Introdução: A disfunção do sistema nervoso autônomo (disfunção autonômica ou dissautonomia) tem sido associada à fisiopatologia da fibromialgia em pacientes adultos. A modulação cardíaca em resposta ao exercício foi demonstrada em uma série de estudos em adultos com fibromialgia que evidenciaram reduzida capacidade aeróbia, assim como o comprometimento autonômico cardíaco e incompetência cronotrópica, que é a incapacidade de aumentar a frequência cardíaca concomitante ao aumento da intensidade do exercício. No entanto, a capacidade aeróbica e a disautonomia, definidas a partir da avaliação dos parâmetros do teste de exercício cardiopulmonar, não foram estudadas em pacientes adolescentes com síndrome da fibromialgia (FMJ). Objetivo: Avaliar os parâmetros do teste de exercício cardiopulmonar em pacientes com FMJ e controles saudáveis e as possíveis correlações entre estes parâmetros e a qualidade de vida relacionada à saúde (QVRS), capacidade funcional e dor nos pacientes FMJ. Métodos: Estudo transversal multicêntrico incluindo 25 pacientes com FMJ e 25 controles saudáveis. Ambos os grupos participavam somente das aulas de educação física na escola. O teste de exercício cardiopulmonar de esforço em esteira permitiu avaliar a resposta cardiorrespiratória durante o exercício. A resposta cronotrópica foi avaliada pela medida da reserva cronotrópica. Foram avaliados dor, capacidade funcional e QVRS. Resultados: A mediana da idade atual foi similar nos pacientes com FMJ e controles saudáveis (15 vs. 15 anos, p=0,890), assim como o índice de massa corporal (p=0,332), gênero feminino (p=1,000) e estágios de Tanner (p=0,822). A mediana dos parâmetros da QVRS (escore total de saúde física e saúde psicossocial) foi significativamente menor nos pacientes com FMJ versus controles, de acordo com o autorrelato dos pacientes e de seus pais (p < 0,001). A mediana do pico FC [181 (150-198) vs. 197 (181-202) bpm, p < 0,001], da reserva cronotrópica (RC) [84 (53-98) vs. 99 (84-103) %, p < 0,001] e da FC de repouso à FC de pico [96 (65-181) vs. 127 (61-185) bpm, p=0,010] foram significantemente menores nos pacientes com FMJ quando comparados aos controles saudáveis. A mediana do ?FCR1 [15 (3-39) vs. 35 (9-52) bpm, p < 0,001], deltaFCR2 [37 (20-57) vs. 51 (32-94) bpm, p < 0,001], VO2 de pico [32.34 (24.24-39.65) vs. 36.4 (28.56-52.71) ml/kg/min, p=0,005], velocidade máxima [5 (4-6.3) vs. 5.9 (4.0-6.3) mph, p=0,001], tempo de exaustão [11.5 (8.5-14.5) vs. 14 (11-18) minutos, p < 0,001] e capacidade de trabalho [3.37 (2.04-5.6) vs. 3.89 (2.91-6.55) W/kg, p=0,006] foram significativamente menores nos pacientes com FMJ quando comparados aos controles. A frequência da incompetência cronotrópica (<= 80%) foi significativamente maior nos pacientes com FMJ versus controles (p=0,0006). Conclusões: Este estudo identificou incompetência cronotrópica e recuperação atenuada da FC em pacientes com FMJ, indicando disfunção autonômica / Introdução: Autonomic nervous system dysfunction (also named autonomic disturbance or dysautonomia) has been linked to physiopathology of adult patients with fibromyalgia. Cardiac modulation in response to exercise in case series of adult fibromyalgia revealed reduced aerobic capacity, as well as cardiac autonomic impairment and chronotropic incompetence, which is the inability to increase heart rate with an increase in exercise intensity. However, to our knowledge treadmill cardiorespiratory test and to assess aerobic capacity and dysautonomia has not been studied in adolescents with JFM patients. Objective: To assess cardiorespiratory exercise test parameters in Juvenile fibromyalgia syndrome (JFM) patients and healthy controls and possible correlations between these parameters and health-related quality of life (HRQL), functional ability and pain in JFM patients. Methods: A multicenter cross-sectional study included 25 JFM patients and 25 healthy controls. Both groups were engaged only in the physical education classes in school. A treadmill graded cardiorespiratory test was performed and heart-rate (HR) response during exercise was evaluated by the chronotropic reserve (CR). Pain, functional ability and HRQL were assessed. Results: The median current age was similar in JFM and controls (15 vs. 15years, p=0.890), as well as body mass index (p=0.332), female gender (p=1.000) and Tanner stages (p=0.822). The medians of HRQL parameters (total score/physical health/psychosocial health) were significantly lower in JFM versus controls according to patient and parent self-reports (p<0.001). The median of peak HR [181 (150-198) vs. 197 (181-202) bpm, p < 0.001], chronotropic reserve [84 (53-98) vs. 99 (84-103)%, p < 0.001] and resting to peak [96 (65-181) vs. 127 (61-185) bpm, p=0.010] were significantly lower in JFM compared to controls. The median of ?HRR1 [15 (3-39) vs. 35 (9-52) bpm, p < 0.001], deltaHRR2 [37 (20-57) vs. 51 (32-94) bpm, p < 0.001], peak VO2 [32.34 (24.24-39.65) vs. 36.4 (28.56-52.71) ml/kg/min, p=0.005]; peak speed [5 (4-6.3) vs. 5.9 (4.0-6.3) km/h, p=0.001], time to exhaustion [11.5 (8.5-14.5) vs. 14 (11-18) minutes, p < 0.001] and working capacity on power [3.37 (2.04-5.6) vs. 3.89 (2.91-6.55) W/kg, p=0.006] were significantly lower in JFM compared to controls. The frequency of chronotropic incompetence ( <= 80%) was significantly higher in JFM versus controls (p=0.0006). Conclusions: This study identified chronotropic incompetence and delayed HR recovery in JFM patients, indicating autonomic dysfunction

