Made available in DSpace on 2016-01-26T12:51:39Z (GMT). No. of bitstreams: 1 andrelisavendramiparra_tese.pdf: 942682 bytes, checksum: bd373115099c234d8c536d942f318ec0 (MD5) Previous issue date: 2012-01-19 / Background: Chagas disease is a public health and social problem in Latin America due to its high incidence, morbidity and mortality. Chagas cardiomyopathy is manifested mainly by sudden cardiac death, chronic systolic heart failure, thromboembolism, ventricular arrhythmias and advanced atrioventricular block. The right ventricular pacing is a common treatment modality in patients with chronic systolic heart failure secondary to Chagas cardiomyopathy with advanced atrioventricular block. However, it is unknown if the clinical course or the prognosis of patients with right ventricular pacing is worse than that seen in non-paced patients. Aim: Establish the role of permanent pacemaker implantation on the prognosis of patients with Chagas disease heart failure. Methods: All patients with chronic systolic heart failure secondary to Chagas cardiomyopathy followed at our institution between January 2000 and December 2008 were considered for the study. A model of Cox proportional hazards regression was used to determine the role of right ventricular pacing as an independent predictor of all-cause mortality in this population. The Kaplan-Meier curves were constructed to estimate the probability of survival in patients with and without right ventricular pacing, which were compared by the log rank test. Results: A total of 216 patients were enrolled; 116 (55%) were not treated with right ventricular pacing, but 100 (45%) patients were paced. One hundred and ten (51%) patients died during the study. No difference was observed in the mortality rate in paced (54%) in comparison to non-paced (56%) (p = 0.24). Pacemaker therapy for ventricular pacing was not a predictor of all-cause mortality in either univariate or multivariate analysis. Median follow-up was 19 (8, 43) months. However / Introdução: A doença de Chagas é um grave problema de saúde pública e social em países da América Latina devido a sua alta incidência, morbidade e mortalidade. A cardiomiopatia chagásica manifesta-se principalmente por morte súbita cardíaca, insuficiência cardíaca crônica sistólica, tromboembolismo, arritmias ventriculares e bloqueio atrioventricular avançado. A estimulação ventricular direita, através do implante de marcapasso unicameral, é uma modalidade de tratamento frequente em pacientes com insuficiência cardíaca crônica sistólica secundária à cardiomiopatia chagásica, que apresentam bloqueio atrioventricular avançado. No entanto, não se sabe a estimulação cardíaca em ventrículo direito, a longo prazo, teria efeitos maléficos sobre a função cardíaca desses pacientes. Objetivo: Avaliar o efeito do implante de marcapasso definitivo com estimulação ventricular direita no prognóstico de pacientes com Insuficiência Cardíaca Crônica Sistólica secundária à cardiomiopatia Chagásica. Métodos: Todos os pacientes com insuficiência cardíaca crônica secundária a cardiomiopatia chagásica seguido em nossa instituição entre janeiro de 2000 a dezembro de 2008 foram considerados para o estudo. Um modelo de riscos proporcionais de Cox foi utilizado para determinar o papel da estimulação elétrica ventricular direita como um fator de predição independente de mortalidade geral para esta população. As curvas de Kaplan-Meier foram construídas para estimar a probabilidade de sobrevida em pacientes com e sem marcapasso cardíaco de estimulação ventricular direita, que foram comparadas pelo teste de log rank. Resultados: Um total de 216 pacientes foram incluídos no estudo, 116 (55%) não possuíam marcapasso cardíaco artificial implantado, e 100 (45%) eram portadores de marcapasso cardíaco artificial. Cento e dez (51%) pacientes foram a óbito durante o estudo; não houve diferença significativa na taxa de óbito entre pacientes portadores (54%) e não portadores (56%) de marcapasso cardíaco artificial (p=0,24). A terapia com marcapasso definitivo de estimulação ventricular direita não foi um preditor de mortalidade geral e nem de hospitalização, quer na análise univariada ou na multivariada. A mediana de acompanhamento foi de 19 (8, 43) meses. Porém o tratamento com digoxina, o não tratamento com betabloqueadores e a concentração de sódio plasmático igual ou menor que 140mEq/L foram preditores independentes de mortalidade tanto na univariada como na multivariada (p<0,005). O tempo médio de uso de marcapasso foi de 54 ± 51 meses. Probabilidade de sobrevida aos 12, 24, 36 e 48 meses foi de 84%, 67%, 58% e 46%, respectivamente, em pacientes com marcapasso, e 94%, 85%, 80% e 74%, respectivamente, em pacientes sem marcapasso (p>0,05). Conclusão: A estimulação do ventrículo direito não é um preditor independente de mortalidade geral em pacientes com cardiomiopatia chagásica com insuficiência cardíaca crônica sistólica.

