Introduction: Rheumatoid arthritis (RA) is a chronic disease and one of the more common auto-immune diseases. Patients with RA rely almost solely on pharmaceutical intervention to manage the disease. Autonomic impairment has been proven in previous studies on patients with RA. The positive effect of exercise on autonomic impairment has also previously been demonstrated, but not in the RA population. The purpose of this study was firstly to confirm autonomic impairment in a South African based female population with RA and secondly to evaluate the effect of exercise on the autonomic cardiac function (as measured by short-term heart rate variability), disease activity and functional capacity. Methods: The study was conducted at the University of Pretoria during 2009 and 2010. In the first phase of the study female RA patients were recruited from all rheumatology practices in Pretoria and healthy controls were recruited from family and friends of the research team and of the RA group. Cardiac autonomic function was compared between the two groups by means of short-term heart rate variability. Three techniques were used: time domain, frequency domain and Poincare plot analysis. In the second phase of the study, females with confirmed RA were randomly assigned to an exercise group and a control group. The exercise group was requested to train under supervision two to three times per week for a period of twelve weeks, while the control group continued with their sedentary lifestyle. At study completion the two groups were compared for the effect of exercise intervention on the following three aspects: <ul><li> Autonomic function (as measured by heart rate variability) </li><li> Disease activity (as measured by Disease Activity Score, Visual Analogue Scale and Health Activity Questionnaire) </li><li> Functional capacity (as measured by strength, flexibility and aerobic capacity) </li></ul> Results: In the first phase of the study comparing females with RA (n=45) to healthy females (n=39), the basal heart rate was significantly higher in the RA group. In the supine position significant differences existed between the RA group and the control group (p ≤ 0.01). Indicators of parasympathetic activity showed significantly lower variation in the RA group [RMSSD=14.70, pNN50=0.50, SD1=10.50, HF(ms2)=31] compared to the control group [RMSSD=29.40, pNN50=7.8, SD1=20.9, HF(ms2)=141.00]. Indicators of sympathetic variation were also significantly lower in the RA Group [SD2=36.70, LF(ms2)=65) compared to the Control group (SD2=49.50, LF(ms2)=175]. In the standing position 8 variables indicated autonomic impairment by significant differences (p≤0.01) between the 2 groups. The response of the RA Group to an orthostatic stressor showed less vagal withdrawal, [p-values for RMSSD=0.038, pNN50=0.022, SD1=0.043 and HF(ms2)=0.008 respectively]; and lower sympathetic response [p-values for SD2=0.001 and LF(ms2)<0.001] when compared to the Control group. In the second phase of the study, comparing an RA exercise group to a RA sedentary group, three aspects were evaluated: 1. Heart rate variability At baseline the control group (n=18) had significantly higher variability compared to the exercise group (n=19) for most heart rate variability (HRV) indicators. At study completion the variables showing significant changes (p=0.01 to 0.05) favoured the exercise group in all instances. Wilcoxon signed rank tests were performed to assess changes within groups from start to end. The exercise group showed significant improvement for most of the standing variables, including measurements of combined autonomic influence e.g. SDRR (p=0.002) and variables indicating only vagal influence e.g. pNN50 (p=0.014). The control group mostly deteriorated with emphasis on variables measuring vagal influence [RMSSD, pNN50, SD1 and HF(ms2)]. 2. Disease activity At baseline the two groups were comparable. At the end of the intervention, the exercise group had significant improvement for the tender joint count (p=0.015), swollen joint count (p=<0.001), physician global assessment (p=0.003) and DAS score (p=0.003) compared to the control group. To assess changes that happened within each group from start to end, Wilcoxon signed rank tests were performed. The exercise group improved significantly with regards to tender joint count (p=0.002), swollen joint count (p=0.001), physician global assessment (p=0.001), DAS score (0.001) and the visual analogue scale (p=0.032). The sedentary group improved significantly only in the health assessment questionnaire (p=0.032). 3. Functional capacity Comparing the groups at baseline the exercise group had better knee- and hip flexion on the left hand side but it took them longer to complete the arm curl test. At study completion the exercise group was mostly favoured with regards to flexibility (significant p-values ranging between 0.001 – 0.049), strength (handgrip right p<0.001, leg strength p=0.035, arm curl test p=0.010, sit to stand test p=0.025) and aerobic fitness (1 mile walk test p<0.001 and VO2 max p=0.007). Changes within each group were assessed by Wilcoxon signed rank tests. The exercise groups showed significant changes for many parameters in the three categories, i.e. flexibility (8 of 18), strength (5 of 5), and aerobic fitness (4 of 8). The control group mostly deteriorated in flexibility, while their strength also improved, but not to the same extent as for the exercise group. Their aerobic fitness did not change. Discussion: In the first phase of this study, using standardised methods to measure short-term HRV, females with RA showed less variability compared to a healthy age- and sex matched control group. An inability of the autonomic nervous system to efficiently compensate to internal and external environmental changes may predispose RA patients to arrhythmias thereby increasing cardiovascular mortality. All 3 methods used showed the same outcome, implying decreased HRV and thus an increased risk for arrhythmias in RA patients. Evaluating the autonomic nervous system might be critical in planning management of RA. In the second phase study results indicated that twelve weeks of exercise intervention, had a positive effect on cardiac autonomic function as measured by short-term HRV, in females with RA. Several of the standing variables indicated improved vagal influence on the heart rate. Exercise can thus potentially be used as an instrument to improve cardiac health in a patient group known for increased cardiac morbidity. The exercise programme was also effective in decreasing perception of pain as well as disease activity in female RA patients. Given our findings it seems warranted to include physical exercise as part of the treatment prescription of patients with class I and II RA. Lastly this research has shown that regular, controlled exercise for RA patients with controlled disease can decrease joint stiffness and improve joint mobility, strength and aerobic capacity without exacerbating pain or disease activity. Also, if one observes the decline in the sedentary group for many parameters, it is important to note that this happened over a relative short time period and that even a small change may have a detrimental impact on the RA patient. The current report supports previous literature on autonomic impairment in patients suffering from RA as well as the meaningful positive effect of exercise on disease activity and functional capacity. It is the only study on the effect of an exercise intervention on the cardiac autonomic function of RA patients. Future research in this field should aim for larger study samples, longer intervention periods and perhaps add analysis of blood pressure variability to support results obtained by HRV analysis. / Thesis (MD)--University of Pretoria, 2012. / Internal Medicine / unrestricted

