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Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-03-27T18:40:16Z No. of bitstreams: 1 lucasarantesberg.pdf: 3559702 bytes, checksum: 8d9fe16ad120323abea361847f6073ee (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-03-28T16:27:14Z (GMT) No. of bitstreams: 1 lucasarantesberg.pdf: 3559702 bytes, checksum: 8d9fe16ad120323abea361847f6073ee (MD5) / Made available in DSpace on 2018-03-28T16:27:14Z (GMT). No. of bitstreams: 1 lucasarantesberg.pdf: 3559702 bytes, checksum: 8d9fe16ad120323abea361847f6073ee (MD5) Previous issue date: 2018-02-23 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As fibras de Purkinje são estruturas fundamentais no processo de propagação do estímulo elétrico do coração. Para que ocorra a contração dos músculos dos ventrículos é necessário que estas fibras estimulem o miocárdio de maneira sincronizada. Porém, certas alterações nas propriedades das células que compõem estas fibras podem proporcionar uma dessincronização do ritmo cardíaco. Isto pode ocorrer através de falhas na propagação do estímulo elétrico devido a bloqueios que ocorrem nas junções que ligam as fibras de Purkinje com o músculo do ventrículo, de modo que esta condição é considerada um estado de risco para arritmias cardíacas. No entanto, a obtenção da estrutura das fibras de Purkinje a partir de um paciente específico é uma tarefa difícil e ela é mandatória para que sejam realizados estudos envolvendo a atividade elétrica do coração. Grande parte destas dificuldades decorre do fato da velocidade de propagação nas fibras de Purkinje ser extremamente rápida, da ordem de 2 a 4 m/s, tornando assim as medições experimentais um desafio. Este trabalho tem por objetivo investigar e analisar quais propriedades podem afetar a velocidade de propagação e o tempo de ativação nas fibras de Purkinje, tais como a geometria das células, a sua condutividade, o acoplamento das fibras com o tecido ventricular e o número de bifurcações existentes na rede. Com intuito de atingir este objetivo, diversas redes de Purkinje foram geradas variando estes parâmetros a fim de se realizar uma análise de sensibilidade. Para a implementação do modelo computacional foi utilizada a equação do monodomínio para descrever matematicamente o fenômeno. Foram utilizados dois modelos celulares específicos para células de Purkinje a fim de modelar as correntes iônicas. A solução numérica foi calculada através do Método dos Volumes Finitos. Os resultados do presente trabalho se mostraram de acordo com os obtidos na literatura, de modo que o modelo foi capaz de validar de maneira satisfatória determinados comportamentos que ocorrem na condução do estímulo elétrico através das fibras de Purkinje, como a velocidade de propagação e o tempo de ativação nestas estruturas. Além disso, o modelo foi capaz de reproduzir o atraso característico na propagação que acontece nas Junções-Músculo-Purkinje. / Purkinje fibers are fundamental structures in the process of propagation of the electrical stimulus of the heart. In order for contraction of the muscles of the ventricles to occur, these fibers need to stimulate the myocardium in a synchronized manner. However, certain changes in the properties of the cells composing these fibers may provide a desynchronization of the heart rate. This can occur through failures in the propagation of the electrical stimulus due to blockages occurring at the junctions that attach the Purkinje fibers to the ventricle muscle, so that this condition is considered a risk state for cardiac arrhythmias. However, obtaining the structure of Purkinje fibers from a specific patient is a difficult task and it is mandatory for studies involving the electrical activity of the heart. Most of these difficulties arise from the fact that the propagation velocity in the Purkinje fibers is extremely fast, ranging from 2 to 4 m/s, thus making experimental measurements a challenge. This work aims to investigate and analyze which properties may affect the propagation velocity and activation time in Purkinje fibers, such as cell geometry, conductivity, coupling of fibers with ventricular tissue and number of bifurcations in the network. In order to reach this goal, several Purkinje networks were generated by varying these parameters in order to perform a sensitivity analysis. For the implementation of the computational model was used the monodomain equations to describe mathematically the phenomenon. Two specific cellular models for Purkinje cells were used to model the ionic currents. The numerical solution was calculated using the Finite Volume Method. The results of the present work were in accordance with those obtained in the literature, so that the model was able to validate in a satisfactory way certain behaviors that occur in the conduction velocity and the activation time of the Purkinje fibers. In addition, the model was able to reproduce the characteristic delay on the propagation that occur at the Purkinje-Muscle-Junctions.

