O desenvolvimento de insuficiência cardíaca após infarto agudo do miocárdio (IAM) está intimamente associado com alterações profundas na geometria, estrutura e função cardíaca, conhecido por \"remodelamento ventricular\". Um crescente número de evidências sugere que uma resposta inflamatória acentuada ou prolongada pós-infarto resulta em um remodelamento patológico, comprometendo a função ventricular esquerda que se configura como um dos principais preditores de mortalidade após infarto agudo do miocárdio. Estudos recentes têm investigado a modulação da inflamação pelo sistema autonômico, principalmente por meio da estimulação vagal (elétrica e medicamentosa), possibilitando uma nova abordagem terapêutica para a modulação da inflamação no IAM. Nesse sentido, o presente estudo avaliou o efeito da estimulação elétrica dos aferentes barorreceptores na modulação autonômica e o possível efeito da mesma na modulação da resposta inflamatória pós infarto agudo do miocárdio em ratos. Os animais foram divididos em 3 grupos: Grupo Sham (SHAM): 5 animais não infartados sem tratamento; Grupo infartado não estimulado (IAM): 10 animais infartados sem tratamento e Grupo infartado e estimulado (IAM+EST): 10 animais infartados tratados com estimulação elétrica do nervo depressor aórtico (NDA). Foram realizadas cinco sessões de 30 min de estimulação do NDA entre os dias 1 e 3 pós IAM. A corrente elétrica aplicada foi capaz de reduzir a PAM durante o período da estimulação em mais de 30 mmHg e não houve diferença de resposta ao estímulo elétrico quando comparados os três dias de sessões. A relação LF/HF, que reflete o equilíbrio simpático-vagal global, apresentou-se elevada no grupo IAM (0,36±0,066) quando comparada aos grupos SHAM (0,18±0,015) e IAM+EST (0,16±0,022). Dessa forma, foi possível observar que os parâmetros HF e LF, importantes indicadores da função autonômica, foram semelhantes entre os grupos SHAM e IAM+EST, demonstrando efeito benéfico da estimulação elétrica do NDA na manutenção da modulação autonômica. A sensibilidade barorreflexa (BPM/mmHg) ficou diminuída no grupo IAM (ITR=1,44±0,20; IBR=-0,82±0,15) quando comparado com o grupo SHAM (ITR=2,79±0,58; IBR=-1,10±0,43). O grupo IAM+EST apresentou uma melhor sensibilidade barorreflexa induzida (ITR=3,40±0,18; IBR=-3,32±0,43) e espontânea em relação ao grupo IAM, sendo semelhante ou maior quando comparado ao grupo SHAM. A função cardíaca avaliada por meio da ecocardiografia revelou uma melhor função sistólica no grupo IAM+EST (Fração de Ejeção (%)=53±3,8) quando comparado ao grupo IAM (Fração de Ejeção (%)=43±2,0). Analisando o percentual de colágeno na lesão, o grupo IAM apresentou valores significativamente maior (14,24±1,75) quando comparado com os grupos SHAM (0,85±0,04) e IAM+EST (5,35±0,46). A análise imuno-histoquímica mostrou uma maior concentração (número de células por campo) de macrófagos M1 no grupo IAM (131,13±11,75) em relação ao grupo IAM+EST (95,46±16,27) e um maior número de macrófagos M2 no grupo IAM+EST (143,69±15,23) quando comparado com o grupo IAM (96,38±22,35). Marcadores de estresse oxidativo indicaram um maior conteúdo carbonílico de proteínas (nmol/mg) no grupo IAM (2,24±0,09) em relação ao grupo IAM+EST (1,96±0,07). O grupo IAM+EST apresentou uma maior atividade da enzima SOD (USOD/mg) (5,55±0,04) quando comparado ao grupo IAM (5,16±0,06). Esses achados sugerem que a estimulação elétrica do NDA foi capaz de modular a resposta inflamatória pós IAM levando a um remodelamento menos patológico e melhorando os índices da função cardíaca avaliados por ecocardiografia, apresentando-se como uma nova abordagem terapêutica na prevenção do desenvolvimento de insuficiência cardíaca pós IAM / The development of heart failure following acute myocardial infarction (AMI) is closely associated with deep changes in cardiac geometry, structure and function, known as \"ventricular remodeling\". A growing body of evidence suggests that a marked or prolonged post-infarction inflammatory response leads to a pathologic remodeling, impairing the left ventricle function that is the most important predictor of heart failure development. Recent studies have investigated the modulation of inflammation by the autonomic system, mainly by electrical or drug vagal stimulation, making possible a new therapeutic approach for the modulation of the inflammation in the AMI. Our study evaluated the effect of the electrical stimulation of the aortic depressor nerve (ADN) on autonomic modulation and the possible effect on inflammatory response post AMI. The animals were divided into 3 groups: Sham Group (SHAM) - 5 animals not infarcted without treatment; Infarcted group (AMI) - 10 infarcted animals without treatment; Infarcted and stimulated group (AMI+EST) - 10 infarcted animals treated with electrical stimulation of the ADN. Five sessions of 30 min of ADN stimulation were performed between days 1 and 3 post AMI. The electric current was able to reduce the median arterial pressure during the stimulation