the alpha-subunit of the rapid delayed rectifier potassium channel are modelled, by reparametrizing the IKr current formulation and by fitting it to mutant experimental data. The modified potassium current was then incorporated into the Courtemanche-Ramirez-Nattel (CRN) model and single cell simulations have been performed to study the mutations¿ effects on action potential and current traces, as well as, restitution properties, in right and left atrium. Both mutations produced a shortening of the action potential duration at 90% of repolarization (APD90), a higher current peak and lower APD values in the restitution curves. T895M yielded also to a reduction in the maximum slope of restitution curve. Tissue patch simulations revealed that T895M and T436M provide a substrate to initiate and maintain re-entries during the 5 seconds of simulation. Rotor¿s meandering in T895M appears more stable with a less extended area and more regular pattern than in T436M. Investigation on 3D atria and torso models will be necessary to provide further insights in understanding the mechanisms behind these genetic mutations.

[EN] Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-a-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our threeprotocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.

Every sheet in described files contains a table of numbers (doubles), resulting from the transformation of a three-dimensional matrix. To do so, the first three columns of each table contain the Coordinates x, y and z or z' of the original matrix respectively (no units). They range from -3 to 1.5. Coordinates were calculated as the logarithm of the ratio of a drug concentration (C) over the concentration that is required to inhibit a 50% of a given ion channel current (Half inhibitory concentration or IC50). They represent the block effect of such drug on four main currents which control the Action Potential shape and duration, namely, the rapid component of the potassium delayed rectifier current (IKr), the slow component of the potassium delayed rectifier current (IKs), the late sodium current (INaL) and the calcium type L current (ICaL). The following formulae can be used to deduce mentioned Coordinates: x = log_10(C/(IC_50 (I_Kr))) ; y = log_10(C/(IC_50 (I_CaL ) )); z = log_10(C/(IC_50 (I_CaL)); and z' = log_10(C/(IC_50 (I_NaL)). These are indeed part of the Hill equation (Hill coefficient set to 1), where G is the channel’s resulting conductance and G0 is the channel’s control conductance: G_[x || y || z || z'] = G_0·1/(1+C/(IC_(50, [x || y || z || z'] ) )) = G_0·1/(1+10^([x || y || z || z']) ). Conductances of the four main currents are thus translated into cardiac cellular or tissue models to study the effect of a wide range of drug concentrations. The following parameters were obtained and summarized in currently described files. Detailed methods of the performed simulations, as well as biomarker calculations, can be consulted in [1]., This repository contains the Matlab functions used in [1] and six Excel files named “Tx matrix KrKsCaL.xlsx”, “Tx matix KrNaLCaL.xlsx”, “TqNet matrix KrKsCaL.xlsx”, “TqNet matrix KrNaLCaL.xlsx”, "Ttirang matrix KrKsCaL.xlsx" and “Ttirang matrix KrNaLCaL.xlsx”. These files contain the value of three arrhythmogenic indices proposed in [1] (Tx, TqNet and Ttriang) resulting from simulations of drug effects on the action potential. The simulations were performed in a modified version of the O’Hara-Rudy model (ORd) [2] of human endocardial ventricular cells (492.536 simulations). References: [1]. Llopis J., Gomis-Tena J., Cano J., Romero L., Saiz J., Trenor B. In-Silico Classifiers for Assessment of Drug Proarrhythmicity. 2020 (Currently under revision) [2]. O’Hara, T.; Virág, L.; Varró, A.; Rudy, Y. Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Comput. Biol. 2011, 7 (5), e1002061.

[EN] Assessment of drug cardiotoxicity is crucial in the development of new compounds and is typically addressed by evaluating the blockade they cause in the potassium human ether-à-go-go related gene (hERG) channels. Our objective is to develop a classifier to determine the preference for binding to the different states of a drug. We created a set of 2600 virtual blockers with different affinities and kinetics to the conformational states of the channel divided into 13 classes. Simulations were carried out using three stimulation protocols that enhance the probabilities of the channel to occupy a certain state. Three measurements were taken for each of the simulations: IC50, the recovery constant of the IKr potassium current and an estimation of the time required for the simulation to be stable. Therefore, we obtained 9 variables for each of the blockers studied. A two-step classifier was developed, trained and evaluated. First, we used support vector machines on the IC50 to separate the 13 classes into three groups with 4, 5 and 4 classes respectively. Secondly, we used neural networks on each group with all the variables to finally classify the blockers. The three classifiers obtained an overall accuracy on the test group of 90.83, 88.66 and 89.16% for each of the groups respectively.

[EN] Genetic mutations affecting genes encoding for ion channel protein structures have been associated with the presence of atrial fibrillation (AF) in healthy individuals. The aim of this study is to model and simulate the effects of two gain-of-function mutations found in literature, T895M and T436M, and affecting the rapid delayed rectifier potassium current. Courtemanche human atrial model has been chosen to reproduce myocytes behaviour and an optimization algorithm has been employed to fit model parameters to experimental data. Single cell and tissue patch simulations have been performed to study the effects of the two mutations in control, paroxysmal and permanent AF conditions, both in right and left atrium. 0D simulations revealed that both mutations cause an increase in IKr current, leading to action potential duration shortening and flattening of restitution curves, especially in presence of the mutation T895M. Initiation of a re-entrant activity in 2D simulations were possible both in case of T895M and T436M. The study reports the arrhythmogenicity of the two mutants and reveals T895M having a stronger effect with respect to T436M, in particular in control rather than in paroxysmal and permanent AF conditions. Differences in the dynamics of the two mutations highlight the importance of a patient-specific approach in planning targeted drug therapies.

