Air Pollution and Cardiac Diseases: A Review of Experimental Studies.

Air pollution is associated with around 6.5 million premature deaths annually, which are directly related to cardiovascular diseases, and the most dangerous atmospheric pollutants to health are as follows: NO2, SO2, CO, and PM. The mechanisms underlying the observed effects have not yet been clearly defined. This work aims to conduct a narrative review of experimental studies to provide a more comprehensive and multiperspective assessment of how the effect of atmospheric pollutants on cardiac activity can result in the development of cardiac diseases. For this purpose, a review was carried out in databases of experimental studies, excluding clinical trials, and epidemiological and simulation studies. After analyzing the available information, the existence of pathophysiological effects of the different pollutants on cardiac activity from exposure during both short-term and long-term is evident. This narrative review based on experimental studies is a basis for the development of recommendations for public health.

Characterization of airborne particulate matter and its toxic and proarrhythmic effects: A case study in Aburrá Valley, Colombia.

Particle matter (PM) is a complex mixture of particles suspended in the air, mainly caused by fuel combustion from vehicles and industry, and has been related to pulmonary and cardiovascular diseases. The Metropolitan Area of Aburrá Valley in Colombia is the second most populous urban agglomeration in the country and the third densest in the world, composed of ten municipalities. Examining the physicochemical properties of PM is crucial in comprehending its composition and its effects on human health, as it varies based on the socioeconomic dynamics specific to each city. This study characterized the PM collected from the north, south, and central zones to evaluate its chemical composition and morphology. Different elements such as silicon, carbon, aluminum, potassium, calcium, sodium, iron, magnesium, and copper and the presence of unburned fuel, motor oil, and silicon fibers were identified. In vitro and in silico studies were conducted to evaluate the toxicity of the PM, and it was found that the PM collected from the central zone had the greatest impact on cell viability and caused DNA damage. The in silico study demonstrated that PM has concentration-dependent proarrhythmic effects, reflected in an action potential duration shortening and an increased number of reentries, which may contribute to the development of cardiac arrhythmias. Overall, the results suggest that the size and chemical composition of ambient PM can induce toxicity and play an important role in the generation of arrhythmias.

Atrial proarrhythmic effect of lead as one of the PM10 metal components of air pollution. An in-silico study.

Particulate matter (PM) is considered the most severe environmental pollution problem due to its serious effects on human health associated with an increased risk of cardiovascular morbidity and mortality. In this work, a physicochemical characterization of PM10 from the city of Medellin was developed. The results evince that lead (Pb) is one of the most abundant elements since it is present in all analyzed samples. Therefore, Pb was chosen to perform an in-silico study to assess its effects on atrial arrhythmias generation. For this purpose, we developed a model representing the Pb2+ blocking effect on the L-type calcium channel. This formulation was incorporated in a human atrial cell mathematical model and in 2D and 3D models of human atria. The simulations showed a proarrhythmic effect at high Pb2+ concentrations, through shortening of action potential duration inducing the generation of reentrant activity and atrial flutter. The results contribute to the knowledge about the cardiac physiopathological processes, triggered by lead as one of the main PM10 metal components of air pollution, that yields the generation of arrhythmias.

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study.

Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF.

Immuno-Electrophysiological Mechanisms of Functional Electrical Connections Between Recipient and Donor Heart in Patients With Orthotopic Heart Transplantation Presenting With Atrial Arrhythmias.

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Importancia del mapeo óptico de cultivos de cardiomiocitos HL-1 en estudios electrofisiológicos / Importance of the optical mapping of HL-1 cardiomyocyte cultures in electrophysiological studies

Introducción: El desarrollo de herramientas para investigar la actividad electrofisiológica cardiaca ha permitido profundizar en el conocimiento sobre los mecanismos subyacentes a las arritmias cardiacas. Los sistemas de mapeo óptico constituyen una tecnología que responde a la necesidad de superar varios obstáculos en la experimentación. Objetivo: Proporcionar una visión general de la importancia del mapeo óptico en cultivos celulares HL-1, en las investigaciones en electrofisiología cardiaca. Métodos: Se realizó una revisión sobre los estudios electrofisiológicos que involucran la línea celular HL-1 utilizando la técnica de mapeo óptico. Conclusiones: Los trabajos se caracterizan por la implementación de la técnica respecto a la tecnología de los equipos de mapeo, a la utilización de diferentes colorantes y al objetivo de la investigación. Están enfocados en el estudio de mecanismos arritmogénicos, procesos de estiramiento mecánico o remodelación del tejido y en el análisis de nuevos biomateriales. Lo anterior, sustenta la relevancia del mapeo óptico en la investigación cardiaca(AU)