period by more than 30 mmHg in all sessions. The LF/HF ratio, which reflects the global sympathetic-vagal balance, was elevated in the AMI group (0.36±0.066) when compared to SHAM (0.18±0.015) and AMI+EST (0.16±0.022). Thus, it was possible to observe that the HF and LF parameters, important indicators of autonomic function, were similar between the SHAM and AMI+EST groups, demonstrating the beneficial effect of ADN electrical stimulation on the maintenance of autonomic modulation. The baroreflex sensitivity (BPM/mmHg) was reduced in the IAM group (ITR=1.44±0.20; IBR=-0.82±0.15) when compared to the SHAM group (ITR=2.79±0.58; IBR=1.10±0.43). The IAM+EST group presented higher induced baroreflex sensitivity (ITR=3.40±0.18; IBR=-3.32±0.43) and spontaneous compared to the AMI group, being similar or higher when compared to the SHAM group. Cardiac function assessed by echocardiography revealed a better systolic function in the AMI+EST group (Ejection Fraction %=53±3,8) when compared to the AMI group (Ejection Fraction %=43±2,0). Regarding collagen deposition in the lesion (% of collagen), the AMI group presented significantly higher values (14.24±1.75) when compared to SHAM (0.85±0.04) and AMI+EST (5.35±0, 46). Immunohistochemical analysis showed a higher concentration (cells per field) of M1 macrophages in the AMI group (131.13±11.75) in comparison to the AMI+EST group (95.46±16.27) and a higher number of M2 macrophages in the AMI+EST group (143.69±15.23) when compared to the AMI group (96.38±22.35). Oxidative stress markers indicated a higher carbonyl content of proteins (nmol/mg) in the AMI group (2.24±0.09) in comparison to the AMI+EST group (1.96±0.07). The IAM+EST group had a higher activity of the superoxide dismutase enzyme (USOD/mg) (5.55±0.04) when compared to the AMI group (5.16±0.06). These findings suggest that the electrical stimulation of the ADN was able to modulate the inflammatory response post AMI, leading to a less pathological remodeling and improving the indexes of the cardiac function evaluated by echocardiography, presenting as a new therapeutic approach in the prevention of heart failure development after AMI

The neurophysiological pathways associated with beat-to-beat regulation of mean arterial pressure are well known. Less known are the control dynamics associated with short term maintained of arterial blood pressure about a homeostatic set point.The baroreflex (BRx), the most rapid and robust of neural reflexes within the autonomic nervous system, is a negative feedback controller that monitors and regulates heart rate and blood pressure. By leveraging the parasympathetic and sympathetic divisions of the autonomic nervous system, the BRx can change blood pressure within a single heart beat. To better understand these controller dynamics, a classic BRx reflexogenic experimental preparation was carried out. This thesis reconfirmed previous observations of an electrically-evoked sexually-dimorphic peak depressor response in the BRx of Sprague-Dawley rats and verified that these functional reflexogenic differences carry over to sustained electrical paradigms. Further, it uncovered interesting recovery dynamics in both blood pressure and heart rate. The rat aortic depressor nerve was used as an experimental target for electrical activation of the parasympathetic-mediated reduction in mean arterial pressure. The duration, frequency, and patterning of stimulation were explored, with emphasis on differences between sexes. By measuring the normalized percent decrease in mean arterial pressure as well as the differences in beats per minute during rest and during stimulation,the null hypothesis was rejected.<br>

by Yeung Yuk-Ching. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 119-129). / Abstracts in English and Chinese. / Abstract in English --- p.ii / Abstract in Chinese --- p.v / Glossary --- p.viii / Acknowledgements --- p.x / Publications Arising From this Thesis --- p.xii / List of Tables --- p.xviii / List of Figures --- p.xix / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Definition of Heart Rate Variability --- p.1 / Chapter 1.2 --- Physiology --- p.1 / Chapter 1.2.1 --- Review of Autonomic Nervous System and Influence of Heart Rate --- p.1 / Chapter 1.2.2 --- The Role of Baroreceptors in the Control of Circulation --- p.4 / Chapter 1.2.3 --- The Control and Physiological Importance of Heart Rate --- p.7 / Chapter 1.2.3.1 --- Normal Heart Rate --- p.7 / Chapter 1.2.3.2 --- Autonomic Control of Heart Rate --- p.8 / Chapter 1.2.3.2.1 --- Sympathetic Effects --- p.8 / Chapter 1.2.3.2.2 --- Vagal Effects --- p.8 / Chapter 1.2.3.3 --- Reflexes Influencing Heart Rate --- p.9 / Chapter 1.2.3.3.1 --- Baroreceptors --- p.10 / Chapter 1.2.3.3.2 --- Chemoreceptors --- p.10 / Chapter 1.2.3.3.3 --- Atrial Receptors --- p.11 / Chapter 1.2.3.3.4 --- Coronary Chemoreflex --- p.11 / Chapter 1.2.3.3.5 --- Other Reflexes --- p.12 / Chapter 1.2.3.4 --- Influence of Complex Events on Heart Rate --- p.12 / Chapter 