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[ES] La población mundial en países desarrollados está envejeciendo y con ello existe un aumento de enfermedades en gran medida causadas por la edad. Las nuevas tecnologías médicas pueden ayudar a detectar, diagnosticar y tratar estas enfermedades y con ello ahorrar dinero, tiempo y recursos de los sistemas sanitarios. Las tecnologías inalámbricas implantables han abierto un nuevo panorama para la próxima generación de tecnologías médicas. Frecuencias como la Ultra Wide-Band (UWB) de 3.1 a 10.6 GHz están siendo consideradas para la nueva generación de dispositivos inalámbricos para dentro del cuerpo humano. Las características como el reducido tamaño de las antenas, la baja potencia de transmisión y la alta velocidad de datos son las más buscadas en este tipo de dispositivos. El problema surge porque el cuerpo humano depende de la frecuencia de modo que a mayores frecuencias, mayores son las pérdidas por propagación. Conociendo el canal de transmisión se puede solventar el problema de las altas pérdidas. Esta tesis tiene como objetivo caracterizar el canal de radio frecuencia (RF) para la nueva generación de dispositivos médicos implantables. Para caracterizar el canal se han empleado tres diferentes metodologías: simulaciones numéricas, medidas en phantom y experimentos en animales vivos. Las medidas en phantom fueron realizadas en un nuevo sistema de medidas expresamente disen¿ados para medidas de dentro a fuera del cuerpo humano en la banda de frecuencias UWB. Además, se utilizó un novedoso recipiente con dos capas de phantom imitando la zona gastrointestinal del cuerpo. Estos phantoms fueron creados para este tipo de medidas y son extremadamente precisos a las frecuencias UWB. Para los experimentos en animales se utilizaron cerdos y se intentó reproducir en ellos las medidas previamente realizadas en phantom. Las simulaciones software se realizaron con la intención de replicar ambas metodologías. Una vez realizados los experimentos se realizó un extensivo estudio del canal en dominio frecuencial y temporal. Mas en detalle, se compararon las antenas usadas en la recepción y transmisión, el efecto de la grasa en el canal, la formas del recipiente contenedor de phantom y las componentesmulticamino. Como resultado se ha propuesto un modelo de propagación del canal para la banda baja de las frecuencias UWB (3.1 -5.1 GHz) para la zona gastrointestinal del cuerpo humano. Este modelo de propagación ha sido validado utilizando las tres metodologías previamente descritas y comparada con otros estudios existentes en literatura. Finalmente, se midió el canal de propagación para una determinada aplicación a bajas frecuencias con señales UWB. También se realizaron medidas del canal de propagación en la zona cardíaca del cuerpo humano desde un punto de vista de seguridad de datos. Los resultados obtenidos en esta tesis confirman los beneficios que tendría la utilización de frecuencias UWB para las futuras generaciones de dispositivos médicos implantables. / [CA] La població mundial a països desenvolupats està envellint-se i enfrontant-se a un augment d'infermetats principalment causades per la edat. Les noves tecnologies mèdiques poden ajudar a detectar, diagnosticar i tractar aquestes malalties, estalviant diners, temps i recursos sanitaris. Els dispositius implantables sense fils han generat un nou panorama per a les noves generacions de dispositius mèdics. Les freqüències com la banda de UWB estan sent considerades per a les futures tecnologies implantables. La reduïda grandària de les antenes, la baixa potència de transmissió i les altes velocitats de dades son característiques buscades per als dispositius implantables. Per contra, els éssers humans depenen de la freqüència en el sentit que a majors freqüències, majors les pèrdues per propagació quan el senyal travessa el cos humà d'interior a exterior. Per solventar aquestes pèrdues el canal de propagació s'ha d'entendre i conèixer de la millor manera possible. Aquesta tesi doctoral te com a objectiu caracteritzar el canal de radio freqüència (RF) per a la nova generació de dispositius mèdics implantables. S'han emprat tres metodologies diferents per a realitzar aquesta caracterització: simulacions software, mesures amb fantomes i experiments amb animals vius. Els experiments amb fantomes es van realitzar a un sistema de mesures dissenyat expressament per a les transmissions de dins a fora del cos humà a les freqüències UWB. També es van utilitzar un contenidor per als fantomes de dues capes, imitant l'area gastrointestinal dels humans. Per als experiments a animals es van emprar porcs, replicant els experiments al laboratori en fantomes de la forma més semblant possible. Les simulacions software foren dissenyades per a imitar les experiments amb fantomes i animals. Després dels experiments el canal de propagació es va investigar exhaustivament des del domini freqüèncial i temporal. S'ha observat com les antenes en transmissió i recepció afecten al senyal, la influència de la grassa, la forma del contenidor de fantoma i les possibles contribucions multicamí. Finalment es proposa un nou model de propagació per a les baixes freqüències UWB (3.1 a 5.1 GHz) per a la zona GI del cos humà. El model es va validar utilitzant les tres metodologies abans esmentades i també foren comparades amb model ja existents a la literature. Finalment des d'un punt de vista aplicat, el canal es va avaluar per al senyal UWB a baixes freqüències (60 MHz). A més a més, per a la nova generació de marcapassos sense fil es va investigar el canal des d'un punt de vista de