Introduction: The development of tools to study cardiac electrophysiological activity has made it possible to broaden knowledge about the mechanisms underlying cardiac arrhythmias. Optical mapping systems constitute a technology that responds to the need to overcome several hurdles in experimentation. Objective: Provide an overview of the importance of optical mapping in HL-1 cell cultures in cardiac electrophysiology research. Methods: A review was conducted of electrophysiological studies involving the HL-1 cell line using the optical mapping technique. Conclusions: The studies are characterized by implementation of the technique with respect to the technology of mapping equipment, the use of different colorants and the purpose of the research. They focus on the study of arrhythmogenic mechanisms, mechanical stretch processes or tissue remodeling as well as the analysis of new biomaterials. The above substantiates the relevance of optical mapping in cardiac research(AU)

The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation.

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation.

Electroanatomical mapping based on discrimination of electrograms clusters for localization of critical sites in atrial fibrillation.

Locating critical sites on the atrial surface during AF to guide the ablation procedures is an open problem. Electrogram-guided approaches have been proposed. However, electrograms (EGM) are complex and not well-described type of signals and anatomically-based pulmonary vein isolation remains been recommended as the cornerstone procedure. We introduce a method that builds an electroanatomical map to visualize the distribution of different morphological patterns of the EGM signals over the atrial surface. The proposed scheme uses EGM signals recorded with a commercial cardiac mapping. Likewise, two morphological and two non-linear features are computed from each single EGM. Patterns are discriminated using a semi-supervised clustering approach that does not need a priory definition of EGM morphologies or classes. The method was tested under two scenarios: a set of EGM signals recorded in AF patients and a set of signals obtained from 2D simulations of atrial conduction sustained by rotors. Our method was able to locate the clusters in a map of the atrial surface of each patient. These locations allow the specialist to study the distribution of critical AF sites. The method was able to locate the pivot point of the rotors in the 2D models. Our results suggest that the proposed method is a potential assisting tool for guided ablation procedures. Further clinical studies are needed to establish the relationship between clusters and arrhythmogenic substrates in AF, and to validate the usefulness of the method to locate critical conduction sites in patients.

Entropy Mapping Approach for Functional Reentry Detection in Atrial Fibrillation: An In-Silico Study.

Catheter ablation of critical electrical propagation sites is a promising tool for reducing the recurrence of atrial fibrillation (AF). The spatial identification of the arrhythmogenic mechanisms sustaining AF requires the evaluation of electrograms (EGMs) recorded over the atrial surface. This work aims to characterize functional reentries using measures of entropy to track and detect a reentry core. To this end, different AF episodes are simulated using a 2D model of atrial tissue. Modified Courtemanche human action potential and Fenton-Karma models are implemented. Action potential propagation is modeled by a fractional diffusion equation, and virtual unipolar EGM are calculated. Episodes with stable and meandering rotors, figure-of-eight reentry, and disorganized propagation with multiple reentries are generated. Shannon entropy ( S h E n ), approximate entropy ( A p E n ), and sample entropy ( S a m p E n ) are computed from the virtual EGM, and entropy maps are built. Phase singularity maps are implemented as references. The results show that A p E n and S a m p E n maps are able to detect and track the reentry core of rotors and figure-of-eight reentry, while the S h E n results are not satisfactory. Moreover, A p E n and S a m p E n consistently highlight a reentry core by high entropy values for all of the studied cases, while the ability of S h E n to characterize the reentry core depends on the propagation dynamics. Such features make the A p E n and S a m p E n maps attractive tools for the study of AF reentries that persist for a period of time that is similar to the length of the observation window, and reentries could be interpreted as AF-sustaining mechanisms. Further research is needed to determine and fully understand the relation of these entropy measures with fibrillation mechanisms other than reentries.

