The mechanical contraction of the heart is tightly coupled to rapid and concerted electrical excitation of the cardiac muscle. This electrical activity is facilitated by a highly synchronized conduction system consisting of channels, pumps, and transporters that facilitate the flow of charged ions between cellular compartments, the cytoplasm, and the interstitial fluid between cells. The biophysical properties of these membrane proteins have been studied for many years, but their role in the generation of potentially lethal cardiac arrhythmias and their interactions with drugs remains an important field of research. The cardiac isoform of the voltage-gated Na+-channel, Nav1.5, has garnered widespread interest because of its role in the generation of electrical impulses in the cardiac myocyte, its association with congenital conduction disorders and acquired cardiac arrhythmias, and its unique pharmacological properties. The Congenital Long QT Syndrome Type 3 (LQT3) arises from heritable mutations in SCN5A - the gene encoding Nav1.5 - that disrupt the inactivation process responsible for imparting a refractory period and that often cause a sustained depolarizing late current (INaL). The gain of function depolarizing currents arising from LQT3 mutant channels cause a prolongation of the ventricular action potential and leave patients susceptible to asynchronous electrical activity, ventricular arrhythmias, and sudden cardiac death. The disruption of channel inactivation can arise through a wide range of modalities, including changes in inactivation voltage-dependence and kinetics, and has been shown to occur with varying degrees of severity. Because of this range of phenotypes there is heterogeneity in the risk factors for arrhythmia and sudden cardiac death and in the utility of Na+-channel blocking antiarrhythmic drugs. Moreover, INaL has been implicated as a proarrhythmic and potentiating factor in several acquired cardiac ailments including heart failure, ischemia, and hypertrophy. There is therefore a large unmet need for improved understanding of INaL and mechanisms of its selective inhibition, and LQT3 mutant channels provide a reliable experimental model for this class of cardiac arrhythmias. This study will employ a combination of electrophysiological and computational methods to unravel mechanisms by which mutant Nav1.5 produces pro-arrhythmic currents and the interactions of different disease-causing mutant channels with a set of clinically relevant antiarrhythmic drugs. Chapter 1 of this study presents a functional characterization of one LQT3 mutation, F1473C, that was discovered in a patient with severe QT prolongation, frequent ventricular arrhythmias, and a poor response to pharmacological intervention. This mutation gives rise to INaL by a mechanism that is functionally distinct from the mechanism discovered previously in the canonical LQT3 mutation, ΔKPQ (1505-1507del), and causes a unique response to channel inhibitors. In order to better understand the mechanisms of this divergent pharmacology, Chapter 2 presents the development of a series of computational models which explore the gating dysfunctions that cause INaL and how these pathological changes can influence the predicted safety and efficacy of pharmacological intervention. These models predict that the majority of mutation- specific drug effects can be attributed to differential mutant channel gating, but raise the possibility that mutations may directly alter the physical chemical interaction between drugs and channels. Finally, Chapter 3 presents an attempt to explore this possibility using an innovative chemical biology technique - the site-specific incorporation of unnatural amino acids - that allows for the measurement of precise chemical interactions hypothesized to vary in a mutation-dependent manner. The findings presented in this work promote the need for patient-specific screening of antiarrhythmic agents and lay the groundwork for the use of in silico systems analysis of cardiovascular pharmacology.

Atrial fibrillation (AF) is the most common cardiac arrhythmia causing morbidity and mortality. Despite recent advances, developing effective and safe anti-AF pharmaceutical therapies remains challenging and is prone to adverse effects in the ventricles. Atrial-selective therapies are promising in managing AF. A better understanding of the role of the atrial-specific ion channels in the atrial arrhythmogenesis and contractility, as well as the anti-AF effects of blocking these channels is of interests. Also, a 3D ventricle-torso model capable of modelling ventricular electrical activities and the resulting electrocardiogram (ECG) is a valuable tool in evaluating the selectiveness and safety of an anti-AF pharmaceutical therapy. In part I, the role of an atrial-specific ion channel, IKur, in atrial electrical and mechanical activities and the potential of the current as a pharmaceutical target for anti-AF therapies were investigated in silico. The role of IKur in atrial arrhythmogenesis and mechanical contraction was revealed by elucidating the functional impacts of the KCNA5 mutations exerting either gain- or loss-in-function, on the atria. First, novel IKur models were developed and incorporated into multiscale biophysical models of human atrial electrophysiology to assess the effects of mutated IKur on atrial electrical dynamics. Then, a family of single cell human atrial electromechanical models was developed and incorporated into an updated 3D anatomical electromechanical model of human atria to clarify the effects of mutated IKur on the atrial contractile function. Finally, the antiarrhythmic effect of IKur block was assessed together with INa and other K+-current block. It was shown that the gain-of-function in IKur impaired atrial contractility and promoted atrial arrhythmogenesis by shortening the APD, whereas the down-regulated IKur exerted positive inotropic effects and increased the susceptibility of the atria to the genesis of early-afterdepolarisations. Both simulated IKur and INa block in human-AF demonstrated antiarrhythmic effects; the multi-channel block exerted synergistic anti-AF effects and enhanced the AF-selectivity of INa inhibitions. In Part II, a human ventricle-torso model was developed through proposing a new family of single cell ventricular models accounting for transmural, apicobasal and interventricular electrical heterogeneities and integrating an updated 3D biophysical and anatomical model of human ventricles with a heterogeneous anatomical model of a human torso. First, using the model, the role of heterogeneities in the genesis of T-wave was revealed. Then, ECG manifestations of bundle branch block and ventricular ischaemia were simulated. Finally, the platform was applied to investigate the impact of a long-QT-linked mutation (KCNQ1-G269S) on the ventricles and ECG. Good agreement between simulated and experimental/clinical ECG was reached under both normal and diseased conditions. It was shown that the apicobasal heterogeneity had a more pronounced effect on the T-wave than other heterogeneities. Simulations of the KCNQ1-G269S elucidated the causal link between the mutation and ECG manifestations of the patients.

