A hiperatividade simpática é uma característica marcante da insuficiência cardíaca (IC). Estudos apontam alterações na sensibilidade quimiorreflexa como um mecanismo potencial para essa alteração autonômica. Por outro lado, sabe-se que o treinamento aeróbico e o treinamento muscular respiratório reduzem a atividade nervosa simpática muscular (ANSM). Objetivo: Neste estudo nós testamos as seguintes hipóteses: 1) o treinamento respiratório combinado ao treinamento aeróbico potencializa a melhora na ANSM, no fluxo sanguíneo muscular (FSM) e na força muscular respiratória, em pacientes com IC; 2) o treinamento respiratório e o treinamento aeróbico melhoram o controle quimiorreflexo da ANSM. Métodos: Foram incluídos pacientes com idade entre 30 e 70 anos, fração de ejeção do ventrículo esquerdo <= 40% e classe funcional II/III (NYHA). Os pacientes foram randomizados em 4 grupos: 1) controle (não treinado, n=10), 2) treinamento respiratório (n=11), 3) treinamento aeróbico (n=9) e 4) treinamento combinado (respiratório + aeróbico, n=9). A ANSM foi avaliada pela técnica de microneurografia e o FSM pela técnica de pletismografia de oclusão venosa. O controle quimiorreflexo periférico foi avaliado pela inalação de mistura gasosa hipóxica (10% de O2 e 90% N2) e o controle quimiorreflexo central pela inalação de mistura gasosa hipercapnica (7% CO2 e 93% O2). A capacidade funcional foi avaliada pelo teste cardiopulmonar. A força muscular respiratória foi avaliada pela pressão inspiratória máxima (PI Máx) e pelas pressões esofágica, gástrica e transdiafragmática. A qualidade de vida foi avaliada pelo questionário de Minessota. O treinamento aeróbico de moderada intensidade teve duração de 40 minutos, 3 vezes por semana, durante 4 meses. O treinamento respiratório consistiu em treinamento muscular inspiratório com carga de 60% da PI Máx, 30 minutos por dia, 5 dias por semana durante 4 meses. Resultados: Os treinos respiratório, aeróbico e combinado diminuíram a ANSM e aumentaram o FSM em repouso. A comparação entre os grupos não mostrou diferenças de respostas entre os grupos treinados. Os treinamentos aeróbico e combinado aumentaram a capacidade funcional (VO2 pico e carga pico). A PI Máx foi maior nos pacientes submetidos ao treinamento respiratório e combinado. A qualidade de vida melhorou nos 3 grupos treinados. O treino aeróbico e o treino respiratório reduziram a resposta de ANSM durante a estimulação dos quimiorreceptores periféricos. Não foram observadas alterações no grupo controle. Conclusão: Ambos, o treinamento respiratório e o treinamento aeróbico, melhoram o controle neurovascular em repouso. Contudo, o treinamento respiratório combinado ao treinamento aeróbico não causa benefício adicional no controle neurovascular, em pacientes com IC. O treinamento respiratório e o treinamento respiratório melhoram a resposta de ANSM à estimulação dos quimiorreceptores periféricos / Introduction: Sympathetic hyperactivity is a hallmark of heart failure (HF). Studies indicate that changes in chemoreflex sensitivity as a potential mechanism for this autonomic alteration. On the other hand, it is known that aerobic training and respiratory muscle training reduce muscular sympathetic nerve activity (MSNA). Objective: In this study we tested the following hypotheses: 1) combined respiratory training and aerobic training promove a more pronuciate effect on MSNA, muscle blood flow (MBF) and respiratory muscle strength in HF patients; 2) respiratory training and aerobic training improve chemorreflex control of MSNA. Methods: Patients aged 30 to 70 years, left ventricular ejection fraction <= 40% and functional class II / III (NYHA) were included. Patients were randomized into 4 groups: 1) control (Untrained, n = 10), 2) respiratory training (n = 11), 3) aerobic training (n = 9) and 4) combined training (n= 9). The MSNA was evaluated by the microneurography technique and the MBF by the venous occlusion plethysmography technique. Peripheral chemoreflex control was evaluated by inhaling hypoxic gas mixture (10% O2 and 90% N2) and the central chemoreflex control by inhaling the hypercapnic gas mixture (7% CO2 and 93% O2). The functional capacity was evaluated by the cardiopulmonary test. Respiratory muscle strength was assessed by maximal inspiratory pressure (PI Max) and by esophageal, gastric and transdiaphragmatic pressure. Quality of life was assessed by the Minnesota Questionnaire. Aerobic training was conducted for four months, 3 times per week, for 40 min at moderate intensity. Respiratory training consisted of inspiratory muscle training for four months, 5 times per week for 30 min, at 60% of PI Max. Results: Respiratory, aerobic and combined training reduced the MSNA and increased the MBF at