Late diagnosis of pseudohypoparathyroidism in adulthood. Case series / Pseudohipoparatiroidismo diagnosticado tardíamente en la adultez, una serie de casos

Abstract Introduction: Pseudohypoparathyroidism (PHP) is a rare hereditary disease, characterized by hypocalcemia/hyperphosphatemia secondary to peripheral resistance to parathyroid hormone (PTH). PHP diagnosis is usually precluded since hypocalcemia is considered as the primary diagnosis, thus delaying further diagnostic studies and preventing an adequate management of this clinical condition. Materials and methods: Retrospective review of the databases of the Endocrinology departments of two tertiary care centers of Medellin, Colombia from January 2012 to December 2016. Patients diagnosed with PHP based on clinical presentation and confirmatory laboratory values were included. Results: Four patients met the inclusion criteria. All PHP cases were diagnosed in adulthood despite strong early clinical and laboratory evidence of the disease. Three patients were diagnosed with Fahr's syndrome and two with Albright's hereditary osteodystrophy. The mean values obtained were PTH of 376.8 pg/mL, calcium of 6.17 mg/dL and phosphorus of 6.55 mg/dL. Conclusions: PHP is a rare disorder. This paper describes four PHP cases diagnosed during adulthood. Emphasis should be placed on the judicious approach to the patient with hypocalcemia and hyperphosphatemia with increased PTH and normal renal function, since these symptoms strongly suggest a diagnosis of PHP.

Resumen Introducción. El pseudohipoparatiroidismo (PHP) es una condición rara caracterizada por hipocalcemia e hiperfosfatemia secundarias a resistencia periférica a la hormona paratiroidea (PTH). Es frecuente que la hipocalcemia sea establecida de forma equivocada como diagnóstico primario y que el diagnóstico definitivo de PHP sea tardío, difiriendo los estudios y el manejo específico que exigen estos pacientes. Materiales y métodos. Se revisaron de forma retrospectiva las bases de datos de endocrinología de dos centros terciarios de Medellín, Colombia, desde enero de 2012 a diciembre de 2016. Se incluyeron pacientes con diagnóstico de PHP por presentación clínica y valores confirmatorios de laboratorio. Resultados. Cuatro pacientes cumplieron los criterios de inclusión. Todos los casos fueron diagnosticados en la adultez a pesar de tener evidencia temprana, clínica y bioquímica de la enfermedad. Tres pacientes tenían síndrome de Fahr y dos tenían osteodistrofia hereditaria de Albright. Los valores medios registrados fueron PTH de 376.8 pg/mL, calcio de 6.17 mg/dL y fósforo de 6.55 mg/dL. Conclusiones. El PHP es un trastorno raro; se describen cuatro casos diagnosticados de forma tardía en la adultez. Se enfatiza en el enfoque juicioso del paciente con hipocalcemia, la cual, en presencia de hiperfosfatemia con PTH elevada y función renal normal, debe hacer sospechar el diagnóstico de PHP.

Atrial Rotor Dynamics Under Complex Fractional Order Diffusion.

The mechanisms of atrial fibrillation (AF) are a challenging research topic. The rotor hypothesis states that the AF is sustained by a reentrant wave that propagates around an unexcited core. Cardiac tissue heterogeneities, both structural and cellular, play an important role during fibrillatory dynamics, so that the ionic characteristics of the currents, their spatial distribution and their structural heterogeneity determine the meandering of the rotor. Several studies about rotor dynamics implement the standard diffusion equation. However, this mathematical scheme carries some limitations. It assumes the myocardium as a continuous medium, ignoring, therefore, its discrete and heterogeneous aspects. A computational model integrating both, electrical and structural properties could complement experimental and clinical results. A new mathematical model of the action potential propagation, based on complex fractional order derivatives is presented. The complex derivative order appears of considering the myocardium as discrete-scale invariant fractal. The main aim is to study the role of a myocardial, with fractal characteristics, on atrial fibrillatory dynamics. For this purpose, the degree of structural heterogeneity is described through derivatives of complex order γ = α + jß. A set of variations for γ is tested. The real part α takes values ranging from 1.1 to 2 and the imaginary part ß from 0 to 0.28. Under this scheme, the standard diffusion is recovered when α = 2 and ß = 0. The effect of γ on the action potential propagation over an atrial strand is investigated. Rotors are generated in a 2D model of atrial tissue under electrical remodeling due to chronic AF. The results show that the degree of structural heterogeneity, given by γ, modulates the electrophysiological properties and the dynamics of rotor-type reentrant mechanisms. The spatial stability of the rotor and the area of its unexcited core are modulated. As the real part decreases and the imaginary part increases, simulating a higher structural heterogeneity, the vulnerable window to reentrant is increased, as the total meandering of the rotor tip. This in silico study suggests that structural heterogeneity, described by means of complex order derivatives, modulates the stability of rotors and that a wide range of rotor dynamics can be generated.