INTRODUÇÃO: O treinamento físico é considerado como um importante recurso terapêutico no que concerne a melhora da disfunção física observada em adultos com lúpus eritematoso sistêmico. Entretanto, até o momento não há estudos longitudinais que avaliaram os possíveis efeitos terapêuticos de um programa de treinamento físico em crianças e adolescentes com lúpus eritematoso sistêmico juvenil (LES-J). OBJETIVO avaliar a segurança e a eficácia de um de um programa de treinamento físico aeróbio supervisionado de 12 semanas no aumento da capacidade cardiorrespiratória em pacientes com LES-J. MÉTODOS: Dezenove crianças e adolescentes com LES-J foram aleatoriamente randomizadas em dois grupos: treinamento físico aeróbio (LESJ TF, n=10; 12,9 + 2,3 anos) e grupo controle (LES-J C, n=9; 13,0 + 1,8 anos). Dez crianças saudáveis (CS) pareadas por idade e peso corporal foram recrutadas como controle. As crianças foram submetidas a um teste de esforço cardiorrespiratório máximo em esteira ergométrica antes e após 12 semanas de intervenção para determinação do consumo de oxigênio de pico (VO2pico), reserva cronotrópica (RC) e a frequência cardíaca de recuperação no primeiro (deltaFCR1) e segundo minuto (deltaFCR2) após exercício. RESULTADOS: Os pacientes com LES-J que não realizaram treinamento físico aeróbio não apresentaram alteração em qualquer dos parâmetros cardiorrespiratórios analisados (p > 0,05). Por outro lado, os pacientes com LES-J que foram submetidos ao programa de treinamento físico aeróbio demonstraram um aumento significativo no tempo de exercício (p = 0,01; TE = 1,07), na velocidade de pico (p = 0,01; TE = 1,08), no VO2 pico (p = 0,04; TE = 0,86), na RC (p = 0,06; TE = 0,83), e na deltaFCR1 e deltaFCR2 (p = 0,003; TE = 1,29 e p = 0,0008; TE = 1,36, respectivamente). Além disso, os parâmetros cardiorrespiratórios foram comparáveis após o período de intervenção entre os pacientes com LES-J submetidos ao treinamento físico aeróbio e os CS, tal como evidenciado pela análise ANOVA (p > 0,05, LES-J TF vs CS). O índice de atividade da doença SLEDAI-2K manteve-se estável ao longo do estudo. CONCLUSÃO: Este estudo demonstrou pela primeira vez que um programa de treinamento físico aeróbio de intensidade moderada sob supervisão pode ser seguro e eficaz no aumento da capacidade cardiorrespiratória e do controle autonômico cardíaco em pacientes com LES-J / INTRODUCTION: Exercise training has emerged as a promising therapeutic strategy to counteract physical dysfunction in adult systemic lupus erythematosus. However, no longitudinal studies have evaluated the effects of an exercise training program in childhood-onset systemic lupus erythematosus (C-SLE) patients. PURPOSE: To evaluate the safety and the efficacy of a supervised aerobic training program in improving the cardiorespiratory capacity in childhood-onset systemic lupus erythematosus (C-SLE) patients. METHODS: Nineteen physically inactive C-SLE patients were randomly assigned into two groups: trained (TR, n=10, supervised moderate-intensity aerobic exercise program) and non-trained (NT, n=9). Gender-, BMI- and age-matched healthy children were recruited as controls (C, n=10) for baseline (PRE) measurements only. C-SLE patients were assessed at PRE and after 12 weeks of training (POST). Main measurements included exercise tolerance and cardiorespiratory measurements in response to a maximal exercise (i.e.: peak VO2, chronotropic reserve [CR], and the heart rate recovery [deltaHRR] (i.e. the difference between HR at peak exercise and at both the first [deltaHRR1] and second [deltaHRR2] minutes of recovery after exercise). RESULTS: The C-SLE NT patients did not present changes in any of the cardiorespiratory parameters at POST (p > 0.05). In contrast, the exercise training program was effective in promoting significant increases in time-to-exhaustion (p=0.01; ES=1.07), peak speed (p=0.01; ES=1.08), peak VO2 (p=0.04; ES=0.86), CR (p=0.06; ES=0.83), and in deltaHRR1 and delta HRR2 (p=0.003; ES=1.29 and p=0.0008; ES=1.36, respectively) in the CSLE TR when compared with the NT group. Moreover, cardiorespiratory parameters were comparable between C-SLE TR patients and C subjects after the exercise training intervention, as evidenced by the ANOVA analysis (p > 0.05, TR vs. C). SLEDAI-2K scores remained stable throughout the study. CONCLUSION: A 3-month aerobic exercise training was safe and capable of ameliorating the cardiorespiratory capacity and the autonomic function in C-SLE patients