[EN] Background: Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterized by alteration of the action potential (AP) propagation. Under persistent AF, myocytes undergo electrophysiological and structural remodeling, which involves fibroblast proliferation and differentiation, modifying the substrate for AP propagation. The aim of this study was to analyze the effects on the AP of fibroblast-myocyte coupling during AF and its propagation in different regions of the atria. Methods: Isolated myocytes were coupled to different numbers of fibroblasts using the established AP models and tissue simulations were performed by randomly distributing fibroblasts. Fibroblast formulations were updated to match recent experimental data. Major ion current conductances of the myocyte model were modified to simulate AP heterogeneity in four different atrial regions (right atrium posterior wall, crista terminalis, left atrium posterior wall, and pulmonary vein) according to experimental and computational studies. Results: The results of the coupled myocyte-fibroblast simulations suggest that a more depolarized membrane potential and higher fibroblast membrane capacitance have a greater impact on AP duration and myocyte maximum depolarization velocity. The number of coupled fibroblasts and the stimulation frequency are determining factors in altering myocyte AP. Strand simulations show that conduction velocity tends to homogenize in all regions, while the left atrium is more likely to be affected by fibroblast and AP propagation block is more likely to occur. The pulmonary vein is the most affected region, even at low fibroblast densities. In 2D sheets with randomly placed fibroblasts, wavebreaks are observed in the low density (10%) central fibrotic zone and when fibroblast density increases (40%) propagation in the fibrotic region is practically blocked. At densities of 10 and 20% the width of the vulnerable window increases with respect to control but is decrea

[EN] Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and the most important cause of embolic stroke, requiring new technologies for its better understanding and therapies. Recent approaches to map the electrical activity during AF with multi-electrode systems aim at localizing patient-specific ablation targets of reentrant patterns. However, there is a critical need to determine the accuracy of those mapping systems. We performed computer simulations as a numerical approach of systematically evaluating the influence of far-field sources on the electrical recordings and detection of rotors. Methods We constructed 2 computer models of atrial tissue: (i) a 2D sheet model with varying non-active cells area in its center, and (ii) a whole realistic 3D atrial model. Phase maps were built based on the Hilbert transform of the unipolar electrograms recorded by virtual 2D and 3D multi-electrode systems and rotors were tracked through phase singularities detections. Results Analysis of electrograms recorded away from the 2D atrial model shows that the larger the distance between an electrode and the tissue model, the stronger the far-field sources contribution to the electrogram is. Importantly, even if an electrode is positioned in contact with the tissue, the electrogram contains significant contributions from distal sources that blur the distinction between anatomical and functional reentries. Moreover, when mapping the 3D atrial model, remote activity generated false phase singularities at locations without local reentrant excitation patterns. Conclusions Far-field contributions to electrograms during AF reduce the accuracy of detecting and interpreting reentrant activity.

[ES] La predicción de efectos adversos de los fármacos se ha convertido en una prioridad tanto para las empresas farmacéuticas como para las agencias reguladoras. Hasta ahora, este tipo de estudios se han realizado de forma experimental fijándose en la prolongación del intervalo QT del electrocardiograma o en la duración del potencial de acción celular. Sin embargo, existen otros biomarcadores asociados a la arritmogénesis, como los que se agrupan dentro del protocolo TRIaD (del inglés): Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. También pueden encontrarse otro tipo de biomarcadores que evalúan la propagación del estímulo en el tejido, como la ventana vulnerable (VW) o la dispersión transmural de la refractariedad (TRD), también muy útiles para evaluar la proarritmicidad de fármacos. Como el proceso de descubrimiento y desarrollo de nuevos fármacos está lejos de ser satisfactorio, varias iniciativas internacionales están estudiando la posibilidad de utilizar la simulación de la actividad cardíaca para la predicción del efecto de los fármacos. En el previo Trabajo de Fin de Grado se desarrollaron herramientas software para evaluar la cardiotoxicidad en fármacos bloqueadores de la componente rápida de la corriente diferida de potasio (IKr). En dicho trabajo se simuló el comportamiento de estas sustancias sobre la actividad eléctrica de una célula cardiaca excitable ventricular humana con la implementación del protocolo TRIaD. En el presente Trabajo de Fin de Máster se estudia el efecto de los fármacos a nivel unidimensional y analizar sus efectos en la VW y la TRD. El desarrollo de las herramientas necesarias para la simulación de estos nuevos biomarcadores a nivel de fibra ha resultado complejo. Para ello se ha modificado el programa de fibra ventricular de O¿Hara y Rudy (2011) en el que se ha reemplazado el modelo de la corriente del canal hERG con el mo, [EN] The prediction of adverse effects of drugs has become a priority for both pharmaceutical companies and regulatory agencies. Until now, this type of studies has been carried out in an experimental noting in the prolongation of the QT interval of the electrocardiogram or in the cellular action potential duration. However, there are other biomarkers associated with arrhythmogenesis, such as the TRIaD protocol: Triangulation, Reverse use dependence, beat-tobeat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Another type of biomarkers that evaluate the propagation of the stimulus in the tissue can be founded, such as the vulnerable window (VW) or the transmural refractoriness dispersion (TRD), also very useful to evaluate the proarrhythmicity of drugs. As the process of discovery and development of new drugs is far from being satisfactory, several international initiatives are studying the possibility of using cardiac activity simulation to predict the effect of drugs. In the previous Trabajo de Fin de Grado, software tools were developed to evaluate the the cardiotoxicity of drugs that block the fast-delayed-current potassium component (I"#). In that work, the electrical activity of human cardiac cells was simulated by applying the TRIaD protocol. In the present Trabajo de Fin de Máster is studied the effect of the drugs to one-dimensional level and the analysis of his effects in the VW and the TRD. The development of the necessary tools for the simulation of these new biomarkers to a fibrelevel has been complex. For this, the fibre-model of O¿Hara and Rudy (2011) has been modified, in which the current model of the hERG channel has replaced with the Fink¿s (2008) Markov model, that allows to include the effect of drugs more precisely. Besides, a series of functions and protocols to calculate the VW and TRD biomarkers to a multicellular level have been developed. Finally, a multiscale study of the drugs has, [CA] La predicció d'efectes adversos dels fàrmacs s'ha convertit en una prioritat tant per a les empreses farmacèutiques com per a les agències reguladores. Fins ara, aquest tipus d'estudis s'han realitzat de forma experimental fixant-se en la prolongació de l'interval QT de l'electrocardiograma o en la duració del potencial d'acció cel·lular. No obstant açò, existixen altres biomarcadors associats a l'arritmogénesi, com els que s'agrupen dins del protocol TRIaD (de l'anglès): Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. També poden trobarse un altre tipus de biomarcadors que avaluen la propagació de l'estímul en el teixit, com la finestra vulnerable (VW) o la dispersió transmural de la refractarietat (TRD), també molt útils per a avaluar la proarritmicitat de fàrmacs. Donat que el procés de descobriment i desenvolupament de nous fàrmacs està lluny de ser satisfactori, diverses iniciatives internacionals estan estudiant la possibilitat d'utilitzar la simulació de l'activitat cardíaca per a la predicció de l'efecte dels fàrmacs. En el previ Treball de Fi de Grau previ es van desenvolupar eines programari per a avaluar la cardiotoxicitat en fàrmacs bloquejadors de la component ràpida del corrent diferit de potassi (IKr). En aquest treball es va simular el comportament d'aquestes substàncies sobre l'activitat elèctrica d'una cèl·lula cardíaca excitable ventricular humana amb la implementació del protocol TRIaD. En el present Treball de Fi de Màster s'estudia l'efecte dels fàrmacs a nivell unidimensional i analitzar els seus efectes en la VW i la TRD. El desenvolupament de les eines necessàries per a la simulació d'aquests nous biomarcadors a nivell de fibra ha resultat complex. Per a açò s'ha modificat el programa de fibra ventricular d'O’Hara i Rudy (2001) en el qual s'ha reemplaçat el model del corrent del canal hERG amb el model de Markov de Fink (2008), q