Effect of the electrograms density in detecting and ablating the tip of the rotor during chronic atrial fibrillation: an in silico study.

AIMS: Identification in situ of arrhythmogenic mechanisms could improve the rate of ablation success in atrial fibrillation (AF). Our research group reported that rotors could be located through dynamic approximate entropy (DApEn) maps. However, it is unknown how much the spatial resolution of catheter electrodes could affect substrates localization. The present work looked for assessing the electrograms (EGMs) spatial resolution needed to locate the rotor tip using DApEn maps. METHODS AND RESULTS: A stable rotor in a two-dimensional computational model of human atrial tissue was simulated using the Courtemanche electrophysiological model and implementing chronic AF features. The spatial resolution is 0.4 mm (150 × 150 EGM). Six different lower resolution arrays were obtained from the initial mesh. For each array, DApEn maps were constructed using the inverse distance weighting (IDW) algorithm. Three simple ablation patterns were applied. The full DApEn map detected the rotor tip and was able to follow the small meander of the tip through the shape of the area containing the tip. Inverse distance weighting was able to reconstruct DApEn maps after applying different spatial resolutions. These results show that spatial resolutions from 0.4 to 4 mm accurately detect the rotor tip position. An ablation line terminates the rotor only if it crosses the tip and ends at a tissue boundary. CONCLUSION: A previous work has shown that DApEn maps successfully detected simulated rotor tips using a high spatial resolution. In this work, it was evinced that DApEn maps could be applied using a spatial resolution similar to that available in commercial catheters, by adding an interpolation stage. This is the first step to translate this tool into medical practice with a view to the detection of ablation targets.

Dynamic approximate entropy electroanatomic maps detect rotors in a simulated atrial fibrillation model.

There is evidence that rotors could be drivers that maintain atrial fibrillation. Complex fractionated atrial electrograms have been located in rotor tip areas. However, the concept of electrogram fractionation, defined using time intervals, is still controversial as a tool for locating target sites for ablation. We hypothesize that the fractionation phenomenon is better described using non-linear dynamic measures, such as approximate entropy, and that this tool could be used for locating the rotor tip. The aim of this work has been to determine the relationship between approximate entropy and fractionated electrograms, and to develop a new tool for rotor mapping based on fractionation levels. Two episodes of chronic atrial fibrillation were simulated in a 3D human atrial model, in which rotors were observed. Dynamic approximate entropy maps were calculated using unipolar electrogram signals generated over the whole surface of the 3D atrial model. In addition, we optimized the approximate entropy calculation using two real multi-center databases of fractionated electrogram signals, labeled in 4 levels of fractionation. We found that the values of approximate entropy and the levels of fractionation are positively correlated. This allows the dynamic approximate entropy maps to localize the tips from stable and meandering rotors. Furthermore, we assessed the optimized approximate entropy using bipolar electrograms generated over a vicinity enclosing a rotor, achieving rotor detection. Our results suggest that high approximate entropy values are able to detect a high level of fractionation and to locate rotor tips in simulated atrial fibrillation episodes. We suggest that dynamic approximate entropy maps could become a tool for atrial fibrillation rotor mapping.

