Orientador: Stephen Hyslop / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T23:44:30Z (GMT). No. of bitstreams: 1 Dias_Lourdes_D.pdf: 2781638 bytes, checksum: 00a6161d21fa428051e65ae4993b92c1 (MD5) Previous issue date: 2009 / Resumo: As peçonhas do gênero bothrops causam hipotensão, no entanto as alterações cardíacas e hemodinâmicas, associadas com este fenômeno não têm sido bem investigadas. Neste estudo, analisamos as alterações cardiovasculares causadas pela peçonha de Bothrops alternatus (urutu) em cães e, avaliamos a cardiotoxicidade desta peçonha em átrio direito isolado de rato. Em cães anestesiados com isoflurano, a peçonha (0,3 mg/kg, i.iv.) causou hipotensão imediata atingindo o ápice aos 5 minutos, seguida por uma lenta recuperação para níveis não significativamente diferentes do basal após 2h. Não foi observada recuperação no grupo tratado com a dose de 1,0 mg/kg. A hipotensão foi acompanhada por uma queda abrupta do débito cardíaco, dos trabalhos tanto do ventrículo direito quanto do esquerdo, bem como do volume e índice sistólico, os quais permaneceram reduzidos até o final do experimento. Não ocorreu alteração significativa na freqüência cardíaca, no ECG, nos valores pressóricos pulmonares, nos níveis dos gases sanguíneos (pO2, pCO2, HCO3, SBCe e SBEc), e nem nos parâmetros metabólicos (pH, lactato, glicose e creatinoquinase), porém, foi observado um aumento significativo nos níveis de lactato desidrogenase logo no início do envenenamento. Nenhuma alteração histológica no tecido cardíaco foi observada, no entanto, observou-se microaneurismas e alguma descamação epitelial nos túbulos renais. Houve uma diminuição rápida da peçonha circulante, após a administração i.v., que ainda foi detectada aos 240 minutos. A peçonha de B. alternatus (0,5; 1,0 e 2,0 mg/ml) não alterou a frequência atrial, mas reduziu significativamente a força contrátil (redução máxima de ~76%) e aumentou acentuadamente a liberação de creatinoquinase (CK) e creatinoqunase - MB (CK-MB). A análise histopatológica mostrou extensa mionecrose dos cardiomiócitos. A peçonha dialisada (1,0 mg/ml, membrana de 2000 Da) contra NaCl 0,9 % (24h a 4 °C) não alterou a redução progressiva na força contrátil, enquanto que o aquecimento (100 °C, 20 min) aboliu esta redução; A liberação de CK e CK-MB não foi alterada pela diálise e pelo aquecimento. A atropina, o atenolol e propranol, a cimetidina ou a indometacina não alteraram a força contrátil atrial, no entanto o L-NAME - inibidor da NOS, atenuou a redução na contratilidade, sugerindo um possível envolvimento do NO na resposta induzida pela peçonha. Estes resultados mostram que em cães, a peçonha de B. alternatus produziu acentuadas alterações cardiovasculares, envolvendo uma ação cardíaca direta, com poucas alterações metabólicas. A peçonha é também tóxica para átrio isolado de rato, provavelmente em função dos efeitos proteolíticos e/ou de PLA2. / Abstract: Bothrops snake venoms cause hypotension, but the hemodynamic and cardiac alterations associated with this phenomenon have not been extensively investigated. In this study, we examined the cardiovascular changes caused by Bothrops alternatus (urutu) venom in anesthetized dogs and examined the cardiotoxicity of the venom in rat isolated rat atria. In isofluorane-anesthetized dogs, venom (0.3 mg/kg, i.v.) caused immediate hypotension that was maximal within 5 min followed by a slow recovery to levels not significantly different from pre-venom values after 2 h; no recovery was seen with a venom dose of 1 mg/kg. The hypotension was accompanied by an abrupt decrease in cardiac output, left and right ventricular systolic work, and systolic indices and volume that persisted without recovery until the end of the experiment. There were no significant changes in heart rate, ECG, pulmonary hemodynamics, blood gas levels (pO2, pCO2, HCO3, SBCe and SBEc) and metabolic parameters (blood pH, lactate, glucose and creatine kinase); however, a slight, significant increase in lactate dehydrogenase was seen soon after venom. There were no histological alterations in cardiac tissue, but microaneurysms and epithelial desquamation were seen in renal