Дисертації з теми "Exercise Apnea"

Continuous positive airway pressure (CPAP) is the primary therapy administered for those afflicted with obstructive sleep apnea (OSA). We examined the effects of CPAP therapy on physiological variables during a ramped exercise. The five male, OSA patients had mean values and standard deviations for RDI=60.7 +/- 19.1, BMI=29.9 +/- 2.9, and age=56 +/- 16.1 yr. Subjects were examined before and after 4 wk of CPAP therapy. After 4 wk of CPAP therapy, patient responses to exercise showed a 17.6%, (p<0.05) improvement in rating of perceived exertion (RPE) at identical power outputs (60% of the individual's apparent functional capacity). Statistical significance was not attained (p>0.05) upon analysis of the following parameters at 60% of the individuals maximum workload although there was a trend showing a decrease in these variables: heart rate (6% improvement), VO2 (11.7% improvement) systolic blood pressure (4% improvement), and rate pressure product (8.6% improvement). This data shows that the decrease in RPE during 60% of the individual's maximum predicted HR reserve corresponded with an increase in sleep quality (mean increase of 40%, 3.2 units) as measured by the Pittsburgh Sleep Quality Index before and after 4 wk of CPAP therapy. It was concluded that the improvement in exercise tolerance could be attributed to the subjective feelings of improved sleep quality after 4 wk of CPAP therapy. Key Words: Obstructive sleep apnea---CPAP--- exercise---physiological responses.
Master of Science

Obstructive sleep apnea (OSA) is estimated to affect 2 to 4 percent of the adult population (Young T 1993, Skomro and Kryger 1999). However, an estimated 80 to 90 percent of adults with moderate to severe OSA may be clinically undiagnosed. Identification of those at risk and their subsequent diagnosis is, obviously, of great concern to clinicians. This investigation included three distinct research aims, which were the following: (1): In order to establish reliability of hemodynamic measures to be used during exercise testing, a study was conducted on the acetylene single-breath cardiac output (Qc) technique in 15 healthy subjects. This was completed in order to establish reliability of exercise Qc and total peripheral resistance (TPR), these responses could then be investigated acutely in the context of evaluating the relation of these measures to markers of disease in OSA patients. (2): The primary research aim was to describe the extent to which graded exercise testing may reveal abnormalities in hemodynamic function in obstructive sleep apnea (OSA) patients, particularly with respect to cardiac output (Qc), mean arterial pressure (MAP), and TPR that may be related to polysomnography (PSG) markers of OSA severity. Cardiorespiratory and hemodynamic responses that were evaluated included the following: peak oxygen consumption (VO2pk), end-tidal carbon dioxide production (PETCO2), end-tidal oxygen pressure (PETO2), heart rate (HR), blood pressure (systolic = SBP and diastolic = DBP), rate pressure product (RPP), TPR and its derivatives including MAP and Qc, in OSA patients. A global biochemical marker of vascular function, 24-hour urinary nitrite/ nitrate elimination was also determined for each patient. (3): The last aim was included in order to provide qualitative information concerning treatment, subjective sleep and daytime function, and physical activity levels of the OSA patients in this investigation as well as to give insights into the special challenges and potential for doing trials involving nCPAP and physical exercise training with OSA patients. Results from this study can be used to improve clinical evaluation procedures as well as to better understand underlying mechanisms relative to the link between cardiovascular disease and OSA
Ph. D.

In order to clarify the effects of a single night of CPAP titration on various cardiovascular, gas exchange, and perceptual measures, we conducted submaximal ramping exercise tests to an intensity of ~75% of the heart rate reserve in five male subjects. Means and standard deviation for their age and BMI were 57.0±14.7 years and 30.5±7.2, respectively. The baseline exercise test was administered immediately after the patients arose from bed, following an overnight PSG diagnostic evaluation. The exercise test was repeated within ~2 weeks of completion of an overnight CPAP evaluation trial. Patients reported experiencing improved sleep quality (50%) after the CPAP titration, based on comparison of morning questionnaire responses from the diagnostic PSG vs. CPAP titration. Statistical significance was not attained (p>0.05) upon analysis of the following parameters at 60% of the individuals maximum workload although there were changes in the mean values of the variables from the diagnostic PSG vs CPAP titration. The following changes were noted: heart rate increased by 6%, systolic blood pressure decreased by 6%, and the rate pressure product decreased by 5.8%. Respiratory variables changed as follows: VO2 decreased by 5.3% and VE decreased by 8.5%. The perceptual measure rate of perceived exertion (RPE) decreased by 17.5%. These preliminary findings demonstrate that self-reports of sleep quality in patients with diagnosed OSA improved after a single night of CPAP titration, even in a setting wherein the total time of CPAP sleep and reduction of apneas, hypopneas, and hypoxemic episodes are highly variable. Additionally, sleep structure revealed a marked increase in slow wave (53.2%) and REM (30.4%) sleep with CPAP titration in comparison to the diagnostic PSG. It was concluded that CPAP titration effectively improves sleep structure and patient ratings of sleep quality, but does not have significant effects on cardiorespiratory responses to submaximal endurance exercise.
Master of Science

The purpose of the current study was to test the hypothesis that chronic hypoxia associated with sleep-disordered breathing relates to abnormal Nitric Oxide (NO) production and vascular endothelial growth factor (VEGF) expression patterns that contribute to aberrancy of specific determinates of cardiovascular and cardiopulmonary function before, during, and after graded exercise. These patterns may further reflect pathologic alteration of signaling within the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt-1) transduction network. To this end, 7 medically diagnosed OSA patients (3 male, 4 female), mean age 48 years and 7 apparently healthy control subjects (3 male, 4 female), mean age 42 years, underwent baseline venous blood draws and maximal bicycle ergometry. Mononuclear cells isolated from peripheral blood were utilized as reporter cells for measurement of VEGF, Akt-1, hypoxia inducible factor-1 alpha (HIF-1 alpha), and vascular endothelial growth factor receptor-2 (VEGFR2) gene expression by redundant oligonucleotide DNA microarray and real-time PCR technologies. Circulating angiogenic progenitor cells expressing VEGFR2 were profiled by flow cytometry. Plasma and serum concentrations of VEGF, nitrates/nitrites, catecholamines, and dopamine were measured by enzyme-linked immunosorbent assay (ELISA) and high performance liquid chromatography (HPLC). Arterial blood pressure, cardiac output, oxygen consumption and total peripheral resistance were determined at Baseline, 100W, and peak ergometric stress by standard techniques. There were no apparent differences (p < .05) observed in biochemical markers relating to vascular function and adaptation including, serum nitrates/nitrites, norepinephrine, dopamine, and plasma VEGF. No differences were found relative to cardiac output, stroke volume, cardiopulmonary or myocardial oxygen consumption, expired ventilation, heart rate, arteriovenous oxygen difference, total peripheral resistance, and mean arterial pressure. Due to methodological issues related to the redundant oligonucleotide DNA microarray and real-time PCR gene expression analyses, results of these experiments were uninterpretable. Thus, the research hypothesis was rejected. Conversely, significant (p < .05) differences were observed in waist: hip ratios, recovery: peak systolic blood pressure ratio at 1 minute post-exercise and %VEGFR2 expression. OSA was associated with elevations in both waist: hip ratios and recovery: peak systolic blood pressure ratio at 1 minute post-exercise as well as significant depression of %VEGFR2 profiles. Moreover, significant negative correlations were found regarding waist: hip ratios and %VEGFR2 expression (r = -.69;p =.005) and recovery: peak systolic blood pressure ratio at 1 minute post-exercise and %VEGFR2 expression (r = -.65;p =.01). These findings did not provide evidence that NO-dependent vasoactive mechanisms are suppressed nor did they support the supposition that angiogenic mechanisms are pathologically activated in sleep-disordered breathing.
Ph. D.

Obstructive sleep apnea (OSA) is a type of sleep apnea that is common, complicated, and a major contributor to cardiovascular diseases, neurocognitive impairment, and mortality. This disease has additional negative impacts on patients' lives by contributing to daytime sleepiness and low productivity at work as well as absenteeism and work-related injuries. Several studies have been conducted to assess the relationship between cardiovascular exercises and OSA; however, a definite conclusion is lacking. The purpose of this quantitative cross-sectional study was to assess the relationship between cardiovascular exercise participation and OSA by examining the relationship between total cardiovascular exercise participation per week and OSA as well as the relationship between body mass index (BMI) and OSA among adults over normal weight in the United States. Secondary data from the National Sleep Research Resource (NSRR) were used for analyses. Logistic regression was used to test the hypotheses. The Social-Ecological Model (SEM) guided the study. The findings of the study suggested that doing moderate cardiovascular exercise participation per week (0.1 and 200 minutes) had no relationship with OSA while doing higher cardiovascular exercise participation (>200 minutes) per week had relationship with OSA by increasing the odds (AOR = 2.1, CI: 1.048-4.060) of having severe OSA. BMI had no relationship with OSA. Individuals with OSA and a higher BMI could use the findings of this study to participate in an exercise program that might benefit their health and decrease the risk of exacerbated symptoms which could lead to an improved quality of life and decreased burden associated with OSA.

Obstructive sleep apnea (OSA) is a serious disorder that affects up to 24% of middle-aged males. The substantial cost and inconvenience associated with polysomnography limits the number of people who seek treatment. Therefore, information concerning exercise tolerance and hemodynamic function in obstructive sleep apnea (OSA) patients may add new and clinically meaningful information to the process of grading disease severity and/or assessing treatment outcomes. Objectives: The primary objective of this study was to explore relationships between polysomnography (PSG) markers of sleep function and resting and exercise measures of hemodynamic function in patients diagnosed with mild-to-severe OSA. A family of clinical markers including heart rate (HR), blood pressure (BP), cardiac index (CI), stroke volume index (SVI), total peripheral resistance (TPR), and oxygen uptake (VO2) were assessed in this study. A second objective was to explore differences in hemodynamic function at rest and during graded exercise in OSA patients versus control subjects matched for age and body mass index (BMI). A final objective was to evaluate the extent that treatment with nCPAP alone, or combined with a moderate aerobic exercise training program impacted markers of hemodynamic function (results not reported here). Methods: Eleven newly diagnosed OSA patients [5 male, 6 female; age: 46.5 + 12.0 yrs; respiratory disturbance index (RDI) = 30.2 + 15.0] and 10 apparently healthy control subjects (4 male, 6 female; age: 39.8 + 6.9 yrs) completed daytime resting measurements of heart rate variability (HRV) and blood pressure (BP); and underwent a maximal cycle ergometer exercise test at baseline and 6 wk post-treatment initiation. Pearson product moment correlations were calculated between PSG markers of sleep function and: (1) daytime measures of HRV; (2) BP; and (3) submaximal and peak exercise measures of hemodynamic function. Independent t tests were used to explore differences between OSA patients and controls. Results: Stage 1 sleep duration was significantly related to daytime SBP (r = 0.69; P < 0.05) and MAP (r = 0.72; P < 0.05). Daytime MAP (P = 0.01) and DBP (P = 0.02) were significantly different between groups. Exercise testing yielded the following results: RDI was significantly related to HR at 60 watts (r = -0.70; P = 0.02) and 100 watts (r = -0.69; P = 02); stage 2 sleep duration was inversely related to CI at 60 (r = -0.76; P = 0.03) and 100 watts. In addition, stage 1 sleep duration was significantly correlated with TPR at 60 watts (r = 0.70; P = 0.06) and 100 watts (r = 0.71; P = 0.05). At peak exercise, a significant relationship was noted between peak HR and stage 2 sleep duration (r = -0.73; P = 0.02); and RDI (r = -0.66; P = 0.03). Furthermore, relative VO2pk was positively correlated to REM sleep duration (r = 0.62; P = 0.04). Conclusions: Distinct patterns exist in measures of daytime HRV and BP may provide physicians unique and clinically useful information. In addition, peak exercise capacity is reduced in the OSA patient and may be related to a blunted HR response to graded exercise.
Ph. D.