PATRONES SIMPLES DE ABLACIÓN PARA LA TERMINACIÓN DE ROTORES EN FIBRILACIÓN AURICULAR CRÓNICA. ESTUDIO DE SIMULACIÓN / SIMPLE ABLATION PATTERNS FOR TERMINATING ROTORS IN CHRONIC ATRIAL FIBRILLATION. A SIMULATION STUDY / PADRÕES SIMPLES ABLAÇÃO DE RESCISÃO DE ROTORES COM FIBRILAÇÃO ATRIAL CRÔNICA. ESTUDO DE SIMULAÇÃO

La fibrilación auricular (FA) es la arritmia más común en la práctica clínica y por la que más se consulta en los servicios médicos. Recientemente, se ha propuesto un mecanismo de mantenimiento de la FA, el cual consiste en la existencia de uno o varios rotores que activan el tejido a alta frecuencia. La ablación es uno de los tratamientos para la FA, en FA crónica son necesarios patrones de ablación complejos, por lo que actualmente se busca el patrón ideal con un mínimo número de líneas de ablación. En este trabajo se simula la actividad de un rotor en un modelo 2D de tejido auricular humano, bajo condiciones de FA crónica y se localiza su centro de giro (tip). Se proponen y evalúan seis diferentes patrones simples de ablación compuestos por un número reducido de líneas. El estudio demostró que aquellos patrones que atraviesan o encierran el tip del rotor y que adicionalmente se prolongan hasta una frontera de conducción son eficaces en la terminación del rotor.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and the most consulted in medical services. Recently it has been proposed a mechanism for maintaining the AF, which consists in one or more rotors activating the tissue at high frequency. Ablation is one of the treatments for AF, for chronic AF is needed complex ablation patterns, so currently it has been looking for an ideal pattern with a minimum number of ablation lines. In this work activity of a rotor was simulated in a 2D model of human atrial tissue, under chronic AF conditions, and the center of rotation (tip) was located. Six different simple ablation patterns composed of a limited number of lines were proposed and evaluated. The study showed that those patterns that passed through or encloses the tip of the rotor and additionally were extended to a conduction boundary are effective in the termination of the rotor.

A fibrilação atrial (FA) é a arritmia mais comum na prática clínica e na consulta que a maioria dos serviços médicos. Recentemente, é proposto um mecanismo para a manutenção da FA, que é a existência de um ou mais rotores que activam o tecido com elevada frequência. A ablação é um tratamento para fibrilação atrial em padrões crônicos de ablação de FA necessárias são complexas, por isso eles estão atualmente buscando o padrão ideal, com um número mínimo de linhas de ablação. Neste documento, a actividade de um rotor é simulada em um modelo em 2D do tecido atrial humano, sob condições de AF crónica e o seu centro de rotação (ponta) está localizado. São propostos e avaliados seis diferentes padrões de ablação individuais compostos de um pequeno número de linhas. O estudo mostrou que as que passam através de padrões ou encerram a ponta do rotor e se estendem para além de um limite de condução são eficazes na cessação do rotor.

IDENTIFICACIÓN DE ZONAS SUSCEPTIBLES DE ABLACIÓN EN FIBRILACIÓN AURICULAR PERMANENTE IMPLEMENTANDO ENTROPÍA APROXIMADA EN UN MODELO 2D / IDENTIFICATION OF TARGET SITES FOR ABLATION DURING PERMANENT ATRIAL FIBRILLATION IMPLEMENTING APPROXIMATE ENTROPY IN A 2D MODEL / IDENTIFICAÇÃO DE ÁREAS SUSCETÍVEIS DE ABLAÇÃO PERMANENTE DE FIBRILAÇÃO ATRIAL NA IMPLEMENTAÇÃO ENTROPY APROXIMADO UM MODELO 2D

La fibrilación auricular (FA) es la arritmia cardiaca más común. La ablación con catéter se ha convertido en la principal estrategia terapéutica para el tratamiento de la FA paroxística, sin embargo, los resultados en FA permanente no son completamente satisfactorios. Se propone la ablación de los electrogramas auriculares complejos fragmentados (CFAE) para la terminación de un rotor como mecanismo de mantenimiento de FA permanente. El objetivo de este trabajo es caracterizar los CFAE mediante la implementación de entropía aproximada (ApEn) y correlacionarlos con el tip de un rotor simulado. Para esto, se desarrolló un modelo 2D de tejido de aurícula humana bajo condiciones de FA permanente; se registraron electrogramas unipolares durante la actividad del rotor y se desarrolló un algoritmo para la medida de ApEn. La ApEn permitió localizar los CFAE con una alta precisión y relacionarlos con el tip del rotor. Por lo que este índice podría ser muy eficaz en la identificación de zonas susceptibles de ablación.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Catheter ablation has become the main therapeutic strategy for the treatment of paroxysmal AF, however, results in permanent AF are not completely satisfactory. Ablation of complex fractionated atrial electrograms (CFAE) is proposed for the termination of a rotor as mechanism of permanent AF maintenance. The aim of this work is to characterize the CFAE by implementing approximate entropy (ApEn) and to correlate with the tip of a simulated rotor. For this, a 2D model of human atrial tissue under permanent FA conditions was developed. Unipolar electrograms were recorded during the rotor activity and an algorithm to measure ApEn was developed. The ApEn allowed locate the CFAE with high precision and relate them to the tip of the rotor. So this index could be very effective in identifying target sites for ablation.