tubules. Circulating venom decreased rapidly after i.v. administration, but was still detectable after 240 min. Venom (0.5, 1.0 and 2.0 mg/ml) did not affect the beating rate of rat isolated right atria but significantly reduced the contractile force (maximal reduction of ~76%) and markedly increased the release of creatine kinase (CK) and CK-MB. Histological analysis revealed extensive myonecrosis. Venom dialysis (1.0 mg/ml; membrane nominal MW cut-off = 2000 Da) against 0.9% NaCl (24 h, 4°C) did not affect the decrease in contractile force whereas heating (100°C, 20 min) abolished the venom-induced reduction; CK and CK-MB release was also unaltered by dialysis but attenuated by heating. The decrease in atrial contractility was unaffected by atropine, atenolol, propranolol, cimetidine or indomethacin, but was attenuated by L-NAME, an inhibitor of nitric oxide synthase, indicating a possible role for nitric oxide in the venom-induced response. These results show that in dogs B. alternatus produces marked cardiovascular alterations involving a direct cardiac action, with little role for metabolic changes. The venom is also toxic to rat atria, probably as a result of venom proteolytic and/or phospholipase A2 activity. / Doutorado / Farmacologia / Doutor em Farmacologia

Orientador: Stephen Hyslop / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T05:11:43Z (GMT). No. of bitstreams: 1 Rodrigues_MarianaAcedoPitocco_M.pdf: 2686415 bytes, checksum: 93b2ceba582a84158f4ce0d23348a829 (MD5) Previous issue date: 2010 / Resumo: Serpentes do gênero Bothrops são a principal causa de acidentes ofídicos no Brasil. Acidentes envolvendo a Bothrops jararacussu (jararacuçu) resultam em envenenamento moderado e grave, devido principalmente à grande quantidade de peçonha injetada por esta espécie. Entre os efeitos observados, o quadro de hipotensão e de choque são fatores importantes a serem considerados. Neste trabalho, avaliamos as alterações cardíacas causadas pela peçonha de B. jararacussu em átrio direito isolado de rato. A incubação das preparações com peçonha (0,025, 0,050, 0,1 e 0,2 mg/ml) resultou em uma marcada contratura atrial em altas concentrações que levou a uma redução progressiva da força contrátil e a freqüência atrial, especialmente na maior concentração utilizada (0,2 mg/ml). A maior concentração da peçonha também causou uma marcada liberação de CK-BM e desorganização das fibras musculares atriais. A peçonha aquecida (100°C, 20 min) aboliu esta atividade enquanto a diálise não alterou significativamente essas respostas. O fracionamento da peçonha de B. jararacussu em cromatografia por gel filtração e troca iônica nos forneceu a fração (III3) que reproduziu todas as alterações funcionais e morfológicas vistas com a peçonha bruta. SDS-PAGE da fração III3, na presença e ausência de ditiotreitol e ß-mecaptoetanol revelaram uma massa molecular de ~28 KDa e 14 KDa, respectivamente, semelhantes às bothropstoxinas, as principais PLA2 miotóxicas desta peçonha. Os antivenenos comerciais utilizados (botrópico e botrópico/crotálico) se mostraram eficientes em neutralizar os efeitos produzidos pela peçonha bruta tanto na força e freqüência atriais como na liberação de CK-MB e nas alterações histológicas. A pré-incubação com antagonistas farmacológicos (bloqueadores de receptores adrenérgicos, histaminérgicos, muscarínicos, e inibidores da ciclooxigenase e óxido nítrico sintase) não afetou significativamente as alterações induzidas pela peçonha. Estes resultados indicam que as alterações induzidas pela peçonha de B. jararacussu estão envolvidas diretamente com o dano a fibra muscular atrial mediada provavelmente através da atividade das PLA2 miotóxicas. / Abstract: The genus Bothrops is the principal cause of snakebite in Brazil. Bites by Bothrops jararacussu (jararacuçu) result in moderate to severe envenoming partly because of the large amount of venom injected by this species. Hypotension and circulatory shock are important systemic manifestations associated with bites by this species. In this work, we examined the cardiac alterations caused by B. jararacussu venom in rat isolated right atria. Incubation of atria with venom (0.025, 