Obstructive sleep apnea syndrome (OSAS) is a serious disorder that affects an estimated 24% of middle-age males, and 9% of middle-aged females. In addition, a large portion of individuals with OSAS go undiagnosed. OSAS is associated with several adverse health problems, including the metabolic syndrome. Therefore, there is a clear need to identify new methods for assessing OSAS risk. The exercise test has been used effectively as a diagnostic and prognostic tool for those at high risk for cardiovascular disease and hypertension. Research into the cardiopulmonary responses to exercise testing in young adult men with OSAS has not been examined. Objectives: The objectives of this study were to: 1) evaluate whether OSAS is characterized by exaggerated ventilatory responses to ramp exercise testing, with a secondary aim to evaluate if variations in serum leptin concentration might exert a regulatory in ventilatory responses during exercise; 2) To evaluate whether autonomic control of the cardiovascular response during exercise is distorted by OSAS in young overweight men, as manifested by a blunting of heart rate and exaggeration of blood pressure responses.; 3) To explore whether various simple clinical measures and response patterns from graded exercise testing might serve to discriminate between young men with and without OSAS. Methods: For objectives one and two, 14 obese men with OSAS [age = 22.4 ± 2.8; body mass index (BMI) = 32.0 ± 3.7; apnea-hypopnea index (AHI) = 22.7 ± 18.5], 16 obese men without OSAS (age = 21.4 ± 2.6; BMI = 31.4 ± 3.7), and 14 normal weight subjects (objective 2) (age = 21.4 ± 2.1; BMI = 22.0 ± 1.3) were recruited. For objective three, 91 men (age = 21.6 ± 2.8; AHI range = 0.6 â 60.5; BMI range = 19.0 â 43.9) were recruited. Subjects completed a ramp cycle ergometer exercise test, and a fasting blood sample was obtained to measure plasma leptin and blood lipid levels. Repeated measures ANOVA and stepwise linear regression was used to examine objectives 1 and 2. For objective 3, stepwise linear regression and receiver operator curve (ROC) analysis was utilized. Results: Ventilation (VE), the ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) were greater in the OSAS subjects vs. the overweight subjects without OSAS (P = 0.05, P < 0.05 and P < 0.005, respectively) at all exercise intensities. Heart rate (HR) recovery was attenuated in the overweight OSAS subjects compared to the No-OSAS and Control groups throughout 5 minutes of active recovery (P = 0.009). Oxygen uptake, HR, and blood pressure did not differ throughout exercise. Leptin was not associated with ventilatory responses at any exercise intensity. Linear regression analysis revealed hip-to-height ratio (HHR), hip circumference (HC), triglyceride levels, and recovery systolic blood pressure ratio (SBPR) at 2 and 4 minutes were independent predictors of AHI (model fit: R2 = 0.68, p <0.0001). ROC analysis determined that percent body fat, HHR, and recovery HR at 2 minutes and 4 minutes were the best single predictors of OSAS risk (AUC = 0.77 for each measure, p = 0.003). Conclusions: Unique ventilatory and hemodynamic characteristics to maximal exercise testing are exhibited in young men with OSAS. These characteristics may be related to alterations in the sympathetic nervous system and chemoreceptor activation, and may be early clinical signs in the progression of OSAS. These exercise characteristics, along with anthropometric and body composition measures may provide useful information in identifying young men at risk for OSAS.
Ph. D.

Obstructive Sleep Apnea (OSA) is becoming an increasingly prevalent health problem, affecting 4% of men and 2% of women in North America. OSA is associated with many debilitating side-effects and co-morbidities; the most common being excessive daytime sleepiness (EDS), which effects the majority of OSA sufferers. EDS is negatively associated with physical activity (PA) and exercise. As a result, EDS may decrease the levels of PA performed by OSA patients. Previous research has revealed that the OSA population engages in less physical activity than the average healthy population. Studies show that CPAP treatment positively impacts EDS, and therefore; may impact PA. The primary purpose of this study was to objectively measure OSA patients' PA levels prior to CPAP treatment and 8 weeks after treatment initiation to assess whether CPAP treatment' impacts PA levels.Actigraph GT 1 M measures PA was assessed at baseline (prior to CPAP) and 8-weeks after. initiation of CPAP treatment. At each time frame, cardiovascular., blood data, body composition, and maximal cycle ergometer exercise measures were obtained. Also, subjective questionnaires, 1 reflective of sleep apnea and 1 regarding PA, were completed by the subjects.Six male subjects with severe OSA (AHI = 41.2 ± 28.4 events/hr) started and completed the study. No significant changes occurred in PA, represented as steps/day nor mean activity counts/day, throughout the 8 weeks of CPAP treatment. Significant changes were found in diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, and Epworth sleepiness scale scores. No significant changes occurred in any other body composition, heart rate, systolic blood pressure, triglycerides, and blood glucose. Exercise parameters, total test time, peak Watts, and V02max trended toward an increase and maximal heart rate and blood pressure toward a decrease, but none changed significantly.In conclusion, these results demonstrated that 8 weeks of CPAP treatment was not successful in increasing PA levels of severe OSA patients. The OSA subjects were categorized as sedentary according to their steps/day. Compliance to CPAP could have been an issue with subjects' average nightly usage ranging from 1.85 – 6.6hours/night. Consequently, more research regarding OSA patients PA habits and CPAP treatments effects on PA should be investigated.
School of Physical Education, Sport, and Exercise Science

Heart Rate Variability (HRV) currently is utilized when assessing the risk of mortality in individuals suffering from coronary heart disease or diabetic neuropathy. Research has shown that patients with Obstructive Sleep Apnea (OSA) also show a decrease in HRV, as well as an increase in sympathetic drive characterized by an increase in the low-frequency component of HRV. HRV, in conjunction with other indicators, may represent a non-invasive, low cost method for the confirmation of severity of OSA in some patients and therefore may represent an additional tool for the assessment of risk in these individuals. This becomes especially true when urinary catecholamines, fitness level, and quality of life (QOL) assessment are included. The purpose of this study was to determine if a correlation exists between severity of OSA as assessed by respiratory distress index (RDI) and the selected measures HRV, fitness, QOL, and catecholamine output. Subjects were 6 men and 5 women who were recently diagnosed with OSA by polysomnographic (PSG) study. HRV and blood pressure was measured during two consecutive trials consisting of 512 heartbeats. Catecholamine levels were determined by HPLC following 24-hour urine collection. Fitness levels were established following cycle ergometer testing and QOL following questionnaire completion. Subjects with lower weight, BMI, and neck circumference had significantly higher parasympathetic influence as analyzed through the amount of high frequency component of HRV (r =.738, .726, .789, respectively; p<0.05). Respiratory distress index (RDI) was negatively related to the average heart rate (HR=RR average, r = -.610, p<0.05), while the amount of total sleep (r = .657, p<0.05) and REM sleep (r = .739, p<0.01) increased as HR increased. The average HR was correlated to the predicted VO2max (r = .677, p<0.05). When the frequency components of HRV, fitness, QOL, and catecholamines were combined, the association to RDI increased dramatically (r = .984, p = .02). The results indicate that as the severity of OSA increases, markers of fitness, QOL, and sleep decrease. There is also an inverse relationship between autonomic function and severity of OSA. It is concluded that HRV and fitness levels are inversely related to the severity of OSA, and that these measures may be developed into a risk assessment tool for use in OSA patient evaluatio
Master of Science

Obstructive sleep apnea (OSA) is common in older U.S. adults and the prevalence is anticipated to rise in this age group along with obesity, a prominent risk factor for OSA. Recently, OSA was determined to be highly prevalent among patients with abdominal aortic aneurysm (AAA) disease. Objectives: Examine associations between OSA risk and physical activity (PA), metabolic syndrome (MetSyn), and exercise responses to cardiopulmonary exercise testing (CPET) in elderly patients with AAA disease. Methods: Elderly patients (n=326 for Studies 1 and 2; n=114 for Study 3) newly diagnosed with small AAAs (aortic diameter "2.5 and < 5.5 cm) were recruited. Data collection for all participants included: extraction of medical history and drug information from medical records; completion of a physical examination to assess resting vital signs and anthropometrics; fasting blood draw for several biochemical analyses; completion of a cardiopulmonary exercise test (CPET); and completion of interviews and questionnaires for health history, PA, and OSA risk. Results: 57% of subjects were High-risk for OSA and 17% were classified in the highest-risk Berlin Risk Score (BRS) 3 group; these subjects reported fewer blocks walked/day, flights of stairs climbed/day, and expended fewer Calories when engaged in these activities compared to Low-risk counterparts, independent of obesity. Among those at High-risk for OSA, 45% had MetSyn. Subjects with the highest BRS also had the highest prevalence of MetSyn and values for the MetSyn component biomarkers. Exercise capacity and physiological responses at rest, during exercise, and recovery were similar between groups at High- and Low-risk for OSA. Conclusions: Reduced levels of PA among elderly AAA patients at High-risk for OSA could have unfavorable implications for cardiovascular disease (CVD) risk and all-cause and CVD mortality.  Subjects demonstrating the most clinical symptoms of OSA showed a significantly higher prevalence for MetSyn and several of the biomarkers that determine MetSyn. In clinical practice, the BRS may be useful for identifying those AAA patients at increased risk for both OSA and MetSyn.
Ph. D.

Obstructive sleep apnea (OSA) is a disorder that affects a significant portion of middle-aged adult population. Patients exhibit recurring episodes of upper airway obstruction during sleep that decrease blood oxygen concentration (hypoxia) and are terminated by brief arousals. Epidemiologically, OSA has been extensively linked to cardiovascular dysfunction and is an independent risk factor for the development of hypertension. The proposed mechanism of cardiovascular dysfunction in patients is chronic sympathoexcitation and altered vascular tone, with a predominance of the vasoconstrictor endothelin-1 (ET-1) and removal of the vasodilator nitric oxide (NO). Means to reduce the effects of ET-1 and increase synthesis of NO may have beneficial effects on the cardiovascular co-morbidity commonly associated with OSA. OBJECTIVES: The major aim of this study was to assess the relative importance of circulating biomarkers of ET-1 and NO in hemodynamic function in OSA patients. Potential production of ET-1 by circulating mononuclear cells was also measured to assess their contribution to plasma ET-1 levels. Biomarker levels before and after 12 wk of continuous partial airway pressure (CPAP) therapy were used to assess standard treatment. Mild/moderate exercise training was initiated with CPAP therapy in a subgroup of OSA patients to evaluate the potential benefits of physical activity on hemodynamic function and NO and ET-1 levels. METHODS: Overall, 16 newly diagnosed OSA patients (5 female, 11 male; age 45.4 ± 2.7 yr; RDI 24.6 ± 4.0 events/hr) were selected for study. Seven apparently healthy control volunteers (5 female, 2 male; age 39.43 ± 2.6 yr) screened for OSA served as control subjects. Blood pressure was recorded over one complete day and prior to, during, and following maximal exercise testing on a cycle ergometer. Blood samples were taken prior to exercise testing and assessed for nitrate and nitrite by HPLC and for big endothelin-1 and ET-1 by ELISA. Relative gene expression of preproendothelin-1 was measured by real-time RT-PCR. Following initial testing, patients were stratified into either a standard therapy group (nCPAP) or a standard therapy group with a mild/moderate intensity aerobic training regimen (nCPAP+Ex). Baseline testing was repeated following 12 wk of treatment. Statistical significance was set at p < 0.05 a priori. RESULTS: 24 hr ambulatory systolic and diastolic blood pressure were elevated in OSA patients vs. control subjects (systolic: 128.9 ± 3.8 mmHg vs. 108.8 +- 1.3 mmHg, respectively; diastolic: 97.5 ± 2.0 mmHg vs. 82.1 ± 1.9 mmHg, respectively). OSA patients experienced significant elevations in systolic (OSA 209.7 ± 5.7 mmHg; Control 174.5 +- 6.2 mmHg) and mean arterial pressures (OSA 125.8 ± 3.2 mmHg; Control 109.05 ± 4.5 mmHg) at peak exercise. No differences in nitrate, nitrite, or big endothelin-1 were noted. Plasma endothelin-1 concentrations were below assay detection limit. Big endothelin-1 levels were significantly correlated with BMI in both OSA patients (r=0.955; p=0.001) and control subjects (r=0.799; p=0.045). Relative gene expression of preproendothelin-1 was not elevated in OSA patients (0.40 ± 0.20 fold increase over control subjects). Group nCPAP usage was above minimum therapeutic threshold, but was non-uniform in both groups, with an overall range of 182 to 495 min mean usage per night. A mild/moderate exercise training program failed to elicit a training response through standard hemodynamic or cardiopulmonary indices. Plasma nitrite levels rose from 55.3 ± 4.7 μg/ml to 71.0 ± 7.6 μg/ml in the nCPAP group. CONCLUSIONS: Moderate OSA is associated with elevated blood pressure at rest and during exercise stress that bears no relationship to circulating biomarkers of NO and ET-1 or immune preproendothelin production in patients without diagnosed hypertension. nCPAP therapy failed to elicit significant improvements in hemodynamic function, with or without moderate exercise. Plasma nitrite levels rose following nCPAP therapy, indicating a possible increase in basal nitric oxide formation. Higher intensity exercise regimens may be needed to elicit the positive benefits of exercise training in OSA patients without significant cardiovascular dysfunction.
Ph. D.