A fibrilação atrial (FA) é a arritmia cardíaca mais comum. A ablação por cateter tornou-se a principal estratégia terapêutica para o tratamento da fibrilação atrial paroxística, no entanto, resulta em FA permanente não são completamente satisfatórios. Ablação de fones de ouvido eletrocardiogramas complexos fragmentada (CFAE) para a conclusão de um rotor como um mecanismo de manutenção da FA permanente, é proposto. O objetivo deste trabalho é caracterizar o CFAE através da implementação de entropia aproximada (ApEn) e correlacioná-los com a ponta de um rotor simulado. Para isso, um modelo em 2D do tecido atrial humano sob condições de FA permanente desenvolvido; unipolares electrogramas foram registados durante a actividade do rotor e um algoritmo para medir ApEn desenvolvido. O ApEn permitido CFAE localizar com precisão elevada e relacioná-los com a ponta do rotor. Portanto, esta taxa pode ser muito eficaz na identificação de áreas suscetíveis a ablação.

LOCALIZACIÓN DE FOCOS ECTÓPICOS DURANTE FIBRILACIÓN AURICULAR PERMANENTE, MEDIANTE UN NUEVO ÍNDICE OHF. ESTUDIO DE SIMULACIÓN / ECTOPIC FOCI LOCATION DURING PERMANENT ATRIAL FIBRILLATION USING A NEW INDEX OHF. A SIMULATION STUDY / LOCALIZAÇÃO DE FOCOS ECTÓPICOS DURANTE FIBRILAÇÃO ATRIAL PERMANENTE EM UM NOVO ÍNDICE OHF. ESTUDO DE SIMULAÇÃO

La fibrilación auricular (FA), en ciertos casos, es mantenida por focos ectópicos de actividad automática, organización espacio temporal y de alta frecuencia. La ablación de estos sitios da como resultado la terminación de la FA en un alto porcentaje en paciente con FA paroxística, sin embargo, en pacientes con FA permanente estos sitios son difíciles de reconocer debido a la capacidad de las aurículas remodeladas para ser activadas a altas frecuencias. Es necesario un método más preciso para acotar mejor estas zonas. En el presente trabajo se plantea desarrollar un nuevo índice, a partir de los índices de frecuencia dominante (DF) e índice de organización (IO), para la identificación de estas zonas. Para esto, se simularon episodios de FA permanente mantenidos por focos ectópicos de actividad continua en tres diferentes regiones, implementando un modelo 3D de aurícula humana. Se obtuvieron electrogramas en toda la superficie auricular y se calculó su DF and IO. El índice OHF (Organization High Frequency), se calculó como el producto entre el valor de la DF y del IO de cada uno de los electrogramas y se crearon mapas de falso color sobre el modelo 3D. Los resultados muestran que el índice OHF es capaz de identificar el foco ectópico de actividad continua durante episodios de FA permanente simulados.

Atrial fibrillation in some cases is maintained by ectopic foci with automatic activity, spatiotemporal organization and high frequency. Ablating these sites results in the AF termination in a high percentage of patients with paroxysmal AF, however, in patients with permanent AF these sites are difficult to recognize due to the ability of the remodeled atria to be activated at high frequencies. A more accurate method is needed to delimit better these areas. In the present work, we developed a new index, based on dominant frequency (DF) and organization index (OI), to identify these areas. For this, we simulated permanent AF episodes maintained by ectopic foci with continuous activity in three different regions, implementing a 3D model of human atrium. Electrograms were obtained across the atrial surface and its DF and IO were calculated. The OHF index (Organization High Frequency), was calculated as the product of the DF and IO values of individual electrograms and we created false color maps in the 3D model. The results show that the OHF index is able to identify ectopic foci of continuous activity during simulated permanent AF episodes.