Introdução - Alterações cardíacas na anemia falciforme (AF) são frequentes e iniciam-se precocemente. Há evidências de que exista também disfunção na regulação do sistema nervoso autônomo o que pode contribuir com eventos de morbidade. Objetivos Avaliar a modulação autonômica cardíaca por meio da variabilidade da frequência cardíaca em crianças e adolescentes com anemia falciforme. Método - Estudo analítico no qual foi realizada uma comparação da variabilidade da frequência cardíaca em 45 crianças e adolescentes, menores de 20 anos, com anemia falciforme, com um grupo controle pareado um a um por idade e sexo. A frequência cardíaca foi obtida pelo frequencímetro de pulso e analisada, batimento a batimento. Estes pacientes são usuários do ambulatório de hematologia pediátrica do Sistema Único de Saúde. Esta pesquisa está em consonância com a resolução 466/2012 do Ministério da Saúde. Resultados - Observamos diferença significativa nos índices do domínio da frequência (VLF, LF, HF e LF/HF). Estas diferenças não foram observadas nos pacientes em uso de hidroxiureia. Conclusão - Existe uma disfunção autonômica na AF que ocorre desde a infância, podendo estar relacionada a uma menor modulação do simpático e uma maior modulação do parassimpático. Esta diferença não foi observada em pacientes em uso de hidroxiureia / Introduction - Cardiac changes in sickle cell disease (AF) are frequent and begin early. There is evidence that there is also dysfunction in the regulation of the autonomic nervous system, which may contribute to morbidity events. Objectives - To evaluate the autonomic cardiac modulation by heart rate variability in children and adolescents with sickle cell anemia. Method - An analytical study comparing the heart rate variability of 45 children and adolescents, younger than 20 years, with sickle cell anemia, with a control group matched one by one by age and sex. The heart rate was obtained by pulse frequency and analyzed, beat by beat. These patients are attending the pediatric hematology outpatient of the National Health System. Results - We observed a significant difference in the frequency domain indexes (VLF, LF, HF and LF / HF). The results of this study are in agreement with resolution 466/2012 of the Ministry of Health of Brazil. These differences were not observed in patients taking hydroxyurea. Conclusion - There is an autonomic dysfunction in AF that occurs from childhood, and may be related to a lower modulation of the sympathetic and greater modulation of the parasympathetic. This difference was not observed in patients taking hydroxyurea

estudo da variabilidade da frequência cardíaca (VFC) é um método que vem sendo usado para a análise da função autonômica cardiovascular frente aumentos da poluição atmosférica por material particulado (MP) em diversas populações, porém esse efeito em controladores de tráfego e taxistas permanece pouco compreendido especialmente durante o exercício. Objetivos: O presente estudo teve o objetivo de avaliar a resposta autonômica, ao repouso e ao exercício, frente variações da concentração de poluição (MP2,5) em indivíduos cronicamente expostos. Métodos: Foram estudados 75 trabalhadores da cidade de São Paulo divididos em grupo trabalhadores do tráfego (GTT; n=57) e grupo de trabalhadores florestais (GTF; n=18), posteriormente os 75 sujeitos foram novamente divididos pela presença ou ausência de comorbidades dando origem ao grupo hipertensão e/ou diabetes (GHD; n=21) e grupo sem comorbidades (GSC; n=54). As medidas de MP2,5 foram realizadas por monitoramento individual da exposição ao poluente e as avaliações ambulatoriais da VFC foram realizadas em 4 dias diferentes, tanto ao repouso quanto durante o exercício leve. Resultados: Foi observado que aumentos de 10g/m3 de PM2,5 levam a redução de HFms2 ao repouso no GTT sem nenhuma alteração durante o exercício. Por outro lado o GTF não apresentou mudanças durante o repouso, entretanto, durante o exercício o aumento do poluente leva a redução parassimpática (RMSSD), além disso, uma variável observada como interveniente nessa mudança foi a carga horária diária de trabalho exercida. Quando separados por comorbidades o GHD apresentou redução parassimpática ao repouso (HFms2 e HFnu) além de aumento simpático (LFnu) e ao exercício redução predominantemente parassimpática (RMSSD, LFms2, HFms2), já o GSC apresentou somente redução do LFms2 ao repouso sem alterações no exercício. Conclusão: Pequenos aumentos nas concentrações de MP2,5 levaram a alterações autonômicas em sujeitos cronicamente expostos, além disso essas alterações são mais