Introdução: Alterações autonômicas e reduzido desempenho cognitivo têm sido reportados em pacientes com apneia obstrutiva do sono (AOS). Estudos anteriores demonstraram que o treinamento físico (TF) reduz a atividade nervosa simpática muscular (ANSM) durante testes que exige maior demanda cognitiva em pacientes obesos e com insuficiência cardíaca. O objetivo do estudo foi avaliar o efeito do TF na ANSM e no desempenho executivo durante o teste de controle inibitório e sustentação da atenção em pacientes com AOS. Métodos: Trinta e três pacientes com AOS (índice de apneia e hipopneia = 43 ± 5 eventos por hora de sono, idade = 52 ± 1 anos, índice de massa corporal = 30 ± 1 kg/m2) e sem outras comorbidades foram randomizados em grupo não treinado (n = 15) e grupo treinado (n = 18). A ANSM (microneurografia), frequência cardíaca (eletrocardiograma), pressão arterial média (método oscilométrico) foram coletados durante 4 minutos em repouso seguido pela aplicação de 3 minutos do Stroop Color Word Test (SCWT), conhecido como teste de estresse mental. O consumo de oxigênio no pico do exercício (VO2 pico) foi avaliado pela ergoespirometria. O desempenho executivo foi avaliado pelo total de cores corretas faladas durante 3 minutos de SCWT. O TF consistiu de 3 sessões semanais de exercício aeróbio, exercícios resistidos e flexibilidade pelo período 6 meses. Resultados: Os grupos foram semelhantes no início do estudo em relação ao nível de escolaridade, mini exame de estado mental, índice de massa corporal, VO2 pico, fração de ejeção, frequência cardíaca, pressão arterial de repouso e percepção subjetiva de estresse (P > 0,05). O TF aumentou o consumo de oxigênio pico (P < 0,05), reduziu o IAH (P < 0,05), índice de despertares (P < 0,05) e os eventos de dessaturação de O2 durante o sono (P < 0,05). O TF também reduziu a ANSM tanto na condição basal como durante o esforço cognitivo ao longo da aplicação do SCWT (P < 0,05). No período pré e pós dos grupos não treinado e treinado, a frequência cardíaca e pressão arterial média durante o SCWT não diferiu entre os grupos (P > 0,05), entretanto, ambos os grupos apresentaram um aumento significativo (P < 0,05) da frequência cardíaca (nos 3 minutos de SCWT) em relação ao basal e aumento da pressão arterial média (no 2º e 3º minutos de SCWT) em relação ao basal e ao 1º minuto de SCWT. Após a intervenção o grupo treinado obteve maior quantidade de cores corretas faladas durante 3 minutos de SCWT quando comparado ao grupo não treinado (P < 0,05). Conclusões: O TF reduziu a ANSM e melhorou o desempenho executivo durante o teste de SCWT em pacientes com AOS. Estes efeitos estão associados a um menor risco de eventos cardiovasculares, assim como melhor desempenho na realização de tarefas que exijam maior demanda cognitiva nos pacientes com AOS moderada a grave
Introduction: Autonomic alterations and reduced cognitive performance have been reported in patients with obstructive sleep apnea (OSA). Previous studies have shown that exercise training (ET) reduces muscle sympathetic nerve activity (MSNA) during tests that demand greater cognitive demand in obeses and heart failure patients. The aim of the study is to evaluate the effect of physical training on MSNA and executive performance during the inhibitory control and attention span test in patients with OSA. Methods: Thirty-three patients with OSA (apnea and hyponea índex = 43 ± 5 events per hour of sleep, age = 52 ± 1 years, body mass index = 30 ± 1 kg/m²) and without other comorbidities were randomized into a untrained group (n = 15) and exercise-trained group (n = 18). The MSNA (microneurography), heart rate (electrocardiogram), mean arterial pressure ( oscillometric methods) were collected during 4 minutes at rest followed by the 3-minute application of the Stroop Color Word test (SCWT), known as mental stress test. Oxygen consumption at peak exercise (VO2 peak) was evaluated by ergospirometry. Executive performance was assessed by the total correct colors spoken during 3 minutes of SCWT. The ET consisted of 3 weekly sessions of aerobic exercise, resisted exercises and flexibility for the 6-month period. Results: The groups were similar in relation to level of schooling, mini mental state examination, body mass index, VO2 peak, ejection fraction, heart rate, resting blood pressure and subjective perception of stress (P > 0.05). The ET increased the peak oxygen consumption (P < 0.05), reduced AHI (P < 0.05), arousal index (P < 0.05) and O2 desaturation events (P < 0.05) and weight (P < 0.05). The ET also reduced MSNA both at baseline and during cognitive effort throughout the SCWT application (P < 0.05). Heart rate and mean arterial pressure during SCWT did not differ between groups (P > 0.05); however, both groups showed a significant increase (P < 0.05) in heart rate (in the 3 minutes of SCWT) in baseline and increase mean arterial pressure (at the 2nd and 3rd minutes of SCWT) in relation to the baseline and at the 1st minute of SCWT. The exercise-trained group obtained the highest amount of correct colors spoken during 3 minutes of SCWT when compared to the control group (P < 0.05). Conclusions: The ET reduces MSNA and improves executive performance during the SCWT test in patients with OSA. These effects are associated with a lower risk of cardiovascular events, as well as better performance in tasks requiring greater cognitive demand in patients with moderate to severe OSA

Introdução: A prevalência da apneia obstrutiva do sono (AOS) entre pessoas com mais de 70 anos atinge até 95%. As opções de tratamento incluem o uso de pressão positiva nas via aérea, dispositivos intraorais e mudança de estilo de vida. Programa de exercícios aeróbicos ou combinados mostrou reduzir o índice de apneia-hipopneia (IAH) em adultos de meia-idade. No entanto, o efeito do treinamento resistido sobre a gravidade da AOS de pessoas idosas é controverso. O objetivo do presente estudo é avaliar o impacto do treinamento resistido no IAH e identificar possíveis mediadores do efeito do exercício. Métodos: Estudo randomizado, mascarado, controlado, em grupo paralelo. Indivíduos entre 65 e 80 anos, com IAH entre 20 e 50 eventos/hora na poligrafia respiratória foram atribuídos aleatoriamente para 12 semanas de treinamento de força ou grupo controle. IAH foi o principal desfecho. Índice de massa corporal (IMC) e teor de água corporal foram testados como mediadores. Espessura do músculo, força máxima e função física também foram avaliadas. Resultados: A amostra incluiu 23 indivíduos, 57% homens, com média de idade de 71±5 anos, alocados para treinamento (n=12) e grupo controle (n=11). O IAH basal nos grupos de treinamento e controle foi, respectivamente, 30±7/h e 29±9/h. No seguimento, o IAH mostrou significativa interação tempo × grupo. Não foi observada correlação entre Delta IAH e Delta IMC ou Delta teor de água corporal. A interação tempo × grupo permanece significativa após ajustar o modelo GEE para esses possíveis mediadores. Conclusão: Treinamento resistido a curto prazo em pessoas idosas é viável e muda de forma favorável a severidade da AOS e desfechos funcionais. As alterações no IMC e no teor de água corporal não parecem mediar a redução da IAH. Estudos futuros em amostras maiores de pessoas idosas são necessários.
Introduction: Obstructive sleep apnea (OSA) prevalence among persons older than 70 years reaches up to 95%. The treatment options include use of positive airway pressure, intraoral devices, and lifestyle changes. Aerobic or combined exercise program has been shown to reduce the apnea-hypopnea index (AHI) in middle-aged adults. However, the effect of resisted training on OSA severity of older persons is controversial. The aim of the present study is to evaluate the impact of resisted training on the AHI and to identify possible mediators of the effect of exercise. Methods: This was a randomized, masked, controlled, parallel group trial. Subjects between 65 and 80 years, with AHI between 20 and 50 events/hour in the respiratory polygraphy were assigned randomly to 12 weeks of strength training or control groups. AHI was the main outcome. Body mass index (BMI) and bodily water content were tested as mediators. Muscle thickness, maximum strength, and physical function were assessed also. Results: The sample included 23 subjects, 57% men, aged 71±5 years, randomized to training (n=12) and control groups (n=11). The baseline AHI in the training and control groups were, respectively, 30±7/h and 29±9/h. At follow-up, the AHI showed significant time × group interaction. No correlation was observed between Delta AHI and delta BMI or delta bodily water content. The time × group interaction remains significant after adjusting the GEE model for these possible mediators. Conclusion: Short-term resisted training in older persons is feasible and changes favorably OSA severity and functional outcomes. Changes in BMI and in bodily water content do not seem to mediate the reduction in AHI. Future studies in larger samples of older persons are necessary.