1.2.3.4.1 --- Respiratory Influence --- p.12 / Chapter 1.2.3.4.2 --- Effects of Decreases in Venous Return --- p.13 / Chapter 1.2.3.4.3 --- Exercise --- p.13 / Chapter 1.2.3.5 --- Physiological Importance of Heart Rate --- p.14 / Chapter 1.3 --- Spectral Analysis of Blood Pressure and Heart Rate Variability in Evaluating Cardiovascular Regulation --- p.14 / Chapter 1.4 --- Clinical Relevance --- p.15 / Chapter 1.4.1 --- Increased Sympathetic Activity --- p.15 / Chapter 1.4.2 --- Reduced Parasympathetic Activity --- p.15 / Chapter 1.4.3 --- Low Heart Rate Variability --- p.16 / Chapter 1.4.4 --- Depressed Baroreflex Sensitivity --- p.17 / Chapter 1.4.5 --- Prognostic Value of Heart Rate Variability in Disease States --- p.17 / Chapter 1.4.6 --- Abnormality of Autonomic Nervous System in Heart Failure --- p.17 / Chapter 2 --- METHODS FOR ASSESSING HEART RATE VARIABILITY --- p.20 / Chapter 2.1 --- Time Domain Analysis of Heart Rate Variability --- p.20 / Chapter 2.1.1 --- Statistical Methods --- p.21 / Chapter 2.1.2 --- Geometric Methods --- p.22 / Chapter 2.2 --- Spectral Analysis of Heart Rate Variability --- p.23 / Chapter 2.3 --- "Nonlinear Indices (fractal, entropy, chaos theory)" --- p.27 / Chapter 3 --- HEART FAILURE --- p.28 / Chapter 3.1 --- Heart Rate Variability in Heart Failure --- p.28 / Chapter 3.2 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability Analysis in Heart Failure --- p.34 / Chapter 3.3 --- Effect of Respiratory Rates on Baroreceptor Function in Heart Failure --- p.34 / Chapter 3.4 --- Effect of Treatment on Heart Rate Variability in Heart Failure Patients --- p.35 / Chapter 4 --- AIMS --- p.39 / Chapter 4.1 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability --- p.39 / Chapter 4.2 --- Effect of Slow Breathing --- p.39 / Chapter 4.3 --- Effect of Therapeutic Interventions in Chronic Heart Failure --- p.39 / Chapter 4.3.1 --- A Comparison of Celiprolol with Metoprolol --- p.39 / Chapter 4.3.2 --- A Comparison of Carvedilol with Metoprolol --- p.40 / Chapter 5 --- STUDIES --- p.41 / Chapter 5.1 --- Impact of Changes in Respiratory Frequency and Posture on Power Spectral Analysis of Heart Rate and Systolic Blood Pressure Variability in Normal Subjects and Patients with Heart Failure --- p.41 / Chapter 5.1.1 --- Subjects --- p.41 / Chapter 5.1.2 --- Recording Technique and Protocol --- p.42 / Chapter 5.1.3 --- Signal Acquisition --- p.42 / Chapter 5.1.4 --- Power Spectral Analysis --- p.43 / Chapter 5.1.5 --- Statistical Analysis --- p.46 / Chapter 5.1.6 --- Results --- p.46 / Chapter 5.1.7 --- Discussion --- p.52 / Chapter 5.1.8 --- Summary --- p.56 / Chapter 5.2 --- Slow Breathing Increases Arterial Baroreflex Sensitivityin Patients with Chronic Heart Failure --- p.57 / Chapter 5.2.1 --- Subjects --- p.57 / Chapter 5.2.2 --- Assessment of Baroreflex Sensitivity --- p.57 / Chapter 5.2.3 --- Statistical Analysis --- p.58 / Chapter 5.2.4 --- Results --- p.59 / Chapter 5.2.5 --- Discussion --- p.62 / Chapter 5.2.6 --- Summary --- p.63 / Chapter 5.3 --- β-Blockers in Heart Failure: a Comparison of a Vasodilating β- Blocker with Metoprolol on Heart Rate Variability by 24 Hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.65 / Chapter 5.3.1 --- Trial Design --- p.65 / Chapter 5.3.2 --- Study Patients --- p.65 / Chapter 5.3.3 --- Study Measurements --- p.66 / Chapter 5.3.4 --- Statistical Analysis --- p.67 / Chapter 5.3.5 --- Results --- p.67 / Chapter 5.3.6 --- Discussion --- p.80 / Chapter 5.3.7 --- Summary --- p.81 / Chapter 5.4 --- Effect of β-Blockade on Baroreceptor and Autonomic Function in Heart Failure-Assessment by Short Term Spectral Analysis --- p.83 / Chapter 5.4.1 --- Trial Design and Study Patients --- p.83 / Chapter 5.4.2 --- Recording Technique and Protocol --- p.83 / Chapter 5.4.3 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.83 / Chapter 5.4.4 --- Reproducibility --- p.84 / Chapter 5.4.5 --- Statistical Analysis --- p.84 / Chapter 5.4.6 --- Results --- p.84 / Chapter 5.4.7 --- Discussion --- p.93 / Chapter 5.4.8 --- Summary --- p.97 / Chapter 5.5 --- β-Blockade in Heart Failure: A Comparison of Carvedilol with Metoprolol on HRV by 24 hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.98 / Chapter 5.5.1 --- Trial Design and Patient Demographics --- p.98 / Chapter 5.5.2 --- Study Measurements --- p.98 / Chapter 5.5.3 --- Statistical Analysis --- p.99 / Chapter 5.5.4 --- Results --- p.99 / Chapter 5.5.5 --- Discussion --- p.105 / Chapter 5.5.6 --- Conclusions --- p.107 / Chapter 5.6 --- Comparison of Carvedilol and Metoprolol on Baroreceptor Gain in Heart Failure by Short Term Spectral Analysis --- p.108 / Chapter 5.6.1 --- Study Design --- p.108 / Chapter 5.6.2 --- Study Patients --- p.108 / Chapter 5.6.3 --- Recording Technique and Protocol --- p.108 / Chapter 5.6.4 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.108 / Chapter 5.6.5 --- Statistical Analysis --- p.109 / Chapter 5.6.6 --- Results --- p.109 / Chapter 5.6.7 --- Discussion --- p.112 / Chapter 5.6.8 --- Summary --- p.112 / Chapter 6 --- "GENERAL DISCUSSION, LIMITATIONS & CONCLUSIONS" --- p.113 / Chapter 6.1 --- Discussion --- p.113 / Chapter 6.2 --- Conclusions --- p.117 / Chapter 7 --- REFERENCES --- p.119