seguretat de dades. Els resultats obtinguts a aquesta tesi confirmen els avantatges d'emprar la banda de freqüències UWB per a la nova generació de dispositius médics implantables. / [EN] The current global population in developed countries is becoming older and facing an increase in diseases mainly caused by age. New medical technologies can help to detect, diagnose and treat illness, saving money, time, and resources of physicians. Wireless in-body devices opened a new scenario for the next generation of medical devices. Frequencies like the Ultra Wide-band (UWB) frequency band (3.1 - 10.6 GHz) are being considered for the next generation of in-body wireless devices. The small size of the antennas, the low power transmission, and the higher data rate are desirable characteristics for in-body devices. However, the human body is frequency ependent, which means higher losses of the radio frequency (RF) signal from in- to out-side the body as the frequency increases. To overcome this, the propagation channel has to be understood and known as much possible to process the signal accordingly. This dissertation aims to characterize the (RF) channel for the future of in-body medical devices. Three different methodologies have been used to characterize the channel: numerical simulations, phantom measurements, and living animals experiments. The phantom measurements were performed in a novel testbed designed for the purpose of in-body measurements at the UWB frequency band. Moreover, multi-layer high accurate phantoms mimicking the gastrointesintal (GI) area were employed. The animal experiments were conducted in living pigs, replicating in the fairest way as possible the phantom measurement campaigns. Lastly, the software simulations were designed to replicate the experimental measurements. An in-depth and detail analysis of the channel was performed in both, frequency and time domain. Concretely, the performance of the receiving and transmitting antennas, the effect of the fat, the shape of the phantom container, and the multipath components were evaluated. Finally, a novel path loss model was obtained for the low UWB frequency band (3.1 - 5.1 GHz) at GI scenarios. The model was validated using the three methodologies and compared with previous models in literature. Finally, from a practical case point of view, the channel was also evaluated for UWB signals at lower frequencies (60 MHz) for the GI area. In addition, for the next generation of leadless pacemakers the security link between the heart and an external device was also evaluated. The results obtained in this dissertation reaffirm the benefits of using the UWB frequency band for the next generation of wireless in-body medical devices. / Pérez Simbor, S. (2019). In-body to On-body Experimental UWB Channel Characterization for the Human Gastrointestinal Area [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/133034 / TESIS

Une accélération de la fréquence cardiaque (FC) au repos est observée chez les femmes enceintes. Au dernier trimestre, la FC accélère en moyenne de 15%, ce qui représente un facteur de risque dans le développement d’arythmies de novo ou dans l’exacerbation d’arythmies cardiaques préexistantes. Ceci est dangereux pour la mère ainsi que pour le fœtus. Cependant, les mécanismes responsables de ce changement cardiovasculaire restent peu connus. Notre laboratoire a récemment démontré que la grossesse était associée à une augmentation de la densité du courant pacemaker (If) et du courant calcique de type L (ICaL), ainsi qu’à des changements de l’homéostasie calcique dans les cellules de nœud sinusal (NS) de souris. Sachant que les concentrations plasmatiques en œstrogènes sont significativement augmentées pendant la grossesse et que ces hormones sexuelles féminines ont la capacité de modifier les propriétés électrophysiologiques du cœur, l’hypothèse de ce projet de recherche est que les œstrogènes jouent un rôle important dans l’augmentation de la FC associée à la grossesse et régulent les propriétés électrophysiologiques du NS. Les objectifs de ce projet de recherche sont de déterminer le rôle du 17β-œstradiol (E2) dans l’augmentation de la FC, d’examiner si ces effets sont régulés par les récepteurs aux œstrogènes alpha (ERα) et/ou bêta (ERβ) ainsi que d’évaluer les différents mécanismes de régulation de l’E2 sur l’électrophysiologie du NS. Des souris femelles adultes non-gestantes (2-4 mois) déficientes en ERα (ERKOα) ou en ERβ (ERKOβ) ont reçu un traitement chronique à l’E2 (30 μg deux fois par jour pendant quatre jours) simulant les concentrations plasmatiques en E2 retrouvées en fin de grossesse (23,3 ± 5,0 nM) chez la souris. L’analyse des électrocardiogrammes de surface montrent que la FC des souris ERKOβ (ERKOβ : 511 ± 15 bpm; ERKOβ +E2 : 580 ± 10 bpm, n = 10, p < 0,001) est significativement accélérée suivant le traitement à l’E2. Toutefois, la FC demeure inchangée chez les souris ERKOα (ERKOα : 520 ± 16 bpm; ERKOα +E2 : 530 ± 21 bpm, n = 7, p = 0,114). La méthode du patch-clamp en mode courant-imposé a permis de démontrer une accélération de l’automaticité des cellules du NS des souris ERKOβ suivant le traitement à l’E2, se traduisant par une augmentation de la fréquence des potentiels d’action spontanés (ERKOβ : 284 ± 24 bpm, n = 8; ERKOβ +E2 : 354 ± 23 bpm, n = 15, p = 0,0395) et par une pente de dépolarisation diastolique plus rapide (ERKOβ : 82 ± 12 mV/s, n = 8; ERKOβ +E2 : 140 ± 14 mV/s, n = 15, p < 0,003). En lien avec ces résultats, le patch-clamp en mode voltage-imposé a permis de démontrer que la densité de If est augmentée suivant un traitement à l’E2 (à -90 mV : ERKOβ : -6,6 ± 0,7 pA/pF, n = 12-15; ERKOβ +E2 : -11 ± 1 pA/pF, n = 9-11, p < 0,05). Cependant, If est similaire chez les souris ERKOα traitées ou non à l’E2. De plus, des cardiomyocytes humains dérivés de cellules souches pluripotentes induites de type nodal (N-hiPSC-CM) ont une accélération de la fréquence des potentiels d’action (CTL : 69 ± 5 bpm, n = 12; +E2 : 99 ± 6 bpm, n = 14, p < 0,001) ainsi qu’une augmentation de la densité de If (à -90 mV : CTL : -0,95 ± 0,14 pA/pF, n = 7-10; +E2 : -1,62 ± 0,17 pA/pF, n = 13-14, p < 0,05) suivant le traitement à l’E2. L’administration d’E2 ne modifie pas la fréquence des transitoires calciques des cellules de NS des souris ERKOα (139 ± 15, n = 13-14; +E2 : 142 ± 14, n = 15-16, p = ns) et ERKOβ (142 ± 11, n = 14-15; +E2 : 147 ± 13, n = 15-16, p = ns). En lien avec ces résultats, le courant ICaL des N-hiPSC-CM est inchangé suivant le traitement d’E2 (à 0 mV : CTL : -14,0 ± 1,3 pA/pF, n = 12-13; +E2 : -14,5 ± 1,4 pA/pF, n = 22, p = ns). En conclusion, l’accélération de l’automaticité cardiaque associée à la grossesse est, entre autres, expliquée par une augmentation de la densité de If, régulée par la voie de signalisation E2-ERα. Cependant, les changements de l’homéostasie calcique observés pendant la grossesse sont indépendants des niveaux élevés en œstrogènes. Les résultats obtenus sur les N-hiPSC-CM concordent avec ce qui est observé dans les cellules de NS de souris, ce qui démontre l’applicabilité humaine des résultats. Notre étude contribue à élucider l’influence de la grossesse et le rôle des hormones sexuelles féminines sur la fonction du NS et l’automaticité cardiaque. Ultimement, notre travail pourrait aider à développer une meilleure gestion des arythmies associées aux fluctuations hormonales féminines et/ou à la grossesse. / An increased heart rate (HR) is observed in pregnant women. In fact, in the last trimester, in average, the HR increases by 15%, which is a known risk factor to developing cardiac arrhythmias or exacerbating pre-existing arrhythmias. This can lead to major consequences for both the mother and fetus. However, the mechanisms underlying this increased HR remain largely unexplored. Our laboratory recently demonstrate that pregnancy is associated with an increased density of the pacemaker current (If) and the L-type calcium current (ICaL) as well as changes in calcium homeostasis of mouse sinoatrial node (SAN) cells. Knowing that estrogens are increased during pregnancy and that these sex hormones can modify cardiac electrophysiological properties, we hypothesized that estrogens play a key role in the pregnancy-induced increased HR and regulate the SAN electrophysiological properties. Our research project aims to determine the role of 17β-estradiol (E2) on the pregnancy-induced increased HR, to determine if these effects are regulated through estrogen receptor alpha (ERα) and/or beta (ERβ) and to study the E2 underlying mechanisms on SAN electrophysiology. Non-pregnant female mice (2-4 months) lacking ERα (ERKOα) or ERβ (ERKOβ) received a chronic E2 treatment (30 μg twice daily for four days) mimicking E2 concentrations found in late pregnancy (23.3 ± 5.0 nM). Surface electrocardiogram analysis showed a significant increased HR in ERKOβ mice (ERKOβ: 511 ± 15 bpm; ERKOβ +E2: 580 ± 10 bpm; n = 10; p<0.001) following E2 administration. However, the HR remains unchanged in ERKOα mice (ERKOα: 520 ± 16 bpm; ERKOα +E2: 530 ± 21 bpm, n = 7, p = 0.114). Following E2 treatment, current-clamp method demonstrates an increase SAN cells automaticity in ERKOβ mice, resulting in an increase in the spontaneous action potential frequency (ERKOβ : 284 ± 24 bpm, n = 8; ERKOβ +E2 : 354 ± 23 bpm, n = 15, p = 0.0395), associated with a steeper diastolic depolarization slope (ERKOβ : 82 ± 12 mV/s, n = 8; ERKOβ +E2 : 140 ± 14 mV/s, n = 15, p < 0.003), a major determinant of cardiac automaticity. In line with these results, voltage-clamp data showed an increased If density in SAN cells of ERKOβ mice treated with E2 (at -90 mV: ERKOβ: -6.6 ± 0.7 pA/pF, n = 12-15; ERKOβ +E2: -11.0 ± 1.3 pA/pF, n = 9-11, p < 0.05). Nevertheless, If density was similar in E2-treated ERKOα mice. E2-treated nodal-like human-induced pluripotent stem cell-derived cardiomyocytes (N-hiPSC-CM) also showed an increased spontaneous action potential frequency (CTL : 69 ± 5 bpm, n = 12; +E2 : 99 ± 6 bpm, n = 14, p < 0.001) and If density (at -90 mV: CTL: -0.95 ± 0.14 pA/pF, n = 7-10; +E2: -1.62 ± 0.17 pA/pF, n = 13-14, p < 0.05). Following E2 administration, the rate of calcium transient was similar in SAN cells from ERKOα (139 ± 15, n = 13-14; +E2 : 142 ± 14, n = 15-16, p = ns) and ERKOβ (142 ± 11, n = 14-15; +E2 : 147 ± 13, n = 15-16, p = ns) mice. In line with these results, no modification was seen on ICaL density in E2-treated N-hiPSC-CM (at 0 mV: CTL: -14.0 ± 1.3 pA/pF, n = 12-13; +E2: -14.5 ± 1.4 pA/pF, n = 22, p = ns). In conclusion, the increased cardiac automaticity observed during pregnancy is, in part, explained by an increased If density. This mechanism is mediated by the E2-ERα pathway. In the other hand, calcium homeostasis changes detected during pregnancy appear to be mediated by an E2-independent mechanism. Finally, results obtained on N-hiPSC-CM are consistent with our observations on mouse SAN cells, demonstrating the human applicability of our results. This study provides novel insight on the effects of female sex hormones on the SAN functions. Ultimately, this information can lead to improved management of arrhythmias associated with female hormone fluctuations and/or pregnancy-induced arrhythmias.