evidentes nos sujeitos portadores de hipertensão e diabetes do que nos indivíduos saudáveis / The study of heart rate variability (HRV) is a method that has been used for the analysis of cardiovascular autonomic function front air pollution increases by particulate matter (PM) in many populations, but the effect on traffic controllers and taxi drivers remains poorly understood especially during exercise. Objectives: This study aimed evaluate the autonomic response, at rest and during exercise, compared to variations in the pollution concentration (PM2, 5) in chronically exposed subjects. Methods: We studied 75 workers of the city of São Paulo divided into group traffic workers (GTT, n=57) and group of forest workers (GTF, n=18), subsequently the 75 subjects were again divided by comorbidities presence or absence leading the group hypertension and/or diabetes (GHD, n=21) and group without comorbidities (GSC, n=54). PM2,5 measures were performed by individual monitoring of pollutants exposure and ambulatory HRV ratings were performed on 4 different days, both at rest and during light exercise. Results: We found that 10g/m3 of PM2,5 increases lead to HFms2 reduction at rest in GTT with no change during exercise. Moreover GTF showed no changes at rest, however, during exercise, pollutant increased leads to parasympathetic reduction (RMSSD) and the daily workload performed also observed as a intervener variable in this change. When separated by the comorbidities, GHD decreased parasympathetic at rest (HFms2 and HFnu) as well as increased sympathetic (LFnu) and exercise predominantly parasympathetic (RMSSD, LFms2, HFms2), the GSC has had only reduced LFms2 at rest without changes in exercise. Conclusion: Small increases in the PM2,5 concentrations led autonomic changes in subjects chronically exposed furthermore these changes are more evident in subjects with hypertension and diabetes than in healthy individuals

La thérapie par compression médicale est reconnue comme une composante essentielle dans le traitement des pathologies veineuses et demeure incontournable dans la prise en charge des affections veineuses aux différents stades de la pathologie (jambes lourdes, œdèmes, ulcères). Si le bénéfice est reconnu par les patients eux-mêmes ainsi que par les médecins, il n’existe à l’heure actuelle que peu d’éléments permettant de quantifier ce bénéfice. Dans ce contexte, l’objectif de ces travaux de thèse est d’apporter des éléments de compréhension et d’objectiver les effets bénéfiques des bas médicaux de compression (BMC) aux niveaux physiologique, neurophysiologique et comportemental. Trois axes de recherche ont été dégagés. Le premier axe de recherche est l’étude de l’effet de la compression sur l’activité microcirculatoire cutanée dans les membres inférieurs en utilisant le dispositif Hématron, dispositif ambulatoire exclusif d’évaluation de l’activité microcirculatoire cutanée. Les résultats ont montré une amélioration de l’activité microcirculatoire pour différentes classes de BMC et pour différentes positions. Ces résultats tendraient à mettre en cause l’hypothèse, largement admise, que les BMC améliorent le retour veineux principalement en diminuant la section des veines (superficielles voire profondes). La deuxième piste de recherche concerne l’objectivation de l’amélioration de la qualité de vie liée au port des BMC, généralement exprimée subjectivement par les personnes atteintes de pathologie veineuse. Les résultats préliminaires montrent que l’analyse de la variabilité cardiaque permet de mettre en évidence une relation entre le paramètre indicateur de l’activité de la balance sympatho-vagale et le port de la compression médicale au cours d’une journée. Compte tenu de la grande dispersion des résultats, cette étude serait à poursuivre sur une population plus large pour aboutir à des conclusions fiables. Le dernier axe de recherche est lié à l’impact du port des BMC sur le comportement du sujet et plus précisément sur sa déambulation. Les patients déclarent une fatigue physique dans les membres inférieurs moins intense en fin de journée grâce à la compression médicale. Notre hypothèse est que le port des BMC impacterait directement la dynamique de la déambulation. Pour évaluer la cinétique de la marche, nous avons conçu, développé et validé une instrumentation intégrant des capteurs accéléromètres. Des tests préliminaires ont permis de dégager des paramètres pertinents caractéristiques de la déambulation. La prochaine étape sera de conduire une campagne d’expérimentation destinée à objectiver la fatigue comportementale en fin d’après-midi mesurée avec ou sans compression médicale portée au cours de la journée. / Medical compression therapy is recognized as an essential component in the treatment of venous diseases and is indispensable in the treatment of venous diseases at different stages