INTRODUÇÃO: Prévios estudos demonstraram que o treinamento físico melhora o controle barorreflexo da freqüência cardíaca em ratos geneticamente hipertensos. Contudo, o efeito do treinamento físico no controle barorreflexo da atividade nervosa simpática e da freqüência cardíaca em pacientes com hipertensão não é conhecido. Desta forma, foram objetivos deste estudo testar as hipóteses de que o treinamento físico poderia melhorar o controle barorreflexo da atividade nervosa simpática muscular (ANSM) e da freqüência cardíaca em pacientes hipertensos, e que o treinamento físico poderia reduzir os níveis de ANSM e pressão arterial nesses pacientes. MÉTODOS: Vinte pacientes hipertensos, sem uso de medicamentos, foram subdivididos em dois grupos: grupo hipertenso treinado (n=11, idade: 46±2 anos) e grupo hipertenso sedentário (n=9, idade: 42±2 anos). Um grupo de indivíduos normotensos pareados por idade (n=12, idade: 42±2 anos) também foi estudado. O controle barorreflexo da ANSM (microneurografia) e da freqüência cardíaca (ECG) foram avaliados pelo método de infusão venosa de doses crescentes de fenilefrina e nitroprussiato de sódio, e analisados pela equação de regressão linear. A pressão arterial foi medida batimento a batimento pelo método oscilométrico automático. O treinamento físico consistiu de três sessões por semana, com duração de 60 minutos cada, por um período de 4 meses. RESULTADOS: Antes das intervenções, em condições basais, os níveis de pressão arterial e ANSM foram semelhantes entre os grupos hipertensos, mas significativamente aumentados quando comparados com o grupo normotenso. O controle barorreflexo da ANSM e da freqüência cardíaca foi semelhante entre os grupos hipertensos, mas significativamente diminuídos quando comparados ao grupo normotenso. Nos pacientes hipertensos, o treinamento físico reduziu os níveis de pressão arterial (P<0,01) e ANSM (P<0,01), e significativamente aumentou o controle barorreflexo da ANSM e da freqüência cardíaca durante aumentos (P<0,01 e P<0,03, respectivamente) e diminuições (P<0,01 e P<0,03, respectivamente) na pressão arterial. Além disso, após o treinamento físico, não foi mais observada, a diferença inicial na sensibilidade barorreflexa arterial entre os pacientes hipertensos e indivíduos normotensos. Nenhuma mudança significativa foi observada no grupo hipertenso sedentário. CONCLUSÔES: O treinamento físico restaura o controle barorreflexo da ANSM e da freqüência cardíaca em pacientes hipertensos. Adicionalmente, o treinamento físico normaliza os níveis da ANSM e reduz os níveis de pressão arterial nesses pacientes. / Previous studies demonstrated that exercise training improves the baroreflex control of heart rate in spontaneously hypertensive rats. However, the effects of exercise training on baroreflex control of sympathetic nerve activity and heart rate in patients with hypertension are unknown. We hypothesized that exercise training would improve baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate in hypertensive patients and that exercise training would reduce MSNA and blood pressure in these patients. Twenty never-treated hypertensive patients were randomly divided into 2 groups: exercise-trained (n=11, age: 46±2 years) and untrained (n=9, age: 42±2 years) patients. An age-matched normotensive exercise-trained group (n=12, age: 42±2 years) was also studied. Baroreflex control of MSNA (microneurography) and heart rate (ECG) was assessed by stepwise intravenous infusions of phenylephrine and sodium nitroprusside and analyzed by linear regression. Blood pressure was monitored on a beat-to-beat basis. Exercise training consisted of three 60-minute exercise sessions per week for 4 months. Under baseline conditions (before training), blood pressure and MSNA were similar between hypertensive groups but significantly increased when compared with the normotensive group. Baroreflex control of MSNA and heart rate was similar between hypertensive groups but significantly decreased when compared with the normotensive group. In hypertensive patients, exercise training significantly reduced blood pressure (P<0.01) and MSNA (P<0.01) levels and significantly increased baroreflex control of MSNA and heart rate during increases (P<0.01 and P<0.03, respectively) and decreases (P<0.01 and P<0.03, respectively) in blood pressure. The baseline (preintervention) difference in baroreflex sensitivity between hypertensive patients and normotensive individuals was no longer observed after exercise training. No significant changes were found in untrained hypertensive patients. In conclusion, exercise training restores the baroreflex control of MSNA and heart rate in hypertensive patients. In addition, exercise training normalizes MSNA and decreases blood pressure levels in these patients.