L'impédance d'entrée d'une antenne miniature est fortement affectée par des facteurs environnementaux à l'origine de pertes de puissance réduisant l'efficacité énergétique des têtes radiofréquences dans les applications RF, en particulier dans la télémétrie des implants cardiaques. Le but de mes études est de développer une unité de calibration d'impédance d'antenne très faible consommation capable d'adapter toute variation de l'impédance d'entrée de l'antenne à l'impédance de la source radiofréquence. La première partie de mon étude est axée sur la conception au niveau système d'une approche nouvelle de calibration automatique du système. Un réseau d'adaptation automatique d'impédance sans coupleur et fonctionnant de façon directe est étudié et permet d'optimiser la taille du dispositif, la vitesse de l'adaptation, la consommation d'énergie et les performances globales. Deuxièmement, une nouvelle méthode de synthèse du réseau d'adaptation variable est proposée pour réduire fortement la complexité globale de l'algorithme d'adaptation. La troisième partie de mon étude est axée sur la fabrication d'un démonstrateur hybride fonctionnant dans la bande médicale MICS afin de valider le concept auto adaptatif d'impédance. Un banc expérimental qui comprend une antenne immergée dans son milieu connectée au démonstrateur piloté par un microcontrôleur a été mis en place et a permis d'atteindre un coefficient de réflexion jusqu'à -30dB avec un temps de calibration inférieur à 1ms. La dernière partie de mon travail consiste à concevoir le circuit d'adaptation automatique d'impédance d'antenne très faible consommation fonctionnant dans la bande ISM 2.4GHz en utilisant la technologie CMOS 0.13um. Antenna input impedance is highly affected by environmental factors increasing the losses or reducing the power efficiency of the radiofrequency transceiver in many RF applications such as in implantable pacemaker device telemetry. The purpose of my study is to develop a low power fully integrated antenna-impedance tuning unit to match any variation of the antenna impedance to the source. The first part of my study is focused on the system-level design of a new approach to automatically match the system. A couplerless single step automatic matching network is investigated to optimize the die size, the speed, the power consumption and the overall performance. Second, a new method for synthesizing an automatic matching network is developed reducing strongly the overall complexity of the matching algorithm. The third part of my study is focused on the fabrication of a hybrid demonstrator operating at the Medical Implantable Communication Service (MICS) frequency band to validate the concept. An experimental set-up including the antenna tuning unit, a microcontroller and a pacemaker antenna connected to the demonstrator was done achieving a reflection coefficient up to -30dB, an overall tuning time less than 1ms. The last part of my work is to design the entire automatic matching network circuit in 0.13um CMOS technology including a front-end transceiver designed under ultra low power constraints and operating at 2.4GHz ISM frequency band. The additional items overall power consumption is less than 1.5mW under 1.2V supply voltage.

Encore en 2015, un grand nombre d’individus décèdent de pathologies du rythme cardiaque non contrôlées ou d’un manque de disponibilité de donneurs d’organes compatibles. Le génie tissulaire en créant, réparant ou améliorant la fonction des tissus est une option prometteuse afin de diminuer la mortalité associée à ces pathologies. L’objectif global de mon projet de recherche était de développer des outils et d’étudier l’impact fonctionnel des différents stimuli (mécanique et électrique) de l’environnement cardiaque dans le but de définir des conditions optimisées de culture pour la fabrication de tissu de remplacement par génie tissulaire. Cette thèse présente le développement d’un bioréacteur; un système qui optimise les conditions pour la culture cellulaire. L’efficacité du bioréacteur est validée par des expériences de culture cellulaire qui se concentrent sur la prolifération cellulaire, l’organisation cellulaire, l’expression génique et protéique de même que sur l’activité contractile spontanée. En premier lieu, nos résultats montrent, bien que la fréquence de contraction moyenne mesurée reste inchangée, une augmentation significative du nombre de cas de réentrées pour les cultures sur verre comparativement aux cultures sur Polydimethylsiloxane. Une augmentation de l’instabilité spatiotemporelle a été démontrée lorsque les cardiomyocytes étaient déposés sur un support de Polydimethylsiloxane et cette dernière corrèle avec une diminution non-significative de l’ARNm de la connexine-43 et une augmentation significative de l’ARNm pour CaV3.1 et HCN2. La culture sur Polydimethylsiloxane est également associée avec une plus forte réponse à l’isoprotérénol (β-adrénergique) et à l’acétylcholine (parasympathique). En second lieu, nous présentons les résultats du développement de notre bioréacteur en mettant l’emphase sur les caractéristiques (composantes accessibles, étirement uniaxial, électrode de carbone, stimulation biphasique) tout en validant notre approche pour optimiser les conditions de culture et améliorer la rentabilité des étapes de production du tissu de remplacement. Pour finir, nous partageons une nouvelle approche d’évaluation des caractéristiques contractiles de cellules cardiaques en culture. Nous avons développé des algorithmes qui utilisent les données de vidéomicroscopie pour valider l’impact de stimuli, évaluer l’hétérogénéité du signal enregistré et détecter des conditions favorables au développement d’arythmies. / In 2015, there are still a large number of people who die due to diseases of uncontrolled heart rhythm or due to lack of availability of compatible donor organs. Tissue engineering aim to create, repair or improve the function by different techniques. Tissue engineering is a viable option to reduce the mortality associated with many heart conditions. The overall goal of my PhD research was to study the functional impact of different stimuli in cardiac environment (mechanical and electrical stimulation) on cardiac cell cultures. This, in order to define optimized culture conditions for the production of replacement tissue using tissue engineering. This thesis presents the stages of creation and development of a bioreactor; a system that permits the culture of cardiac cells by integrating various stimuli. The optimization of culture conditions by using the bioreactor was confirmed by cell culture experiments that focus on cell proliferation, cell organization, gene and protein expression as well as on spontaneous activity. In the first place, our results show that although mean frequency of spontaneous activity remained unaltered, incidence of reentrant activity was significantly higher in samples cultured on glass compared to PDMS substrates. Higher spatial and temporal instability of the spontaneous rate activation was found when cardiomyocytes were cultured on PDMS, and correlated with decreased connexin-43 (unsignificant) and a significant increased CaV3.1 and HCN2 mRNA levels. Compared to cultures on glass, cultures on PDMS were associated with the strongest response to isoproterenol (β-adrenergic) and acetylcholine (parasympathetic). Secondly, we present the design of our bioreactor with an emphasis on its characteristics and by putting in perspective the relevance of our approach to optimize culture conditions and to improve profitability culture experiences and production stages of replacement heart tissue. Finally, a new approach is proposed to evaluate the characteristics of the contractile cells in culture which allows to validate the functional impact of stimuli, evaluate the heterogeneity in the beating behavior of the cells and to detect localized abnormal activity that could favour arrhythmia.