[ES] Hoy en día, una de las causas más importantes de morbilidad y mortalidad en países desarrollados son las arritmias cardiacas. Por este motivo su prevención y tratamiento son uno de los principales desafíos de los sistemas de salud. Las mutaciones genéticas, cuyo estudio se ha extendido en los últimos años, tienen gran importancia en la producción de estas arritmias. El objetivo de este trabajo final de máster es modelizar la mutación RyR2R4497C del canal de liberación de calcio del retículo sarcoplasmático (RyR2) y la mutación del tipo CASQ2(-/-) de la proteína calsequestrina. Para la modelización de la mutación del RyR2 se ha utilizado una herramienta de ajuste automático de parámetros. El modelo matemático celular empleado ha sido el de cardiomiocito ventricular desarrollado por Grandi y colaboradores (2010) con las modificaciones introducidas por Moreno y colaboradores (2013), que incorpora un modelo de Markov del canal RyR. Para la mutación CASQ2(-/-) nos hemos basado en el modelo desarrollado por Yang y colaboradores (2015) y lo hemos adaptado para incluirla en el modelo matemático utilizado en este estudio. Para el estudio poblacional se han modificado las principales corrientes de membrana en un rango de ±100% de su valor en control siguiendo una distribución uniforme. Para evaluar la importancia de las corrientes modificadas en la población se ha realizado una correlación entre dichas corrientes y los biomarcadores estudiados. El modelo de la mutación RyR2R4497C reproduce los biomarcadores para la mutación, es decir, un pico máximo de calcio intracelular de 4.63 y 5.53 mM a 2Hz con y sin beta estimulación respectivamente y 3.70 y 4.37 mM a 3Hz con y sin beta estimulación. Un tiempo de pico del calcio intracelular de 22.70 y 25.70 ms a 2Hz con y sin beta estimulación y 29.90 y 31.60 ms a 3Hz con y sin beta estimulación. La adaptación la mutación CASQ2(-/-) reproduce las alteraciones electrofisiológicas observadas, esto es la aparición de actividad eléctr, [EN] ABSTRACT Nowadays, cardiac arrhythmias are one of the most important causes of mortality and morbidity in developed countries. For this reason, their prevention and treatment are among the main challenges for the health services. Genetic mutations, which study has seen an increase in recent years, do play an important role in the appearance of such arrhythmias. The objective of this end of master project is to model the RyR2R4497C mutation of the sarcoplasmático reticulum calcium release channel (RyR2) and the CASQ2(-/-) type mutation of the protein calsequestrin. In order to model the RyR2 mutation an automatic optimization tool has been used. The mathematical cellular model that has been used is the one developed by Grandi et al. (2010) with the modifications introduced by Moreno et al. (2013), this model includes a Markov formulation for the RyR2 channel. For the CASQ2(-/-) mutation we have adapted an existing model developed by Yang et al. (2015) and include it in the mathematical model used in this study. For the population analysis we have modified the main membrane currents in a range of ±100% of its nominal value according to a uniform distribution. To evaluate the importance of the modified currents in the population a correlation analysis has been carried out between these currents and the studied biomarkers. The model of the RyR2R4497C mutation reproduces the biomarkers observed for the mutation, that is, a maximum intracellular calcium peak of 4.63 and 5.53 mM at 2Hz with and without beta stimulation respectively and 3.70 and 4.37 mM at 3Hz with and without beta stimulation. An intracellular calcium time to peak of 22.70 and 25.70 ms at 2Hz with and without beta stimulation and 29.90 and 31.60 ms at 3Hz with and without stimulation. The adaptation of the CASQ2(-/-) mutation reproduces the electrophysiological alterations observed experimentally, that is the appearance of ectopic electrical activity between pulses of the simulations and spontaneous a

[EN] Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35¿94% of the simulation time, depending on the basket¿s position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.