The assessment of Myocardial Blood Flow (MBF) is an important measure in clinical practice for evaluating the health of the heart. Multiple imaging methods have been employed to measure MBF, including applications of nuclear medicine, x-ray and contrast enhanced Magnetic Resonance Imaging (MRI). However, each of these modalities suffers from drawbacks, such as invasiveness due to radiation or intravenous contrast injection, difficulty in quantitation, and limited repeatability. The aim of this thesis was to develop a non-invasive, quantitative and repeatable MRI method for the measurement of MBF, by applying the techniques of Arterial Spin Labelling (ASL). A novel cardiac ASL sequence was designed and thoroughly tested by simulation and phantom experiment. The method was applied in vivo in three slices of the human heart, to our knowledge the first cardiac ASL acquisition in multiple slices, in ten healthy volunteers. The resulting values of mid-ventricular MBF, averaged over multiple measurements, compared well with the literature values from multiple modalities. Repeat measures were then used in order to characterise the reproducibility and variation inherent in the method, showing that the expected change in MBF would be detectable with the ASL sequence. Segmental values of MBF, according to the AHA standard model, were also calculated and these compared well to previous PET literature. This work has been published in the journal Magnetic Resonance in Medicine. Further to this work, the new cardiac ASL sequence was optimised with the ultimate goal of single breath hold acquisitions. The optimised sequence was shown to improve the results in terms of the balance between good signal-to-noise ratio and reducing spatial and temporal variation in MBF values. Though improvements were made, there remained a large variation in the measured values of MBF, meaning single breath hold acquisition in a clinical context is not yet practical. In addition to the optimisation, the online scanner reconstruction software was altered to produce parametric maps of both T₁ and MBF direct to the scanner operator. The sequence, along with online reconstruction is available for use in our laboratory for future clinical trials in the heart and liver.

Thesis. 1976. M.S.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science. / Microfiche copy available in Archives and Engineering. / Includes bibliographical references. / M.S.

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2016-07-26T14:42:42Z No. of bitstreams: 1 liliangoraieb_tese.pdf: 804095 bytes, checksum: 06542107c917aa2ae6717d3edf30330c (MD5) / Made available in DSpace on 2016-07-26T14:42:42Z (GMT). No. of bitstreams: 1 liliangoraieb_tese.pdf: 804095 bytes, checksum: 06542107c917aa2ae6717d3edf30330c (MD5) Previous issue date: 2013-11-28 / Introduction: Due to the large number of congenital heart disease with several surgical treatment variables involved, it has not yet been established objective protocols for mechanical ventilation weaning in the postoperative period of cardiac surgery. Objectives: To determine the duration of mechanical ventilation (MV) and the success or failure of extubation using an adapted protocol to spontaneous respiratory test in children undergoing cardiac surgery. Patients and methods: A prospective study with 43 operated patients in the Intensive Care Unit under mechanical ventilation for 24 hours or more. They were randomized into two groups: A - Routine (19) and B - Protocol (24). In A, extubation followed routine multidisciplinary team management of intensive care unit. In B, the patients were considered suitable to spontaneous respiratory test after an evaluation. The extubation would occur with the success of the test (120 minutes). The groups were also evaluated according to the severity of the estimated risk. Fisher Bi-Caudal and unpaired student´s t tests were applied. The study was approved by the Research Ethics Committee. Results: There was no statistically significant difference between groups regarding the duration of mechanical ventilatioon (P= 0.81), as well as the success or failure of extubation (P=0.40). Regarding severity, no statistically significant differences were found when evaluated for MV time (P = 0.45 - RACHS 1 and 2) (P=0.59 - RACHS 3 and 4), as well as to success or failure of extubation (P=0.67 - RACHS 1 and 2) ( P= 0.49 - RACHS 3 and 4). Conclusions: The use of the SRT protocol for two hours has not shown to be superior to MV time or to the success or failure of extubation in patients undergoing surgical repair of congenital heart defects. / Introdução: Devido ao grande