of the disease (heavy legs, edema and ulcers). Although the benefit is recognized by the patients themselves and by physicians, there is at present little evidence to quantify this benefit. Against this background, the aim of this thesis is to provide more understanding and objectify the benefits of compression stockings (MCS) on in terms of physiology, neurophysiology and gait dynamics. Three areas of research were identified and studied. The first line of research is the study of the effect of compression on skin microcirculatory activity in the lower limbs using the Hematron ambulatory device. The results showed an improvement in skin blood flow activity for different classes of MCS and at different positions. These results would tend to challenge the widely accepted assumption that MCS improve venous return primarily by decreasing the cross-sectional area of (superficial or deep) veins. The second line of research involves the objectification of the improvement in the quality of life resulting from the wearing of MCS, usually this is expressed subjectively by people with venous disease. Preliminary results show that the analysis of heart rate variability highlights a relationship between the indicators of sympathovagal balance activity and the use of medical compression during the day. Given the wide dispersion in the results, this study should be carried out on a larger population to draw more reliable conclusions. The last line of research relates to the impact of MCS on the behavior and, in particular, the gait of the subject. Patients report that physical fatigue in the lower limbs is less prevalent at the end of the day with compression therapy. Our hypothesis is that the wearing of MCS has a direct impact on gait. To evaluate the kinetics of walking, we have designed, developed and validated an instrumentation involving accelerometers sensors. Preliminary tests have yielded relevant parameters characteristic of gait dynamics. The next step is to conduct an experimental campaign to objectify behavioral fatigue, with or without the wearing of medical compression, at the end of the afternoon.

The aim of this thesis was to validate the use of infrared thermography (IRT) to non-invasively measure stress and/or pain in cattle. The main approach was to measure changes in heat emitted from superficial capillaries around the eye (referred to as eye temperature) in response to various aversive husbandry procedures used routinely on farms. In addition, various exogenous challenges were given to investigate the role of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) in regulating the eye temperature response. No evidence was found to support the hypothesis that an increase in eye temperature was due to HPA activity in cattle. A rapid drop in eye temperature occurred immediately after disbudding, an electric prod, startling and shouting. It is suggested that this was caused by the redirection of blood from the capillary beds via sympathetically-mediated vasoconstriction. Therefore, the role of the ANS was tested by measuring eye temperature, heart rate variability (HRV) and plasma catecholamine responses simultaneously. Somatic pain from disbudding and initial responses to surgical castration included a synchronised drop in eye temperature, increases in catecholamines and changes in HRV indicative of increased sympathetic activity. The role of the sympathetic nervous system was further confirmed by a drop in eye temperature that occurred following an epinephrine challenge. In contrast, deeper visceral pain from castration caused a more marked increase in eye temperature and changes in HRV indicative of increased parasympathetic tone. The underlying mechanism driving the increase in eye temperature is unknown; however, it is possible that it may be caused by vasodilation due to increased parasympathetic activity. These differences in ANS responses to different procedures, detected by IRT and HRV, may be due to the nature of the pain and the relative fear associated with the procedure. In summary, this research showed that during stress or pain, the heat emitted from superficial capillaries around the eye changes as blood flow is regulated under ANS control and these changes can be quantified using IRT. A combination of IRT and HRV is a non-invasive way to measure ANS activity and assess acute welfare impacts of husbandry practices in cattle. Further research using pharmacological inhibition and stimulation of the ANS activity would be beneficial to fully understand the underlying regulatory mechanisms of the eye temperature and HRV responses in cattle and other species during stress and/or pain. The full capability of IRT and HRV for detection of disease and emotional states and the effects of different intensities of pain, individual traits and previous experience also deserve attention.