[ES] Hoy en día, la mayoría de los estudios relacionados con el comportamiento eléctrico del corazón y sus alteraciones consisten en ensayos experimentales, principalmente en animales. Una alternativa que se encuentra en auge son los modelos computacionales de cardiomiocitos. Estos modelos ofrecen numerosas ventajas frente a los ensayos experimentales entre las que destacan la gran reproducibilidad y repetibilidad y la posibilidad de realizar modificaciones para simular condiciones anómalas y sus tratamientos. Las mutaciones en genes relacionados con las células cardiacas suelen derivar en alteraciones de la función celular que conllevan la aparición de fenómenos adversos como las arritmias. Los modelos computacionales pueden ser adaptados para reproducir los cambios experimentales observados en portadores de las mutaciones. Gracias a estos modelos personalizados es posible estudiar posteriormente los efectos que fármacos o tratamientos tienen sobre las células o el tejido. En el trabajo final de grado presentado a continuación, se han desarrollado una serie de herramientas computacionales para evaluar el efecto de alteraciones en la dinámica de calcio. Las herramientas se han programado en Matlab y para facilitar su uso se ha creado una sencilla interfaz gráfica que implementa todas las funciones y permite realizar el análisis completo. Para probar el funcionamiento de la herramienta, se ha realizado un análisis de sensibilidad de determinados biomarcadores electrofisiológicos con las velocidades de transición del modelo de Markov del canal de liberación de calcio del retículo sarcoplasmático (RyR2). Los biomarcadores estudiados son: el pico máximo del potencial de membrana, los valores máximos de la concentración de calcio en los compartimentos celulares, la probabilidad del estado abierto del canal RyR2, el tiempo de pico de la concentración intracelular de calcio, el pico máximo de la corriente de calcio tipo L (ICaL) y el periodo del potencial de membrana (BCL, [EN] Nowadays, most of the studies related to the electrical behaviour of the heart and its alterations are experimental, mainly on animals. Computational models of cardiac myocytes are an alternative which is becoming more relevant in recent years. These models offer a wide range of advantages over experimental techniques, reproducibility, repeatability and the possibility of making modifications to simulate abnormal conditions and treatments being the most important. Mutations in genes related to cardiac cells often results in alterations of the cellular function that may lead to adverse effects such as arrhythmia. Computational models can be modified to reproduce the experimental changes produced by a mutation. Further comprehension of the effect of treatments and drugs on cells and tissues can be achieved by using these models. In this bachelor’s degree final project, a series of software tools have been developed to analyse the effect of alterations in the calcium dynamics. The tools have been programmed on Matlab and a simple user interface has been created for facilitate its use. A sensitivity analysis of certain biomarkers with the transition rates of the Markov model for the sarcoplasmic reticulum calcium release channel (RyR2) has been conducted by using these tools. The studied biomarkers are: maximum peak of the membrane potential, maximum value if the calcium concentration in the cell model compartments, RyR2 channel open state probability, time to peak of the intracellular calcium concentration, maximum peak of the type L calcium current (ICaL) and the basic cycle length (BCL) of the action potential. The effects of a shift on the type L calcium current’s activation gate (dL) have also been studied. The results of this sensitivity analysis have been used to propose a model for the RyR2’s R420Q mutation based on the experimental changes reported by Wang et al. (2017). These changes are: increased time to peak of the intracellular calcium concentration a, [CA] Avui dia, la majoria dels estudis relacionats amb el comportament elèctric del cor i les seues alteracions consisteixen en assajos experimentals, principalment en animals. Una alternativa que es troba en auge són els models computacionals de cardiomiòcits. Aquests models ofereixen nombrosos avantatges enfront dels assajos experimentals entre les quals destaquen la gran reproductibilitat i repetibilitat i la possibilitat de realitzar modificacions per a simular condicions anòmales i els seus tractaments. Les mutacions en gens relacionats amb les cèl·lules cardíaques solen derivar en alteracions de la funció cel·lular que comporten l'aparició de fenòmens adversos com les arítmies. Els models computacionals poden ser adaptats per a reproduir els canvis experimentals observats en portadors de les mutacions. Gràcies a aquests models personalitzats és possible estudiar posteriorment els efectes que fàrmacs o tractaments tenen sobre les cèl·lules o el teixit. En el treball final de grau presentat a continuació, s'han desenvolupat una sèrie d'eines computacionals per a avaluar l'efecte d'alteracions en la dinàmica de calci. Les eines s'han programat en Matlab i per a facilitar el seu ús s'ha creat una senzilla interfície gràfica que implementa totes les funcions i permet realitzar l'anàlisi completa. Per a provar el funcionament de l'eina, s'ha realitzat una anàlisi de sensibilitat de determinats biomarcadors electrofisiològics amb les velocitats de transició del model de Markov del canal d'alliberament de calci del reticle sarcoplasmàtic (RyR2). Els biomarcadors estudiats són: el pic màxim del potencial de membrana, els valors màxims de la concentració de calci en els compartiments cel·lulars, la probabilitat de l'estat obert del canal RyR2, el temps de pic de la concentració intracel·lular de calci, el pic màxim del corrent de calci tipus L (ICaL) i el període del potencial de membrana (BCL basic cycle length). També s'ha estudiat l'efecte del desplaçament de la comp

[EN] Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models (O'Hara, T., et al. PLos Comput. Biol. 2011, 7, e1002061) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current (I-Ks and I-Kr, respectively) and the L-type calcium current (I-CaL) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC50 based test.

[EN] Potassium levels in the plasma, [Kþ]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0 mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [Kþ]o levels of approx. 3.0 mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main Kþ-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1 mM) in [Kþ]o result in significant alterations in two different Kþ currents, IK1 and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane Kþ currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.