O organismo está sujeito a diversos estímulos estressantes que afetam processos fisiológicos. Embora as alterações de pressão arterial e frequência cardíaca sejam comuns frente à exposição ao estresse, elas podem variar de acordo com os diferentes estressores, tipo de estresse, duração, frequência e intensidade do estímulo aversivo utilizado. O estresse é capaz de alterar em animais a regulação autonômica e reflexos respiratórios, como a atividade do barorreflexo, quimiorreflexo e variabilidade da frequência cardíaca. Além disso, o estresse também é capaz de alterar o comportamento, que são melhorados com o uso de antidepressivos, como a fluoxetina. Nesse sentido, o presente estudo teve como objetivo avaliar se o mesmo tipo de estressor (homotípico) ou diferentes estressores (heterotípico) modulam as respostas cardiovasculares e respiratórias ativadas pelo barorreflexo e quimiorreflexo, respectivamente, além da variabilidade da frequência cardíaca. Além disso, verificar se o tratamento com crônico ou agudo com fluoxetina é capaz de prevenir as alterações ocasionas pelo estresse crônico. Para isto, foram utilizados ratos Wistar, pesando entre 350 a 500g que foram submetidos ao estresse crônico repetido (ECR, homotípico) ou estresse crônico variado (ECV, heterotípico) durante 14 dias consecutivos. Sete dias antes do início dos protocolos de estresse crônico foi iniciado o tratamento com fluoxetina agudo, onde os animais só receberam fluoxetina no dia do experimento ou crônico, em que os animais receberam fluoxetina todos os dias até o dia do experimento, completando 21 dias de tratamento. Os animais ECR e ECV apresentaram uma menor preferência por sacarose, demonstrando comportamento de anedonia, que foi prevenida com o tratamento crônico com fluoxetina. Adicionalmente, ambos os protocolos de estresse demonstraram uma tendência ao aumento nos níveis de corticosterona basais, no entanto os resultados não foram significativos. Ambos os grupos de estresse crônico também apresentaram uma diminuição no peso corporal, entretanto os animais do grupo controle e ECR tratados cronicamente com fluoxetina apresentaram uma diminuição pronunciada do peso corporal quando comparados com seus controles. O ECR aumentou os componentes taquicárdico e bradicárdico do barorreflexo, adicionalmente, o tratamento crônico com fluoxetina preveniu o aumento dos componentes simpático e parassimpático do barorreflexo, porém induziu a redução desses componentes no grupo controle. O tratamento agudo com fluoxetina diminuiu apenas o componente bradicárdico de todos os grupos estressados e controle. Ambos os protocolos de estresse crônico promoveram uma diminuição na modulação simpato-vagal e no ganho do barorreflexo espontâneo, indicando uma hiperatividade simpática, que foi reduzida pelo tratamento crônico e agudo com fluoxetina. Entretanto o tratamento agudo aumentou o número de sequências barorreflexas do tipo UP (aumentos sucessivos de pressão arterial). O ECR e ECV também atenuaram a magnitude da resposta pressora frente à ativação do quimiorreflexo, que foi prevenida com ambos os tratamentos com fluoxetina. Os protocolos de estresse diminuíram os parâmetros basais de ventilação minuto (VE), volume corrente (VT) e aumentou a frequência respiratória (fR), além de aumentar a magnitude da frequência respiratória frente (?fR) a ativação do quimiorreflexo. No mesmo sentido, os tratamentos com fluoxetina aumentaram a magnitude da ?fR, porém apenas o tratamento crônico com fluoxetina preveniu as alterações no parâmetros basais respiratórios de VT e fR. Os achados do presente estudo demonstram que o estresse crônico provoca comportamento do tipo depressivo, além de alterar as respostas autonômicas de barorreflexo e quimiorreflexo e variabilidade cardiocirculatória (PAS e IP), o que pode desencadear patologias no sistema cardiovascular e respiratório. Adicionalmente, nosso trabalho é um dos primeiros a demonstrar que o tratamento crônico com fluoxetina previne a maioria das alterações ocasionadas pelo estresse crônico frente a essas alterações autonômicas / The body is submitted to various stressful stimuli that may affect many physiological processes. Although blood pressure and heart rate oscilations are common during exposure to stress, they can vary according to the different stressors type, duration, frequency and intensity of the aversive stimulus. Several studies suggest that stress can alter the autonomic regulation and respiratory reflexes, such as the baroreflex, chemoreflex activities and heart rate variability. In addition to cardiovascular disorders, chronic stress can also induce behavioral changes that are similar to depression in humans and are reversed by antidepressants, such as fluoxetine. In this way, the present study aimed to assess whether the same type of stressor (homotypic) or different stressors (heterotypic) are able to alter cardiovascular and respiratory responses activated by baroreflex and chemoreflex, respectively. We also aimed to verify the heart rate variability and if the chronic treatment with fluoxetine is able to prevent occasional alterations by chronic stress. For this purpose, male Wistar rats were used, weighing between 350 -500g. They underwent repeated chronic stress (RCS, homotypic) or unpredictable chronic stress (UCS, heterotypic) for 14 consecutive days. Seven days before starting the stress protocols was started the chronic or acute treatment with fluoxetine, until the day of the experiment, completing 21 days of treatment. The RCS and UCS animals have a lower preference for sucrose, demonstrating anhedonia behavior, which was prevented by chronic treatment with fluoxetine. Additionally, both stress protocols showed a tendency to increase basal levels of corticosterone, but the results were not significant. Our results showed that both stress groups have a decrease in body weight, however the control animals and RCS chronically treated with fluoxetine showed a marked decrease in body weight compared to their controls. The RCS increased tachycardia and bradycardia baroreflex components, however chronic treatment with fluoxetine prevented the increase of the sympathetic and parasympathetic components of the baroreflex, but induced a reduction of these components in the control group. Acute treatment with fluoxetine only decreased