Orientador: Heitor Moreno Júnior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T14:35:44Z (GMT). No. of bitstreams: 1 Gordo_WladimirMignone_D.pdf: 1165758 bytes, checksum: fd111068b22725bae91f0f03257cf0f9 (MD5) Previous issue date: 2014 / Resumo: Em pacientes hipertensos resistentes, frequentemente obesos, tanto a pressão arterial elevada como a obesidade contribuem para a disfunção vascular. Além disso, resultados prévios demonstraram que distúrbios autonômicos estão relacionados com a obesidade e hipertensão e que a redução da variabilidade da frequência cardíaca (VFC) pode representar um fator de risco para a hipertensão. Para melhor entender a relação entre a disfunção autonômica e a hipertensão arterial resistente (HAR), este trabalho teve a finalidade de avaliar a associação entre a VFC, obesidade e função vascular na HAR. Trinta e sete pacientes com hipertensão arterial resistente foram selecionados. Os parâmetros da VFC foram obtidos a partir da gravação ambulatorial simultânea com Holter/MAPA de 24 horas e analisados no domínio do tempo. A função endotelial foi avaliada com a técnica da vasodilatação mediada pelo fluxo (VMF) e a rigidez arterial pela velocidade da onda de pulso (VOP). Encontramos correlação positiva entre o desvio padrão de todos os intervalos RR normais (SDNN) e o desvio padrão das médias dos intervalos RR normais calculados em intervalos de 5 min (SDANN) com a VMF (r = 0,56, p = 0,001; r = 0,48, p = 0,006, respectivamente) mas não com a VOP. Além disso, SDNN foi negativamente correlacionada com o índice de massa corporal e circunferência da cintura (r = -0,44, p = 0,01; r = -0,34, p = 0,04, respectivamente). Esses achados reforçam a importância da hiperativação do sistema nervoso simpático em hipertensos resistentes obesos. Além disso, a associação entre os parâmetros da VFC e a disfunção endotelial e obesidade sugerem um potencial mecanismo fisiopatológico na resistência à terapia anti-hipertensiva / Abstract: Resistant hypertensive patients are generally overweight or obese, either high blood pressure as obesity contribute to vascular damage. Moreover, previous data showed that autonomic imbalance is related to obesity as well as hypertension. Reduced heart rate variability (HRV) may represent a risk factor for hypertension. In order to better understand the relationship between impaired autonomic function and resistant hypertension (RHTN), we aimed to evaluate the association between HRV, obesity and vascular function in RHTN. Thirty-seven resistant hypertensive patients were selected. Parameters of HRV were derived from the simultaneous recording of 24-hour Holter ambulatory electrocardiographic /ABPM and analyzed in time domain. Endothelial function was assessed by flow mediated dilation (FMD) technique and arterial stiffness by pulse wave velocity (PWV). We found positive correlation between standard deviation of all normal RR intervals (SDNN) and standard deviation of mean RR interval in all 5-minute segments of a 24-hour recording (SDANN) with FMD (r = 0.56, p= 0.001; r = 0.48, p = 0.006, respectively) but not with PWV. In addition, SDNN was negatively correlated with body mass index and waist circumference (r = -0.44, p = 0.01; r = -0.34, p = 0.04, respectively). These data strengthen the importance of sympathetic overactivity in obese resistant hypertensive subjects. Furthermore, the relationship between HRV parameters with endothelial dysfunction and obesity suggest a potential pathophysiological mechanism in RHTN / Doutorado / Farmacologia / Doutor em Farmacologia