La fibrilación auricular es una de las arritmias cardíacas más comunes observadas en la práctica clínica. Por lo tanto, es de vital importancia desarrollar nuevas tecnologías destinadas a diagnosticar y acabar con este tipo de arritmia, para mejorar la calidad de vida de los pacientes y reducir los costes de los sistemas nacionales de salud. En los últimos años ha aumentado el uso de las nuevas técnicas de mapeo auricular, basadas en sistemas multi-electrodo para mapear la actividad eléctrica en humanos. Dichas técnicas permiten localizar y ablacionar los impulsores de la fibrilación auricular, como son las fuentes focales o los rotores. Sin embargo, todavía existe incertidumbre sobre su precisión y los procedimientos experimentales para su análisis están limitados debido a su carácter invasivo. Por lo tanto, las simulaciones computacionales son una herramienta muy útil para superar estas limitaciones, al permitir reproducir con fidelidad las observaciones experimentales, dividir el problema bajo estudio en sub-estudios más simples, y realizar investigaciones preliminares imposibles de llevar a cabo en el práctica clínica. Esta tesis doctoral se centra en el análisis de la precisión de los sistemas de mapeo multi-electrodo a través de modelos y simulaciones computacionales. Para ello, desarrollamos modelos realistas multi-escala con el objetivo de simular actividad eléctrica auricular reentrante, en primer lugar en una lámina de tejido auricular, y en segundo lugar en las aurículas completas. Posteriormente, analizamos los efectos de las configuraciones geométricas multi-electrodo en la precisión de la localización de los rotores, mediante el uso de agrupaciones multi-electrodo con distancias inter-electrodo equidistantes, así como a través de catéteres de tipo basket con distancias inter-electrodo no equidistantes. Después de calcular los electrogramas unipolares intracavitarios, realizamos mapas de fase, detecciones de singularidad de fase para rastrear los rotore, Atrial fibrillation is one of the most common cardiac arrhythmias seen in clinical practice. Therefore, it is of vital importance to develop new technologies aimed at diagnosing and terminating this kind of arrhythmia, to improve the quality of life of patients and to reduce costs to national health systems. In the last years, new atrial mapping techniques based on multi-electrode systems are increasingly being used to map the atrial electrical activity in humans and localise and target atrial fibrillation drivers in the form of focal sources or rotors. However, significant concerns remain about their accuracy and experimental approaches to analyse them are limited due to their invasive character. Therefore, computer simulations are a helpful tool to overcome these limitations since they can reproduce with fidelity experimental observations, permit to split the problem to treat into more simple substudies, and allow the possibility of performing preliminary investigations impossible to carry out in the clinical practice. This PhD thesis is focused on the analysis for accuracy of the multielectrode mapping systems through computational models and simulations. For this purpose, we developed realistic multiscale models in order to simulate atrial electrical reentrant activity, first in a sheet of atrial tissue and, then, in the whole atria. Then, we analysed the effects of the multi-electrode geometrical configurations on the accuracy of localizing rotors, by using multi-electrode arrays with equidistant inter-electrode distances, as well as multi-electrode basket catheters with non-equidistant inter-electrode distances. After computing the intracavitary unipolar electrograms, we performed phase maps, phase singularity detections to track rotors, and dominant frequency maps. We finally found out that the accuracy of multi-electrode mapping systems depends on their position inside the atrial cavity, the electrode-to-tissue distance, the inter-electrode distance, and the, La fibril·lació auricular és una de les arítmies cardíaques més comuns observades en la pràctica clínica. Per tant, és de vital importància desenvolupar noves tecnologies destinades a diagnosticar i acabar amb aquest tipus d'arítmia, per tal de millorar la qualitat de vida dels pacients i reduir els costos dels sistemes nacionals de salut. En els últims anys, ha augmentat l'ús de les noves tècniques de mapeig auricular, basades en sistemes multielèctrode per a mapejar l'activitat elèctrica auricular en humans. Aquestes tècniques permeten localitzar i ablacionar els impulsors de la fibril·lació auricular, com són les fonts focals o els rotors. No obstant això, encara hi ha incertesa sobre la seua precisió i els procediments experimentals per al seu anàlisi estan limitats a causa del seu caràcter invasiu. Per tant, les simulacions computacionals són una eina molt útil per a superar aquestes limitacions, en permetre reproduir amb fidelitat les observacions experimentals, dividir el problema sota estudi en subestudis més simples, i realitzar investigacions preliminars impossibles de dur a terme en el pràctica clínica. Aquesta tesi doctoral es centra en l'anàlisi de la precisió del sistemes de mapeig multielèctrode mitjançant els models i les simulacions computacionals. Per a això, desenvolupàrem models realistes multiescala per tal de simular activitat elèctrica auricular reentrant, en primer lloc en una làmina de teixit auricular, i en segon lloc a les aurícules completes. Posteriorment, analitzàrem els efectes de les configuracions geomètriques multielèctrode en la precisió de la localització dels rotors, mitjançant l'ús d'agrupacions multielèctrode amb distàncies interelèctrode equidistants, així com catèters de tipus basket amb distàncies interelèctrode no equidistants. Després de calcular els electrogrames unipolars intracavitaris, vam realitzar mapes de fase, deteccions de singularitat de fase per a rastrejar els rotors, i mapes de freqüència dominants. Finalment

Every sheet in described files contains a table of numbers (doubles), resulting from the transformation of a three-dimensional matrix. To do so, the first two columns and the first row of each table contain the Coordinates x, y and z of the original matrix respectively (no units). They range from -3 to 1 for the x and y axis (first and second column) and from -3 to 0 for the z axis (first row). The nature of the remaining numbers differs between files: APD.xlsx contains the Action Potential Duration at 90% repolarization (APD90) values in milliseconds, QT.xlsx contains QT interval durations in milliseconds, Tx_APD.xlsx contains Tx values calculated from the tables in APD.xlsx and Tx_QT.xlsx contains Tx values calculated from the table in QT.xlsx. Coordinates were calculated as the logarithm of the ratio of a drug concentration (C) over the concentration that is required to inhibit a 50% of a given ion channel current (Half inhibitory concentration or IC50). They represent the block effect of such drug on three main currents which control the Action Potential shape and duration, namely, the rapid component of the potassium delayed rectifier current (IKr), the slow component of the potassium delayed rectifier current (IKs) and the calcium type L current (ICaL). The following formulae can be used to deduce mentioned Coordinates: x = log_10(C/(IC_50 (I_Kr))) ; y = log_10(C/(IC_50 (I_Ks ) )); z = log_10(C/(IC_50 (I_CaL))). These are indeed part of the Hill equation (Hill coefficient set to 1), where G is the channel’s resulting conductance and G0 is the channel’s control conductance: G_[x || y || z] = G_0·1/(1+C/(IC_(50, [x || y || z] ) )) = G_0·1/(1+10^([x || y || z]) ). Conductances of the three main currents are thus translated into cardiac cellular or tissue models to study the effect of a wide range of drug concentrations. The following parameters were obtained and summarized in currently described files. 1. APD90 values were obtained through simulation of the elect, This repository contains four Excel 2017 files named “APD.xlsx”, “QT.xlsx”, “Tx_APD.xlsx” and “Tx_QT.xlsx”. APD.xlsx and Tx_APD.xlsx files contain three sheets (called “Epi”, “Mid” and “Endo”), whereas the rest contain only one sheet (called “QT”). These files contain the results of simulations performed in the O’Hara-Rudy model (ORd) [1] of human ventricular cells (206.766 simulations) and tissue (7072 simulations), which consist of APD90 and QT intervals as well as a new index called Tx extracted from both APD and QT values. References: [1]. O’Hara, T.; Virág, L.; Varró, A.; Rudy, Y. Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Comput. Biol. 2011, 7 (5), e1002061. [2]. Romero L., Cano J., Gomis-Tena J., Trenor B., Sanz F., Pastor M., Saiz J. In silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk. Journal of Chemical Information and Modeling. 2017 (Currently in revision).