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

L'obésité est associée à une morbidité cardiovasculaire et métabolique accrue. La littérature récente souligne l'importance du sommeil comme élément contributif de l'obésité. En effet, cette relation est bidirectionnelle : le sommeil peut participer à la pathogenèse de l'obésité et cette dernière joue également un rôle étiologique dans le développement des anomalies respiratoires nocturnes, en particulier du syndrome d'apnées du sommeil (SAOS). L'activité physique régulière constitue une modalité importante de la prise en charge de l'obésité et du SAOS et peut participer à la maîtrise des facteurs de risque cardiovasculaires et métaboliques. Cependant, quel que soit l'âge, l'obésité et le SAOS ont souvent été associés à une intolérance à l'effort.Dans ce travail de thèse nous avons donc exploré la relation entre l'activité physique, l'obésité, le sommeil et les facteurs de risque cardiovasculaire et métabolique associés chez des adultes en surpoids/obèses présentant un SAOS et des adolescents obèses, population dans laquelle ce risque est en cours d'installation.Après avoir montré l'importance de l'activité physique spontanée dans la maîtrise de l'hypertension artérielle du soir chez des personnes porteurs d'un SAOS à haut risque cardiovasculaire et la faiblesse des niveaux d'AP dans cette population, nous avons vérifié l'effet du SAOS sur la condition physique aérobie et l'oxydation lipidique dans un groupe de participants SAOS non obèses.La surcharge graisseuse thoracique peut majorer la contrainte ventilatoire à l'exercice et contribuer à l'intolérance à l'effort dans l'obésité. Nous avons recherché si les facteurs ventilatoires pouvaient rendre compte de l'intolérance à l'effort de l'adolescent obèse. Cette population dans laquelle la morbidité cardio-métabolique n'est pas encore complètement installée, a été choisie pour limiter l'impact de cette dernière sur la condition physique et isoler les facteurs ventilatoires éventuellement responsables de cette intolérance. Nous avons mis en évidence une respiration à plus bas niveau de volume pulmonaire ainsi qu'une contrainte ventilatoire et un essoufflement majorés lors d'un exercice avec port du poids (marche), réversibles par un programme d'exercice de 12 semaines; réversibilité pouvant expliquer une partie de l'amélioration de la condition physique induite par l'entraînement. Nous avons également confirmé la présence d'anomalies métaboliques et cardiovasculaires précoces chez le jeune obèse (inflammation, stress oxydant, insulino-résistance) et une altération de la qualité et de la durée du sommeil.Compte tenu des difficultés à perdre du poids dans la durée, nous avons étudié l'effet d'un programme d'exercice seul, sans restriction calorique, sur les marqueurs pré-cliniques de morbidité métabolique et vasculaire ainsi que le sommeil dans un groupe d'adolescents obèses. Nous avons montré une correction partielle des anomalies métaboliques et cardiovasculaires, une amélioration des quantité et qualité de sommeil ainsi qu'une augmentation des niveaux d'activité physique malgré l'absence de perte de poids. Les adolescents qui diminuaient le plus leur masse grasse viscérale bénéficiaient le plus d'améliorations métaboliques.Le maintien à long terme des acquis après un réentraînement en clinique constitue un enjeu important. Ainsi, une partie méthodologique de ce travail avait pour but d'évaluer la transférabilité sur le terrain d'indicateurs métaboliques mesurés en laboratoire (i.e. Lipoxmax et point de croisement glucido-lipidique) en vue de favoriser la mise en œuvre d'Activités Physiques Adaptées. Cette étude a permis de souligner la nécessité d'une détermination spécifique en fonction de l'activité physique adaptée envisagée.En conclusion, nos résultats soulignent l'intérêt majeur de l'activité physique et de l'exercice (sans restriction calorique) dans la prise en charge de la personne en surpoids ou obèse présentant ou non un SAOS
Obesity is a major public health issue and is associated with increased cardiovascular and metabolic morbidity. Recent studies underline the potential bidirectional association between sleep and obesity: sleep seems to contribute to the pathogenesis of obesity and obesity also appears to play an etiological role in the development of sleep disturbances, such as obstructive sleep apnea (OSA). Physical activity is an important modality for the treatment of obesity and OSA and can contribute to decreasing cardiovascular and metabolic risk factors. However, both obesity and OSA have been associated with exercise intolerance.In this thesis, we explored the relation between physical activity, exercise, obesity, sleep and associated cardiovascular and metabolic risk factors in overweight/obese adults with OSA and obese adolescents.We showed that physical activity is the major determinant for evening blood pressure in adults with OSA presenting high cardiovascular risk. We then explored the effects of OSA on cardiorespiratory fitness and lipid oxidation in non-obese adults with OSA. Accumulation of chest wall fat can increase ventilatory constraint during exercise and may contribute to exercise intolerance in obesity. Thus, we aimed to verify the role of ventilatory factors in obese adolescents' exercise tolerance. We chose this population because their cardiovascular and metabolic risk factors are not fully established therefore we could isolate the effects of ventilatory factors on exercise tolerance. Our results showed that obese adolescents breathed at lower lung volumes and presented ventilatory constraint during weight-bearing exercise (walking). Exercise training improved breathing strategy by restoring breathing at higher lung volumes and decreasing ventilatory constraint. We also confirmed the presence of cardiovascular and metabolic abnormalities (inflammation, oxidative stress, insulin-resistance) and altered sleep quality and quantity. Long-term maintenance of weight loss is difficult to achieve, thus we examined the effects of exercise training alone, without dietary restriction, on markers of cardiovascular metabolic morbidity and sleep in obese adolescents. In the absence of weight loss, we showed improved metabolic and cardiovascular anomalies, improved sleep quality and quantity as well as increased spontaneous physical activity. The subgroup of participants who lost the most visceral fat demonstrated greater improvements in insulin-resistance and inflammation. Maintaining the beneficial effects of an exercise rehabilitation program is of particular importance. Thus, a methodological part of this thesis focused on the transferability of metabolic indices measured in a laboratory (i.e. Lipoxmax and crossover point) onto the field in order to prescribe Adapted Physical Activities. This study suggests the need to perform specific tests to use these indices outside of a clinical setting.In conclusion, our results highlight the major role of physical activity and exercise (without dietary restriction) in the prevention and treatment of overweight/obesity with or without OSA

INTRODUÇÃO. Estudos anteriores demonstraram que pacientes com síndrome metabólica (SMet) e apnéia obstrutiva do sono (SAOS) apresentam hiperativação simpática e hipersensibilidade quimiorreflexa. Neste trabalho, testamos as hipóteses de que: 1) dieta hipocalórica associada à treinamento físico (D+TF) melhora a sensibilidade quimiorreflexa em pacientes com SMet e 2) Os efeitos da D+TF seriam mais pronunciados em pacientes com SMet+AOS que em pacientes sem AOS (SMet-AOS). MÉTODOS. Vinte e sete pacientes nunca tratados da SMet (ATP-III) foram alocados em: 1) SMet+AOS (n = 15, 53±2 anos) e 2) SMet-OSA (n = 12, 43±2 anos). A AOS foi caracterizada por um índice de apnéia-hipopnéia (IAH)> 15 eventos / hora (polissonografia). Atividade nervosa simpática muscular (ANSM) foi avaliada pela técnica de microneurografia e pressão arterial (PA) pelo método oscilatório. A sensibilidade quimiorreflexa periférica foi avaliada através da inalação de uma mistura gasosa contendo 10% O2 e 90% N2 com titulação de CO2; e a sensibilidade quimiorreflexa central através da inalação de 7% CO2 e 93% O2 por 3 min. A dieta hipocalórica foi de -500 kcal da taxa metabólica de repouso e o treinamento físico se estendeu por 4 meses, 3 vezes/ semana. RESULTADOS. A associação da D+TF reduziu semelhantemente peso corporal (5,5±0,7 e 6,2±0,6 kg, P = 0,44), circunferência abdominal (CA, 5,6±1,2 e 5,4±1,0 cm, P = 0,91), PA sistólica (10,9±3,2 vs 13,3±3,5 mmHg, P = 0,62) e diastólica (8,5±1,6 vs 8,3±1,4 mmHg, P = 0,95) e, similarmente, o aumento do consumo de oxigênio de pico (20±5,9 e 16±7,3%, P = 0,69) em pacientes com SMet+AOS e SMet-AOS. A D+TF, reduziu significativamente o IAH (38±6,2 vs 18±3,9 eventos / hora, P = 0,01) e aumentou a saturação mínima de O2 (81±2,3 vs 84±1,9 %, P = 0,01) em pacientes com SMet+AOS. Durante a estimulação hipóxica, D+TF reduziu significativamente os níveis de ANSM tanto em pacientes com SMet+AOS (41±1,9 versus 33±2,0 impulsos/ min, P = 0,02) como em SMet-AOS (36±3,2 versus 28±1,7 impulsos/ min, P = 0,05). Durante a estimulação hipercápnica, D+TF reduziu significativamente os níveis de ANSM em pacientes com SMet+AOS (39±2,0 versus 30±1,1 impulsos/ min, P = 0,0005), mas não em pacientes com SMet- AOS. CONCLUSÕES. Tratamento não-farmacológico como D+TF melhora o controle quimiorreflexo periférico da ANSM em pacientes com síndrome metabólica. Esta mudança autonômica é mais pronunciada em pacientes com SMet+AOS, nos quais D+TF melhora tanto o controle quimiorreflexo periférico como o central. Além disso, D+TF melhora o distúrbio do sono em pacientes com SMet+AOS. Sendo assim, estes resultados sugerem que D+TF pode reduzir o risco cardiovascular em pacientes com SMet e AOS
INTRODUCTION. Previous studies have shown that patients with metabolic syndrome (MetS) and obstructive sleep apnea (OSA) have sympathetic hyperactivation and chemoreflex hypersensitivity. We tested the hypothesis that: 1) Hypocaloric diet associated with exercise training (D+ET) would improve chemoreflex sensitivity in patients with MetS and 2) The effects of D+ET would be more pronounced in patients with MetS+OSA than in patients without OSA (MetS-OSA). METHODS. Twenty three never treated MetS patients (ATP-III) were allocated into: 1) MetS+OSA (n=15, 53±2 yrs); and 2) MetS-OSA (n=12, 43±2 yrs). OSA was characterized by an apnea-hypopnea index (AHI) >15 events/hour (polysomnography). Muscle sympathetic nerve activity (MSNA) was evaluated by microneurography technique and blood pressure (BP) by oscillatory method. Peripheral chemoreflex sensitivity was evaluated by inhalation of 10%O2 and 90%N2 with CO2 titrated, and central chemoreflex by 7%CO2 and 93%O2 for 3 min. The hypocaloric diet was set at -500 kcal of the resting metabolic rate and exercise training extended over 4 months, 3 times/ week. RESULTS. D+ET similarly reduced body weight (5.5±0.7 and 6.2±0.6kg, P=0.44), waist circumference (WC, 5.6±1.2 and 5.4±1.0 cm, P=0.91), systolic BP (10.9±3.2 vs. 13.3±3.5 mmHg, P=0.62) and diastolic BP (8.5±1.6 vs. 8.3±1.4 mmHg, P=0.95), and similarly increased peak oxygen consumption (20±5.9 and 16±7.3%, P=0.69) in MetS+OSA and MetS-OSA patients. D+ET significantly reduced AHI (38±6.2 vs. 18±3.9 events/hour, P=0.01) and minimal O2 saturation (81±2.3 vs. 84±1.9%, P=0.01) in MetS+OSA patients. D+ET significantly reduced MSNA levels during hypoxia in MetS+OSA (41±1.9 vs. 33±2.0 bursts/min, P=0.02) and MetS-OSA (36±3.2 vs. 28±1.7 bursts/min, P=0.05) patients. D+ET significantly reduced MSNA levels during hypercapnia in MetS+OSA patients (39±2.0 vs. 30±1.1 bursts/min, P= 0.0005), but not in MetS-OSA patients. CONCLUSIONS. Non-pharmacological treatment based on D+ET improves peripheral chemoreflex control of MSNA in patients with MetS. This autonomic change is more pronounced in patients with MetS+OSA, in whom D+ET improves both peripheral and central chemoreflex controls. In addition, D+ET improves sleep disorder in patients with MetS+OSA. Altogether, these findings suggest that D+ET reduce cardiovascular risk in patients with MetS+OSA

A síndrome de Down (SD) é a alteração cromossômica mais comum nos seres humanos e traz consigo algumas co-morbidades como: hipotonia muscular, baixo condicionamento cardiorrespiratório e obesidade. A prática de exercícios físicos diminui o risco desses fatores, o que pode contribuir para melhora da qualidade de vida e autonomia dessas pessoas. Este estudo teve por objetivo avaliar o impacto de um programa de exercícios físicos para pessoas com síndrome de Down. Participaram desse estudo 21 pessoas com SD com idades entre 18 e 32 anos. Foram avaliados: adesão ao programa, condicionamento cardiorrespiratório, força muscular, composição corporal, equilíbrio postural, nível de atividade física diário dos participantes da pesquisa e de seus principais cuidadores e a correlação entre estes, o risco para Síndrome da Apneia Obstrutiva do Sono (SAOS) e as principais barreiras que influenciavam essas famílias a adotarem a prática de exercício físico. Houve boa adesão ao programa. Os resultados mostraram aumento da força muscular, melhora no condicionamento cardiorrespiratório e equilíbrio postural. Não houve diferença para composição corporal e no nível de atividade física dos participantes e de seus principais cuidadores no pós-programa. Houve correlação moderada em atividade física moderada e vigorosa (AFMV) e correlação forte em passos diários entre os participantes e seus principais cuidadores. A falta de tempo disponível, de condições financeiras, falta de incentivo e de interesse em praticar exercício foram fatores mencionados pelos principais cuidadores como os mais impeditivos para inclusão do exercício físico em seu cotidiano. Conclui-se que a prática de exercícios traz benefícios à saúde das pessoas com SD, e que há correlação positiva no nível de atividade física das pessoas com SD e de seus principais cuidadores
The Down syndrome (DS) is the most common chromosomal alteration in humans and brings some comorbidities such as muscle hypotonia, low physical conditioning and obesity. Physical exercise reduces these risk factors, which can contribute to the improvement of quality of life and autonomy of DS individuals. This study aim evaluate the impact of physical exercise program in individuals with DS. Twenty one DS individuals with 18-32 years old were evaluated in: adherence to the program, cardiorespiratory fitness, muscle strength, body composition, balance, level of physical activity, the risk for sleep apnea syndrome and the information about the obstacles that influenced these caregivers and the DS to adhere to regular exercise in their daily. After physical exercise program, were observed increase in muscle strength, cardiorespiratory fitness and balance. The body composition and physical activity level of the participants and their caregivers not changed, and there was a moderate correlation between in the moderate vigorous physical activity (MVPA) and strong correlation steps day between the participants and the carevigers. The lack of available time, financial conditions, lack of incentive and interest in practicing exercise was factors impeding to include exercise in their daily. It was concluded that the practice of exercise brings benefits to the health of people with DS, and that there is a correlation of physical activity and people of their caregivers