rest. The comparison between the groups did not show differences of responses among the trained groups. Aerobic and combined training increased functional capacity (peak VO2 and peak load). PI Max was higher in patients submitted to combined and respiratory training. Quality of life improved in the 3 trained groups. Aerobic training and respiratory training reduced the MSNA response during stimulation of peripheral chemoreceptors. No changes were observed in the control group. Conclusion: Both respiratory training and aerobic training improve neurovascular control at rest. However, respiratory training combined with aerobic training does not cause additional benefit in neurovascular control in patients with systolic HF. Respiratory training and respiratory training improve the MSNA response to stimulation of peripheral chemoreceptors

Introdução: Pacientes com cardiopatia chagásica têm hiperatividade do sistema nervoso simpático, piorando o prognóstico destes pacientes. Estão bem estabelecidos os benefícios do treinamento físico aeróbico (TF) no controle autonômico cardiovascular e na musculatura esquelética de pacientes com cardiopatia e disfunção ventricular. A hipótese da tese seria que o TF melhorasse a função autonômica cardiovascular e a estrutura e metabolismo muscular de pacientes com cardiopatia chagásica crônica (CCC) mesmo com função sistólica preservada, tendo em vista que parte destes pacientes evolui para a forma dilatada com disfunção ventricular e suas graves consequências. Objetivo: Avaliar o efeito do TF no controle autonômico cardiovascular e no tecido muscular esquelético em pacientes com CCC e função sistólica preservada. Métodos: Foram incluídos pacientes com duas reações sorológicas positivas para a doença de Chagas, alterações eletrocardiográficas, fração de ejeção do ventrículo esquerdo >= 55% e idade entre 30 e 60 anos. Vinte e quatro pacientes foram submetidos à primeira série de avaliações e foram randomizados em dois grupos: doze pacientes com CCC e função ventricular sistólica preservada submetidos ao TF além do seguimento clínico (ChT) e doze pacientes com CCC e função ventricular sistólica preservada não submetidos ao TF, apenas ao seguimento clínico (ChNT). Após quatro meses, oito pacientes finalizaram o protocolo de treinamento físico (ChT, n=08) e dez pacientes finalizaram o seguimento clínico (ChNT, n=10). A atividade nervosa simpática muscular (ANSM) foi avaliada pela técnica de microneurografia e o fluxo sanguíneo muscular (FSM) pela técnica de pletismografia de oclusão venosa. Variabilidade da frequência cardíaca e da pressão arterial foram analisadas utilizando sinais da frequência cardíaca captadas pelo eletrocardiograma e sinais da pressão arterial captados pelo finometer. A sensibilidade barorreflexa cardíaca foi avaliada com infusão de drogas vasotivas. A capacidade funcional foi avaliada pelo teste cardiopulmonar. A biópsia do músculo vasto-lateral foi realizada para as análises histológicas das fibras musculares e para avaliação da expressão gênica de Atrogin-1 e MuRF-1. O programa de TF foi realizado durante quatro meses, constando de 3 sessões semanais supervisionadas com duração aproximada de 60 minutos. Resultados: Como marcadores de TF, houve redução da frequência cardíaca de repouso e aumento do consumo de oxigênio pico. O TF diminuiu a hiperatividade simpática, colaborando para o aumento do FSM. O treinamento físico reduziu tanto a ANSM, quanto a atividade simpática cardíaca e vasomotora, e melhorou a sensibilidade barorreflexa cardíaca. A redução da ANSM esteve associada a redução da hiperatividade cardiovascular, melhora da sensibilidade barorreflexa cardíaca e redução da expressão gênica de Atrogin-1 e MuRF-1. Após período de quatro meses, o grupo ChT apresentou menor expressão gênica de Atrogin-1 em relação ao grupo ChNT. Conclusão: O TF provocou expressiva melhora na disfunção autonômica, no FSM e na capacidade funcional de pacientes com CCC e função sistólica preservada. Adicionalmente, a redução da ANSM esteve associada a melhora da sensibilidade barorreflexa cardíaca, redução do tônus simpático cardiovascular e redução da expressão gênica de Atrogin-1 e MuRF-1, genes envolvidos na atrofia muscular / [thesis]. São Paulo: Faculdade de Medicina, Universidade de São Paulo; 2017. Background: Patients with chagasic cardiomyopathy have sympathetic nervous system hyperactivity, worsening the prognosis of these patients. The benefits of aerobic training (ET) in cardiovascular autonomic control and skeletal muscle of heart failure patients are well established. The thesis hypothesis was that ET improves cardiovascular autonomic function and structure and metabolism muscle in chronic chagasic cardiopathy (CCC) patients even though