There is a significant comorbidity between anxiety/depression and functional gastrointestinal syndromes, such as irritable bowel syndrome (IBS) and functional dyspepsia. The pathophysiological link between emotions and the gut is not known. A model of an emotional motor system (EMS) which reacts to interoceptive and exteroceptive stress has been proposed. EMS consists of specific brain structures including anterior cingulate cortex (ACC), amygdala, hippocampus and hypothalamus and mediates their communication to the rest of the body (including the gastrointestinal tract) through the hypothalamus-pituitary-adrenal (HPA) axis, the autonomic nervous system (ANS) and by a pain modulation system. The aim of this thesis was to test the EMS model by studying the relationship between symptoms of anxiety and depression and IBS-like symptoms in patients with recurrent unipolar depression, in patients with IBS and in a sample of a normal Swedish population. The peripheral limb of EMS (ANS, HPA axis and the pain modulations system) was tested in patients with IBS and control subjects. Spectral heart rate variability was used to investigate ANS function in patients with refractory IBS and in healthy controls. The HPA axis function was tested by a weight adjusted low dose dexamethasone suppression test in control subjects. The influence of catecholamine degradation on pain modulation was tested by analyzing val158met catechol-o-methyl transferase (COMT) polymorphism in patients with IBS and in control subjects. We found a significant relationship between symptoms of anxiety/depression and IBS-like symptoms in patients with recurrent unipolar depression, in patients with IBS and in a sample of the normal population. Interestingly, patients with recurrent unipolar depression in remission had no more IBS-like symptoms than controls, indicating that the gastrointestinal symptoms may resolve when depression is treated to remission. Patients with IBS have an increased mid-frequency power in rest and in supine position (after tilt test) compared to healthy controls indicating an increased sympathetic ANS drive. The symptoms of diarrhea and early satiety has in the litterature been associated to the stimulation of corticotropin releasing hormone (CRH) receptors and was also in our study related to HPA axis function tested by a low dose dexamethasone test. Interestingly both hypo- and hyperfunction of the HPA axis was related to these symptoms in control subjects. The val158met COMT polymorphism was associated to IBS-like symptoms. Control subjects with IBS-like symptoms (defined by the upper quartile in total GSRS-IBS score) had a higher frequency of the met/met and a significantly lower frequency of the val/met genotype. Also patients with IBS tended to have a lower frequency of the heterozygous val/met genotype so we conclude that this genotype may be protective against IBS/IBS like symptoms. In addition, the val/val genotype in patients with IBS was associated to diarrhea symptoms. Conclusions: Our results support the model of an emotional motor system in the genesis of functional gastrointestinal symptoms by the finding of the association of IBS-like symptoms and mood disturbances, and by finding alterations in the peripheral limbs of EMS (ANS, HPA axis and catecholamines) in subjects with IBS and IBS-like symptoms.

Des lacunes existent au niveau des connaissances concernant les modifications cardiovasculaires manifestées avant l’établissement d’obésité et en absence d’hyperlipidémie. Dans cette optique, la présente étude a testé l'hypothèse générale qui stipule que l’administration d’une diète riche en gras pour une période de 8 semaines chez les rats femelles influence négativement la fonction et le remodelage cardiaque, avant le développement de l’obésité et en absence d’hyperlipidémie et d’hyperglycémie. Afin de répondre à cette problématique, des rats femelles Sprague-Dawley ont été assignés à une diète standard (SD; 12,5% lipides, kcal) ou riche en gras (HF; 42% lipides, kcal) pour une période de 8 semaines. Cette durée était insuffisante pour induire le développement d’une dyslipidémie ou une augmentation significative de la masse corporelle chez les animaux HF(329±14g) comparativement aux rates SD (300±10g). Toutefois, une hypertension artérielle s’est développée chez les rates HF (130±4 vs 108±6 mmHg, p<0,05), accompagnée d’une altération des relaxations aortiques dépendantes de l’endothélium (relaxation maximale : 22±5% versus 53±8%, pour les animaux HF et SD respectivement, p<0,05). L’administration orale chronique de l’antioxydant resvératrol (RES; 20 mg·kg-1·jr-1) a prévenu le développement de ces altérations pathologiques, attestant d’une implication du stress oxydant. Au niveau cardiaque, le RES n’a toutefois pas inhibé le développement de fibrose périvasculaire secondaire à l’administration de la diète riche en gras. Suite à une insulte d’ischémie-reperfusion, la taille (SD : 0,29±0,09 versus HF : 0,32±0,13 cm), l’épaisseur (SD : 0,05±0,02 versus HF : 0,06±0,01 cm) et le contenu en collagène α1 type 1 (SD : 0,21±0,04 versus HF : 0,20±0,04 unités arbitraires/mm2) de la cicatrice du coeur infarci des rats HF étaient comparables au coeur infarci des rats SD. Malgré ces similitudes, le taux