Introdução: A pericardiectomia é o tratamento de escolha para pacientes com pericardite constritiva crônica sintomática, entretanto, o impacto do procedimento na capacidade cardiopulmonar e fisiologia cardiorrespiratória durante a vigília e sono é pouco estudado. Objetivo: Avaliar o impacto da cirurgia de pericardiectomia sobre a capacidade funcional de pacientes com pericardite constritiva crônica sintomática. Métodos: Trata-se de estudo observacional prospectivo com 25 pacientes consecutivos com diagnóstico de pericardite constritiva crônica submetidos à pericardiectomia. Foram realizados os seguintes procedimentos uma semana antes e seis meses após a pericardiectomia: avaliação clínica e antropométrica, avaliação da qualidade de vida e do sono, dosagem dos níveis séricos de BNP, ecocardiograma transtorácico, teste cardiopulmonar de esforço, polissonografia noturna completa. Resultados: A idade média foi 45 anos, com predomínio do sexo masculino (76%). A etiologia foi principalmente idiopática (76%), seguida por tuberculose (12%). O ecocardiograma revelou fração de ejeção do ventrículo esquerdo preservada e dilatação de veia cava inferior (92%) na maioria dos pacientes. Todos os pacientes foram submetidos à pericardiectomia de frênico a frênico via esternotomia mediana, sem circulação extracorpórea. Após a pericardiectomia, houve redução da: classe funcional III/IV (56% vs. 8%, p < 0,001), ascite (72% vs. 12%, p < 0,001) e edema de membros inferiores (88% vs. 24%, p < 0,001) em relação ao pré-operatório. O teste cardiopulmonar revelou melhora do VO2 pico (18,7 ± 5,6 vs. 25,2 ± 6,3 mL/kg/min, p < 0,001), limiar anaeróbico (13,1 ± 3 vs. 17,7 ± 5,5 mL/kg/min, p < 0,001) e velocidade na esteira rolante de 2,5 (2-2,5) para 3 (2,5-3,3) mph, p=0,001. Na análise multivariada, a idade foi o único preditor independente da variação de VO2 (r=-0,658, p=0,003). Os níveis séricos de BNP apresentaram redução significativa de 143 (83,5-209,5) pg/mL para 76 (40-117,5) pg/mL, p=0,011. A polissonografia noturna completa no pré-operatório demonstrou a presença de apneia do sono moderada/ grave (IAH >= 15 eventos/hora) em 13 pacientes, com predomínio de hipopneias. Não houve mudança significativa do índice de apneia-hipopneia após a pericardiectomia: IAH pré 15,6 (8,3-31,7) vs. IAH pós 14,6 (5,75-29,9), p=0,253; entretanto, houve melhora da qualidade do sono (Pittsburgh pré 7,8 ± 4,10 vs. Pittsburgh pós 4,7 ± 3,7, p < 0,001). O IAH apresentou correlação positiva com os níveis de BNP (r=0,418, p=0,037) e EuroSCORE (r=0,480, p=0,015) no pré-operatório. Conclusão: Pacientes com pericardite constritiva crônica sintomática apresentaram, seis meses após a cirurgia de pericardiectomia, melhora da capacidade cardiopulmonar, da classe funcional e da qualidade de vida. A apneia do sono se mostrou frequente e apresentou correlação com níveis séricos de BNP e EuroSCORE no pré-operatório. O índice de apneia-hipopneia não apresentou mudanças significativas após a pericardiectomia. A despeito disso, houve melhora da qualidade do sono
Introduction: Pericardiectomy is the treatment of choice for patients with symptomatic chronic constrictive pericarditis; however, the impact of the procedure on cardiopulmonary capacity and cardiorespiratory physiology during wakefulness and sleep has been poorly studied so far. Objective: To evaluate the impact of pericardiectomy surgery on functional capacity of patients with symptomatic chronic constrictive pericarditis. Methods: This is a prospective observational study with 25 consecutive patients diagnosed with chronic constrictive pericarditis submitted to pericardiectomy. The following procedures were performed one week before and six months after pericardiectomy: clinical and anthropometric evaluation, quality of life and sleep evaluation, serum BNP levels, transthoracic echocardiography, cardiopulmonary exercise test, complete nocturnal polysomnography. Results: The mean age was 45, with a predominance of males (76%). The etiology was mainly idiopathic (76%), followed by tuberculosis (12%). The echocardiogram revealed preserved left ventricular ejection fraction and inferior vena cava dilatation (92%) in most patients. All patients underwent phrenic to phrenic pericardiectomy via median sternotomy, without extracorporeal circulation. After pericardiectomy there was a reduction in: functional class III / IV (56% vs. 8%, p < 0.001), ascites (72% vs. 12%, p < 0.001) and lower limb edema (88% vs. 24%, p < 0.001) as compared to the preoperative period. The cardiopulmonary test revealed improvement in VO2 peak (18.7 ± 5.6 vs. 25.2 ± 6.3 mL/kg/min, p < 0.001), anaerobic threshold (13.1 ± 3 vs. 17.7 ± 5.5 mL/kg/min, p < 0.001) and velocity on the treadmill from 2.5 (2-2.5) to 3 (2.5-3.3) mph, p=0.001. In multivariate analysis, age was the only independent predictor of VO2 variation (r = -0.658, p = 0.003). Serum BNP levels showed a significant reduction from 143 (83.5-209.5) pg/mL to 76 (40-117.5) pg/mL, p=0.011. The complete nocturnal polysomnography in the preoperative period showed moderate / severe sleep apnea (AHI >= 15 events / hour) in 13 patients, predominantly hypopnea. There was no significant change in apnea-hypopnea index after pericardiectomy: AHI pre 15.6 (8.3-31.7) vs. AHI post 14.6 (5.75-29.9), p= 0.253; however, there was improvement in sleep quality (Pittsburgh pre 7.8 ± 4.10 vs. Pittsburgh post 4.7 ± 3.7, p < 0.001). AHI presented a positive correlation with BNP levels (r=0.418, p=0.037) and EuroSCORE (r=0.480; p=0.015) in the preoperative period. Conclusion: Patients with symptomatic chronic constrictive pericarditis showed improvement in cardiopulmonary capacity, functional class and quality of life six months after pericardiectomy. Sleep apnea was frequent and correlated with serum levels of BNP and EuroSCORE in the preoperative period. The apnea-hypopnea index did not show significant changes after pericardiectomy. Nevertheless, there was an improvement in sleep quality

Chez l'homme, l'hypoxie correspond à une inadéquation entre les besoins tissulaires et les apports en oxygène. Cet état est une caractéristique commune à l'exposition à l'altitude et au syndrome d'apnées obstructives du sommeil (SAOS), bien que celle-ci soit continue dans le premier cas et intermittente et nocturne dans le second.L'hypoxie d'altitude entraine une altération des performances cognitives et motrices. La réduction de la performance à l'exercice en altitude a longtemps été attribuée à une altération du métabolisme musculaire du fait d'une réduction de l'apport en oxygène. Les perturbations cérébrales induites par l'hypoxie pourraient également avoir un rôle majeur dans cette limitation.Le SAOS, véritable enjeu de santé publique, est associé à des troubles cognitifs pouvant ainsi influencer le fonctionnement quotidien des patients souffrant de ce syndrome et résulter en une somnolence diurne excessive, une baisse de la qualité de vie ou encore une réduction de la productivité au travail et des performances scolaires. Le fait que ces altérations cérébrales puissent influencer les capacités motrices et à l'effort des patients atteints d’apnées obstructives du sommeil reste en revanche à investiguer.Au cours de ce travail de thèse, nous nous sommes intéressés à deux modèles d’exposition hypoxique et à leurs conséquences cérébrales et neuromusculaires. Nous avons tout d’abord étudié l'effet d'une exposition à l'hypoxie d'altitude aigue (quelques heures) et prolongée (plusieurs jours) sur la fonction neuromusculaire et ses répercussions à l'exercice chez le sujet sain. Nous avons ensuite étudié l'influence du modèle d'hypoxie intermittente associé au SAOS sur la fonction neuromusculaire et la tolérance à l'exercice de ces patients. Nous avons ainsi cherché à caractériser les altérations cérébrales à l'exercice en lien avec ce syndrome et leur réversibilité suite à un traitement en ventilation par pression positive continue.Chez le sujet sain, nous avons démontré que la performance à l'exercice impliquant une masse musculaire réduite (fléchisseurs du coude) n'était pas limitée par une fatigue centrale accrue après 1 et 5 jours d'exposition à une altitude de 4350 m. Nous avons mis en évidence que la dysfonction musculaire (force et endurance réduites) observée chez le patient SAOS est associée à un déficit d'activation supraspinal et une augmentation de l'inhibition intracorticale. De plus, nos résultats suggèrent qu'une altération de la réponse cérébrovasculaire à l'exercice puissent impacter négativement la tolérance à l'exercice des patients souffrant d'un SAOS sévère. Ces altérations neuromusculaires et cérébrovasculaires n'étaient pas corrigées après un traitement de huit semaines par ventilation nocturne en pression positive continue soulignant la nature persistante de ces altérations cérébrales
In humans, hypoxia is defined as the mismatch between tissue requirement and oxygen delivery. This condition is a common feature between high-altitude exposure and obstructive sleep apnea syndrome (OSA), although it is continuous in the first instance and intermittent and nocturnal in the second one.High-altitude exposure causes an impairment in cognitive and motor performance. The reduction in exercise performance observed under hypoxic condition has been mainly attributed to altered muscle metabolism due to impaired oxygen delivery. However, hypoxia-induced cerebral perturbations may also play a major role in exercise limitation.OSA, a major public health concern, is associated with cognitive impairment that can alter patients' daytime functioning and result in excessive daytime sleepiness, reduced quality of life and lowered work productivity and school performance. The fact that these cerebral alterations can influence motor and exercise performance in patients with obstructive sleep apnea remains to be investigated.In this thesis, we investigated two different models of hypoxic exposure and their cerebral and neuromuscular consequences. First, we assessed the effect of acute (several hours) and prolonged (several days) high-altitude exposure on the neuromuscular function and its repercussions during exercise in healthy subject. Then, we then investigated the model of intermittent hypoxia associated with OSA and its influence on the neuromuscular function and exercise tolerance in these patients. We seeked to characterize cerebral alterations during exercise associated with this syndrome and their reversibility following continuous positive airway pressure treatment.In healthy subject, we showed that exercise performance involving a small muscle mass (elbow flexors) was not limited by an exacerbated amount of central fatigue after 1 and 5 days of high-altitude exposure (4,350 m). We highlighted that muscle dysfunction (reduced strength and endurance) was associated with a supraspinal activation deficit and an increase in intracortical inhibition. Moreover, our results suggest that an alteration in cerebrovascular response during exercise may contribute to reduced exercise tolerance observed in patients with severe OSA syndrome. The neuromuscular and cerebrovascular abnormalities were not reversed following an eight-week continuous positive airway pressure treatment, highlighting the persistent nature of the cerebral alterations