[ES] La predicción de efectos adversos de los fármacos se ha convertido en una prioridad tanto para las empresas farmacéuticas como para las agencias reguladoras. Hasta ahora, este tipo de estudios se han realizado de forma experimental fijándose en la prolongación del intervalo QT del electrocardiograma o en la duración del potencial de acción celular. Sin embargo, existen otros biomarcadores asociados a la arritmogénesis, como los que se agrupan dentro del protocolo TRIaD (del inglés): Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Como el proceso de descubrimiento y desarrollo de nuevos fármacos está lejos de ser satisfactorio, varias iniciativas internacionales están estudiando la posibilidad de utilizar la simulación de la actividad cardíaca para la predicción del efecto de los fármacos. En el presente Trabajo de Fin de Grado se ha desarrollado una nueva herramienta de software para evaluar la cardiotoxicidad en fármacos bloqueadores de la componente rápida de la corriente diferida de potasio (IKr) simulando el comportamiento de estas sustancias sobre la actividad eléctrica de una célula cardiaca excitable ventricular humana. Para ello se ha realizado la implementación informática del protocolo experimental TRIaD. Para ello se ha utilizado el modelo de cardiomiocito ventricular humano de O¿Hara y Rudy (2001) al cual se le ha modificado el modelo de la corriente del canal hERG con el modelo de Markov de Fink et al. (2008) que permite incluir el efecto de fármacos de un modo más detallado. Esta herramienta se ha implementado utilizando C y Matlab. Para facilitar su uso, se ha creado una sencilla interfaz gráfica para que pueda ser utilizada por personal sin conocimientos de programación, dotándose, además, con una ventana de resultados unificada para facilitar la interpretación de los resultados. Finalmente, se ha realizado un estudio con una gran varieda, [EN] The prediction of adverse drug effects has become a priority for both pharmaceutical companies and regulatory agencies. Until now, this kind of studies have been carried out in experimentally, paying attention to the prolongation of QT-interval of the electrocardiogram or the action potential duration. However, other biomarkers associated with arrhythmogenesis have been proposed, like those obtained with the TRIaD Protocol: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. As the process of discovery and development of new drugs is far from being successful, several international initiatives are studying the possibility of using the simulation of cardiac activity to predict the effect of drugs. In this Bachelor¿s Degree Final Project, a new software tool has been developed to evaluate the cardiotoxicity of drugs that block the fast-delayed-current potassium component (IKr) by simulating the effects of these substances on the electrical activity of a human ventricular excitable cardiac cell. For this purpose, a computational implementation of the experimental protocol TRIaD has been developed that uses a modified version of the human ventricular cardiomyocyte model of O'Hara and Rudy (2001) where the formulation of the HERG channel current has been replaced by the Markovian formulation proposed by Fink et al. (2008), which allows the inclusion of the drug-channel interaction more precisely. This tool has been implemented using C and Matlab. To ease its use, a simple graphical interface has been created, so that it can be used by personnel without programming experience. Besides, this tool provides a unified results window to help with the interpretation of the results. Finally, a study has been conducted using this tool with a wide variety of virtual drugs to shed light on the relationship between the characteristics of drugs and biomarkers of proarrhythmic

[EN] Abnormal intracellular Ca2+ handling is the major contributor to the depressed cardiac contractility observed in heart failure. The electrophysiological remodeling associated with this pathology alters both the action potential and the Ca2+ dynamics, leading to a defective excitation contraction coupling that ends in mechanical dysfunction. The importance of maintaining a correct intracellular Ca2+ concentration requires a better understanding of its regulation by ionic mechanisms. To study the electrical activity and ionic homeostasis of failing myocytes, a modified version of the O'Hara et al. human action potential model was used, including electrophysiological remodeling. The impact of the main ionic transport mechanisms was analyzed using single-parameter sensitivity analyses, the first of which explored the modulation of electrophysiological characteristics related to Ca2+ exerted by the remodeled parameters. The second sensitivity analysis compared the potential consequences of modulating individual channel conductivities, as one of the main effects of potential drugs, on Ca2+ dynamic properties under both normal conditions and in heart failure. The first analysis revealed the important contribution of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) dysfunction to the altered Ca2+ homeostasis, with the Na+/Ca2+ exchanger (NCX) and other Ca2+ cycling proteins also playing a significant role. Our results highlight the importance of improving the SR uptake function to increase Ca2+ content and restore Ca2+ homeostasis and contractility. The second sensitivity analysis highlights the different response of the failing myocyte versus the healthy myocyte to potential pharmacological actions on single channels. The result of modifying the conductances of the remodeled proteins such as SERCA and NCX in heart failure has less impact on Ca2+ modulation. These differences should be taken into account when designing drug therapies.

[EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.

[EN] This article shows the tracking of the transversal competences applied to different subjects in different engineering degrees of the Polytechnic University of Valencia (UPV), allowing us to obtain a broad view on the transversal competences. We focus on the comparison of the materials developed in each subject for the design and proposed activities of teaching - learning as well as in the design of specific evaluation instruments, obtaining evidence, etc. Finally, the evaluation strategies carried out as well as the obtained results are shown. The subjects analyzed in this paper are related because the belong to Engineering taught at UPV, by members of the teaching innovation group EITACURTE, which make periodic meetings in order to exchange ideas about their teaching experiences., [ES] En este artículo se realiza un seguimiento del trabajo realizado en competencias transversales en diferentes asignaturas de distintas titulaciones de ingeniería de la Universitat Politècnica de València (UPV), permitiéndonos obtener una visión amplia sobre éstas. Nos centramos en la comparación de los materiales desarrollados en cada asignatura para el diseño y propuesta de actividades de enseñanza - aprendizaje, así como en el diseño de instrumentos de evaluación y la recopilación de evidencias. Finalmente se muestran las estrategias de evaluación llevadas a cabo, así como los resultados obtenidos. Las asignaturas analizadas en este artículo son impartidas por los profesores pertenecientes al grupo de innovación docente EITACURTE, los cuales realizan reuniones periódicas para intercambiar ideas sobre sus experiencias docentes.