preserved systolic function, considering that part of these patients develop the dilated form with ventricular dysfunction and its serious consequences. Objectives: To evaluate the effects of ET on cardiovascular autonomic control and skeletal muscle tissue in CCC patients and preserved systolic function. Methods: Patients with two positive serological reactions for Chagas disease, electrocardiographic alterations, left ventricular ejection fraction >= 55% and age between 30 and 60 years were included. Twenty-four patients underwent the first stage of evaluations and were randomized into two groups: Twelve CCC patients and preserved systolic ventricular function submitted to ET in addition to clinical follow-up (ET group) and twelve CCC patients and preserved systolic ventricular function submitted to only clinical follow-up not submitted to ET (NoET group). After four months, eight patients completed the ET protocol (ET, n = 08) and ten patients completed clinical follow-up (NoET, n = 10). Muscular sympathetic nerve activity (MSNA) was measured using microneurography technique and muscle blood flow (MBF) by the venous occlusion plethysmography technique. Heart rate and blood pressure variability were analyzed using heart rate signals captured by the electrocardiogram and blood pressure signals captured by the finometer. Cardiac baroreflex sensitivity was evaluated by infusion of vasoactive drugs. Functional capacity was determined by cardiopulmonary exercise test. Vastus lateralis muscle biopsy was performed for the histological analysis of muscle fibers and for the Atrogin-1 and MuRF-1 gene expression evaluation. ET program consisted of three 60-minute exercise sessions per week for four months. Results: As ET markers, there was a reduction in resting heart rate and an increase in peak oxygen consumption. ET reduced the sympathetic hyperactivity, contributing to the increase of the MBF. ET reduced both MSNA, as well as cardiac and vasomotor sympathetic activity, and improved cardiac baroreflex sensitivity. Reduction of MSNA was associated with a reduction in cardiovascular hyperactivity, improved cardiac baroreflex sensitivity, and reduced Atrogin-1 and MuRF-1 gene expression. After the four-month period, the ET group presented lower Atrogin-1 gene expression than the NoET group. Conclusion: ET improved significantly autonomic dysfunction, MBF and functional capacity of CCC patients and preserved systolic function. In addition, the reduction of ANSM was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced Atrogin-1 and MuRF-1 gene expression, genes involved in muscle atrophy

Sabe-se que a ativação do Sistema Nervoso Simpático (SNS) induz osteopenia via adrenoceptores b2 (b2-AR). Para investigar se o hormônio tireoideano (HT) interage com o SNS para regular a massa óssea, estudamos o efeito do HT em associação com isoproterenol ou propranolol (agonista e antagonista b-adrenérgicos) e avaliamos o efeito do HT em camundongos com elevado tônus simpático, devido à dupla inativação gênica do a2A-AR e a2C-AR (a2A/a2C-AR-/-), autorreceptores que inibem a liberação de noradrenalina. Vimos que esses animais apresentam um fenótipo de alta massa óssea, apesar do elevado tônus simpático e de intacta sinalização b2-adrenérgica, sugerindo que o a2A-AR e/ou a2C-AR, além do b2-AR, possam mediar ações do SNS no osso. O propranolol limitou e o isoproterenol acentuou os efeitos deletérios do HT no esqueleto, já os animais a2A/a2C-AR-/- apresentaram resistência à osteopenia induzida pela tireotoxicose, o que sugere que há interação entre SNS e o HT para regular a massa óssea, e que esta depende tanto do b2-AR como do a2A- e/ou a2C-AR. / It is known that the sympathetic nervous system (SNS) activation induces ostepenia, via b2-adrenoceptors (b2AR). To investigate if thyroid hormone (TH) interacts with the SNS to regulate bone mass, we studied the effect of TH in association with isoproterenol or propranolol (b-adrenergic agonist and antagonist) and evaluated the effect of TH in mice with a chronic elevated sympathetic tone, due to double disruption of a2A-AR and a2C-AR (a2a/a2c-AR-/-), autoreceptors that inhibit noradrenalin release. We showed that KO mice present a high bone mass phenotype in spite of an elevated sympathetic tone and of intact b2-adrenergic signaling, which suggests that a2A- and/or a2C-AR, besides b2-AR, may also mediate the SNS actions in the bone. Propranolol limited and isoproterenol accentuated the deleterious effects of TH in the skeleton, while a2A/a2C-AR-/- mice presented resistance to the T3-induced osteopenia, which suggest that there is an interaction between the SNS and TH to regulate bone mass, and that it is dependent on b2-AR and a2A-AR and/or a2C-AR signaling.