INTRODUÇÃO: Pacientes com síndrome metabólica (SMet) apresentam aumento na atividade nervosa simpática muscular (ANSM) e diminuição no ganho do controle barorreflexo arterial (CBR). E, a apnéia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrada em pacientes com SMet, exacerba essas disfunções autonômicas. Sabe-se que a incidência dos disparos e o padrão oscilatório da ANSM dependem do ganho (sensibilidade) e do tempo de retardo (latência) do CBR da ANSM (CBRANSM). Contudo, o padrão oscilatório da ANSM e o tempo de retardo do CBRANSM em pacientes com SMet associada ou não à AOS são desconhecidos. Além disso, estudos prévios demonstram que o treinamento físico associado à dieta hipocalórica (TF+D) diminui a incidência dos disparos da ANSM e aumenta o ganho do CBR em pacientes com SMet. No entanto, os efeitos de TF+D no padrão oscilatório da ANSM e no ganho e tempo de retardo do CBRANSM em pacientes com SMet associado ou não a AOS permanecem desconhecidos. MÉTODOS: Foram estudados quarenta e quatro pacientes com SMet (critérios do ATP III), sem uso de medicamentos, que foram divididos em dois grupos de acordo com a presença da AOS (SMet-AOS, n=23 e SMet+AOS, n=21). Um grupo controle saudável (n=12) foi, também, incluído no estudo. Para avaliar o efeito da intervenção, os pacientes foram divididos consecutivamente em quatro grupos: 1- Sedentário sem AOS (SMet-AOS Sed, n=10); 2- Sedentário com AOS (SMet+AOS Sed, n=10); 3- TF+D sem AOS (SMet-AOS TF+D, n=13) e; 4- TF+D com AOS (SMet+AOS TF+D, n=11). Os grupos TF+D foram submetidos ao treinamento físico aeróbio (40 min, 3 vezes por semana) associado à dieta hipocalórica (-500 kcal/dia) durante quatro meses e os grupos sedentários não realizaram a intervenção (TF+D) e somente receberam orientações clínicas. A AOS foi determinada através do índice de apneia e hipopneia (IAH) >15 eventos/hora (polissonografia). A ANSM (microneurografia), pressão arterial (batimento a batimento, método oscilométrico), padrão oscilatório da ANSM (relação dos componentes de baixa frequência-BF, e alta frequência-AF da ANSM, BFANSM/AFANSM, análise espectral autorregressivo monovariada) e o CBRANSM espontâneo (ganho e tempo de retardo, análise espectral autorregressivo bivariada) foram avaliados durante o repouso na posição deitada por 10 minutos. RESULTADOS: No período pré-intervenção, os pacientes com SMet-AOS e SMet+AOS apresentaram redução no BFANSM/AFANSM (P=0,01 e P<0,001, respectivamente) e no ganho do CBRANSM (P=0,01 e P<0,001, respectivamente), em comparação com o grupo Controle. E, os pacientes com SMet+AOS apresentaram menor BFANSM/AFANSM (P=0,02) e ganho do CBRANSM (P<0,001) em comparação com SMet-AOS. Ainda, o tempo de retardo do CBRANSM estava aumentado no grupo SMet+AOS em comparação com os grupos SMet-AOS e Controle (P=0,01 e P<0,001, respectivamente). Após a intervenção TF+D, ambos os grupos SMet-AOS e SMet+AOS apresentaram redução do peso corporal, circunferência abdominal e pressão arterial sistólica e aumento consumo de oxigênio no pico do exercício. Nos pacientes com SMet-AOS, o TF+D aumentou o BFANSM/AFANSM (P<0,05) e o ganho do CBRANSM (P<0,01). Nos pacientes com SMet+AOS, o TF+D aumentou o nível de saturação mínima de O2 (P=0,02) durante a polissonografia, o BFANSM/AFANSM (P=0,001) e o ganho do CBRANSM (P<0,01) e, diminuiu o IAH (P<0,01) durante a polissonografia e o tempo de retardo do CBRANSM (P=0,01). Nenhuma alteração foi observada em ambos os grupos sedentários. CONCLUSÕES: O TF+D aumenta o padrão oscilatório da ANSM e o ganho do CBRANSM em pacientes com SMet, independentemente da presença da AOS. No entanto, este efeito é mais pronunciado em pacientes com SMet+AOS, já que após a intervenção o tempo de retardo do CBRANSM foi também diminuído nestes pacientes
INTRODUCTION: Patients with metabolic syndrome (MetS) have increased muscle sympathetic nerve activity (MSNA) and decreased arterial baroreflex control (BRC). Obstructive sleep apnea (OSA), a comorbidity often found in patients with MetS, exacerbates these autonomic dysfunctions. It is known that burst incidence and the oscillatory pattern of MSNA depend on the gain (sensitivity) and the time delay (latency) of BRC of MSNA (BRCMSNA). However, the oscillatory pattern of MSNA and the time delay of BRCMSNA in patients with MetS either with or without OSA are unknown. Moreover, previous studies have shown that exercise training associated with hypocaloric diet (ET+D) decreases the burst incidence of MSNA and increases the gain of BRC in patients with MetS. However, the effects of ET+D on the oscillatory pattern of MSNA and on the gain and time delay of BRCMSNA in patients with MetS with or without OSA remain unknown. METHODS: Forty-four never-treated MetS patients (ATP III criteria) were allocated in two groups according to the presence of OSA (MetS-OSA, n=23 and MetS+OSA, n=21). A healthy control group (n=12) was also included in the study. To evaluate the effect of the intervention, patients were consecutively divided into four groups: 1- Sedentary without OSA (MetS-OSA Sed, n=10); 2- Sedentary with OSA (MetS+OSA Sed, n=10); 3- ET+D without OSA (MetS-OSA TF+D, n=13) and 4- ET+D with OSA (MetS+OSA ET+D, n=11). ET+D groups were submitted to aerobic exercise (40 min, 3 times per week) associated to hypocaloric diet (-500 kcal / day) for four months and sedentary groups did not perform the intervention (ET+D) and only received clinical orientations. OSA was determined by the apnea-hypopnea index (AHI) >15 events/hour (polysomnography). The MSNA (microneurography), blood pressure (beat-to-beat basis, oscillometry method), oscillatory pattern of MSNA (relationship of the components of low frequency - LF, and high frequency - HF of MSNA, LFMSNA/HFMSNA, monovariate autoregressive spectral analysis) and spontaneous BRCMSNA (gain and time delay, bivariate autoregressive spectral analysis) were evaluated during rest at lying position for 10 min. RESULTS: In the pre-intervention period, patients with MetS-OSA and MetS+OSA showed reduced LFMSNA/HFMSNA (P=0.01 and P<0.001, respectively) and gain of BRCMSNA (P=0.01 and P<0.001, respectively) compared to Control group. And, the patients with MetS+OSA had lower LFMSNA/HFMSNA (P=0.02) and gain of BRCMSNA (P<0.001) compared to MetS- OSA. The time delay of BRCMSNA was higher in MetS+OSA group compared to MetS-OSA and Control groups (P=0.01 and P<0.001, respectively). After ET+D, both groups MetS-OSA and MetS+OSA decreased body weight, waist circumference and systolic blood pressure and increased peak oxygen uptake during exercise. In patients with MetS-OSA, the ET+D increased LFMSNA/HFMSNA (P<0.05) and the gain of BRCMSNA (P<0.01). In patients with MetS+OSA, ET+D increased minimum oxygen saturation level (P=0.02) during polysomnography, the LFMSNA/HFMSNA (P=0.001) and the gain of BRCMSNA (P<0.01) and decresed AHI (P<0.01) during polysomnography and the time delay of BRCMSNA (P=0.01). No alterations were observed in both sedentary groups. CONCLUSION: ET+D increase the oscillatory pattern of MSNA and the gain of BRCMSNA in patients with MetS, regardless of the presence of OSA. However, this effect is more pronounced in patients with MetS+OSA, since after intervention the time delay of BRCMSNA was also diminished in these patients

L'exercici físic de molt elevada intensitat i la síndrome d'apnea obstructiva del son (SAOS) són dues causes emergents de patologia cardiovascular que poden promoure canvis maladaptatius a nivell vascular i cardíac. Aquests canvis podrien ser la base de l'increment del risc de malaltia ateroscleròtica i de fibril·lació auricular (FA) en individus amb aquestes condicions. Un dels punts centrals de la present tesi és l'anàlisi del remodelat cardiovascular associat a la pràctica d'exercici físic a dosis molt elevades i l'exploració dels possibles mecanismes fisiopatològics associats. Amb aquesta finalitat es va utilitzar un model animal de rata corredora en cinta rodant en la qual es van comparar els canvis provocats per diferents dosis d'activitat física (intensa i moderada). S'ha demostrat que l'exercici d'alta intensitat, contràriament a l'exercici moderat, promou un remodelat advers de la paret de l'aorta amb un increment de fibrosi acompanyat d'una reducció de les seves propietats elàstiques. Alhora s'ha observat un remodelat estructural patològic de l'artèria caròtida i dels vasos intramiocàrdics associat a l'exercici intens. Les diferents dosis d'exercici s'associen a patrons característics d'expressió de miARNs en la paret aòrtica que podrien constituir un mecanisme regulador important. A més, s'ha confirmat que l'exercici d'alta intensitat en el nostre model animal promou la fibrogènesi auricular. El sildenafil ha previngut el desenvolupament de fibrosi únicament en la cavitat esquerra auricular, suggerint una possible acció directa sobre el miocardi. El TGF-β sembla jugar un paper clau en l'efecte protector del sildenafil. D'altra banda, la SAOS té una sèrie d’efectes (hipòxia i hipercàpnia intermitent, pressió intratoràcica que es torna molt negativa i microdespertars) que a llarg termini poden promoure l'aparició de complicacions cardiovasculars. El model crònic descrit en aquesta tesi és un model no invasiu que es pot aplicar a l'exploració de diferents conseqüències de la SAOS: la hipòxia i hipercàpnia intermitent i els esforços respiratoris. El model de SAOS ha promogut una dilatació de l'aorta i un engruiximent de la seva paret. A nivell fisiopatològic, s'ha demostrat la importància de l'estrès oxidatiu i de l'activació del sistema RAA en la promoció del remodelat vascular. Els resultats suggereixen que el tractament amb cèl·lules mare mesenquimals (CMMs) podria resultar beneficiós, atenuant el remodelat vascular induït per la SAOS. A més, la SAOS ha promogut el desenvolupament de fibrosi auricular promoguda per una acció proinflamatòria i per una reducció en la degradació del col·lagen en la qual la MMP-2 hi juga un paper principal. Les CMMs poden tenir un paper potencial en la prevenció del remodelat fibròtic auricular possiblement a través d'un mecanisme antiinflamatori.
High intensity resistance training and obstructive sleep apnea (OSA) are emerging risk factors for cardiovascular disease that may promote maladaptative changes in the vessels and the heart. These changes could lead to an increased risk of atherosclerotic burden and atrial fibrillation (AF), affecting individuals under such conductions. One of the main goal of this doctoral thesis is the analysis of the cardiovascular remodelling associated with very-high doses of exercise and its physiopathology. A rat model subjected to aerobic treadmill training is used to compared the changes induced by different exercise doses (very-high and moderate). We demonstrated that intense exercise, unlike moderate exercise, promote an adverse aortic wall remodelling with fibrosis and decreased elastic proprieties. Also, intense exercise induce pathologic structural remodeling of the carotid artery and intramyocardial vessels. Exercise-dose- dependent miRNA profile expression in the aorta may regulate this response. Moreover, our study supported that intense exercise induce atrial fibrogenesis. Sildenafil specifically prevented the increase of fibrosis in the left atria, suggesting a direct action within the myocardium. TGF-β likely contributes to this protective effect. OSA is characterized by intermittent hypoxia and hypercapnia, negative intratoracic pressures and arousals, that may ultimately induce cardiovascular complications. Here, we use a chronic non-invasive OSA rat model involving both thoracic pressure swings and intermittent hypoxia and hypercapnia to explore its cardiovascular consequences. In our model, OSA promote aortic dilatation and increase wall thickness. We demonstrate that increased oxidative stress and RAAS upregulation likely mediate these effects. Results suggest that mesenchymal stem cells (MSC ) infusions could prevent OSA-induced aortic remodeling. Moreover, OSA promoted an increase in atrial fibrosis, which can be mediated in part by the systemic and local inflammation and by decreased collagen-degradation, possibly due to a MMP-2 downregulation. MSC might potentially prevent the atrial profibrotic remodelling induced by OSA by blunting the inflammatory response and normalizing MMP-2 synthesis.