número de cardiopatias congênitas com diversas variáveis envolvidas no tratamento cirúrgico, ainda não estão estabelecidos protocolos objetivos de desmame da ventilação mecânica no pós-operatório de cirurgia cardíaca pediátrica. Objetivos: Verificar se o uso do protocolo de desmame com teste de respiração espontânea de 120 minutos tem impacto no tempo de ventilação mecânica e no sucesso ou insucesso da extubação para crianças que não foram extubadas nas primeiras 24 horas após a intervenção cirúrgica. Casuística e método: Estudo prospectivo realizado em unidade de terapia intensiva cardiopediátrica com 45 pacientes operados em ventilação mecânica por 24 horas ou mais. Foram randomizados em dois grupos: A - rotina (21) e B - protocolo (24). No A, a extubação seguiu conduta de acordo com a equipe multidisciplinar da unidade de terapia intensiva. No B, após avaliação os pacientes eram considerados aptos ao teste de respiração espontânea. A extubação ocorria com o sucesso do teste (120 minutos). Os grupos também foram avaliados de acordo com a gravidade pelo risco estimado. Aplicaram-se os testes de Fisher Bi-Caudal e t não pareado. O estudo foi aprovado pelo Comitê de Ética em Pesquisa. Resultados: Não houve diferença estatística significativa entre os grupos quanto ao tempo de ventilação mecânica (P = 0,81), assim como quanto ao sucesso ou insucesso da extubação (P = 0,40). Com relação à gravidade, também não foram encontradas diferenças estatísticas significativas quando avaliados quanto ao tempo de ventilação mecânica (P=0,45 – RACHS 1 e 2) e (P=0,59 – RACHS 3 e 4), assim como quanto ao sucesso ou insucesso da extubação (P = 0,67 – RACHS 1 e 2) e (P = 0,49 – RACHS 3 e 4). Conclusões: A utilização desse protocolo com teste de respiração espontânea de duas horas não demonstrou ser superior quanto ao tempo de ventilação mecânica e ao sucesso ou insucesso na extubação de pacientes submetidos à correção cirúrgica de defeitos cardíacos congênitos.

Submitted by Maurício Gianfrancesco Filippi null (mauriciofilippi@terra.com.br) on 2017-02-13T18:05:19Z No. of bitstreams: 1 Dissertação Maurício G Filippi oficial.pdf: 3286618 bytes, checksum: 2e08ac3322153696d51497bfacf1f0f8 (MD5) / Rejected by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo a orientação abaixo: O arquivo submetido está sem a ficha catalográfica. A versão submetida por você é considerada a versão final da dissertação/tese, portanto não poderá ocorrer qualquer alteração em seu conteúdo após a aprovação. Corrija esta informação e realize uma nova submissão com o arquivo correto. Agradecemos a compreensão. on 2017-02-15T17:11:59Z (GMT) / Submitted by Maurício Gianfrancesco Filippi null (mauriciofilippi@terra.com.br) on 2017-02-16T22:41:18Z No. of bitstreams: 1 Dissertação Maurício G Filippi.pdf: 3283472 bytes, checksum: fa27139485cf995a23ebdca2e069dd69 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-02-20T18:00:33Z (GMT) No. of bitstreams: 1 fillipi_mg_me_bot.pdf: 3283472 bytes, checksum: fa27139485cf995a23ebdca2e069dd69 (MD5) / Made available in DSpace on 2017-02-20T18:00:33Z (GMT). No. of bitstreams: 1 fillipi_mg_me_bot.pdf: 3283472 bytes, checksum: fa27139485cf995a23ebdca2e069dd69 (MD5) Previous issue date: 2016-12-12 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A monitorização eletrocardiográfica ambulatorial, ou método Holter, vem se mostrando como uma ferramenta eficaz na Medicina Veterinária para detectar lesões cardíacas precoces, não só por monitorar a atividade elétrica do coração, como também o controle do sistema nervoso autônomo desse órgão. Sabe-se também que as principais enfermidades infecciosas de cães, como a cinomose e a erliquiose monocítica canina (EMC) provocam lesões consideráveis no coração, comprovadas por exame histopatológico. Já está comprovada a ocorrência de miocardite na EMC, levando a frequente presença de alterações na geração e condução do impulso elétrico cardíaco. O presente estudo analisou a atividade elétrica do coração durante 24 horas, com enfoque na prevalência de arritmias, estudo da variabilidade da frequência cardíaca e na concentração de biomarcadores de cães com EMC crônica (grupo doente) em comparação à animais saudáveis (grupo controle). Quarenta e cinco por cento dos animais do grupo doente possuíram alta frequência de arritmias durante o estudo. A média da concentração de troponina cardíaca I e de creatinokinase MB (CK-MB) foi significativa (0,24 ng/mL ± 0,5; 229 ± 205 UI/mL) em comparação ao grupo controle (0,042 ± 0,07 ng/mL; 126 ± 46,12 UI/mL). O desvio padrão da média de todos os intervalos NN (SDNN) e a porcentagem de intervalos RR adjacentes com diferença