0.050, 0.1 and 0.2 mg/ml) resulted in marked muscle contracture at high concentrations that led to a progressive decrease in contractile force and beating rate, especially at the highest concentration (0.2 mg/ml). The highest venom concentrations also caused a marked release of CK-MB and disorganization of atrial muscle fibers. Heating the venom (100ºC, 20 min) abolished this activity whereas dialysis did not significantly alter the responses. Fractionation of B. jararacussu venom by gel filtration and ion exchange chromatographies yielded a peak (III-3) that reproduced all of the morphological and functional changes seen with the venom. SDS-PAGE of the peak III-3 protein in the absence and presence - mercaptoethanol revealed a molecular mass of ~28 KDa and 14 KDa, respectively, similar to bothropstoxins, the main myotoxic PLA2 of this venom. Bothropic and bothropic/crotalic antivenoms prevented the venom (0.2 mg/ml)-induced decrease in contractile force and atrial rate, as well as the tissue damage (CK-MB release and histological alterations). Pre-incubation with adrenergic, histaminergic and muscarinic receptor antagonists, or with cyclooxygenase and nitric oxide synthase inhibitors, did not significantly affect the venom-induced changes. These results indicate that the B. jararacussu venom-induced alterations probably involve direct to atrial muscle fibers mediated by venom myotoxic PLA2. / Mestrado / Mestre em Farmacologia

Background: Experimental mapping and computer modelling provide important platforms to study the fundamental mechanisms underlying normal and abnormal activation of the heart. However, accurate computer modelling requires detailed anatomical models and needs support and validation from experimental data. Aims: 1) Construction of detailed anatomical heart models with the cardiac conduction system (CCS). 2) Mapping of the electrical activation sequence in rabbit atria to support and validate computer simulation. 3) Mapping of the spontaneous activity in the atrioventricular ring tissues (AV rings), which consist of nodal-like myocytes and can be a source of atrial tachycardia. Methods: High-resolution magnetic resonance imaging (MRI) and computed tomography (CT) were used to provide two-dimensional (2D) images for the construction of the detailed anatomical heart models. Immunohistochemistry and Masson’s trichrome staining were used to distinguish the CCS in the heart. LabVIEW was used in the development of a multi-electrode mapping system. The multi-electrode mapping technique was employed to map the electrical activation sequence of the rabbit atria. The cellular automaton model was used to simulate electrical activation of the rabbit atria. Results: 1) Three detailed anatomical models were constructed, including a detailed three dimensional (3D) anatomical model of the rabbit heart (whole of the atria and part of the ventricles), a 3D anatomical model of the rat heart with the CCS and AV rings, and a 3D anatomical model of the human atrioventricular node. 2) A multi-electrode mapping system was developed. 3) The electrical activation sequence of the rabbit atria was mapped in detail using the multi-electrode mapping system. The conduction velocity in the rabbit atria was measured. The mapping data showed the coronary sinus and the left superior vena cava do not provide an interatrial conduction route during sinus rhythm in the rabbit heart. 4) Electrical activation of the rabbit atria was simulated with the support of the 3D anatomical model of the rabbit atria and the experimental mapping data. 5) The spontaneous activity in the rat AV rings was mapped using the multi-electrode mapping system. Conclusions: The detailed anatomical models developed in this study can be used to support accurate computer simulation and can also be used in anatomical teaching and research. The experimental mapping data from the rabbit atria can be used to support and validate computer simulation. The computer simulation study demonstrated the importance of anatomical structure and electrophysiological heterogeneity. This study also demonstrated that the AV rings could potentially act as ectopic pacemakers.