de décès était significativement (p<0,05) plus élevé chez les rats HF (56%) comparativement aux rats SD (5%). L’approche par électrophysiologie a démontré que l’administration de la diète riche en gras était associée à une augmentation (p<0,05) du nombre d’extrasystoles ventriculaires induites. Cette élévation de l’incidence était associé à une hyperinnervation sympathique fonctionnelle, tel que démontré par une élévation (p<0,05) de la densité des fibres neurofilament-M (HF : 2830±250 versus SD : 2020±260 μm2/mm2) et de la protéine de l’hydroxylase de la tyrosine. La fonctionnalité des jonctions intercellulaires était également atteinte, caractérisée par une latéralisation et internalisation de connexine 43 ainsi qu’une diminution de l’expression de connexine 40 au niveau des disques intercalaires. Ainsi, avant l’établissement de l’obésité et d’une dyslipidémie, les rats femelles modestement hypertendus présentent un phénotype arythmogénique cardiaque en partie dû à une hyperinnervation sympathique et une expression altérée concomitante de la distribution et de l’expression des jonctions intercellulaires. L’absence de symptômes cliniques d’obésité dans la présente étude ne fournit aucun indice au clinicien quant à la susceptibilité accrue aux arythmies ventriculaires. Ainsi, en présence d’une hypertension artérielle modérée chez un patient non-obèse, une mesure de l’activité sympathique par la quantification des niveaux circulants de catécholamines pourrait être bénéfique afin de détecter les patients à risque de mort subite. / Knowledge is insufficient regarding cardiovascular modifications occurring prior to the development of overt obesity and dyslipidemia. In this regard, the present project aimed at testing the hypothesis stipulating that the administration of a high fat diet for an 8-week period in female rats can adversely influence cardiac function and remodeling prior to the development of overt obesity, and in the absence of hyperlipidemia and hyperglycaemia. To directly examine these issues, normal female Sprague-Dawley rats were fed a standard (SD; 12.5% lipid, kcal) or a high-fat diet (HF; 42% lipids, kcal) for 8 weeks. This regimen was insufficient to induce a significant gain in body mass in HF rats (329±14g) as compared to SD rats (300±10g), or any variation in the lipid profile. By contrast, systemic arterial hypertension developed in high fat fed rats (130±4mmHg versus SD, 108±6mmHg, p<0.05), additionally to a significant decrease in acetylcholine-mediated maximal relaxation of isolated aortic rings (HF, 22±5%) compared to rats fed a standard diet (53±8%, p<0.05). Chronic oral administration of the antioxidant resveratrol (RES; 20 mg·kg-1·d-1) prevented the development of both pathological alterations, attesting to the implication of oxidative stress. However, it failed to attenuate the perivascular fibrosis that developed following the administration of the high-fat diet. Following ischemia/reperfusion injury, scar length (SD, 0.29±0.09 versus HF, 0.32±0.13 cm), thickness (SD, 0.05±0.02 versus HF, 0.06±0.01 cm) and collagen α1 type 1 content (SD, 0.21±0.04 versus HF, 0.20±0.04 arbitrary units/mm2) in the infarcted heart of rats fed a high fat diet were similar to infarcted normal rats. Despite these findings, the rate of death was significantly increased (p<0.05) in female rats fed a high fat diet (56%) compared to rats fed a standard diet (5%). An electrophysiology approach revealed that normal female rats fed a high fat diet had an increased incidence (p<0.05) of induced ventricular extrasystoles. In addition, these hearts presented a functional sympathetic hyperinnervation, as reflected by the increased density of neurofilament-M immunoreactive fibres (SD, 2020±260 versus HF, 2830±250 μm2/mm2; p<0.05) and increased protein expression of tyrosine hydroxylase. The gap junction function was also impaired, characterized by lateralization and internalization of connexine 43, and a decreased expression of connexine 40 in intercalated discs of rats fed a high fat diet. Thus, prior to the development of overt obesity and dyslipidemia, female rats with modest hypertension exhibit an arrhythmogenic cardiac phenotype due in part to sympathetic hyperinnervation and a concomitant aberrant pattern of gap junctional protein expression and distribution. The lack of significant clinical manifestations of obesity in the present study does not enable clinicians to suspect the increased susceptibility to ventricular arrhythmias. Hence, in presence of modest hypertension in a non-obese patient, evaluation of the sympathetic activity by the assessment of circulating catecholamine could be helpful in detecting patients at high risk for sudden death.