de duração superior a 50 milissegundos (pnn50%) também foram extremamente singificativos (83 ± 65 e 14,56 ± 20) quando comparado aos animais saudáveis (268 ± 74,6 e 55,87 ± 12,8), respectivamente. Podemos concluir que a EMC crônica possui caráter arritmôgenico, onde há persistente lesão miocárdica e intensa estimulação do sistema nervoso autônomo simpático no coração. / Ambulatorial electrocardiographic monitoring, or Holter method, has been shown to be an effective tool in veterinary medicine to detect early heart lesions, not only to monitor the electrical activity of the heart, but also to control the autonomic nervous system of this organ. It is also known that the main infectious diseases of dogs, such as canine distemper and canine monocytic ehrlichiosis (CME) cause considerable lesions in the heart, proven by histopathological examination. It has already been proven the occurrence of myocarditis in the CME, leading to frequent presence of changes in the generation and conduction of the cardiac electrical impulse. The present study analyzed the electrical activity of the heart during 24 hours, focusing on the prevalence of arrhythmias, heart rate variability study and the biomarkers concentration of dogs with chronic CME (sick group) compared to healthy animals (control group). Forty-five percent of the animals in the diseased group had a high frequency of arrhythmias during the study. The mean concentration of cardiac troponin I and creatinokinase MB (CK-MB) was significant (0.24 ng / mL ± 0.5; 229 ± 205 IU / mL) compared to the control group (0.042 ± 0.07 ng / ML, 126 ± 46.12 IU / mL). The standard deviation of the mean of all NN (SDNN) intervals and the percentage of adjacent RR intervals with a duration difference greater than 50 milliseconds (pnn50%) were also extremely significant (83 ± 65 and 14.56 ± 20) when compared to Healthy animals (268 ± 74.6, 55.87 ± 12.8), respectively. It can be concluded that chronic CME has an arrhythmogenic character, where there is persistent myocardial injury and intense stimulation of the sympathetic autonomic nervous system of the heart. / FAPESP: 2014/11219-6

INTRODUÇÃO: A fadiga é freqüente em pessoas com insuficiência cardíaca e limita a manutenção de um estilo de vida compatível com senso desejável de autonomia e independência. O controle das limitações funcionais é prioridade no cuidado à pessoa com insuficiência cardíaca, mas não há estudos sobre fadiga em amostras de pacientes brasileiros. OBJETIVO: Caracterizar a fadiga em pacientes com insuficiência cardíaca e comparar sua freqüência e intensidade com voluntários sem doença. MÉTODO: Estudo descritivo-exploratório, com 300 pacientes ambulatoriais. (masculino=68,3%, idade média de 54,8(±11,5) anos, escolaridade média de 6,0(±4,1) anos; Classe Funcional I= 44,7%) e 64 voluntários sem doença, acompanhantes de pacientes ambulatoriais (masculino=34,4%, idade média de 33,3(±10,7) anos, escolaridade média de 10,2(±3,2) anos). Foi aplicado instrumento com as escalas de fadiga (Dutch Fatigue Scale - DUFS) de fadiga ao esforço (Dutch Exertion Fatigue Scale - DEFS), o Inventário de Depressão de Beck (IDB), instrumento de avaliação da atividade física (International Physical Activity Questionnaire) e itens para avaliação da dispnéia, tabagismo e terapia medicamentosa. As escalas DUFS e DEFS foram adaptadas para o Brasil e mostraram propriedades psicométricas adequadas (consistência interna, pelo alfa de Cronbach, na DUFS=0,848 e na DEFS=0,922 e solução fatorial que reproduziu suas estruturas originais). O IDB mostrou consistência interna adequada (alfa de Cronbach=0,873). Testes não paramétricos foram aplicados para analisar a associação entre fadiga e fadiga ao esforço (intensidade de fadiga - escore total DUFS; intensidade de fadiga ao esforço - escore total DEFS; freqüência de fadiga substancial - DUFS >=14,5; freqüência de fadiga substancial ao esforço - DEFS>=12,5) com variáveis selecionadas. RESULTADOS: O escore total médio da DUFS nos pacientes (19,4±8,2) foi mais elevado que o dos voluntários (16,8±6,1) (p=0,042); o mesmo ocorreu com a DEFS (pacientes=19,3±3,9; voluntários=12,6±3,9) (p<0,0001). A freqüência de DUFS>=14,5 foi semelhante entre os pacientes e voluntários (p=0,225) e da DEFS>=12,5 foi mais alta entre os pacientes que nos voluntários (p<0,0001). Nos pacientes observou-se maior intensidade de fadiga nas mulheres (p=0,014); na presença de dispnéia (p=0,000); uso de digitálicos (p=0,020); classes funcionais mais elevadas (p=0,000); nos sedentários (p=0,007), entre os com escores de depressão mais elevados (p=0,000) e com distúrbios do sono (p=0,000). A fadiga ao esforço