bradycardic component of all stressed and control groups. Both chronic stress protocols showed a decrease in sympathovagal modulation and spontaneous baroreflex gain, indicating a sympathetic hyperactivity that was decreased by chronic and acute treatment with fluoxetine. Acute fluoxetine treatment increased baroreflexs sequences up. The RCS and UCS also attenuated the magnitude of pressor response, which was prevented by both treatments with fluoxetine. Stress protocols decreased the baseline parameters of VE, VT and increased fR, and increase the magnitude of the respiratory frequency (?fR) by chemoreflex activation. Both treatment with fluoxetine further increased the magnitude of ?fR, but only chronic treatment with fluoxetine prevented the alterations in respiratory baseline parameters VT and fR. The findings of this study demonstrate that chronic stress causes the depressive-like behavior, and change the autonomic responses of baroreflex and chemoreflex and cardiocirculatory variability (PAS and IP), which can trigger diseases in the cardiovascular and respiratory system. In addition, our work is one of the first to show that chronic treatment with fluoxetine prevents most of the changes caused by chronic stress face these autonomic changes

O organismo está sujeito a diversos estímulos estressantes que afetam processos fisiológicos. Embora as alterações de pressão arterial e frequência cardíaca sejam comuns frente à exposição ao estresse, elas podem variar de acordo com os diferentes estressores, tipo de estresse, duração, frequência e intensidade do estímulo aversivo utilizado. O estresse é capaz de alterar em animais a regulação autonômica e reflexos respiratórios, como a atividade do barorreflexo, quimiorreflexo e variabilidade da frequência cardíaca. Além disso, o estresse também é capaz de alterar o comportamento, que são melhorados com o uso de antidepressivos, como a fluoxetina. Nesse sentido, o presente estudo teve como objetivo avaliar se o mesmo tipo de estressor (homotípico) ou diferentes estressores (heterotípico) modulam as respostas cardiovasculares e respiratórias ativadas pelo barorreflexo e quimiorreflexo, respectivamente, além da variabilidade da frequência cardíaca. Além disso, verificar se o tratamento com crônico ou agudo com fluoxetina é capaz de prevenir as alterações ocasionas pelo estresse crônico. Para isto, foram utilizados ratos Wistar, pesando entre 350 a 500g que foram submetidos ao estresse crônico repetido (ECR, homotípico) ou estresse crônico variado (ECV, heterotípico) durante 14 dias consecutivos. Sete dias antes do início dos protocolos de estresse crônico foi iniciado o tratamento com fluoxetina agudo, onde os animais só receberam fluoxetina no dia do experimento ou crônico, em que os animais receberam fluoxetina todos os dias até o dia do experimento, completando 21 dias de tratamento. Os animais ECR e ECV apresentaram uma menor preferência por sacarose, demonstrando comportamento de anedonia, que foi prevenida com o tratamento crônico com fluoxetina. Adicionalmente, ambos os protocolos de estresse demonstraram uma tendência ao aumento nos níveis de corticosterona basais, no entanto os resultados não foram significativos. Ambos os grupos de estresse crônico também apresentaram uma diminuição no peso corporal, entretanto os animais do grupo controle e ECR tratados cronicamente com fluoxetina apresentaram uma diminuição pronunciada do peso corporal quando comparados com seus controles. O ECR aumentou os componentes taquicárdico e bradicárdico do barorreflexo, adicionalmente, o tratamento crônico com fluoxetina preveniu o aumento dos componentes simpático e parassimpático do barorreflexo, porém induziu a redução desses componentes no grupo controle. O tratamento agudo com fluoxetina diminuiu apenas o componente bradicárdico de todos os grupos estressados e controle. Ambos os protocolos de estresse crônico promoveram uma diminuição na modulação simpato-vagal e no ganho do barorreflexo espontâneo, indicando uma hiperatividade simpática, que foi reduzida pelo tratamento crônico e agudo com fluoxetina. Entretanto o tratamento agudo aumentou o número de sequências barorreflexas do tipo UP (aumentos sucessivos de pressão arterial). O ECR e ECV também atenuaram a magnitude da resposta pressora frente à ativação do quimiorreflexo, que foi prevenida com ambos os tratamentos com fluoxetina. Os protocolos de estresse diminuíram os parâmetros basais de ventilação minuto (VE), volume corrente (VT) e aumentou a frequência respiratória (fR), além de aumentar a magnitude da frequência respiratória frente (?fR) a ativação do quimiorreflexo. No mesmo sentido, os tratamentos com fluoxetina aumentaram a magnitude da ?fR, porém apenas o tratamento crônico com fluoxetina preveniu as alterações no parâmetros basais respiratórios de VT e fR. Os achados do presente estudo demonstram que o estresse crônico provoca comportamento do tipo depressivo, além de alterar as respostas autonômicas de barorreflexo e quimiorreflexo e variabilidade cardiocirculatória (PAS e IP), o que pode desencadear patologias no sistema cardiovascular e respiratório. Adicionalmente, nosso trabalho é um dos primeiros a demonstrar que o tratamento crônico com fluoxetina previne a maioria das alterações ocasionadas pelo estresse crônico frente a essas alterações autonômicas / The body is submitted to various stressful stimuli that may affect many physiological processes. Although blood pressure and heart rate oscilations are common during exposure to stress, they can vary according to the different stressors type, duration, frequency and intensity of the aversive stimulus. Several studies suggest that stress can alter the autonomic regulation and respiratory reflexes, such as the baroreflex, chemoreflex activities and heart rate variability. In addition to cardiovascular disorders, chronic stress can also induce behavioral changes that are similar to depression in humans and are reversed by antidepressants, such as fluoxetine. In this way, the present study aimed to assess whether the same type of stressor (homotypic) or different stressors (heterotypic) are able to alter cardiovascular and respiratory responses activated by baroreflex and chemoreflex, respectively. We also aimed to verify the heart rate variability and if the chronic treatment with