Hintergrund: Vegetative Übererregbarkeit ist ein zentrales Symptom der posttraumatischen Belastungsstörung (PTBS), welche durch eine präfrontale Disinhibition des limbischen Systems mit hieraus folgenden maladaptiven peripheren Stressreaktionen erklärt wird. Lange Zeit hat die Forschung den starken Einfluss des Parasympathikus auf die Stressregulation vernachlässigt und durch Erfassung zu weniger Parameter der Komplexität der autonomen Stressregulation nicht ausreichend Rechnung getragen. In dieser Studie sollen die Auswirkungen der sympathovagalen Dysbalance auf alltägliche Stressreaktionen und das Entspannungsvermögen von Frauen mit PTBS im Vergleich zu gesunden Frauen untersucht und Erkenntnisse über verschiedene autonome Regulationsmechanismen gewonnen werden. Hierbei sollen auch medikamentöse Einflüsse berücksichtigt und das subjektive Stressempfinden mit den physiologischen Messwerten korreliert werden. Methoden: 52 Patientinnen (P) und 39 gematchte, gesunde Frauen (K) wurden mit Hilfe eines hämodynamischen Monitorsystems während zweier 5-­minütiger Stresstests (Rechentest: RT, Babyschreien: BS) und in Ruhe untersucht. Mittels EKG-­, Impedanz-­ und Blutdruckmessungen wurden für jeden Herzschlag die folgenden Parameter erhoben: Herzrate (HR), Herzindex (CI), Präejektionszeit (PEP), peripherer Gefäßwiderstandsindex (TPRI), systolischer Blutdruck (sBP), hoch-­ und niederfrequente Herzratenvariabilität (HF-­ und LF-­HRV), Standardabweichung der regulären RR-­‐Intervalle (SDNN) und Barorezeptorsensitivät (BRS). Neben dem globalen Gruppenvergleich wurde auch ein Subgruppenvergleich durchgeführt, bei welchem die Reaktionen der Patientinnen ohne kardial wirksame Medikamente (P0, n=21) jeweils mit denen der Patientinnen mit kardial wirksamer Medikation (P1, n=27) und denen der Kontrollgruppe verglichen wurde. Zu Beginn der Untersuchung, nach jeder Stressphase und nach der abschließenden Entspannungsmusik wurde zudem das subjektive Stressempfinden auf einer SUD-­Skala von 0-­10 erfragt. Ergebnisse: Die HF-­HRV und die BRS von K fielen während des RT ab, während es zu einer Aktivierung der β-­adrenergen Parameter kam (CI↑, HR↑, PEP↓). Das BS verursachte bei K hingegen einen Anstieg von HF-­HRV und BRS, ohne dass hier starke sympathischen Reaktionen beobachtet werden konnten. P lag mit der HF-­HRV während aller Messphasen signifikant unter den Werten von K (p=0,0003). Signifikante Wechselwirkungen konnten für HR (p<0,0001), PEP (p=0,0032), BRS (p=0,0002) und CI (p=0,0106) nachgewiesen werden: während des RT stiegen die HR (p<0,0001) und der CI (p=0,041) von P signifikant schwächer an als bei K, während die PEP entsprechend weniger abfiel (p=0,006). Der Anstieg der BRS während des BS war bei P ebenfalls signifikant geringer ausgeprägt (p=0,009), zu vermehrten sympathischen Reaktionen kam es bei P dennoch ebenfalls nicht. Insgesamt zeigten sich auch keine signifikanten Unterschiede für den sBD. Dafür war das subjektive Stressempfinden von P über alle Messphasen und insbesondere während des BS signifikant höher (p=0,01). Eine geringe Korrelation war hier vor allem mit der HF-­HRV und der HR zu finden, für die meisten Parameter zeigte sich allerdings kein korrelativer Zusammenhang. Im Vergleich zwischen P0 und P1 fanden sich nur für CI, TPRI und SDNN signifikante Gruppenunterschiede (P1: CI↓, TPRI↑, SDNN↓) und für keinen der Parameter konnten im Subgruppenvergleich eine signifikante Wechselwirkung nachgewiesen werden. Insbesondere die HF-­HRV war auch bei P0 signifikant niedriger als bei K (p=0,0432). Das subjektive Stressempfinden beider Subgruppen unterschied sich nicht signifikant. Interpretation: Die gesunden Frauen reagierten während des Rechentests wie erwartet mit einer vagalen Disinhibition und der simultanen Aktivierung β-­adrenerger Aktivitätsparameter. Dies kann als eine aktive Stressbewältigung interpretiert werden. Während des Babyschreiens wurde jedoch offensichtlich eine andere autonome Reaktion ausgelöst, welche sich hauptsächlich in einer gesteigerten Vagusaktivität ausdrückte und kaum Veränderungen der sympathischen Parameter verursachte. Diese Studie zeigt somit als erste unterschiedliche vagale Reagibilitätsmuster auf externe Stimuli bei gesunden Frauen und verdeutlicht so den starken Einfluss der vagalen Modulation auf die verschiedenen Stressreaktionen. Bei den Patientinnen war hingegen bereits in Ruhe ein erniedrigter Vagotonus zu beobachten, welcher unter Stress eine reduzierte Reaktionsfähigkeit zeigte. Insbesondere während des Babyschreiens stiegen die vagalen Parameter bei ihnen nicht vergleichbar stark an. Darüber hinaus war bei den Patientinnen während des Rechnens eine geringere Aktivierung der β-­adrenergen Parameter und zu finden und auch während des Babyschreiens kam es trotz eines stärkeren subjektiven Stressempfindens nicht zu einer verstärkten sympathischen Reaktion. Diese Ergebnisse sprechen somit für eine vorwiegend vagale Dysfunktion bei PTBS im Sinne einer vagalen Hyporeagibilität bei insgesamt reduziertem Vagotonus. Auch wenn die Korrelation niedriger vagaler Werte mit einem erhöhten subjektiven Stressempfinden bei den Patientinnen nur schwach ist, ist sie mit den anderen Ergebnissen dieser Studie gut vereinbar. Stress scheint also möglicherweise auch durch den ausbleibenden Anstieg des Vagotonus zu entstehen und nicht nur durch eine Aktivierung des Sympathikus. Insgesamt muss jedoch eine Diskrepanz zwischen dem starken subjektiven Stresserleben und den nur gering reagierenden physiologischen Parametern hervorgehoben werden. Die kardialen Nebenwirkungen der Medikamente führten bei den Patientinnen lediglich zu einem Shift einiger Werte, nicht zu einem grundsätzlich veränderten Reaktionsmuster.

Thesis (M.S.)--Uniformed Services University of the Health Sciences, 2005. / Typescript (photocopy).