foi mais elevada nos pacientes com dispnéia (p=0,000); que usavam digitálicos (p=0,021); em classe funcional mais elevada (p=0,000); sedentários (p=0,000); com escores de depressão mais elevados (p=0,000) e com distúrbio do sono (p=0,0001). A freqüência de DUFS>=14,5 foi mais elevada naqueles com dispnéia (p<0,0001); uso de betabloqueador (p=0,032); classe funcional mais elevada (p<0,0001); escores de depressão mais elevados (p<0,0001) e naqueles com distúrbio do sono (p<0,0001). Freqüências da DEFS>=12,5 foram mais elevadas na dispnéia (p<0,0001); classe funcional mais elevada (p<0,0001); nos sedentários (p=0,007); escores mais elevados de depressão (p<0,0001) e naqueles com distúrbio do sono (p<0,0001). Não se associaram com qualquer variável de fadiga as seguintes variáveis: índice de massa corporal, uso de inibidor de enzima conversora de angiotensina, idade e tabagismo. DISCUSSÃO: Esses resultados contribuem para o conhecimento sobre sintoma relevante para qualidade de vida e para o cuidado do paciente com insuficiência cardíaca / INTRODUCTION: Fatigue is a frequent symptom in heart failure patients that limits maintaining a life style compatible with a desirable sense of autonomy and independence. Although controlling functional limitations is a priority care goal of heart failure patients there are no studies on fatigue with Brazilian patient samples. OBJECTIVE: To characterize fatigue in heart failure patients and to compare their fatigue frequency and intensity with volunteers without heart failure. METHODS: Descriptive-exploratory study with 300 outpatients (male=68.3%, mean age=54.8(±11,5) years; mean schooling=6,0(±4,1) years; functional class I of heart failure = 44,7%), and 64 volunteers without heart failure, outpatients accompanying (male=34.4%, mean age=33.3(±10.7) years, mean schooling=10.2(±3.2) years). It was applied an instrument with fatigue (Dutch Fatigue Scale - DUFS) and exertion fatigue escales (Dutch Exertion Fatigue Scale - DEFS), Beck Depression Inventory (IDB), International Physical Activity Questionnaire and items to assess dyspnea, smoking and pharmacological treatment. DUFS and DEFS were adapted to Brazilian samples and their psychometric properties were adequate (Cronbach\'s alpha: DUFS=.848; DEFS=.922, and reproduction of the original structure by factor analysis). BDI presented good internal consistency (Cronbach\'s alpha=.873). Non-parametric tests were applied to test associations of fatigue, exertion fatigue (fatigue intensity - DUFS total score; exertion fatigue intensity - DEFS total score; frequency of substantial fatigue - DUFS >=14,5; frequency of substantial exertion fatigue - DEFS>=12,5). RESULTS: Patients mean DUFS total score (19.4±8.2) was higher than volunteers (16.8±6.1) (p=.042); the same occurred with DEFS (patients=19.3±3.9; volunteers=12.6±3.9) (p<.0001). The frequency of DUFS>=14,5 was not different between patients and volunteers (p=.225); frequency of DEFS>=12,5 was higher for patients than volunteers (p<.0001). In the patients group, fatigue intensity was higher for women (p=.014); and also in presence of dyspnea (p=.000); digoxin use (p=0,020); higher functional classes (p=.000); in sedentary patients (p=.007), higher IDB scores (p=.000), and sleep disturbance (p=.000). Exertion fatigue was higher in patients with dyspnea (p=.000); using digoxin (p=.021); in higher functional classes (p=.000); sedentary (p=.000); higher IDB scores (p=.000) and sleep disturbance (p=.0001). Frequency of DUFS>=14,5 was higher in patients with dyspnea (p<.0001); using betablockers (p=.032); higher functional classes (p<.0001); higher IDB scores (p<.0001) and sleep disturbance (p<.0001). Frequency of DEFS>=12,5 was higher in presence of dyspnea (p<.0001); higher functional classes (p<.0001); sedentary patients (p=.007); higher BDI scores (p<.0001) and sleep disturbance (p<.0001). There were no associations of fatigue variables with body mass index, users of angiotensin receptor blockers, age and smoking. DISCUSSION: This study results contribute to the knowledge concerning to a symptom relevant to the quality of life and nursing care of heart failure patients