Orientador: Rosana Almada Bassani / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T18:24:30Z (GMT). No. of bitstreams: 1 Oliveira_ElizangelaSouto_M.pdf: 5397962 bytes, checksum: a6952b7daf58ed6c84d6fb7eecc0d06f (MD5) Previous issue date: 2015 / Resumo: Importantes ajustes cardiovasculares dependentes de estimulação adrenérgica do coração ocorrem no período perinatal. O objetivo deste trabalho foi estudar a resposta cronotrópica a catecolaminas em ratos imaturos, com foco em mecanismos intrínsecos e extrínsecos à via de transdução ?-adrenérgica. Foi determinada a resposta cronotrópica a tiramina (TIR), isoproterenol (ISO), noradrenalina (NA), forskolin (FSK) e 3-isobutil-1-metilxantina (IBMX) em átrios direitos de ratos de 0-23 dias de idade e adultos. No mesmo tecido, foram quantificados os níveis de mRNA de diversas proteínas pela técnica de reação em cadeia de polimerase em tempo real (qRT-PCR). Os principais resultados foram: a) a resposta cronotrópica máxima (Rmax) a TIR e NA exógena mostrou-se deprimida em átrios de ratos de 0-2 dias, enquanto a sensibilidade aos agonistas reduziu-se com o amadurecimento; b) o bloqueio do transportador neuronal de catecolaminas por desipramina foi menos efetivo em causar desvio à esquerda na curva concentração-efeito nos átrios de animais imaturos, e aboliu as diferenças de sensibilidade (mas não de Rmax) à NA; c) a inibição do transportador extraneuronal de monoaminas não modificou o pD2 do ISO em átrios de animais imaturos, os níveis de mRNA para este transportador foram ~30% daqueles em adultos; d) apesar da redução da Rmax à NA em neonatos, não houve diferença na Rmax a ISO, FSK e IBMX entre as diferentes idades; e) o bloqueio de adrenoceptores ?2 com ICI118,551 reduziu Rmax e pD2 do ISO apenas nos átrios de ratos imaturos, indicando contribuição deste subtipo de receptores apenas nos primeiros dias após o nascimento; f) a expressão de adrenoceptores ?2, Gi, Gs e adenilato ciclase (isoforma 1) foi maior em átrios de animais imaturos, enquanto aquela de adrenoceptores ?1 foi semelhante em todos os grupos etários. Conclui-se que os componentes pós-receptor desta via de sinalização já estão presentes no neonato, embora tenha sido detectada aparente imaturidade no acoplamento de adrenoceptores ?1. Entretanto, foram identificados mecanismos compensatórios, tais como a participação de adrenoceptores ?2 e menor remoção neuronal e extraneuronal de catecolaminas. Palavras-chave: átrio direito, receptores adrenérgicos beta, catecolaminas, desenvolvimento pós-natal / Abstract: Important cardiovascular adjustments that depend on the adrenergic regulation of the cardiac function occur during the perinatal period. The goal of this work was to study the chronotropic responsiveness to catecholamines in immature rats, focusing on mechanisms intrinsic and extrinsic to the ?-adrenergic signaling pathway. The chronotropic response to tyramine (TYR), isoproterenol (ISO), norepinephrine (NE), forskolin (FSK), and 3-isobutyl-1-methylxanthine (IBMX) was determined in right atria isolated from 0-23 day-old and adults rats. In the same tissue, mRNA levels of relevant proteins were quantified by real-time polymerase chain reaction (qRT-PCR). The main results were: a) the maximum chronotropic response (Rmax) to TYR and to exogenous NE were lower in rigth atria from 0-2day-old rats, while the sensitivity to the agonists decreased during development; b) inhibition of neuronal norepinephrine transporter by desipramine was less effective at shifting the concentration-effect curve to the left in immature animals, and abolished the differences in sensitivity (but not in Rmax) to NE. c) inhibition of the extraneuronal monoamine transporter did not changed the ISO pD2 in atria from immature animals, in which the mRNA levels for this transporter were ~ 30% of those in adults; d) despite the lower Rmax to NE in neonates, the Rmax to ISO, FSK and IBMX was comparable among ages; e) ?2-adrenoceptor blockade with ICI118,551 