Vinte e seis pacientes com cardiomiopatia hipertrófica e fatores de risco de morte súbita, foram submetidos a implante de cardioversor-desfibrilador implantável de dupla-câmara, com seguimento médio de 19 meses. Observou-se quatro choques em arritmias letais, 4 pacientes apresentaram TVNS e 5 taquiarritmias supraventriculares. Ocorreu um óbito.Conclusões: Observamos: TPSV em 19,2%; TVNS em 15,4% e TVS/FV em 15,4%. Nenhuma variável clínica ou demográfica, discriminou o comportamento clínico ou funcional pós-implante de CDI; a recorrência de síncope pós implante de CDI, não se associou à presença de eventos arrítmicos e a hipertrofia maior que 30 mm se associou à choque precoce do CDI (p=0,003). / During 19 months of average follow-up period, we followed 26 patients with hypertrophic cardiomyopathy and high risk for sudden death, all treated by dual chamber implantable cardioverter-defibrillator. 4 patients had received appropriate ICD discharge, 4 patients with NSVT and 5 supraventricular arrhythmias. One death had occurred. Conclusions: we observed: supraventricular arrhythmias in 19,2%; NSVT in 15,4% and VT/VF in 15,4%. The clinical or demographic outcomes did not suggest any clinical or functional results after ICD implantation; syncope may occur after ICD implantation and no arrhythmias recordered by intracardiac electrograms and left-ventricular-wall thickness greater than 30 mm is associated with early ICD shocks (p=0,003).

Introdução: A terapia de ressincronização cardíaca (TRC) é um tratamento recomendado pelas principais diretrizes mundiais para pacientes com insuficiência cardíaca congestiva (ICC), disfunção ventricular esquerda (FE <= 35%), com tratamento otimizado e distúrbio da condução intraventricular, principalmente pelo ramo esquerdo. Entretanto, 30%-40% dos pacientes selecionados não respondem ao tratamento. As razões desse insucesso não são completamente conhecidas. Existe, portanto, necessidade de desenvolvimento de índices multifatoriais para melhor selecionar e acompanhar a evolução e o prognóstico destes pacientes. Objetivo: Elaborar modelos preditores de risco de óbito cardíaco ou transplante (Tx), em diferentes fases da TRC. Métodos e Casuística: Estudo observacional, prospectivo e analítico, com inclusão de 116 pacientes, entre 01/2008 a 03/2013, sendo 69,8% do sexo masculino, com CF III (68,1%) e IV ambulatorial (31,9%), com BRE em 71,55% e com idade de 64,89 ± 11,18 anos e fração de ejeção (FE) de 29%. Avaliações foram feitas no período pré-implante (tempo 1), 6-12 meses (tempo 2) e 18-24 meses (tempo 3) e correlacionadas com a mortalidade cardíaca/Tx no final do seguimento. Foram estudadas variáveis clínicas, eletrocardiográficas e ecocardiográficas e realizadas análises de regressão de Cox e regressão logística, com a construção da curva ROC. As curvas de sobrevidas foram realizadas pelo método de Kaplan-Meier e comparadas pelo log-rank. Modelos e escores foram elaborados pelas pontuações do \"hazard ratio\", utilizado como variável independente no modelo de regressão logística. Resultados: Ocorreram 29 (25%) óbitos/Tx durante o seguimento de 34,09 ± 17,9 meses. A mortalidade cardíaca/Tx foi de 16,3 % (19 pacientes). Seis pacientes foram transplantados durante o tempo do estudo. No período préimplante (tempo 1), a presença de disfunção de ventrículo direito (VD), FE < 25% e o uso de altas doses de diuréticos (dois ou mais comprimidos de furosemida) mostraram-se com valor independente, com aumento de risco de óbito cardíaco/Tx de 3,9; 4,8 e 5,9 vezes, respectivamente. No tempo 2 (1° ano), as variáveis disfunção de VD, altas doses de diuréticos e internações por ICC foram as variáveis significativas, com aumento de risco 3,5; 5,3 e 12,5 respectivamente. No tempo 3 (2° ano), as variáveis disfunção de VD e classe funcional III/IV foram significativas no modelo multivariado de Cox, com aumento de risco de 12,1 e 7,7. As acurácias dos modelos foram 84,6%; 93% e 90,5%, respectivamente. Conclusão: Os modelos preditores de óbito cardíaco desenvolvidos a partir de variáveis clínicas e ecocardiográficas, obtidas em diferentes fases da TRC, mostraram boa acurácia e podem ajudar na seleção, seguimento, definição de resposta e aconselhamento destes pacientes / Introduction: Cardiac resynchronization therapy (CRT) is indicated for patients with congestive heart failure (CHF), ejection fraction (EF) <= 35%, and bundle branch block. However, 30%-40% do not respond to CRT. Therefore, there is a need to develop multifactorial indexes to better select and follow these patients. Objective: This work aims to develop predictive models for the risk of cardiac death or transplantation (Tx) at different stages of CRT. Methods: We performed a prospective observational study of 116 patients, 69.8% males, functional class (FC) III (68.1%) and IV (31.9%), LBBB in 71.55%, age 64.89 ± 11.18 years. We studied clinical, electrocardiographic, and echocardiographic variables and performed Cox and logistic regression with ROC and Kaplan- Meier curves. Results: The cardiac mortality was 16.3% (19 patients) in the 34.09 ± 17.9 follow-up months. Pre-implantation, the right ventricular dysfunction (RVD), EF <25%, and the use of high doses of diuretics (HDD) increased risk of cardiac death or Tx of 3.9, 4.8, and 5.9 fold, respectively, and in the first year, the variables RVD, HDD, and hospitalizations for CHF increased risk of death of 3.5, 5.3, and 12.5, respectively. In the 2nd year, the variables RVD and FC III / IV (NYHA) were significant in the multivariate Cox model. The accuracies of the models were 84.6%, 93%, and 90.5%, respectively. Conclusions: Cardiac death predictive models were developed in different stages of CRT, and were based on the analysis of simple clinical and echocardiographic variables. The models showed good accuracy and can help in the selection and follow-up of these patients