[EN] The last syllabus of the grades of the Polytechnic University of Valencia (UPV) has changed the perspective of the universitary teaching and has highlighted the importance of the specific and the transversal competences. Therefore, there is a need for grading the transversal competences throughout the degrees and masters of the UPV. Moreover, these transversal competences must be assessed in several subjects. Due to the lack of experience in evaluating these skills, UPV has elaborated scoring rubrics to help professors to assess them. In this work, we review the assessment of the transversal competence "Problem identification and solving” of four subjects of different degrees and courses. In two subjects, special activities have been performed for the evaluation of this competence and scoring rubrics have been used. In the other two subjects, the mark of this skill has been obtained from other marks of the subject. Moreover, we have compared the mark of this skill with the final mark of the subject. Our results show that there is a high correlation between the two marks in the four subjects., [ES] En los últimos planes de estudios de los grados de la Universidad Politécnica de Valencia (UPV) ha cambiado el enfoque de la docencia y se ha resaltado el papel de las competencias, tanto específicas como transversales. Actualmente es necesario evaluar competencias transversales en todos los grados y másteres de la UPV y estas deben ser evaluadas en distintas asignaturas. Ante la falta de experiencia en su evaluación, la UPV ha elaborado rúbricas para ayudar al profesorado en dicha tarea. En este artículo revisamos la evaluación de la competencia transversal “Análisis y resolución de problemas” en cuatro asignaturas de distintos cursos y grados. En dos de estas asignaturas se han realizado actividades especiales para la evaluación de esta competencia y se han utilizado rúbricas para ello. En las otras dos asignaturas, se ha optado por utilizar las calificaciones de los actos de evaluación más relacionados con ella. Además, se ha comparado la calificación de esta competencia con la nota de la asignatura y los resultados muestran que para las cuatro asignaturas existe una alta correlación entre ambas.

[EN] Modeling and simulation of the electrophysiological activity of heart is an efficient and low cost technique to study the mechanisms of arrhythmias generation and to predict the appearance of arrhythymias. Furthermore, it can can be useful to develop more effective antiarrhythmic therapies. Norwadays, the pharmacological treatment of arrhythmias is far from being satisfactory, and in some cases, it can be proarrhythmic. Several studies have shown that the presence of mutations influence the response to drug therapy. The main objective of this work is to investigate the differences in the effects of sodium current blockers in normal conditions and in the presence of a variety of latent generic mutations that affect this current using computing simulation. It will reveal the mutation-drug combinations that are more or less antiarrhythmic. Specifically, the effects of lidocaine, ranolazine and propafenone on action potential duration (APD) and the maximum depolarization velocity (dV/dtmax), which is closely related to the propagation velocity, will be simulated using a canine action potential (AP) model. For this purpose, the INaF and INaL formulations of the most updated canine ventricular PA model (Decker and his collaborators) have been replaced by our version of the model proposed by Nesterenko and collaborators, which is based on canine data and follows the formalism of Markov, which is appropriated to simulate mutations and drugs. The balance of the ionic currents has also been modified to keep a realistic APD and dV/dtmax in the new model (Decker-Nesterenko). To investigate the drug effects in the presence of mutations, a variety of generic mutations has been generated by altering the discrete transition rates between the states of the channel, which selectively modify the different kinetic properties of the channel: steady-state activation, steady-state inactivation and the time constant of inactivation. Six virtual latent mutations were generated, three o, [ES] Actualmente, la modelización y simulación de la actividad electrofisiológica de las células del corazón constituye una técnica eficiente y de coste reducido para el estudio de los mecanismos de generación de arritmias y de predicción de la aparición de éstas, además de ayudar al desarrollo de terapias antiarrímicas más eficaces. Hoy en día el tratamiento farmacológico de las arritmias está lejos de ser satisfactorio, y en algunos casos, pueden resultar proarrítmicos. Diversos estudios han demostrado que las mutaciones pueden influir en los efectos de los fármacos. El objetivo principal de este trabajo consiste en investigar, mediante el modelado y simulación cardiaca, las diferencias en los efectos de fármacos que bloquean la corriente de sodio en condiciones normales y en presencia de una gran variedad de mutaciones genéricas latentes que afectan a esta corriente. Esto nos permitirá discernir qué combinaciones mutación-fármaco son más o menos antiarrítmicas. En concreto, se analizará el efecto de la lidocaína, ranolazina y propafenona en la duración del potencial de acción (APD) y en la derivada máxima de despolarización (dV/dtmax), que está íntimamente relacionada con la velocidad de condución, utilizando un modelo de potencial de acción (PA) canino. Para ello, la INaF y la INaL del modelo de PA canino ventricular más actual (Decker y sus colaboradores) se han reemplazado por nuestra versión del modelo de Nesterenko y sus colaboradores que está basado en datos experimentales caninos y sigue el formalismo de Markov, el cual resulta muy indicado para el estudio de mutaciones y fármacos. También se ha modificado el balance de corrientes para que el modelo resultante (Decker-Nesterenko) tenga un APD y una dV/dtmax lo más realista posible. Para analizar el efecto de los fármacos en presencia de mutaciones, se ha generado una variedad de mutaciones genéricas alterando las velocidades de transición entre los estados del canal y que modifican selectivamente las disti

[ES] El trabajo consiste en el diseño del control de un aparato que utilice un motor eléctrico. El sistema de control deberá ser capaz de controlar la puesta en marcha y el apagado del aparato y la velocidad de giro del motor.

[ES] El trabajo consiste en el diseño del control de un aparato que utilice un motor eléctrico. El sistema de control deberá ser capaz de controlar la puesta en marcha y el apagado del aparato y la velocidad de giro del motor.

[ES] Los títulos que existen en nuestras universidades tienen asociadas muchas y muy diversas competencias debido a que cada asignatura incorpora múltiples aspectos particulares, en ocasiones no suficientemente coordinados con el resto de materias de la titulación. Además, en algunos casos no se comprueba si los alumnos han adquirido estas competencias una vez cursadas las asignaturas. Por esta razón es necesario revisar si se están aplicando las dimensiones competenciales propuestas por la Universidad Politécnica de Valencia, en las asignaturas de sus grados y verificar si los alumnos están adquiriendo esas competencias. En este artículo revisamos las dimensiones competenciales que se incluyen en las guías docentes de tres asignaturas de tres grados ofertados en nuestra universidad y analizamos los resultados de encuestas donde los alumnos analizan en qué medida consideran que han adquirido estas competencias. Este análisis revela que existe un elevado grado de satisfacción del alumnado con la adquisición de competencias de las asignaturas independientemente de la procedencia académica del alumno o de su nota final en la asignatura. Sin embargo, es necesario profundizar en la aplicación práctica de los métodos explicados en las asignaturas, ya que este aspecto es el peor valorado., [EN] Many diverse skills are associated to the grades in our universities because each individual subject incorporates multiple particular aspects, which sometimes are not sufficiently coordinated with the other subjects of the degree. Moreover, in some cases the acquisition of these skills by the students at the end of the course is not checked. The objective of this work is to assess the achievement of the competence dimensions proposed by the Polytechnic University of Valencia in the subjects by the students. In this work, the competency dimensions included in the educational guides of three subjects of three grades are reviewed. Moreover, the results of a survey designed to ask the students about the achievement of the skills included in the guides of their subjects are analyzed. Our work reveals that student expectancies about competence acquisition are highly fulfilled. This observation does not depend on the marks on the subject either the academic origin of the student. However, the practice of the methods explained in the subjects should be more exhaustively considered, as it is the weakest point.