O hormônio tireoidiano (HT) é essencial para o desenvolvimento, maturação e metabolismo ósseos, enquanto que o sistema nervoso simpático (SNS) é, também, um potente regulador do remodelamento ósseo. Demonstrou-se que SNS regula negativamente a massa óssea, agindo via receptores ?2-adrenérgicos (?2-AR), expressos em osteoblastos. O nosso grupo demonstrou que os receptores ?2 adrenérgicos (?2-AR) também medeiam ações do SNS no esqueleto e que são expressos em osteoblastos, osteócitos, condrócitos e osteoclastos. Considerando-se que o HT interage com o SNS para regular uma série de processos fisiológicos, e que o excesso de HT e a ativação do SNS causam perda de massa óssea, levantamos a hipótese de que há interação entre o HT com o SNS para regular a massa óssea. Estudos do nosso grupo vêm sustentando essa hipótese, uma vez que camundongos com inativação gênica dos receptores beta2-AR apresentam resistência à osteopenia induzida por doses tóxicas de HT. Considerando-se, ainda, que a interação do HT com o SNS em vários tecidos e/ou órgãos depende da sinalização beta2 adrenérgica, o presente estudo teve como objetivo avaliar se a interação do HT com o SNS para regular a morfofisiologia óssea envolve o beta2-AR. Para tanto, estudamos o efeito de 10x e 20x a dose fisiológica de triiodotironina (3,5ug ou 7.0ug de T3/100g de massa corporal/dia, respectivamente), por 90 dias, na microaquitetura óssea e em parâmetros biomecânicos do fêmur de camundongos com inativação gênica do beta2-AR (beta2-AR-/-), e nos seus respectivos Selvagens (Selv), os camundongos da linhagem FVB. Como esperado, o tratamento com T3 promoveu efeitos deletérios na microarquitetura trabecular das fêmeas Selv, enquanto alguns desses efeitos foram mais brandos ou inexistentes nos animais beta2-AR-/-, revelando resistência do osso trabecular dos animais knockout (KO) aos efeitos deletérios da tireotoxicose. Em contraste, a microarquitetura femoral dos camundongos machos beta2-AR-/- se mostrou mais sensível aos efeitos deletérios da tireotoxicose, em relação aos respectivos Selv. Quanto ao osso cortical femoral, vimos que o tratamento com T3 aumentou o perímetro endosteal e a área medular nos animais Selv machos e fêmeas, mas não nos animais beta2-AR-/-, o que sugere que o T3 promove reabsorção óssea endosteal no osso cortical, em um mecanismo que depende da via de sinalização do beta2-AR. Vimos, ainda, que o tratamento com T3 causou reduções significativas na carga máxima, tenacidade, rigidez e resiliência do fêmur dos camundongos fêmeas Selv. Em contraste, nenhum desses parâmetros biomecânicos foi afetado pelo tratamento com T3 no fêmur das fêmeas KO, evidenciando, mais uma vez, uma resistência desses animais aos efeitos deletérios da tireotoxicose no tecido ósseo. Por outro lado, os camundongos machos Selv e KO se mostraram resistentes aos efeitos deletérios do tratamento com T3 sobre os parâmetros biomecânicos do fêmur, sugerindo a participação de fatores sexuais na interação do HT com o SNS para regular a morfofisiologia óssea. Em conjunto, os achados do presente estudo corroboram a hipótese de que o HT interage com o SNS através da via dos receptores beta2 adrenérgicos para regular a morfofisiologia óssea, especialmente em fêmeas e no osso cortical / Thyroid hormone (TH) is essential for bone development, maturation and metabolism, while the sympathetic nervous system (SNS) is also a potent regulator of bone remodeling. SNS has been shown to negatively regulate bone mass, acting via beta2-adrenergic (beta2-AR) receptors expressed in osteoblasts. Our group demonstrated that alpha2-adrenergic (alpha2-AR) receptors also mediate SNS actions in the skeleton and are expressed in osteoblasts, osteocytes, chondrocytes and osteoclasts. Considering that TH interacts with the SNS to regulate a series of physiological processes, and that the excess of TH and the activation of the SNS cause loss of bone mass, we hypothesize that there is interaction between TH and the SNS to regulate the bone mass. Studies of our group have supported this hypothesis, since mice with gene inactivation of alpha2-AR present resistance to the osteopenia induced by toxic doses of TH. Considering that the TH-SNS interaction in various tissues and/or organs depends on beta2-adrenergic signaling, the present study aimed to evaluate whether the interaction of TH with the SNS to regulate the bone morphophysiology involves beta2- AR. Therefore, we studied the effect of 10x and 20x the physiological dose of triiodothyronine (3.5ug or 7.0ug of T3/100g body mass/day, respectively), for 90 days, in the bone microarchitecture and biomechanical parameters of the femur mice with beta2-AR gene inactivation (beta2-AR-/-), and of their respective Wild-type (WT) controls, the FVB lineage mice. As expected, T3 treatment promoted deleterious effects on the trabecular microarchitecture of the WT females, while some of these effects were milder or nonexistent in beta2-AR-/- animals, revealing trabecular bone resistance of knockout (KO) animals to the deleterious effects of thyrotoxicosis. In