A fibrilação atrial (FA), em alguns casos, é mantida por focos de actividade ectópica automático, organização e espaço de alta frequência temporal. Ablação desses locais determina a resolução da FA em uma alta porcentagem de pacientes com FA paroxística, no entanto, em pacientes com fibrilação atrial permanente desses sites são difíceis de reconhecer devido à capacidade dos átrios remodelado para ser ativado em alta frequências. Essas áreas para melhor abordagem é necessário um limite mais preciso. Neste artigo propõe-se a desenvolver uma freqüência novos índices com base em índice dominante (DF) e índice de organização (OI) para a identificação dessas áreas. Para isso, episódios de FA permanente mantido por focos ectópicos de atividade contínua em três regiões diferentes, implementando um modelo 3D de átrios humanos foram simulados. Eletrocardiogramas foram obtidos ao longo da superfície auricular e calculado o DF e IO. O OHF (Organização High Frequency) índice foi calculado como o produto do valor do DF e IO de eletrocardiogramas individuais e falsos mapas de cores do modelo 3D é criado. Os resultados mostram que o índice de OHF é capaz de identificar o foco ectópico de actividade contínua durante episódios de FA permanentes simulados.

EFECTO DEL FÁRMACO CLOROQUINA EN LA TERMINACIÓN DE UN ROTOR DURANTE FIBRILACIÓN AURICULAR PAROXÍSTICA. ESTUDIO DE SIMULACIÓN / CHLOROQUINE DRUG EFFECT ON A ROTOR TERMINATION DURING PAROXYSMAL ATRIAL FIBRILLATION. A SIMULATION STUDY / O EFEITO DO MEDICAMENTO CLOROQUINA NO FECHAMENTO DE UM ROTOR DURANTE FIBRILAÇÃO ATRIAL PAROXÍSTICA. SIMULAÇÃO ESTUDO

La fibrilación auricular (FA) es la arritmia más común. Algunos episodios de FA son mantenidos por rotores. La FA paroxística (FAp) se refiere a episodios recurrentes que se autolimitan. Si la FAp no se trata puede convertirse en crónica. Se ha demostrado que la inhibición de las corrientes I KACh e I K1 contribuye a la terminación de la FA. El fármaco antimalárico cloroquina, al inhibir estas corrientes podría ser un fármaco antiarrítmico eficaz en humanos. El objetivo del trabajo es simular los efectos de la cloroquina y estudiar su eficacia en la terminación de un rotor en condiciones de FAp. Para esto, se desarrolló un modelo 2D de tejido auricular en condiciones de FAp. Se implementó un modelo del efecto de la cloroquina sobre las corrientes I K1 e I KACh para estudiar su eficacia en la terminación de un rotor simulado. La cloroquina alargó el potencial de acción a medida que se incrementó su concentración. A concentraciones de 0.3 µM y superiores, finalizó la actividad del rotor. Este es el primer trabajo que ha desarrollado modelos matemáticos del fármaco cloroquina para estudiar su efecto en la terminación de un rotor. Los resultados sugieren que la cloroquina podría ser un potente agente antiarrítmico en el tratamiento de la FAp.

Atrial fibrillation (AF) is the most common arrhythmia. Some AF episodes are maintained by rotors. Paroxysmal AF (pAF) refers to self-limiting recurrent episodes. If the pAF is not treated it could become chronic. It has been demonstrated that inhibition of the I K1 and I KACh currents contributes to AF termination. Antimalarial drug chloroquine by inhibiting these currents could be an effective antiarrhythmic drug in humans. The aim of this work is to simulate the effects of chloroquine and study their effectiveness in the rotor termination in pAF conditions. For this, we developed a 2D model of atrial tissue under pAF conditions. We implemented a model of the effect of chloroquine on I K1 and I KACh currents to study its effectiveness in the termination of a simulated rotor. Chloroquine lengthened the action potential as the concentration increased. At concentrations of 0.3 µM and higher, the activity of the rotor finished. This is the first work that developed a chloroquine mathematical models to study its effect on the rotor termination. The results suggest that chloroquine could be a potent antiarrhythmic drug for the pAF treatment.