Les arythmies ventriculaires conduisant à la mort subite ont été précédemment associées àun type de cellules spécialisées, les fibres de Purkinje (FP). Elles font partie du systèmede conduction cardiaque, et possèdent un rôle majeur dans l’impulsion électrique et l’activationsynchrone des ventricules. Néanmoins, elles peuvent être impliquées dans des phénomènespro-arythmogéniques à l’origine de l’initiation ou du maintien de la fibrillation ventriculaire(FV) au sein de structures normales ou dans le cas d’un large spectre de maladies cardiaques.Cependant, les caractéristiques électrophysiologiques et structurelles des FP etles mécanismes sous-jacents des arythmies liées au Purkinje restent inconnus. Le systèmePurkinje semblerait jouer un rôle important de substrat de l’arythmie en raison de son impactsur l’hétérogénéité transmurale de repolarisation.Six études décrivant les propriétés électrophysiologiques et les propriétés macro/microstructurellesde ventricules gauches de brebis et de ventricules gauches humains ont étédéveloppées en utilisant une combinaison de méthodes classiques et innovantes.Les résultats ont permis de montrer que les FP, à travers leurs jonctions avec le myocarde,modulaient localement la durée du potentiel d'action et jouaient un rôle dans la dispersionde la repolarisation, révélant ainsi le rôle potentiel des FP dans le déclenchement etle maintien de la FV.Ce travail ouvre de nouvelles perspectives thérapeutiques dans le traitement préventifde l'arythmie ventriculaire afin de lutter contre la mort subite d'origine cardiaque. / Arrhythmias that lead to sudden death have previously been associated with a specializedcell type, the Purkinje fibers (PF). They form the cardiac conduction system, and have a majorrole in the electrical impulse and synchronous activation of the ventricles. However, they maybe involved in pro-arrhythmic phenomena causing the initiation or maintenance of ventricularfibrillation (VF) in structurally normal and a broad spectrum of cardiac diseases.Nevertheless, electrophysiological and structural characteristics of PF and mechanismsunderlying Purkinje-related arrhythmias are poorly understood. It is hypothesized thatthe Purkinje system plays an important role as a substrate for arrhythmias due to, in part,its impact on transmural repolarization heterogeneity.Here within are six studies describing electrophysiological and macro/micro structuralproperties of sheep and human left ventricles using a combination of conventional andinnovative methods.Results showed that PF, through junctions with the myocardium, locally modulatedthe action potential duration and played a role in the dispersion of repolarization. Therefore,revealing a potential role for PF in both, trigger and maintenance of VF.This work opens new therapeutic perspectives in preventive treatment of ventriculararrhythmia to fight against sudden cardiac death.

There is a growing consensus that life-threatening cardiac arrhythmias like ven- tricular tachycardia (VT) or ventricular fibrillation (VF) arise because of the formation of spiral waves of electrical activation in cardiac tissue; unbroken spiral waves are associated with VT and broken ones with VF. Several experimental studies have shown that in homogeneities in cardiac tissue can have dramatic effects on such spiral waves. In this thesis we focus on spiral-wave dynamics in mathematical models of human ventricular tissue which contain (a) conduction in homogeneities, (b) ionic in- homogeneities, (c) fibroblasts, (d) Purkinje fibers. We also study the effect of a periodic deformation of the simulation domain on spiral wave-dynamics. Chapter 2 contains our study of “Spiral-Wave Dynamics and Its Control in the Presence of In homogeneities in Two Mathematical Models for Human Cardiac Tissue”; this chapter follows closely parts of a paper we have published [1]. Chapter 3 contains our study of “Spiral-wave dynamics in a Mathematical Model of Human Ventricular Tissue with Myocytes and Fibroblasts”; this chapter follows closely a paper that we have submitted for publication. Chapter 4 contains our study of “Spiral-wave Dynamics in Ionically Realistic Mathematical Models for Human Ventricular Tis- sue: The Effects of Periodic Deformation”; this chapter follows closely a paper that we have submitted for publication. Chapter 5 contains our study of “Spiral-wave dynamics in a Mathematical Model of Human Ventricular Tissue with Myocytes and Purkinje fibers”; this chapter follows closely a paper that we will submit for publication soon. In chapter 2, we study systematically the AP morphology in a state-of-the-art mathematical model of human ventricular tissue due to ten-Tusscher, Noble, Noble, and Panfilov (the TNNP04 model); we also look at the contribution of individual ionic currents to the AP by partially or completely blocking ion channels associated with the ionic currents. We then carry out systematic studies of plane- wave and circular-wave dynamics in the TNNP04 model for cardiac tissue model. We present a detailed and systematic study of spiral-wave turbulence and spa- tiotemporal chaos in two mathematical models for human cardiac tissue due to (a) ten-Tusscher and Panfilov (the TP06 model) and (b) ten-Tusscher, Noble, Noble, and Panfilov (the TNNP04 model). In particular, we use extensive numerical simulations to elucidate the interaction of spiral waves in these models with conduction and ionic in homogeneities. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such in homogeneities. A major goal here is to develop low amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of in homogeneities that occur commonly in cardiac tissue. Therefore, we study a control scheme that has been suggested for the control of spiral turbulence, via low-amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control scheme in the presence of in homogeneities in biophysical realistic models. We find that a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence than other control schemes. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation. In chapter 3, we study the role of cardiac fibroblasts in ventricular tissue; we use the TNNP04 model for the myocyte cell, and the fibroblasts are modelled as passive cells. Cardiac fibroblasts, when coupled functionally with myocytes, can modulate their electrophysiological properties at both cellular and tissue levels. Therefore, it is important to study the effects of such fibroblasts when they are coupled with myocytes. Chapter 3 contains our detailed and systematic study of spiral-wave dynamics in the presence of fibroblasts in both homogeneous and inhomogeneous domains of the TNNP04 model for cardiac tissue. We carry out extensive numerical studies of such modulation of electrophysiological properties in mathematical models for (a) single myocyte fibroblast (MF) units and (b) two-dimensional (2D) arrays of such units; our models build on earlier ones and allow for no, one-way, or two-way MF couplings. Our studies of MF units elucidate the dependence of the action-potential (AP) morphology on parameters such as Ef , the fibroblast resting membrane potential, the fibroblast conductance Gf , and the MF gap-junctional coupling Ggap. Furthermore, we find that our MF composite can show autorhythmic and oscillatory behaviors in addition to an excitable response. Our 2D studies use (a) both homogeneous and inhomogeneous distributions of fibroblasts, (b) various ranges for parameters such as Ggap, Gf , and Ef , and (c) intercellular couplings that can be no, one-way, and two-way connections of fibroblasts with myocytes. We show, in particular, that the plane-wave conduction velocity CV decreases as a function of Ggap, for no and one-way couplings; however, for two-sided coupling, CV decreases initially and then increases as a function of Ggap, and, eventually, we observe that conduction failure occurs for low values of Ggap. In our homogeneous studies, we find that the rotation speed and stability of a spiral wave can be controlled either by controlling Ggap or Ef . Our studies with fibroblast inhomogeneities show that a spiral wave can get anchored to a local fibroblast inhomogeneity. We also study the efficacy of a low-amplitude control scheme, which has been suggested for the control of spiral-wave turbulence in mathematical models for cardiac tissue, in our MF model both with and without heterogeneities. In chapter 4, we carry out a detailed, systematic study of spiral-wave dynamics in the presence of periodic deformation (PD) in two state-of-the-art mathematical models of human ventricular tissue, namely, the TNNP04 model and the TP06 model. To the best of our knowledge, our work is the first, systematic study of the dynamics of spiral waves of electrical activation and their transitions, in the presence of PD, in such biophysically realistic mathematical models of cardiac tissue. In our studies, we use three types of initial conditions whose time evolutions lead to the following states in the absence of PD: (a) a single rotating spiral (RS), (b) a spiral-turbulence (ST) state, with a single meandering spiral, and (c) an ST state with multiple broken spirals for both these models. We then show that the imposition of PD in these three cases leads to a rich variety of spatiotemporal pat- terns in the transmembrane potential including states with (a) an RS state with n-cycle temporal evolution (here n is a positive integer), (b) rotating-spiral states with quasiperiodic (QP) temporal evolution, (c) a state with a single meandering spiral MS, which displays spatiotemporal chaos, (d) an ST state, with multiple bro- ken spirals, and (e) a quiescent state in which all spirals are absorbed (SA). For all three initial conditions, precisely which one of the states is obtained