contrast, the femoral microarchitecture of the male beta2-AR-/- mice was more sensitive to the deleterious effects of thyrotoxicosis, in relation to the respective WT animals. Regarding to the femoral cortical bone, we saw that T3 treatment increased the endosteal perimeter and the medullary area both male and female WT animals, but not in the beta2-AR-/- mice, suggesting that T3 promotes endosteal bone resorption in the cortical bone, in a mechanism that depends on the alpha2-AR signaling pathway. We also found that treatment with T3 caused significant reductions in the maximum load, tenacity, stiffness and resilience of femurs of the WT female mice. In contrast, none of these biomechanical parameters was affected by T3 treatment in the KO females, demonstrating again resistance of these animals to the deleterious effects of thyrotoxicosis on bone tissue. On the other hand, WT and KO male mice were resistant to the deleterious effects of T3 treatment on the biomechanical parameters of the femur, suggesting the participation of sexual factors in the interaction of HT with the SNS to regulate bone morphophysiology. Taken together, the findings of the present study corroborate the hypothesis that TH interacts with the SNS through the beta2 adrenergic receptor pathway to regulate bone morphophysiology, especially in females and cortical bone

Obesity-associated metabolic disorders are amongst the most prevalent causes of death worldwide. Understanding how obesity leads to the development of the Metabolic Syndrome (MetS) and cardiovascular disease (CVD) will enable the development of novel therapies that dissociate obesity from its cardiometabolic complications. Our laboratory views the functional capacity of white adipose tissue (WAT), the organ designed for safe lipid storage, as a key factor in the development of MetS and CVD. At a genetically-defined stage of the aberrant WAT expansion that occurs during obesity, adipocytes undergo a functional failure, resulting in an impaired control of serum free fatty acid (FFA) concentration. In such setting, FFAs and their metabolic derivatives accumulate in other organs, where they cause lipotoxicity, leading to the development of insulin resistance and CVD. We therefore aim to understand the pathophysiological mechanisms that induce adipocyte dysfunction. The past two decades of research have established the immune system as an important regulator of WAT function. The number of adipose tissue macrophages (ATMs), the most abundant immune cell type in WAT, increases during obesity, resulting in WAT inflammation. Multiple genetic and pharmacological intervention studies of murine models of obesity have assigned a causal link between ATM pro-inflammatory activation and WAT dysfunction. However, while the propagation of inflammation in ATMs during obesity has been extensively studied, factors triggering ATM inflammatory activation are less clear. Recently, our lab has observed lipid accumulation in the ATMs isolated from obese mice. Lipid-laden ATMs were pro-inflammatory, leading us to hypothesise that aberrant lipid build-up in macrophages triggers WAT inflammation during obesity. This thesis expands on the initial findings from our lab and describes two novel mechanisms that potentially contribute to lipid-induced inflammatory activation of ATMs. In chapter 3, the role of de novo phosphatidylcholine (PC) synthesis pathway during lipotoxicity in macrophages is addressed. The first part of the chapter demonstrates that lipotoxic environment increased de novo PC synthesis rate in bone marrow-derived macrophages (BMDMs) and ATMs, and that loss of rate-limiting enzyme in de novo PC synthesis pathway, CTP:phosphocholine cytidylyltransferase a (CCTa) diminished saturated FFA-induced inflammation in BMDMs. In the second part, I show that macrophage-specific CCTa deletion did not impact on the development of WAT inflammation or systemic insulin resistance, but had a minor benefitial effect on hepatic gene transcription during obesity. Chapter 4 develops on recent observations of interactions between sympathetic nerves and macrophages in WAT. In the first part of the chapter, I demonstrate that stimulating B2-adrenergic receptor (B2AR), the main receptor for sympathetic neurotransmitter norepinephrine in macrophages, enhanced intracellular triglyceride storage by up-regulating diacylglycerol O-acyltransferase 1 (Dgat1) gene expression in BMDMs. The second part of the chapter shows that macrophage-specific B2AR deletion did not modulate systemic glucose and lipid metabolism during obesity, but mice lacking B2ARs in macrophages demonstrated augmented hepatic glucose production on a chow diet. Furthermore, systemic B2AR blockade or macrophage-specific B2AR deletion in mice did not affect the thermogenic response to cold exposure. Chapter 5 includes the characterisation of B2AR stimulation-induced changes to the global cellular proteome of BMDMs, and a subsequent validation of the role of candidate transcription factors in regulating B2AR agonism-induced gene expression in BMDMs.