fluoxetine is able to prevent occasional alterations by chronic stress. For this purpose, male Wistar rats were used, weighing between 350 -500g. They underwent repeated chronic stress (RCS, homotypic) or unpredictable chronic stress (UCS, heterotypic) for 14 consecutive days. Seven days before starting the stress protocols was started the chronic or acute treatment with fluoxetine, until the day of the experiment, completing 21 days of treatment. The RCS and UCS animals have a lower preference for sucrose, demonstrating anhedonia behavior, which was prevented by chronic treatment with fluoxetine. Additionally, both stress protocols showed a tendency to increase basal levels of corticosterone, but the results were not significant. Our results showed that both stress groups have a decrease in body weight, however the control animals and RCS chronically treated with fluoxetine showed a marked decrease in body weight compared to their controls. The RCS increased tachycardia and bradycardia baroreflex components, however chronic treatment with fluoxetine prevented the increase of the sympathetic and parasympathetic components of the baroreflex, but induced a reduction of these components in the control group. Acute treatment with fluoxetine only decreased bradycardic component of all stressed and control groups. Both chronic stress protocols showed a decrease in sympathovagal modulation and spontaneous baroreflex gain, indicating a sympathetic hyperactivity that was decreased by chronic and acute treatment with fluoxetine. Acute fluoxetine treatment increased baroreflexs sequences up. The RCS and UCS also attenuated the magnitude of pressor response, which was prevented by both treatments with fluoxetine. Stress protocols decreased the baseline parameters of VE, VT and increased fR, and increase the magnitude of the respiratory frequency (?fR) by chemoreflex activation. Both treatment with fluoxetine further increased the magnitude of ?fR, but only chronic treatment with fluoxetine prevented the alterations in respiratory baseline parameters VT and fR. The findings of this study demonstrate that chronic stress causes the depressive-like behavior, and change the autonomic responses of baroreflex and chemoreflex and cardiocirculatory variability (PAS and IP), which can trigger diseases in the cardiovascular and respiratory system. In addition, our work is one of the first to show that chronic treatment with fluoxetine prevents most of the changes caused by chronic stress face these autonomic changes

Introdução: A morte súbita é a principal causa de morte na doença de Chagas, correspondendo de 55 a 65% dos casos. Observa-se que parte destas, ocorre em pacientes com função ventricular esquerda (FEVE) preservada, levando a acreditar que fatores desestabilizadores do substrato arritmogênico exercem um importante papel nestes eventos. Evidências já demonstraram a depressão parassimpática como fator contribuinte na gênese de arritmias diversas em presença de cardiopatia isquêmica. Assim, insiste-se na necessidade de se identificar precocemente quais os pacientes, no contexto da cardiopatia chagásica crônica, apresentam risco aumentado para o desenvolvimento de eventos arrítmicos complexos. Acredita-se que a avaliação autonômica identifique subgrupos distintos de risco. O presente estudo teve como objetivo determinar a sensibilidade do barorreflexo (SBR) em pacientes com doença de Chagas, nas formas indeterminada (GI) e arritmogênica com taquicardia ventricular não sustentada (GII) e com taquicardia ventricular sustentada (GIII) e, secundariamente, avaliar a associação entre a severidade da arritmia ventricular com o grau de comprometimento da SBR. Métodos: 42 pacientes foram submetidos à monitorização cardiovascular não invasiva pelo sistema Task Force ® onde foi determinada a SBR, utilizando o método da fenilefrina e analisada a variabilidade da frequência cardíaca (VFC) no domínio do tempo por meio da eletrocardiografia dinâmica de 24horas e a FEVE, por meio da ecocardiografia. Resultados: Observou-se diferença estatística significativa entre os grupos em relação à SBR em resposta à fenilefrina. O GIII apresentou o menor valor de SBR (6,09 ms/mmHg) quando comparado aos GII (11,84ms/mmHg) e GI (15,23ms/mmHg). Após comparação múltipla entre os grupos, verificou-se diferença significativa entre GI e GIII (p= 0,01). Quando se correlacionou SBR e densidade de extra-sístoles ventriculares (EV), observou-se que todos os pacientes portadores de baixa densidade de EV (< 10/hora) apresentavam SBR preservada (6,1ms/mmHg).Em contrapartida, entre aqueles com alta densidade de EV (>10/hora) somente 59% tinham SBR preservada (p=0,003). Nos pacientes com SBR deprimida (3,0-6,0 ms/mmHg) houve maior densidade de EV (p=0,01). Pacientes com SBR preservada apresentaram tanto função ventricular normal como moderadamente comprometida (66,7% com FEVE<40% e 79,5% com FEVE40%; p=0,62). O mesmo observou-se em pacientes com SBR moderadamente deprimida, (15,4% com FEVE<40% e 33,3% com FEVE40%; p=0,46). Não foi verificada correlação entre SBR e VFC. Ao se aplicar o modelo de regressão logística, observou-se que somente a SBR influenciou o aparecimento da taquicardia ventricular sustentada (p=0.028). Conclusão: A SBR está preservada na forma indeterminada da doença de Chagas e diminuída na forma arritmogênica. O comprometimento da SBR é progressivo e acompanha a evolução da doença, sendo mais intenso nos pacientes com arritmias ventriculares mais complexas. O grau de disfunção autonômica não se correlacionou com a função ventricular, mas, sim, com a densidade e a complexidade das arritmias / Introduction: Sudden death is the main cause of death in Chagas disease, corresponding to 55 to 65% of the cases. Some of these occur in patients with normal or almost normal left ventricular function (LVF), leading us to believe that factors that destabilize the arrhythmogenic substrate play an important role in these events. Evidences show parasympathetic depression to be a contributing factor in the genesis of diverse arrhythmias in the presence of ischemic heart disease. Thus, we insist on the need of an early identification of the patients, in the context of chronic Chagas heart disease, that are at increased risk of developing complex arrhythmic events. It is possible that autonomic