Introdução. A síndrome metabólica (SMet) diminue a capacidade funcional (VO2pico). A apneia obstrutiva do sono (AOS), uma comorbidade frequentemente encontrado nos pacientes com SMet, causa um aumento adicional na atividade nervosa simpática. Testamos as hipóteses que: 1) A sobreposição da SMet e AOS prejudica o VO2pico e as respostas hemodinâmicas, metabólicas e ventilatória durante o teste de esforço cardiopulmonar máximo (TECP); e 2) A hiperativação simpática está envolvida no prejuízo dessas respostas. Métodos. Foram estudados 60 pacientes recém diagnosticados com SMet segundo o ATP-III, sedentários, não medicados, divididos em 2 grupos pelo corte do indíce de apneia-hipopneia (IAH) >= 15 eventos/h: SMet+AOS (49±1,7 anos, n=30), e SMet-AOS (46±1,4 anos, n=30). Um grupo controle saudável pareado por idade foi arrolado (C, 46±1,7 anos, n=16). O IAH foi avaliado pela polissonografia noturna e a atividade nervosa simpática muscular (ANSM) pela microneurografia. No TECP foram avaliados: VO2pico, FC reserva (FCpico-FCrepouso), atenuação da FC na recuperação (deltaFCrec =FCpico-FC no 1º, 2º, 4º e 6º min), comportamento da pressão arterial (PA), duplo produto (PASxFC), ventilação (VE), pulso de oxigênio (VO2/FC), equivalente ventilatório de oxigênio (VE/VO2) e equivalente ventilatório de gás carbônico (VE/VCO2). Resultados. SMet+AOS e SMet-AOS foram semelhantes nas características físicas e nos fatores de risco da SMet. Ambos os grupos com SMet apresentaram maior ANSM comparados com C, sendo que esses níveis foram maiores no SMet+AOS do que no SMet-AOS. O TECP não revelou diferenças nas variáveis ventilatórias e metabólicas entre os grupos. Entretanto, ambos os grupos com SMet apresentaram maiores valores de FCrep e de PAS e PAD (no repouso, durante o exercício, no pico e na recuperação), assim como menor VO2pico e pulso de O2pico, comparados ao C. Ambos os grupos com SMet apresentaram diminuição da FC reserva comparados com C, sendo menor no SMet+AOS comparado com SMet-AOS. SMet+AOS apresentou prejuízo no ?FCrec no 1º (16±2, 18±1 e 24±2 bpm impulsos/min, interação P=0,008), 2º (26±2, 32±2 e 40±3 bpm impulsos/min, interação P < 0,001), 4º (40±2, 50±2 e 61±3 bpm, interação P < 0.001) e 6º min (48±3, 58±2 e 65±3 impulsos/min, interação P < 0,001), enquanto SMet-AOS apresentou prejuízo no ?FCrec no 2º e 4º min comparado com C. Além disso, SMet+AOS apresentou menores valores de deltaFCrec 4º e 6º min comparado ao SMet-AOS. Análises adicionais mostraram uma correlação entre a ANSM e a FCrep (R=-0,37; P < 0,001) e entre a ANSM e o deltaFCrec no 1º (R=-0,35; P=0,004), 2º (R=-0,42; P < 0,001), 4º (R=-0,47; P < 0,001) e 6ºmin (R=-0,35; P=0,006). Conclusão. A sobreposição da AOS diminue o VO2pico e potencializa o prejuízo nas respostas hemodinâmicas durante o exercício e em pacientes com SMet, o que parece ser explicado, pelo menos em parte, pela hiperativação simpática. Portanto, a AOS é uma comorbidade que pode piorar o prognóstico de pacientes com SMet
Introduction. Metabolic syndrome (MetS) decreases functional capacity (peakVO2). Obstructive sleep apnea (OSA), a comorbidity often found in patients with MetS, leads to an additional increase in the sympathetic nerve activity. We tested the hypotheses that: 1) The overlap of MetS and OSA impairs peakVO2 and hemodynamic, metabolic and ventilatory responses during maximal cardiopulmonary exercise testing (CPET); and 2) Sympathetic hyperactivation is involved in this impairment. Methods. We studied 60 newly diagnosed MetS outpatients (ATP III), sedentary, untreated, divided in 2 groups by the cut off the apnea-hypopnea index of (AHI) >= 15 events/h: MetS+OSA (49±1.7yr, n=30), and MetS-OSA (46±1.4yr, n=30). A healthy age-matched control group was also enrolled (C, 46±1.7yr, n=16). The AHI was evaluated by polysomnography and muscle sympathetic nerve activity (MSNA) by microneurography. The variables evaluated from CEPT were: peakVO2, HR reserve (peakHR-restHR), attenuation of HR recovery (deltaHRR=peakHR-HR at 1st, 2nd, 4th and 6th min), blood pressure response (BP), double product (SBPxHR), ventilation (VE), O2 pulse (VO2/HR), ventilatory equivalent ratio for oxygen (VE/VO2) and ventilatory equivalent ratio for carbon dioxide (VE/VCO2). Results. MetS+OSA and MetS-OSA were similar in physical characteristics and risk factors of MetS. Both groups with MetS had higher MSNA compared with C, and these levels were higher in the MetS+OSA compared to MetS-AOS. No differences among groups were found in the CPET on ventilatory and metabolic variables. However, both groups with MetS showed higher restHR, SBP and DBP (at rest, during exercise and at recovery) and lower peakVO2 and peak O2 pulse compared to C. Both MetS groups had lower HR reserve compared with C, with lower levels on MetS+OSA compared with MetS-OSA. MetS+OSA had lower deltaHRR at 1st (16±2, 18±1 and 24±2 bpm, interaction P=0.008), 2nd (26±2, 32±2 and 40±3 bpm, interaction P < 0.001), 4th (40±2, 50±2 and 61±3 bpm, interaction P < 0.001) and 6th min (48±3, 58±2 e 65±3 bpm, interaction P < 0.02), whereas MetS-OSA had lower deltaHRR at 2nd and 4th compared to C. In addition, MetS+OSA had lower deltaHRR at 4th and 6th min compared to MetS-AOS. Further analysis showed association between MSNA with restHR (R=-0,37; P < 0,001) and between MSNA and deltaHRR at 1st (R=-0.35; P=0.004), 2nd (R=-0.42; P < 0.001) 4th (R=-0,47; P < 0,001) and 6thmin (R=-0,35; P=0,006). Conclusion. The overlap of OSA decreases peakVO2 and potentiates the impairement over hemodynamic responses during exercise in patients with MetS, which may be explained, at least in part, by sympathetic hyperactivation. Therefore, OSA is a comorbidity that could worsen the prognosis in MetS patients

Introdução: Os distúrbios respiratórios do sono na forma de apnéia central associada à respiração de Cheyne-Stokes (RCS) e apnéia obstrutiva do sono (AOS), são comuns nos pacientes com insuficiência cardíaca (IC) e podem contribuir para morbimortalidade. A RCS é uma forma exagerada de ventilação periódica (VP) na qual apnéias centrais alternam com períodos de hiperventilação. Em contraste, a AOS resulta em um colapso completo ou parcial da via aérea superior recorrente durante o sono. Objetivo: Fizemos à hipótese que VP durante vigília prediz a RCS durante o sono em pacientes com IC. Métodos: Estudamos pacientes do ambulatório de Cardiopatia Geral, do Instituto do Coração (InCor), recrutados no período de 2001 a 2003, submetidos a avaliação clínica e ecocardiográfica. Os pacientes foram submetidos à monitoração do padrão respiratório em posição supina, com luz acesa por 10 minutos, imediatamente antes do início de registro do sono por polissonografia noturna. Na manhã seguinte, o padrão respiratório foi monitorado por 10 minutos em repouso, os pacientes permaneciam sentados, seguido por teste de exercício cardiopulmonar em bicicleta ergométrica, com medida de fração expirada de CO2 e relação ventilação/CO2 (VE/VCO2). A presença dos distúrbios respiratórios do sono foi determinada através de polissonografia (índice de apnéia-hipopnéia 15 eventos/hora), os pacientes foram divididos nos grupos sem Distúrbio Respiratório do Sono (sem DRS), RCS e AOS. Os resultados estão apresentados como média ± desvio padrão. Resultados: Foram incluídos no estudo 47 pacientes, 5 foram excluídos por falta de coordenação motora e incapacidade de realizar o teste de exercício em bicicleta. O grupo final se constituiu de 42 pacientes (67% masculino, idade = 62±9 anos, fração de ejeção ventricular esquerda = 35±6%), sendo 22 do grupo sem DRS, 11 do grupo RCS e 9 do grupo AOS. Não houve diferenças significativas nos grupos nos parâmetros antropométricos e fração de ejeção ventricular esquerda. O grupo RCS apresentou maior proporção de classe funcional III e IV (p=0,03), menor pressão parcial de dióxido de carbono em repouso (p=0,01) e maior inclinação da curva de relação da ventilação versus produção de dióxido de carbono (VE/VCO2) (p=0,03) do que os grupos sem DRS e AOS. A VP durante a vigília foi presente em 19%, 31% e 36% antes, durante o exercício e antes do sono, respectivamente. Entre os pacientes, a VP durante a vigília (independente do momento) foi presente em 91% nos pacientes com RCS e significativamente menor em 18% e 22% nos pacientes sem DRS e AOS, respectivamente (p<0,001). Ao contrário, entre os pacientes com VP, o sono se caracterizou como sem DRS, RCS e AOS em 25%, 63% e 13% (p<0,05). A sensibilidade e especificidade da VP antes do exercício (sentado) e VP antes do sono (posição supina) para prever RCS foi de 56 e 88% e 91 e 84%, respectivamente. Conclusões: A VP durante a vigília, tanto antes do exercício como antes do sono, prevê a presença da RCS. A presença da VP na vigília não está associada com a AOS. A monitoração do padrão respiratório durante a vigília é um teste simples que pode ser empregado para prever a presença da RCS em pacientes com IC
Introduction: Sleep disordered breathing in the form of central sleep apnea and Cheyne-Stokes respiration (CSR) and obstructive sleep apnea (OSA) are common among heart failure (HF) patients and can independently contribute to morbimortality. CSR is an exaggerated form of periodic breathing (PB) in which central apneas alternate with periods of hyperventilation. In contrast, OSA results from recurrent collapse of upper airway during sleep. Objective: We hypothesize that PB while awake predicts CSR during sleep in patients with HF. Methods: Patients were recruited from one outpatient heart failure clinic (Instituto do Coração, InCor) in the period 2001 until 2003. All patients were submitted respiratory monitoring, for 10 minutes while awake in supine position immediately before overnight polysomnography. In the next morning, the patients were monitored for 10 minutes while sitting in a comfortable chair at rest, followed by cardiopulmonary exercise tests (electromagnetic-braked cycle). The presence of sleep disordered breathing was determined through polysomnography (apnea-hypopnea index 15 events/hour). The patients were divided according to the respiratory pattern during sleep in no-Sleep Disordered Breathing (no-SDB), CSR and OSA. Results: Forty seven patients were included in the study, 5 were excluded because of inability to perform exercise. The final group consisted of 42 patients (67% males, age: 62±9 yr, left ventricular ejection fraction: 35±6%). There were 22 in the no-SDB group, 11 in the CSR group and 9 in the OSA group. There were no significant differences among groups regarding anthropometric measurements and left ventricular ejection fraction. The CSR group presented a significantly increased proportion of NYHA functional class III-IV (p=0.03), lower PETCO2 (p=0.01) and increased VE/VCO2 slope (p=0.03) than no-SDB and OSA groups. PB while awake was present 19%, 31% e 36% before and during exercise and before sleep, respectively. Among patients with no-SDB, CSR and OSA, PB while awake was present in 18%, 91% and 22% (p<0.001). Conversely, among patients with PB while awake, the patients were classified as no-SDB, CSR and OSA in 25%, 63% and 13% (p<0.05). PB while awake before exercise and before sleep had sensitivity and specificity to predict the presence CSR of 56 and 88 % and 91 and 84 %, respectively. Conclusions: PB while awake is tightly linked and predicts CSR during sleep, but not OSA. PB while awake can have use in a simple test for to predict the presence of CSR in patients with HF