Introdução. Apneia obstrutiva do sono (AOS) provoca alterações autonômicas, tais como, hipersensibilidade quimiorreflexa e diminuição da sensibilidade barorreflexa e metaborreflexa muscular que contribuem para a hiperativação simpática em indivíduos que sofrem desse distúrbio. O objetivo desse estudo foi avaliar o efeito do treinamento físico no controle metaborreflexo da atividade nervosa simpática muscular (ANSM) em indivíduos com apneia obstrutiva do sono. Métodos. Todos os indivíduos triados para este estudo foram submetidos à polissonografia noturna convencional e avaliação da capacidade cardiorrespiratória em esforço. Quarenta e um adultos sedentários com AOS moderada e severa foram aleatoriamente divididos em grupo não-treinado (AOSNT, n=21) e treinado (AOST, n=20). A ANSM foi avaliada pela técnica microneurografia, o fluxo sanguíneo muscular (FSM) por pletismografia de oclusão venosa, a frequência cardíaca (FC) pelo eletrocardiograma e a pressão arterial (PA) método oscilométrico automático. Todas as variáveis fisiológicas foram avaliadas simultaneamente durante quatro minutos de repouso, seguido de três minutos de exercício isométrico de preensão manual a 30% da contração voluntária máxima, seguido por dois minutos de oclusão circulatória pós-exercício (OCPE) do segmento corporal previamente exercitado. A ativação seletiva do controle metaborrelfexo foi calculada pela diferença da ANSM do primeiro e segundo minutos da OCPE e a média da ANSM no repouso. Resultados. Os grupos foram semelhantes em gênero, idade, parâmetros antropométricos, parâmetros neurovasculares, parâmetros hemodinâmicos e parâmetros do sono. O treinamento físico reduziu a ANSM e aumentou o FSM no repouso. O treinamento físico diminuiu significativamente os níveis de ANSM e aumentou a resposta de FSM durante o exercício isométrico de preensão manual. O treinamento físico não alterou as respostas de frequência cardíaca e de PA durante o exercício isométrico. Em relação à sensibilidade metaborreflexa, o treinamento físico aumentou significativamente as respostas da ANSM no 1º minuto de OCPE. Não foram observadas diferenças significativas no FSM, FC e PA após o treinamento físico. Conclusões. O treinamento físico aumenta a sensibilidade metaborreflexa muscular em indivíduos com AOS, o que pode contribuir, pelo menos em parte, para a melhora no controle neurovascular durante o exercício nesses pacientes / Introduction. Obstructive sleep apnea (OSA) causes autonomic dysfunction, such as, chemoreflex hypersensitivity and baroreflex impairment and muscle metaboreflex decrease, which contribute to sympathetic overactivity in subjects who suffer from this disturbance. The purpose of this study was evaluated the effect of exercise training on muscle metaboreflex control of muscle sympathetic nerve activity (MSNA) in subjects with OSA. Methods. All individuals selected for this study underwent overnight polysomnography and cardiopulmonary exercise testing. Forty-one untrained adults with moderate to severe OSA were randomly divided into non-trained (AOSNT, n=21) and trained (AOST, n=20) groups. MSNA was assessed by microneurography technique, muscle blood flow (FBF) by venous occlusion plethysmography, heart rate (HR) by electrocardiography and blood pressure (BP) by noninvasively automated oscillometric device. All physiological variables were simultaneously assessed for 4 minutes at rest, followed by three minutes of isometric handgrip exercise at 30% of maximal voluntary contraction, followed by two minutes of postexercise regional circulatory arrest (PECA). Muscle metaboreflex sensitivity was calculated as the difference in MSNA at first and second minute of PECA and MSNA at rest period. Results. AOSNT and AOST groups were similarly in gender, age, anthropometric, neurovascular, hemodynamic and sleep parameters. Exercise training reduced MSNA and increased FBF. Exercise training significantly reduced MSNA levels and increased FBF responses during isometric handgrip exercise. Regarding the metaboreflex sensitivity, exercise training significantly increased MSNA response at 1st minute of PECA. There were no significantly difference in FBF, HR and BP after exercise training. Conclusions. Exercise training increases muscle metaboreflex sensitivity in patients with OSA, which seems to contribute, at least in part, to the improvement in neurovascular control during exercise in these patients

Les anomalies du système nerveux sympathique (SNS) contribuent au développement de certaines pathologies cardiovasculaires comme l'insuffisance cardiaque (IC) et les cardiomyopathies de stress. Ces anomalies impliquent une activation persistante, défavorable du SNS dans l'IC et une activation sympathique épisodique dans les cardiomyopathies de stress. Le rôle du SNS au cours des cardiopathies valvulaires reste quand à lui encore mal connu. Notre travail de thèse avait pour objectif d'analyser par microneurographie l'activité du SNS et sa modulation par les arcs réflexes physiologiques, au cours de l'IC avec ou sans comorbidités (notamment l'anémie, l'insuffisance rénale) ainsi qu'au cours des cardiomyopathies de stress et de la sténose aortique. L'hyperactivité du SNS participe à l'initiation et à la progression de l'IC et constitue un marqueur pronostique mais aussi une cible thérapeutique. Les mécanismes fondamentaux qui sous-tendent l'activation du SNS au cours de l'IC restent encore incertains. Une hypothèse engloberait une diminution des réflexes inhibiteurs, comme le baroréflexe artériel périphérique et une augmentation des réflexes excitateurs, comme le chémoréflexe artériel périphérique. Avec notre premier