Submitted by Sandro Camargo (sandro.camargo@unipampa.edu.br) on 2015-03-08T18:38:21Z No. of bitstreams: 1 117110031.pdf: 1697065 bytes, checksum: 988fb2b0e3a730eaccfd605f9a8beb51 (MD5) / Made available in DSpace on 2015-03-08T18:38:21Z (GMT). No. of bitstreams: 1 117110031.pdf: 1697065 bytes, checksum: 988fb2b0e3a730eaccfd605f9a8beb51 (MD5) Previous issue date: 2013-07-19 / A leishmaniose visceral (LV) é uma zoonose parasitária com distribuição cosmopolita, causada pelo protozoário Leishmania spp. Diversos sistemas orgânicos podem ser afetados diretamente ou indiretamente pelo parasitismo, resultando em aspectos clínicos variáveis e inespecíficos em cães. Relatos isolados com indícios histológicos de acometimento miocárdico em cães com LV sugerem comprometimento deste sistema. Desta forma, objetivou-se com o presente estudo, avaliar os aspectos clínicos e histopatológicos do miocárdio de cães naturalmente infectados com leishmaniose visceral. Para tanto, as características físicas gerais, hematimétricas, bioquímicas (creatinina quinase-CK, fração MB da creatina quinase-CK-MB- e troponina I), radiográficas do tórax, eletrocardiográficas e histopatológicas do miocárdio foram avaliadas em 36 cães portadores de LV (grupo LV - GLV) e comparadas às variáveis médias de 15 cães hígidos (grupo controle- GC), com exceção da avaliação histopatológica, realizada apenas no GLV. Ao exame físico geral observou-se maior prevalência de cães assintomáticos no GC (100%) e polissintomáticos no GLV (66%). Dois cães do GLV apresentaram sopro sistólico de intensidade II/VI e III/VI, em região de foco mitral. Os valores médios de hemácia, hemoglobina e hematócrito foram inferiores nos cães do GLV (p<0,0001), associados a maiores valores de proteína total (p<0,0001), leucócitos totais (p=0,0151), neutrófilos (p=0,0027), CK (p=0,0153) e CK-MB (p=0,0038) quando comparado ao GC. Não foram observadas alterações radiográficas qualitativas ou diferenças quantitativas entre os grupos avaliados (p=0,1228). À eletrocardiografia foi detectada maior incidência de arritmia sinusal respiratória nos cães do GLV (75%) e ritmo sinusal nos cães do GC (60%), atestado pelo teste das proporções (p=0,016). A amplitude média da onda P foi inferior no GLV (p=0,008). Não foram observadas arritmias cardíacas em ambos os grupos, porém foi verificada no GLV a presença de episódios isolados de marcapasso migratório e sinus arrest associados à arritmia sinusal respiratória. A luz da histopatologia do miocárdio foi possível observar a presença de infiltrado inflamatório mononuclear em 77,8% (n=28) dos cães do GLV, sendo a maior prevalência de infiltrado linfoistioplasmocitário de intensidade leve. Conclui-se que os cães com LV do presente estudo apresentaram maior prevalência de aspectos clínicos polissintomáticos, associados à anemia normocítica normocrômica, acompanhada de leucocitose por neutrofilia e hiperproteinemia, elevação da atividade sérica de CK e CK-MB, sem alterações significativas da silhueta cardíaca à radiografia, maior prevalência de arritmia sinusal respiratória com episódios de marcapasso migratório e sinus arrest, relacionados à presença de infiltrado inflamatório mononuclear multifocal leve à histopatologia do miocárdio, com baixa incidência de vasculite necrosante e rara detecção de formas amastigotas da Leishmania sp. / Visceral leishmaniasis (VL) is a worldwide parasite zoonotic, caused by a protozoa Leishmania spp. Several organic systems may be affected directly or indirectly by the parasitism, resulting in variable and unspecific clinical signs in dogs. Myocardial damage in affected dogs is suggested by isolated reports with histological evidences of myocarditis. Therefore, the aim of this study was evaluate the clinical and myocardial histopathologic features of naturally infected dogs with VL. Therefore, general physical characteristics, hematological, biochemical (creatine kinase- CK, MB fraction of creatine kinase and troponin-I) radiographic of the thorax, electrocardiographic and histopathological myocardial were evaluated in 36 dogs with VL (VL group- VLG) and average variables compared to 15 healthy dogs (control group-CG), except for the histopathological evaluation. In the general physical examination was observed higher prevalence of asymptomatic dogs in the control group (100%) and polisymptomatic in GLV (66%). Two dogs of the GLV presented systolic murmur of intensity II / VI and III / VI, in the region of the mitral valve. The mean values of erythrocyte count, haemoglobin and haematocrit were lower in dogs GLV (p <0.0001), associated with higher total protein (p <0.0001), total leukocyte count (p = 0.0151), neutrophils (p = 0.0027), CK (p = 0.0153) and CK-MB (p = 0.0038) when compared to CG. Radiographic evaluation reveal no alterations or differences between groups (p = 0.1228). In the electrocardiography analysis, higher incidence of respiratory sinus arrhythmia with wandering pacemaker and sinus arrest in dogs of GLV (75%) and sinus rhythm in the CG (60%) was attested by the proportions test (p = 0.016). The mean P wave amplitude was lower in GLV (p = 0.008). Cardiac