A fibrilhação auricular (FA) é a arritmia mais comum. Alguns episódios de FA são mantidos por rotores. A FA paroxística (FAp) refere-se a episódios recorrentes que são autolimitantes. Se a FAP não tem nenhum tratamento, pode se tornar crônica. Tem sido demonstrado que a inibição das correntes I KACh e I K1 contribui para o término da AF. O medeicamento antimalárico cloroquina, para inibir essas correntes poderia ser um medicamento anti-arrítmico eficaz em seres humanos. O objetivo deste trabalho é simular os efeitos da cloroquina e estudar a sua eficácia na terminação de um rotor capaz em condições FAp. Para isso, um modelo 2D foi desenvolvido de tecido auricular em condições de FAp. foi implementado um modelo do efeito da Cloroquina sobre as corrente I K1 e I KACh para estudar a sua eficácia na terminação de um rotor simulado. A Cloroquina alongou o potencial de ação na medida em que foi aumentada a sua concentração. Em concentrações de 0,3 µM e superiores, terminou a atividade do rotor. Este é o primeiro trabalho que desenvolveu modelos matemáticos do medicamento cloroquina para estudar seu efeito sobre a terminação de um rotor. Os resultados sugerem que a cloroquina poderia ser um potente agente anti-arrítmico para o tratamento de FAp.

A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship.

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: (1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, (2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, (3) double potentials related with wave fragmentations or blocking lines and (4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.

Dominant frequency and organization index maps in a realistic three-dimensional computational model of atrial fibrillation.

AIMS: To study, using simulation, the spectral characteristics of different patterns of atrial fibrillation (AF) at high spatial resolution. Dominant frequency (DF) and organization index (OI) maps have been used to approximate the location of the focal source of high frequency during AF events. METHODS AND RESULTS: A realistic three-dimensional model of the human atria that includes fibre orientation, electrophysiological heterogeneity, and anisotropy was implemented. The cellular model was modified to simulate electrical remodelling. More than 43 000 electrograms were calculated on the surface, and were processed to reconstitute the DF and OI maps. Atrial fibrillation episodes were triggered by a source of transitory and of continuous activity (both with a cycle length of 130 ms) in five different locations. The maps obtained during the AF events triggered by transitory foci did not show areas with high DF or OI values. When continuous foci were applied, the DF maps show ample zones with high values in the atrium where the focus was applied; while OI maps display smaller areas with high values, always within the areas of high DF and, in three of five locations, this high-value area was located at the site of focus application and at the nearby area. In the other two locations, the area presenting the highest OI values is small and located at the site of focus application, which allowed its precise localization. CONCLUSION: Organization index maps provide a better approximation than DF maps for the localization of ectopic sources of high frequency and continuous activity during episodes of simulated AF in remodelled tissue.

The relative role of refractoriness and source-sink relationship in reentry generation during simulated acute ischemia.

During acute myocardial ischemia, reentrant episodes may lead to ventricular fibrillation (VF), giving rise to potentially mortal arrhythmias. VF has been traditionally related to dispersion of refractoriness and more recently to the source-sink relationship. Our goal is to theoretically investigate the relative role of dispersion of refractoriness and source-sink mismatch in vulnerability to reentry in the specific situation of regional myocardial acute ischemia. The electrical activity of a regionally ischemic tissue was simulated using a modified version of the Luo-Rudy dynamic model. Ischemic conditions were varied to simulate the time-course of acute ischemia. Our results showed that dispersion of refractoriness increased with the severity of ischemia. However, no correlation between dispersion of refractoriness and the width of the vulnerable window was found. Additionally, in approximately 50% of the reentries, unidirectional block (UDB) took place in cells completely recovered from refractoriness. We examined patterns of activation after premature stimulation and they were intimately related to the source-sink relationship, quantified by the safety factor (SF). Moreover, the isoline where the SF dropped below unity matched the area where propagation failed. It was concluded that the mismatch of the source-sink relationship, rather than solely refractoriness, was the ultimate cause of the UDB leading to reentry. The SF represents a very powerful tool to study the mechanisms responsible for reentry.