travail nous rapportons que l'augmentation de l'activité du chémoréflexe périphérique diminue directement la fonction du baroréflexe artériel chez les patients IC et que cette interaction contribue à l'hyperactivité sympathique. Notre équipe avait déjà démontré qu'au cours de l'IC, l'insuffisance rénale (IR) et l'anémie contribuent à l'augmentation de l'activité du SNS. Bien que la dysfonction rénale et l'anémie aient été largement étudiées séparément dans l'IC, des données épidémiologiques suggèrent également que l'IR peut coexister avec l'anémie chez les patients atteints d'IC dans ce qu'on désigne par le "syndrome d'anémie cardio-rénale". Nous avons démontré que ce syndrome au cours de l'IC est associé à une hyperactivité sympathique médiée à la fois par une activation tonique du chémoréflexe périphérique et une atténuation du baroréflexe artériel. Le syndrome du Tako Tsubo est une cardiomyopathie de stress caractérisée par une insuffisance ventriculaire gauche aiguë réversible. La physiopathologie exacte reste inconnue, mais l'hyperactivation sympathique semble jouer un rôle fondamental. Nous avons démontré par microneurographie la présence d'une hyperactivation du SNS dans la phase subaiguë de la maladie associée à une altération du baroréflexe périphérique. La sténose aortique (SA) est, dans les pays développés, la plus fréquente de toutes les maladies cardiaques valvulaires. Le remplacement valvulaire aortique transcathéter (TAVI) est une option thérapeutique émergente chez les patients avec une SA sévère symptomatique à haut risque chirurgical. La SA est associée à une morbi-mortalité cardiovasculaire accrue. Nous avons souhaité apprécier si au cours de la SA il existait une hyperactivité du SNS qui pouvait contribuer à expliquer le pronostic réservé des patients et être la cible du TAVI. Nous avons montré que les patients atteints de SA ont une activité du SNS augmentée et qui est associée à une diminution du gain du baroréflexe périphérique. Le TAVI normalise ces paramètres. Au total, ce travail de thèse a permis d'identifier de nouveaux mécanismes contribuant à l'hyperactivité du tonus sympathique au cours de l'insuffisance cardiaque, de la sténose aortique et de la cardiomyopathie du Tako Tsubo. L'hyperactivité du SNS jouant un rôle critique dans l'insuffisance cardiaque, la connaissance des mécanismes physiopathologiques qui la sous-tendent pourrait permettre l'identification et/ou la validation de nouvelles stratégies pour son traitement. / Sympathetic nervous system (SNS) abnormalities contribute to the development of some cardiovascular diseases such as heart failure (HF) and stress cardiomyopathies. These abnormalities involve persistent, adverse activation of SNS in HF and episodic sympathetic activation in stress cardiomyopathies. Less is still known about the role of SNS in valvular heart diseases. Our PhD work had as a purpose to analyse, by microneurography, the activity of SNS and its modulation by physiological reflex arcs, during HF, with and without comorbidities (including anemia and kidney failure), in stress cardiomyopathies and during aortic stenosis. SNS hyperactivity participates in the initiation and progression of HF being also a prognostic marker and a therapeutic target. The fundamental mechanisms underlying the activation of SNS in HF remain uncertain. One hypothesis would include a decrease in inhibitory reflexes activity, such as peripheral arterial baroreflex and an increase in excitatory reflexes activity, such as peripheral arterial chemoreflex. With our first work we report that the increased activity of peripheral chemoreflex directly decreases the arterial baroreflex function in HF patients and that this interaction contributes to sympathetic hyperactivity. Our team had already shown that during HF, renal dysfunction and anemia contribute to the increased activity of SNS. Although renal dysfunction and anemia have been widely studied separately in HF, epidemiological data also suggest that renal impairment can coexist with anemia in HF patients in the so called "cardio-renal anemia syndrome". We demonstrated that this syndrome during HF is associated with elevated sympathetic activity mediated by both tonic peripheral chemoreflex activation and arterial baroreflex impairment.The Tako Tsubo (TTC) is a stress cardiomyopathy characterized by acute reversible left ventricular failure. The exact pathophysiology remains unknown but sympathetic hyperactivation seems to play a fundamental role. We reported by microneurography the presence of SNS hyperactivation in the subacute phase of the disease associated with impairment in arterial baroreflex.In developed countries, aortic stenosis (AS) is the most prevalent of all valvular heart diseases. Transcatheter aortic valve implantation (TAVI) is an emerging therapeutic option in symptomatic patients with severe AS at high surgical risk. AS is associated with increased cardiovascular morbidity and mortality. We wanted to assess whether in AS sympathetic hyperactivity existed that could help to explain the poor prognosis of these patients and be the target of TAVI. We have shown that AS patients have an increased SNS activity that is associated with reduced peripheral baroreflex gain. The TAVI normalizes these parameters.On the whole this PhD work identified new mechanisms that contribute to SNS hyperactivity in heart failure, aortic stenosis and Tako Tsubo cardiomyopathy. Since SNS hyperactivity plays a critical role in heart failure, knowledge of the pathophysiological mechanisms that underlie it could allow identification and/or validation of new strategies for its treatment.