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of I blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in I channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human l channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of I-Kr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant I-Kr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of I-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the I-Kr, channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of

[EN] There are two mathematical modelling approaches to describe ion channel kinetics in the context of cardiac action potential simulations: the classical Hodgkin & Huxley (HH) gating model formalism and state transitions Markov models (MMs). This last approach is more flexible and it is capable of characterizing state transitions dependent on the state of the channel, consequently being able to match experimental observations on gating currents more accurately and mechanistically. However, the high number of differential equations associated to MMs makes multi-cellular whole-organ simulations very costly from a computational point of view. Moreover, the large number of transition rates implicit in the model also adds difficulties in parameter estimation. These facts raise the question about the existence of conclusive quantitative and qualitative differences in using MM in disadvantage of the HH formalism. The aim of this study is to compare the results obtained with both formalisms when simulating the effects of the delayed rectifier K+ current (IKr) in the action potential in isolated cells. For this purpose, a new mathematical model for IKr based on the HH formalism using the Clancy–Rudy (CRd) dynamics for guinea pig ventricular cells was developed. The dynamic characteristics of the CRd model were fitted using a Non-linear Least Square–Trust Region algorithm to the HH formalism for the same species to obtain the parameters for the HH gating formalism. This new model was incorporated to the 2001 version of the CRd model to simulate: (a) the steady state action potential and ionic currents under physiological an non physiological cycle lengths ranging from 300 to 3500 milliseconds; (b) the APD restitution curve; and (c) the effects of the blockade and enhancements of calcium and potassium currents with the purpose of comparing the behaviour of both models under pharmacological interventions. Our results show similar APD90 values, ionic concentrations and ionic c, [ES] Dos son las modalidades matemáticas para describir la cinética de los canales iónicos para la simulación del potencial de acción cardíaco: el modelo de compuertas con formalismo clásico de Hodgkin & Huxley (HH) y los modelos de estados de Markov (MMs). Este último es más flexible y capaz de caracterizar las transiciones dependientes del estado de los canales iónicos, por lo tanto propicio para reproducir los resultados experimentales de estas corrientes con más precisión. No obstante, el alto número de ecuaciones diferenciales asociado a los modelos de Markov hace que las simulaciones multicelulares cardíacas a nivel de órgano sean de muy alto coste computacional. Además, el alto número de transiciones implícitas en el modelo tiene la dificultad añadida de la estimación e identificabilidad de sus parámetros. Estos hechos inducen la pregunta acerca de la existencia de diferencias cuantitativas y cualitativas que favorezcan la utilización de MM en detrimento de modelos con formalismo de HH. El objetivo de este estudio es comparar los resultados obtenidos con ambos formalismos simulando los efectos de la corriente retardada rectificadora de K+ (IKr) en el potencial de acción de una célula aislada. Con ese propósito, se desarrolló un nuevo modelo de IKr, basado en el formalismo de HH y usando la dinámica del modelo celular ventricular de cobaya de Clancy-Rudy (CRd). Las características dinámicas del modelo de CRd se ajustaron al formalismo de HH para la misma especie usando un algoritmo de Mínimos Cuadrados No Lineal (Región de Confianza) para obtener los parámetros del formalismo de compuertas de HH. Este nuevo modelo fue incorporado a la versión del 2001 del modelo de CRd para simular: (a) el potencial de acción y corrientes iónicas en estado estable en ciclos de longitud fisiológico y no fisiológico en el rango de 300 a 3500 milisegundos; (b) la curva de restitución versus APD; y (c) los efectos del bloqueo e incremento de las corrientes de calcio y potasio con

This computational modelling work illustrates the influence of hyperkalaemia and electrical uncoupling induced by defined ischaemia on action potential (AP) propagation and the incidence of reentry at the Purkinjeventricle interface in mammalian hearts. Unidimensional and bidimensional models of the Purkinjeventricle subsystem, including ischaemic conditions (defined as phase 1B) in the ventricle and an ischaemic border zone, were developed by altering several important electrophysiological parameters of the LuoRudy AP model of the ventricular myocyte. Purkinje electrical activity was modelled using the equations of DiFrancesco and Noble. Our study suggests that an extracellular potassium concentration [K](o) 14 mM and a slight decrease in intercellular coupling induced by ischaemia in ventricle can cause conduction block from Purkinje to ventricle. Under these conditions, propagation from ventricle to Purkinje is possible. Thus, unidirectional block (UDB) and reentry can result. When conditions of UDB are met, retrograde propagation with a long delay (320 ms) may re-excite Purkinje cells, and give rise to a reentrant pathway. This induced reentry may be the origin of arrhythmias observed in phase 1B ischaemia. In a defined setting of ischaemia (phase 1B), a small amount of uncoupling between ventricular cells, as well as between Purkinje and ventricular tissue, may induce UDBs and reentry. Hyperkalaemia is also confirmed to be an important factor in the genesis of reentrant rhythms, since it regulates the range of coupling in which UDBs may be induced.

Background: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. Objective: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. Methods: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. Results: Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+ /Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. Conclusion: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this.

[EN] Ischaemic heart disease is considered as the single most frequent cause of death, provoking more than 7 000 000 deaths every year worldwide. A high percentage of patients experience sudden cardiac death, caused in most cases by tachyarrhythmic mechanisms associated to myocardial ischaemia and infarction. These diseases are difficult to study using solely experimental means due to their complex dynamics and unstable nature. In the past decades, integrative computational simulation techniques have become a powerful tool to complement experimental and clinical research when trying to elucidate the intimate mechanisms of ischaemic electrophysiological processes and to aid the clinician in the improvement and optimization of therapeutic procedures. The purpose of this paper is to briefly review some of the multiscale computational models of myocardial ischaemia and infarction developed in the past 20 years, ranging from the cellular level to whole-heart simulations.