reduced Rmax and ISO pD2 only in atria from immature rats, indicating contribution of this receptor subtype only in the first days after birth; f) ?2-adrenoceptor, Gi, Gs and adenylate cyclase (isoform 1) transcript levels were greater in the atria of immature animals, while that of ?1-adrenoceptor was similar in all age groups. In conclusion, post-receptor components of this signaling pathway seem to already be mature in newborns, although an apparent immaturity in ?1-adrenoceptor coupling was detected. However, compensatory mechanisms were identified, such as the participation of ?2-adrenoceptor and weaker neuronal and extraneuronal catecholamine removal. Keywords: right atria, ?-adrenoceptor, catecholamines, postnatal development / Mestrado / Farmacologia / Mestra em Farmacologia

PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC1, VPAC1, and VPAC2 receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC1 being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC1 agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a log EC50=-9.08±0.15 M (n=7) and a maximum of 96.3±5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP.

PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC1, VPAC1, and VPAC2 receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC1 being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC1 agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a log EC50=-9.08±0.15 M (n=7) and a maximum of 96.3±5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP.

Skybridges and atria between buildings are becoming more and more popular. Most current skybridge connections are either roller or rigid-connections. This dissertation presents an investigation of the structural analysis and optimization of skyscraper systems with hinge-connected skybridges, and compares the results to skyscraper systems with roller-connected skybridges and to skyscraper systems without skybridges altogether. Also presented is an investigation of the structural analysis and optimization of skyscrapers both with and without atria between the buildings. It was assumed that the atria envelope was constructed with cushions made from lightweight, transparent, and flexible Ethylene Tetrafluoroethylene (ETFE). A simplified skyscraper skybridge model (SSSM) was developed to approximate analysis of such systems. The SSSM identifies and includes only the dominant degrees of freedom (DOF's) when assembling the structure stiffness matrix. This greatly reduces computational time and computer memory compared to traditional finite element models (FEM). The SSSM is fast enough to be used with both gradient-based and genetic optimization algorithms. The steps of the SSSM consist of: 1) determination of megacolumn areas, 2) constructing the stiffness matrix, 3) evaluation of volume, weight, mass and period, 4) calculation of lateral force vectors, and 5) calculation of displacement and stress constraints. Three skyscraper systems were analyzed using both the SSSM and a FEM to compare both the accuracy and efficiency of the SSSM. It was found that the SSSM was very accurate for displacements (translations and rotations), and core, megacolumn, outrigger, and skybridge stress. It was also found that the SSSM analysis time was significantly faster and used far less computer memory than FEM. Four skyscraper systems were optimized for two different sites, with varying atria and skybridge conditions, using gradient-based and genetic optimization algorithms. The optimization strategy consisted of a series of executions of the sequential quadratic programming (SQP) algorithm, followed by executions of the generalized reduced gradient (GRG) algorithm, followed by executions of a discrete genetic algorithm. The genetic algorithm made significant progress for two of the systems. Optimal results showed that in some cases hinge skybridges and atria envelope produced significantly lighter systems compared to roller, no skybridge, or without atria envelope cases.