depends on the amplitudes and the frequencies of the PD in the x and y directions. We also suggest specific experiments that can test the results of our simulations. We also study, in the presence of PD, the efficacy of a low-amplitude control scheme that has been suggested, hitherto only without PD, for the control of spiral-wave turbulence, via low-amplitude current pulses applied on a square mesh, in mathematical models for cardiac tissue. We also develop line-mesh and rectangular-mesh variants of this control scheme. We find that square- and line-mesh-based, low-amplitude control schemes suppress spiral-wave turbulence in both the TP06 and TNNP04 models in the absence of PD; however, we show that the line-based scheme works with PD only if the PD is applied along one spatial direction. We then demonstrate that a minor modification of our line-based control scheme can suppress spiral-wave turbulence: in particular, we introduce a rectangular-mesh-based control scheme, in which we add a few control lines perpendicular to the parallel lines of the line- based control scheme; this rectangular-mesh scheme is a significant improvement over the square-mesh scheme because it uses fewer control lines than the one based on a square mesh. In chapter 5, we have carried out detailed numerical studies of (a) a single unit of an endocardial cell and Purkinje cell (EP) composite and (b) a two-dimensional bilayer, which contains such EP composites at each site. We have considered bio- physically realistic ionic models for human endocardial cells (Ecells) and Purkinje cells (Pcells) to model EP composites. Our study has been designed to elucidate the sensitive dependence, on parameters and initial conditions, of (a) the dynamics of EP composites and (b) the spatiotemporal evolution of spiral waves of electrical activation in EP-bilayer domains. We examine this dependence on myocyte parameters by using the three different parameter sets P1, P2, and P3; to elucidate the initial-condition dependence we vary the time at which we apply the S2 pulse in our S1-S2 protocol; we also investigate the dependence of the spatiotemporal dynamics of our system on the EP coupling Dgap, and on the number of Purkinje- ventricular junctions (PVJs), which are measured here by the ratio R, the ratio of the total number of sites to the number of PVJs in our simulation domain. Our studies on EP composites show that the frequency of autorhythmic activity of a P cell depends on the diffusive gap-junctional conductance Dgap. We perform a set of simulations to understand the source-sink relation between the E and P cells in an EP composite; such a source-sink relation is an important determinant of wave dynamics at the tissue level. Furthermore, we have studied the restitution properties of an isolated E cell and a composite EP unit to uncover this effect on wave dynamics in 2D, bilayers of EP composites. Autorhythmicity is an important property of Purkinje cell; it helps to carry electrical signals rapidly from bundle of His to the endocardium. Our investigation of an EP composite shows that the cycle length (CL) of autorhythmic activity decreases, compared to that of an uncoupled Purkinje cell. Furthermore, we find that the APD increases for an EP composite, compared to that of an uncoupled P cell. In our second set of simulations for an EP-composite unit, we have obtained the AP behaviors and the amount of flux that flows from the E to the P cell during the course of the AP. The direction of flow of this flux is an important quantity that identifies which one of these cells act as a source or a sink in this EP composite. We have found that the P cell in an EP composite acts as a stimulation-current source for the E cell in the depolarization phase of the AP, when the stimulus is applied to both cells or to the P cell only. However, the P cell behaves both as a source and a sink when the stimulus is applied to the E cell only. In our third set of simulations for an EP composite unit, we have calculated the restitution of the APD; this plays an important role in deciding the stability of spiral waves in mathematical models for cardiac tissue. Our simulation shows that, for the EP composite with high coupling (Dgap = Dmm~10), the APDR slope decreases, relative to its value for an isolated E cell, for parameter sets P1 and P2, and first increases (for 50 ≤ DI ≤ 100 ms) and then decreases for the parameter set P3 ; however, for low coupling (Dgap = Dmm~100), the variation of the AP D as function of DI, for an EP composite, shows biphasic behavior for all these three parameter sets. We found that the above dynamics in EP cable type domains, with EP composites, depends sensitively on R. We hope our in silico studies of spiral-wave dynamics in a variety of state-of-the- art ionic models for ventricular tissue will stimulate more experimental studies that examine such dynamics.