arrhythmias were not present in both groups, but sinus arrest was present in GLV. The histopathology of the myocardium displayed mononuclear cellinfiltration in 77.8% (n = 28) of the GLV dogs, with higher prevalence of mild lymphohistioplasmocytic inflammatory infiltrate. We conclude that enrolled dogs with LV presented aspect of polisymptomatic clinical features, associated with normochromic normocytic anemia, followed by leukocytosis, neutrophilia, hyperproteinemia, elevation of serum activity of CK and CK-MB, without significant changes of the cardiac silhouette in the radiography or heart rhythm by electrocardiogram, related to the presence of multifocal mild intensity mononuclear cell infiltration in the myocardial, with low incidence of necrotizing vasculitis and rare detection of amastigotes forms of Leishmania sp. on myocardium histopatology.

Dans les dernières décennies, l'impact dû à l'altération de la microstructure du tissu cardiaque dans la survenue de troubles arythmiques (syndrome de Brugada, fibrillation auriculaire, syndromes de repolarisation précoce…) est de plus en plus étudié. Les données expérimentales relatives au fonctionnement et aux régulations intervenant aux échelles cellulaires et subcellulaires (jonctions communiquantes, rôle de certains canaux ioniques) sont de plus en plus nombreuses, et fournissent un cadre adapté aux numériciens pour développer ou affiner des modèles et en valider les comportements. Dans cette thèse, nous proposons le développement et l'étude d'un modèle « microscopique » prenant en compte la géométrie individuelle des cellules et les jonctions communiquantes entre elles. Le modèle vise à comprendre la propagation du potentiel d'action au sein d'un réseau de cellules. Nous établissons ce modèle via une étude du comportement des ions dans les cellules. Ce comportement, décrit par diverses équations de la physique microscopique (électrostatique...), fournit un cadre à partir duquel, en effectuant quelques analyses dimensionnelles et une étude asymptotique, nous dérivons le modèle susmentionné. Puis, nous démontrons l'existence d'une solution à ce modèle à l'aide d'un processus de discrétisation en temps « semi-implicite » et de théorèmes de compacité. Nous proposons ensuite un ensemble de simulations dont l'objet est de comprendre la propagation des potentiels d'action entres cellules au sein d'un réseau, et en particulier le rôle des jonctions communiquantes. Nous étudions différents modèles de jonctions communiquantes, dont un non-linéaire et dépendant du temps. Cette thèse ouvre de nombreuses perspectives, à courte échéance des comparaisons à des observations expérimentales chez la souris, et à plus long terme de recherche sur les mécanismes de propagation à l'échelle cellulaire et leurs impact sur les troubles du rythme cardiaque. / During the last decades, studies regarding the prospective impact of the alterations at the microscopic scale of the heart tissue in the appearance of arrhythmias (Brugada's syndrome, atrial fibrillation, early repolarization syndrome...) have been more numerous. The amount of experimental data regarding the behaviors and regulations that occur at a cellular and a subcellular (gap junctions, role of specific ionic channels) is increasing and these data provide an adapted frame for the computational mathematicians to develop or improve models and confirm their behaviour. In this thesis, we developed and studied a ``microscopic'' model taking into account the individual geometry of the cells and the gap junctions between them. This model is designed to enhance our understanding of the action potential propagation in a network of cells. We extracted this model using a study of the ions movements in the cells. These movements, described by various microscopic physics equations (electrostatic...), and some dimensional analysis, including an asymptotic study, allow us to derive the model. We then show that the problem described by such a model has a solution, via a semi-implicit time discretization process and compacity arguments. Afterwards, we offer numerous simulations in order to enhance our understanding of the action potential propagation between the cells of various networks. We specifically customize the gap junction models we use (a geometric one, a linear one and a non-linear one) to enhance our comprehension. This thesis introduces many questions. On the short-term, on the comparison between experimental data observed on mice cells and our results. On the long-term regarding the mechanisms regulating the action potential propagation, and their impact on the alterations of the cardiac rhythm.