La directive européenne 2013/35/UE précise les exigences minimales pour la protection des travailleurs exposés aux champs électromagnétiques et définit les porteurs d’implants comme travailleurs à risques particuliers. Concernant les porteurs de défibrillateur automatique implantable (DAI) ou de stimulateur cardiaque (SC), l’exposition au champ électrique ou magnétique d’extrêmement basse fréquence crée des inductions à l'intérieur du corps humain pouvant générer une tension perturbatrice susceptible de causer le dysfonctionnement de l’implant. Le sujet de ce travail de thèse porte sur la compatibilité électromagnétique des implants cardiaques soumis à un champ électrique basses fréquences (50/60 Hz). Des simulations numériques ont été effectuées afin de concevoir un banc expérimental pour l’exposition de fantômes incluant des stimulateurs ou des défibrillateurs implantables. Une étude expérimentale a permis d’établir par provocation les seuils de champ électrique permettant d’éviter tout dysfonctionnement éventuel de l’implant. Dans la partie simulation numérique ; un modèle humain virtuel (fantôme numérique contenant un implant cardiaque) a été placé en position debout sous une exposition verticale à un champ électrique. La méthode des éléments finis a été utilisée pour définir les phénomènes induits au niveau de l’implant cardiaque avec une résolution de 2mm (logiciel CST®). Dans la partie expérimentale, un banc d'essai dimensionné pour permettre de générer un champ électrique pouvant atteindre 100 kV/m aux fréquences 50-60 Hz a été conçu, optimisé et réalisé afin d’analyser le comportement des implants cardiaques. Plusieurs configurations ont été étudiées. Sur 54 implants cardiaques actifs testés (43 stimulateurs et 11 défibrillateurs) à des niveaux de champs électriques très élevés (100 kV/m) générés par notre dispositif expérimental, aux fréquences de 50-60 Hz, aucune défaillance n’a été observée pour des niveaux d’exposition publics et pour la plupart des configurations (+99%) sauf pour six stimulateurs cardiaques dans le cas d’une configuration « pire cas » peu réaliste en clinique : mode unipolaire avec une sensibilité maximale et en détection auriculaire. Les implants configurés avec une sensibilité nominale en mode bipolaire résistent bien à des champs électriques dépassant les valeurs seuils telles que définies par 2013/UE/35. / The European Directive 2013/ 35 / EU specify minimum requirements for the protection of workers exposed to electromagnetic fields and define with implants as “workers at particular risk”. Regarding the implantable cardioverter defibrillator wearers (ICD) or pacemaker (PM), exposure to electric or magnetic field of extremely low frequency creates inductions inside the human body that generate interference voltage which may cause the dysfunction of the implant. This thesis investigates the electromagnetic compatibility of cardiac implants subjected to an electric field low frequency (50/60 Hz). Computational simulations are effectuated in order to design an experimental bench for the exposure of a phantom including pacemakers or implantable defibrillators. A provocative study is established to define the electric field thresholds for preventing any malfunction of the implant. In numerical simulations; a virtual human model (digital phantom containing a cardiac implant) was placed in an upright position in a vertical exposure to an electric field. The finite element method was used to define the inductions in the cardiac implant level with a resolution of 2 mm (CST® software). In the experimental part, a test bench designed to allow generating an electric field up to 100 kV / m at frequencies 50-60 Hz was constructed, optimized and employed to investigate the behavior of cardiac implants.Several configurations were studied. 54 active cardiac implants (43 pacemakers and 11 defibrillators) are submitted to very high electric field of 50-60 Hz (up to 100 kV / m) inside the experimental bench. No failure was observed for public exposure levels for most configurations (+ 99%) except for six pacemakers in the case of a configuration clinically almost inexistent: unipolar mode with maximum sensitivity and atrial sensing.The implants configured with a nominal sensitivity in bipolar mode are resistant to electric fields exceeding the low action levels (ALs), even for the most high ALs, as defined by 2013 / 35 / EU