assessment allows the identification of distinct risk subgroups. The objective of this study was to determine the baroreflex sensitivity (BRS) in patients with the indeterminate form of Chagas disease, (GI), and with the arrhythmogenic form of Chagas disease with nonsustained ventricular tachycardia (GII) and sustained ventricular tachycardia (GIII) and to assess the correlation between the severity of ventricular arrhythmia and the degree of BRS impairment. Methods: Forty-two patients were subjected to noninvasive cardiovascular monitoring using the Task Force® system. The phenylephrine method was used to determine BRS, 24- hour dynamic electrocardiography was used to analyze heart rate variability (HRV) over time and echocardiography was used to determine LVF. Results: A statistical difference was observed between the groups regarding their BRS to phenylephrine. GIII presented the lowest BRS value (6.09 ms/mmHg) when compared with GII (11.84ms/mmHg) and GI (15.23ms/mmHg). After multiple comparisons among the groups, a significant difference was found between GI and GIII (p=0.01). When BRS was correlated with ventricular extrasystole (VE) density, all patients who had low VE density (<10/hour) had preserved BRS (6.1ms/mmHg). On the other hand, only 59% of those with high EV density (>10/hour) had preserved BRS (p=0.003). In patients with moderately depressed BRS (3.0-6.0 ms/mmHg) there was a greater density of EV (p=0.01). Patients with preserved BRS had preserved or moderately compromised LVF (66.7% with LVF<40% and 79.5% with LVF40%; p=0.62) as had patients with moderately depressed BRS (15.4% with LVF<40% and 33.3% with LVF40%; p=0.46). There was no correlation between BRS and LVF. When the logistic regression model was applied, only BRS influenced the presence of sustained ventricular tachycardia (p=0.028). Conclusion: BRS is preserved in indeterminate Chagas disease and diminished in the arrhythmogenic form. The BRS impairment is progressive as the disease progresses, being more evident in patients with more complex ventricular arrhythmias. The degree of autonomic dysfunction did not correlate with ventricular function but with the density and complexity of the arrhythmias

Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 5, 2010). Thesis advisor: Paul J. Fadel. "December 2009" Includes bibliographical references.

Motivation: Abdominal obesity (hereafter referred to as "obesity") is becoming the biggest "global epidemic" of our modern times. It is associated with a range of diseases, including cardiovascular diseases and hypertension. Recent research showed that an increase in sympathetic activity is of central importance in the pathogenesis of obesity-related diseases. Increased leptin levels and impaired baroreflex sensitivity have both been independently associated with abdominal obesity and increased sympathetic activity. A perception of poorer health may also contribute to the physiological characteristics of obesity-related diseases. A lack of data regarding sympathetic activity, leptin levels, baroreflex sensitivity and perception of health in Africans, serves as a motivation for conducting this study. Objective: To investigate the contributions of leptin levels, baroreflex sensitivity and perception of health data to increased sympathetic activity in lean and obese African women from South Africa. Methodology: The manuscript presented in Chapter 2 made use of the data obtained in the POWIRS (Profiles of Obese Women with the Insulin Resistance Syndrome) study. A group of 102 urbanized African women, living in the North-West Province of South Africa, was recruited according to body mass indexes. Only 85 subjects were included for analysis due to incomplete datasets. For this study, subjects were divided into lean and obese groups according to their waist circumferences. Anthropometric measurements were done according to standardized methods. Resting cardiovascular measurements were obtained from Finometer observations. Resting, fasting levels of leptin were calculated after radioimmunoassay analyses. Subjective perception of health was determined by means of the 28-item General Health Questionnaire. Comparisons between the groups were done using analysis of covariance (ANCOVA) whilst adjusting for cardiovascular risk factors (age. smoking, alcohol consumption and physical activity). Correlation coefficients were determined to indicate any associations between leptin, baroreflex sensitivity and perception of health with sympathetic activity (represented by heart rate) and other cardiovascular variables. The study was approved by the Ethics committee of the North-West University and all the subjects gave informed consent in writing. The reader is referred to the Methods section in Chapter 2 for a more detailed description of the subjects, study design and analytical procedures used in this dissertation. Results and conclusion: Results from this study indicate that obese African women, compared to lean African women, were older, reported higher physical activity, and exhibited higher diastolic and mean blood pressure, heart rate, cardiac output, arterial compliance, leptin and hypertension prevalence rate values. In lean African women social dysfunction was positively associated with diastolic and mean blood pressure and arterial resistance, and negatively with arterial compliance. In obese African women baroreflex sensitivity was negatively associated with diastolic blood pressure, which could be an indication of impaired baroreflex sensitivity. In this obese group a perception of social dysfunction was associated with decreased heart rate. Although leptin and heart rate were significantly higher in the obese Africans, no significant correlations existed between these variables to reflect leptin's enhancement of sympathetic activity. However, leptin correlated weakly but positively with cardiac output (p = 0.054, r = 0.32). In conclusion, baroreflex sensitivity (although similar between groups) and leptin seem to contribute to blood pressure and thus hypertension in obese African women, possibly through increased sympathetic activity and volume loading. A perception of poorer health, especially a perception of social dysfunction, could possibly contribute to this image. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2007.