Thesis (Ph.D. (Electronical Engineering))--North-West University, Potchefstroom Campus, 2008.

Subjects participating in magnetic resonance imaging (MRI) examinations regularly report anxiety and stress related reactions. This may result in impaired data quality and premature termination of scans. Moreover, cognitive functions and neural substrates can be altered by stress. While prior studies investigated pre–post scan differences in stress reactions only, the present study provides an in-depth analysis of mood changes and hormonal fluctuations during the time course of a typical fMRI session. Thirty-nine subjects participated in the study. Subjective mood, salivary alpha-amylase (sAA) and cortisol were assessed at six time points during the lab visit. Associations between hormonal data and neural correlates of a visual detection task were observed using a region of interest approach applied to the thalamic region. Mood and hormonal levels changed significantly during the experiment. Subjects were most nervous immediately after entering the scanner. SAA was significantly elevated after MRI preparation. A subgroup of n = 5 (12.8%) subjects showed pronounced cortisol responses exceeding 2.5 nmol/l. Preliminary fMRI data revealed an association between sAA levels and left thalamic activity during the first half of the experiment that disappeared during the second half. No significant correlation between cortisol and thalamic activity was observed. Results indicate that an fMRI experiment may elicit subjective and neuroendocrine stress reactions that can influence functional activation patterns.

The central nervous system is largely responsible for receiving sensory information from the environment and determining motor output. Yet, centrally-derived behavior and sensation depends on the optimal maintenance of the cells, tissues, and organs that feed and support these functions. Most of visceral regulation occurs without conscious oversight, making the spinal cord a key site for integration and control. How the spinal cord modulates output to our organs, or sensory information from them, is poorly understood. The overall aim of this dissertation was to better understand spinal processing of both visceral sensory information to and sympathetic output from the spinal cord. I first established and validated a HB9-GFP transgenic mouse model that unambiguously identified sympathetic preganglionic neurons (SPNs), the spinal output neurons for the sympathetic nervous system. Using this model, I investigated the electrophysiological similarities and diversity of SPNs, and compared their active and passive membrane properties to those in other animal models. My results indicate that while many of the same characteristics are shared, SPNs are a heterogeneous group that can be differentiated based on their electrophysiological properties. Since descending monoaminergic pathways have particularly dense projections to sympathetic regions of the spinal cord, I next examined the modulatory role that the monoamines have on spinal sympathetic output. While each neuromodulator tested had a unique signature of action, serotonin and norepinephrine appeared to increase the excitability of individual SPNs, while dopamine had more mixed actions. Since many autonomic reflexes are integrated by the spinal cord, I also questioned whether these reflexes would be similarly modulated. I therefore developed a novel in vitro spinal cord and sympathetic chain preparation, which allowed for the investigation of visceral afferent-mediated reflexes and their neuromodulation by monoamines. This preparation exposed a dichotomy of action, where sympathetic and somatic motor output is generally enhanced by the monoamines, but reflexes mediated by visceral input are depressed. Utilizing the spinal cord and sympathetic chain preparation, I also investigated how the spinal cord modulates visceral sensory information. One of the most powerful means of selectively inhibiting afferent information from reaching the spinal cord is presynaptic inhibition. I hypothesized that both spinal visceral afferents and descending monoaminergic systems would depress transmission of visceral afferents to the spinal cord. My results demonstrated that activity in spinal visceral afferents can lead to spinally generated presynaptic inhibition, and that in addition to depressing synaptic transmission to the spinal cord, the monoamines also depress the intrinsic circuitry that generates this activity-dependent presynaptic inhibition. Taken together, my results indicate that descending monoaminergic pathways act to limit the amount of visceral sensory information reaching the central nervous system and increase sympathetic output, resulting in an uncoupling of output from visceral sensory input and transitioning to a feed-forward, sympathetically dominant control strategy. This combination offers complex modulatory strategies for descending systems.