This experiment investigated lateralized hemispheric regulation of the autonomic nervous system (ANS) among high anxious and nonanxious university undergraduate men using a novel laboratory paradigm. Specifically, this three phase paradigm entailed the administration of a verbal fluency (left frontal) and nonverbal fluency (right frontal) task with or without the threat of a painful stimulus (cold pressor) to high anxious and nonanxious participants. Thus, the cerebrums are hypothesized to be engaged in a dual-task experience requiring the regulation of the ANS and concurrent performance on the verbal or the nonverbal fluency measure. Given the literature which supports relative right hemisphere activation among anxious individuals, it was hypothesized that high anxious men would (1) demonstrate greater physiological arousal to the cold pressor, (2) perform relatively worse on nonverbal fluency measures and demonstrate greater difficulty regulating cardiovascular functioning, and (3) demonstrate relatively lower nonverbal fluency scores and increased physiological arousal when presented with the nonverbal fluency task and cold pressor stimulus simultaneously. The results are evaluated using three perspectives: Heller's (1993) hypothesis, Kinsbourne's Functional Cerebral Distance principle, and lateralized regulation of the sympathetic and parasympathetic nervous system. The results only partially supported the right hemisphere activation hypothesis for anxious individuals, as many of the significant results were counter to hypotheses. Specifically, high anxious men demonstrated lower verbal fluency scores and greater heart rate during the combined stimulus of the cold pressor and verbal fluency task. The data are supportive of relative anterior deactivation among high anxious men. The discussion extends the findings to present questions regarding cerebral regulation of the ANS. Future experiments which may add to the current understanding of lateralized regulation of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) are suggested. / Ph. D.