Introdução: Considerando-se os potenciais efeitos deletérios da estimulação do ventrículo direito (VD), a hipótese desse estudo é que a estimulação unifocal ventricular esquerda (VE) pelo seio coronário é segura e pode proporcionar melhores benefícios clínicos e ecocardiográficos aos pacientes com bloqueio atrioventricular e função ventricular esquerda preservada ou pouco alterada, necessitando apenas da correção da frequência cardíaca. Objetivos: Avaliar a segurança, a eficácia e os efeitos da estimulação ventricular esquerda, utilizando um cabo-eletrodo com fixação ativa, em comparação à estimulação ventricular direita em pacientes com indicação de marca-passo (MP) convencional e função ventricular esquerda normal a moderadamente alterada. Métodos: Trata-se de um estudo clínico, randomizado, simples-cego que incluiu pacientes adultos com indicação de MP convencional por bloqueio atrioventricular avançado e função ventricular sistólica >= 0,40. A randomização aleatória (VD vs. VE) ocorreu antes do procedimento. Os desfechos primários do estudo foram o sucesso, a segurança e a eficácia do procedimento proposto. Os desfechos secundários foram a evolução clínica e alterações ecocardiográficas. Foram empregados os testes qui-quadrado, exato de Fisher e teste t de Student para comparação dos desfechos entre os dois grupos, considerando o nível de significância de 5%. Resultados: De junho de 2012 a janeiro de 2014 foram incluídos 91 pacientes, sendo 36 no grupo VD e 55 no grupo VE. As características basais dos pacientes dos dois grupos foram similares (P = NS). O implante de MP foi realizado com sucesso e sem nenhuma intercorrência em todos os pacientes do grupo VD. No grupo VE, entretanto, dos 55 pacientes inicialmente alocados, o implante do cabo-eletrodo em veias coronárias não foi possível em 20 (36,4%) pacientes. Complicações pós-operatórias foram detectadas apenas no grupo VE. A complicação mais frequente foi a estimulação frênica, detectada em 9 (25,7%) pacientes. Durante o período de seguimento do estudo, não houve hospitalizações por insuficiência cardíaca. Reduções superiores a 10% na fração de ejeção do ventrículo esquerdo foram observadas em 23,5% dos pacientes do grupo VD e em 20,6% dos do grupo VE (P = 0,767). A análise feita pelo Doppler tecidual mostrou que 55,9% dos indivíduos do grupo VD e 43,8% dos do grupo VE apresentaram dissincronia intraventricular ventricular esquerda (P = 0,324). Pelo mesmo método, foi detectado que 91,2% e 68,8% dos pacientes dos grupos VD e VE, respectivamente, apresentavam dissincronia interventricular (P=0,022). Conclusões: A estimulação ventricular esquerda exclusiva, nas condições estudadas, mostrou taxa de sucesso, segurança e eficácia inadequadas. A despeito da melhor sincronia interventricular observada nos pacientes sob estimulação ventricular esquerda, a comparação dos desfechos secundários entre os dois grupos não mostrou diferenças significativas / Background: Considering the potential deleterious effects of right ventricular (RV) pacing, the hypothesis of this study is that isolated left ventricular (LV) pacing through the coronary sinus is safe and may provide better clinical and echocardiographic benefits to patients with bradyarrhythmias and normal ventricular function requiring only the correction of heart rate. Objective: To assess the safety, efficacy and effects of LV pacing using an active-fixation coronary sinus lead compared to RV pacing in patients eligible to conventional pacemaker (PM) implantation. Methods: Randomized, controlled and single-blinded trial in adult patients submitted to PM implantation due to bradyarrhythmias and systolic ventricular function >= 0.40. Randomization (RV vs LV) occurred before PM implantation. Procedural success, safety, and efficacy were the main endpoints. Secondary outcomes were clinical and echocardiographic changes. Chi-square, Fisher\'s exact test and Student\'s t test were used, considering a significance level of 5%. Results: From June/2012 to January/2014, 91 patients were included, 36 in the RV group and 55 in the LV group. Baseline characteristics of patients in both groups were similar. PM implantation was performed successfully and without any complications in all patients in the RV group. Of the 55 patients initially allocated to the LV group, the implant of the active-fixation coronary sinus lead was not possible in 20 (36.4%) patients. The most frequent complication was phrenic nerve stimulation, detected in 9 (25.7%) patients in the LV group. During the follow-up period, there were no hospitalizations for heart failure. Reductions of more than 10% in left ventricular ejection fraction were observed in 23.5% of patients in the RV group and in 20.6% of those in the LV group (P= 0.767). Echo-tissue doppler showed that 91.2% of subjects in the RV group and 68.8% of those in the LV group had interventricular dyssynchrony (P= 0.022). Conclusion: Isolated left ventricular pacing, under the conditions studied, showed an inadequate success rate, safety and efficacy. Despite the better interventricular synchrony observed in LV group, the comparison of secondary outcomes between the two groups did not show significant differences