The aim of this study was to investigate the passive and active parameters affecting energy efficiency of two office buildings with sun spaces, namely the MATPUM Building and the Solar Building on the Middle East Technical University (METU) Campus, Ankara and the effect of sun spaces on temperature patterns within mentioned buildings. Both buildings were oriented in the same direction, namely south. However, the location and the type of the sunspaces differed from each other. The sun space in the MATPUM Building is an atrium which has southerly glazed fa&ccedil / ade. On the other hand, the sun space in the Solar Building is an enclosed conservatory which has southerly glazed fa&ccedil / ades and roof. The effect of sun spaces on temperature patterns within case study buildings was determined by collecting internal temperature and humidity data from different locations within the buildings and external temperature and humidity data on certain days of the week from May to August and October and November. Data loggers were used to collect these data. The collected data was then compared for the two buildings and also for the different months. In conclusion, more heat gain resulting in temperature increase inside the buildings was obtained in conservatories when compared to the atria which have glazed fa&ccedil / ade instead of glazed roof. This was also proved by the analysis of variance method which was used for the comparison of temperature data of two buildings

Master of Science / Department of Computing and Information Sciences / John Hatcliff / The Heart is a specialized muscle that contracts regularly and continuously, pumping blood to the body and the lungs. Heart’s natural Pacemaker, the SA node is responsible for this pumping action by causing a flow of electricity through the heart. These electrical impulses cause the atria and ventricles to contract and thereby pump the blood to different parts of the body. Malfunction of the SA node leads to a disturbance in the heart’s rhythm in which heart beats lower than 60 times a minute ending up with Bradycardia. It also leads to ventricular arrhythmia which disrupts the ability of the ventricles to pump blood effectively to the body. This can cause a loss of all blood pressure leading to cardiac arrest and eventually death. In order to restore the heart’s natural healthy rhythm, an artificial pacemaker is necessary. A Pacemaker adapts to the present condition of the heart and responds to the heart by either pacing or just sensing it. It paces whenever there is some problem in the heart’s electrical activity and inhibits the pace when there is a proper intrinsic beat. There are various modes in which Pacemaker can operate based on the condition of the heart. Ventricles and atria are individually paced in few modes such as VOO, VVT, VVI, AOO, AAT, and AAI and paced together in some modes such as DVI, DI, DDD, DDDR as per the requirement of the heart. The main goal of this report is to understand the various modes, their nomenclature, working strategy, developing the pseudo code and implementing different modes namely VOO, AOO, VVI, AAI, VVT and AAT modes using an academic, dual chamber pacemaker.

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 rotores, y mapas de frecuencia dominantes. Finalmente, descubrimos que la precisión de los sistemas de mapeo multi-electrodo depende de su posición dentro de la cavidad auricular, de la distancia entre los electrodos y el tejido, de la distancia inter-electrodo, y de la contribución de las fuentes de campo lejano. Además, como consecuencia de estos factores que pueden afectar a la precisión de los sistemas de mapeo multi-electrodo, observamos la aparición de rotores falsos que podrían contribuir al fracaso de los procesos de ablación de la fibrilación auricular. / 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 contribution of far field sources. Furthermore, as a consequence of these factors, false rotors might appear and could contribute to failure of atrial fibrillation ablation procedures. / 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, vam descobrir que la precisió dels sistemes de mapeig multielèctrode depèn de la seua posició dins de la cavitat auricular, de la distància entre els elèctrodes i el teixit, de la distància interelèctrode, i de la contribució de les fonts de camp llunyà. A més, com a conseqüència d'aquests factors, es va observar l'aparició de rotors falsos que podrien contribuir al fracàs de l'ablació de la fibril·lació auricular. / Martínez Mateu, L. (2018). Mapping of the electrical activity of human atria. Multiscale modelling and simulations [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/104604 / TESIS