Novel sounds in the auditory oddball paradigm elicit a biphasic dilation of the pupil (PDR) and P3a as well as novelty P3 event-related potentials (ERPs). The biphasic PDR has been hypothesized to reflect the relaxation of the iris sphincter muscle due to parasympathetic inhibition and the constriction of the iris dilator muscle due to sympathetic activation. We measured the PDR and the P3 to neutral and to emotionally arousing negative novels in dark and moderate lighting conditions. By means of principal component analysis (PCA) of the PDR data we extracted two components: the early one was absent in darkness and, thus, presumably reflects parasympathetic inhibition, whereas the late component occurred in darkness and light and presumably reflects sympathetic activation. Importantly, only this sympathetic late component was enhanced for emotionally arousing (as compared to neutral) sounds supporting the hypothesis that emotional arousal specifically activates the sympathetic nervous system. In the ERPs we observed P3a and novelty P3 in response to novel sounds. Both components were enhanced for emotionally arousing (as compared to neutral) novels. Our results demonstrate that sympathetic and parasympathetic contributions to the PDR can be separated and link emotional arousal to sympathetic nervous system activation.

The autonomic nervous system plays an integral role in the modulation of normal cardiac electrophysiology. This is achieved via a complex network of pre- and postganglionic sympathetic and parasympathetic fibers that synapse on extrinsic and intrinsic cardiac ganglia and ultimately directly innervate cardiac myocytes. Alterations in autonomic tone may induce changes in local cellular electrophysiology that may manifest clinically in a number of ways, ranging from changes in heart rate to changes in heart rhythm. These relationships between autonomic tone and the evolution of cardiac dysrhythmias are areas of evolving research, with increasing evidence for a key role for autonomic ganglia in the pathogenesis of atrial fibrillation and sympathetic nerves in the predilection toward ventricular tachycardia in areas of myocardial scar. In this review, we highlight what is known about the anatomy and physiology of the cardiac autonomic nervous system, the evidence supporting the relationship of autonomic tone to clinically significant arrhythmias, and a variety of mechanisms (eg, direct ion channel effects) and diagnostic tools that exist to help define this relationship. Further emphasized are potential future avenues of research needed to elucidate the relationship between changes in normal autonomic tone and the pathogenesis of cardiac arrhythmias.

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

Indiana University-Purdue University Indianapolis (IUPUI) / 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 barorefex (BRx), the most rapid and robust of neural refexes 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 refexogenic experimental preparation was carried out. This thesis recon rmed previous observations of an electrically-evoked sexually-dimorphic peak depressor response in the BRx of Sprague-Dawley rats and veri ed that these functional refexogenic 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.

BACKGROUND: The prevalence of neonatal abstinence syndrome (NAS) is on the rise in the United States, as the epidemic of opioid misuse continues1. Several infants with in utero exposure to opioids are born with NAS, and exhibit symptoms of withdrawal and dependence upon birth when the maternal source of opioid is discontinued2. Due to the novelty of the syndrome, there are several knowledge gaps in current literature that remain to be explored. LITERATURE REVIEW: The exact mechanism of development of NAS in infants remains unknown, yet the clinical symptomatology and results of a few recent studies suggest that there is an association with NAS severity and dysregulation of autonomic nervous system (ANS) functioning in these infants3. In recent years, pharmacological treatments for these infants have become standardized4. However, non-pharmacological treatments have been adopted from treatment guidelines of other high-risk infant populations and their efficacy warrants further evaluation in infants with NAS. Kangaroo care (KC) is a supportive therapy commonly applied to many high-risk infant populations because of its physiologically stabilizing effects5. The therapy has been demonstrated to be especially beneficial in the treatment of preterm infants, a population that similarly requires additional maturation of their ANS upon birth,6. Neurobehavioral theories suggest ANS functioning in infancy is a strong predictor of long-term social, behavioral, and cognitive development outcomes7,8. PROPOSED PROJECT: This prospective cohort study is designed to provide pilot data to establish if KC can be utilized to mature ANS maturation in infants with NAS. CONCLUSIONS AND SIGNIFICANCE: KC is an inexpensive, readily available, low risk intervention that could improve neurobehavioral outcomes in infants with NAS. The results of this study could reduce clinical symptoms, potentiate long-term behavior outcomes, and better define treatment practices for infants with NAS by facilitating a targeted intervention to improve outcomes.

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