A interconsulta cardiológica corresponde a uma parcela considerável das atividades assistenciais e de ensino do cardiologista, refletindo gasto extra de tempo e recursos. Apesar disso, essa atividade não tem recebido a devida atenção da literatura, com poucos estudos sobre o tema. O objetivo do presente estudo foi, primariamente, comparar a evolução clínica dos pacientes envolvidos na interconsulta cardiológica que tiveram as recomendações seguidas pela equipe médica solicitante (grupo ACEITADOR) com aqueles em que as recomendações não foram seguidas (grupo NÃO ACEITADOR). De forma secundária, procuramos identificar as variáveis determinantes da aceitação das sugestões da equipe cardiológica. Para isso, foi realizado um estudo observacional envolvendo pacientes internados no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, para os quais foram solicitadas interconsultas cardiológicas, no período de março a setembro de 2008. Os dados referentes às interconsultas foram coletados pelo investigador de maneira prospectiva a partir do prontuário dos pacientes. Dentre as 589 interconsultas selecionadas para o estudo, 271 consistiam em avaliações clínicas e 318 avaliações pré-operatórias. Em relação à taxa de aceitação das recomendações cardiológicas, 77% dos pacientes foram classificados no grupo ACEITADOR e 23% classificados no grupo NÃO ACEITADOR. A análise da evolução clínica demonstrou que, dentre os pacientes do grupo NÃO ACEITADOR, 38,8% evoluíram de forma desfavorável (piora clínica ou óbito) contra 5,4% dos pacientes do grupo ACEITADOR (P<0,0001). Após análise de regressão logística, pertencer ao grupo NÃO ACEITADOR (P<0,001; OR 10,25; IC 95% 4,45 - 23,62) e a idade dos pacientes (P=0,017; OR 1,04; IC 95% 1,01 1,07) estiveram associados de forma independente a uma evolução clínica desfavorável. Foram identificados quatro preditores independentes de aceitação das recomendações: a realização de visitas de seguimento (P<0,001; OR 2,43; IC 95% 1,48 4,01), reforço verbal das recomendações (P=0,001; OR 1,86; IC 95% 1,23 2,81), número de recomendações sugeridas (P=0,001; OR 0,87; IC 95% 0,80 0,94) e idade dos pacientes (P=0,002; OR 0,98; IC 95% 0,96 0,99). Portanto, na presente análise, a não aceitação das recomendações da equipe cardiológica por parte da equipe médica solicitante esteve associada a uma evolução clínica desfavorável dos pacientes envolvidos. A realização de visitas de seguimento, reforço verbal, número limitado de recomendações e a menor idade dos pacientes estiveram associados a uma maior aceitação das recomendações da equipe cardiológica / Cardiology referral represents an important part of cardiologist activities, accounting for substantial workload and demanding extra time and resources. Despite the importance of these facts, it has received little attention in the medical literature in the last years. The purpose of this study was to compare the clinical outcome of patients involved in cardiology referral who had the cardiologic recommendations followed by the requesting service (ACCEPTING group) with those whose recommendations were not followed (NON-ACCEPTING group). Secondly, we aimed to determine which of the variables involved in cardiology referral were related to acceptance to consultants recommendations. An observational study was performed at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, involving cardiology consultations during the months of March 2008 through September 2008. Data regarding consultations were prospectively extracted from the medical records by a physician-researcher. Among the 589 cardiology consultations selected for the study, 271 were clinical evaluations and 318 were preoperative evaluations. Regarding compliance of the referring service in following the recommendations offered by cardiology team, 77% of patients were classified in the ACCEPTING group and 23% in the NON-ACCEPTING group. A clinical outcome analysis was performed and showed that 38,8% of patients allocated to NON-ACCEPTING group had evolved unfavorably (clinical deterioration or death) against 5,4% of patients allocated to accepting group (P<0.0001). After logistic regression analysis, belong to NON-ACCEPTING group (P<0.001; OR 10.25; CI 95% 4.45 23.62) and patients age (P=0.017; OR 1.04; CI 95% 1.01 1.07) were variables independently associated to an unfavorable clinical outcome. The multivariate analysis indentified 4 independent predictors of acceptance to consultants recommendations: follow-up notes in the chart (P<0.001; OR 2.43; CI 95% 1.48 4.01), personal communication (P=0.001; OR 1.86; CI 95% 1.23 2.81), number of recommendations (P=0.001; OR 0.87; CI 95% 0.80 0.94) and patients age (P=0.002; OR 0.98; CI 95% 0.96 0.99). Therefore, in this analysis of cardiology referral, a poorer acceptance of cardiologic recommendations was associated to an unfavorable clinical outcome. Follow-up notes in the chart, personal communication, limited number of recommendations and lower patients age were associated to greater acceptance of cardiologic recommendations