Le sommeil, de par ses fonctions récupératrices, est essentiel à la vie. Pour autant, la modification du mode de vie et des comportements, tant sédentaires que nutritionnels, sont à l’origine d’une altération du sommeil, conduisant ensemble à des situations d’obésité. Cet excès pondéral s’accompagne fréquemment d’un syndrome d’apnées obstructives du sommeil (SAOS). Lorsque ces deux pathologies sont présentes, les troubles métaboliques s’aggravent et sont à l’origine d’une inflammation de bas grade. A notre connaissance, aucune étude ne s’est intéressée aux bénéfices d’un reconditionnement à l’exercice physique combiné à une modification des habitudes alimentaires, en dehors de ceux induits par la perte de poids, sur ces différents paramètres. L’objectif de ce travail de thèse a donc été, à partir d’une étude ancillaire, d’évaluer le sommeil d’adolescents obèses par polysomnographie (PSG) par comparaison à celui de sujets normo-pondérés. Dans l’étude principale, les effets d’un programme de 9 mois (reconditionnement à l’exercice, activités physiques adaptées, rééquilibre alimentaire) ont été évalués sur l’architecture et la durée du sommeil, le SAOS, les différents facteurs biologiques (inflammatoires, hormonaux, profils glucidique et lipidique) et sur les adaptations physiologiques à l’exercice musculaire, afin de mieux comprendre l’implication de l’endurance aérobie et des troubles du sommeil sur la santé cardio-métabolique. Trente-deux adolescents obèses (âge : 14,6 ans, z-score d’IMC= 4 ,7) ont été recrutés. Toutes les variables ont été analysées en pré et post-intervention. Les résultats montrent une durée de sommeil réduite chez les jeunes obèses avec un SAOS, diagnostiqué chez 58% d’entre eux, malgré une architecture du sommeil satisfaisante. En post-intervention, une perte de poids de 11 kg et une amélioration des paramètres d’adaptation à l’exercice maximal (PMA, VE, VO2pic…) ont été rapportées chez tous les sujets, que le SAOS soit encore, ou non, présent. En effet, ce syndrome s’est normalisé chez 46% d’entre eux. Par ailleurs, grâce à l’intervention, le sommeil s’est amélioré (qualité et quantité). Enfin, la protéine C-réactive basale du groupe SAOS, dont les valeurs atteignaient 11mg/l à l’admission, a considérablement diminué, accompagnée d’une baisse de la leptinémie et d’une hausse de l’adiponectinémie, pouvant expliquer le moindre risque cardio-métabolique. Nos résultats démontrent qu’à l’admission, l’inflammation est liée à l’obésité, alors qu’en post-intervention, sa baisse s’explique par l’augmentation de l’endurance aérobie, et ceci indépendamment du sexe, du poids, de la durée de sommeil et du SAOS. Bien que ce dernier n’ait pas été normalisé chez tous les sujets, sa prévention par l’exercice physique ainsi que celle des troubles métaboliques observés dans ces deux pathologies devrait faire partie intégrante de la prise en charge des jeunes obèses en vue d’atténuer le risque de morbi-mortalité cardiovasculaire à l’âge adulte
Sleep, through its restorative functions, is essential for life. However, lifestyle modifications, sedentary and unhealthy feeding behaviors trigger sleep curtailment and sleep disruption, leading together to weight gain. Obesity is usually associated with obstructive sleep apnea (OSA), and these two diseases both induce metabolic dysfunctions and low-grade systemic inflammation. To the best of our knowledge, no study has assessed the effects of exercise reconditioning and modified food habits on these parameters. The purpose of this work was to assess and compare, from an ancillary study, polysomnographic variables between obese adolescents and normal-weight (NW) controls. In the main study, the effects of a 9-month program (exercise reconditioning, adapted physical activities and modified food habits) on sleep architecture, sleep duration, OSA, biological factors (inflammatory, hormonal, carbohydrates and lipid profiles) and physiological adaptations at exercise were assessed, in order to a better understanding of the roles of cardiorespiratory fitness and sleep disorders on cardio-metabolic health. Thirty-two obese adolescents (age: 14.6 years, BMI z-score: 4.7) were recruited. Every parameters were assessed at admission and post-intervention. Short sleep duration and a high prevalence of OSA (58%) were observed at admission in obese adolescents despite a satisfying sleep architecture, compared with NW controls. Post-intervention, weight loss (11kg) and improved parameters of physiological adaptations at exercise (MAP, VE, VO2peak) were found in every subject and OSA was normalized in 46% of them. Sleep quantity and sleep quality were improved. Decreased C-reactive protein (6.78 vs 10.98 mg/l) and leptin concentrations, and increased adiponectin levels were found, and cardio-metabolic risk (CMR) was decreased. At admission, obesity explains by itself the systemic inflammation whereas the decrease in inflammation, post-intervention, is explained by enhanced cardiorespiratory fitness related to fat-free mass, after controlling for sex, weight loss, change in sleep duration and OSA. Prevention of OSA and metabolic dysfunctions by chronic exercise should be an integral part of the obesity management in youths in order to decrease the risk of cardiovascular morbi-mortality in adulthood

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Introdução: Os estudos que contra-indicam o uso de um aparelho intra-oral (AIO) para tratamento da Síndrome da Apnéia Obstrutiva do Sono (SAOS) na presença de sinais e/ou sintomas da disfunção temporomandibular (DTM), ou que relatam o abandono ou suspensão do seu uso devido à dor causada pela DTM, não seguiram o mesmo critério de diagnóstico para a DTM. Desde que a qualidade de vida dos indivíduos com SAOS e DTM fica ainda mais comprometida devido à presença de ambas as síndromes, é importante um diagnóstico seguro e um tratamento eficaz para a DTM. Entre os tratamentos, os exercícios mandibulares são tidos como terapias de suporte (TS) para as DTM. Objetivo: Avaliar, em indivíduos com SAOS e DTM, a eficácia de uma terapia de suporte com exercícios mandibulares para a DTM, na redução da dor, na melhora da qualidade de vida, com o fim de alcançar o aumento da adesão ao tratamento com o AIO. Casuística e Métodos: Todos os pacientes foram avaliados no início, e após 120 dias de uso do AIO com: Questionário do sono de Fletcher e Lucket, Escala de Sonolência de Epworth, Inventário de qualidade de vida SF 36, polissonografia, diário de sono e de uso do AIO, avaliação clínica e radiográfica dos dentes, das estruturas ósseas e exame da ATM pelos critérios diagnósticos de DTM (RDC). Os pacientes foram aleatoriamente divididos em 2 grupos: terapia de suporte para DTM (TS) e terapia placebo (TP). Resultados: De 87 pacientes com diagnóstico de SAOS leve à moderada e encaminhados para uso de AIO, 45 tiveram diagnóstico confirmado pelo RDC de (DTM). Vinte e nove pacientes cumpriram os 120 dias de tratamento (15 pacientes no grupo da TS, e 14 no grupo da TP). Os pacientes do grupo TS mostraram melhora significativa nas queixas do sono, e melhora em maior número de domínios da qualidade de vida quando comparados com o grupo de TP. No decorrer do avanço do AIO foi observado um número significativamente maior de pacientes com dor persistente no grupo da TP em comparação com o grupo da TS. Houve redução da intensidade da dor no grupo de TS comparado ao grupo TP. Após o avanço do AIO, foi observada maior adesão ao uso do AIO no grupo da TS. Conclusão: A TS com exercícios mandibulares resultou em melhora significativa na qualidade de vida e na qualidade do sono nos pacientes com SAOS e DTM tratados com AIO, além de ter sido efetiva na redução da dor e no aumento na adesão ao tratamento com o AIO.
Introduction: The studies that contra-indicate the use of an oral appliance (OA) for the treatment of Obstructive Sleep Apnea Syndrome (OSA) in the presence of signs and / or symptoms of temporomandibular disorders (TMD), or that report abandonment or suspension of their use due to pain caused by TMD, did not follow the same diagnosis criteria for TMD. Since the quality of life of individuals with OSA and TMD is further compromised by the presence of both syndromes, it is essential a assure diagnosis and a effective treatment for TMD. Among the treatments, the jaw exercises are considered as a supportive therapy (ST) in TMD. Objective: To assess the effectiveness of mandibular exercises, with support therapy for TMD in subjects with OSA and TMD considering the in reduction of pain, improved of the quality of life, and the compliance to treatment with the OA. Patients and Methods: All patients were evaluated prior and to 120 days after the use of the OA by means Fletcher & Lucket sleep questionnaire, the Epworth Sleepiness Scale, the SF-36 Inventory of quality of life, polysomnography, sleep and daily usage OA, clinical and radiographic evaluation of teeth and bone structure, and exam to observed sings and/or symptoms for TMD by the RDC/TMD criteria. The patients were randomized in two groups: support therapy (ST) and placebo therapy (PT). Results: Forty-five out of the 87 patients who were diagnosed with mild to moderate OSA referred to the use of the OA had their diagnosis confirmed by the RDC/TMD. Twenty-nine of those patients completed the 120 days treatment (15 patients in the ST group and 14 in the PT group). Patients in the ST group showed a significant improvement in their sleep complaints and improvement in a higher number of life quality domains when compared to the group of PT. As advances were made in OA positioning a significantly higher number of patients with persistent pain was observed in the PT group, in comparison to the ST group. There was reduction of pain intensity in the ST group compared to PT group. After advancement of the OA, higher compliance to the use of OA was observed in the ST group than in the PT group. Conclusion: Support Therapy with mandibular exercises showed significant improvement in quality of life and quality of sleep in patients with OSA and TMD who were treated with OA, being also effective in reducing pain and the increase the compliance to the OA treatment.
TEDE
BV UNIFESP: Teses e dissertações

Introdução. A baixa capacidade aeróbia é um importante marcador de mau prognóstico e um forte preditor de risco de morte em pacientes encaminhados para o teste de esforço cardiopulmonar (TECP) por razões clínicas. O índice oxygen uptake efficiency slope (OUES), um novo índice de eficiência cardiorrespiratória, tem sido utilizado como marcador submáximo durante o TECP. Estudos recentes sugerem que a leptina pode desempenhar um papel importante na regulação da respiração e, consequentemente, o aumento dos níveis de leptina pode estar relacionado com a diminuição do OUES. No entanto, o impacto da síndrome metabólica (SMet) e da apneia obstrutiva do sono (AOS) no OUES é desconhecido. Objetivo. Investigar o comportamento do OUES em pacientes com SMet, associado ou não à AOS. Métodos. Foram estudados 73 pacientes com SMet (ATP-III), alocados em dois grupos de acordo com o índice de apneia/hipopneia (IAH) obtido na polissonografia noturna: SMet+AOS (IAH >= 15 eventos/hora, n=38, 49±1 anos, 33±0,6 kg/m2) e SMet-AOS (IAH < 15 eventos/hora, n=35, 46±1 anos, 31,8±0,6 kg/m2). Um grupo controle saudável (CS, n=20, 47±1 anos, 26,1±0,8 kg/m2), pareado por idade e gênero, foi também estudado. Os pacientes realizaram as seguintes avaliações: polissonografia; exames laboratoriais (glicemia, triglicérides, colesterol total e frações, leptina e proteína C-reativa); medidas antropométricas (altura, peso corporal, índice de massa corpórea, circunferência abdominal); composição corporal pela bioimpedância; medidas de pressão arterial; e TECP. Resultados. Ambos os grupos com SMet apresentaram prejuízo quando comparados ao grupo CS no peso, índice de massa corpórea e nos fatores de risco da SMet (circunferência abdominal, glicemia, triglicérides, HDL-c e pressão arterial sistólica e diastólica, P < 0,05). No TECP os grupos SMet+AOS e SMet-AOS apresentaram menores valores de consumo de oxigênio pico (VO2pico, 22,2±0,7; 21,7±0,9 e 28,0±1,1 ml/kg/min, respectivamente, Interação; P < 0,001) comparados com CS. Da mesma forma, os grupos SMet tiveram menores: VO2 no limiar anaeróbio (VO2LA), na relação VO2 e carga de trabalho (deltaVO2/deltaW) e no OUES (25,3±0,8; 25,0±0,9 e 31,1±1,2; Interação; P < 0.001) quando comparado com CS. Em análises posteriores, o OUES se correlacionou apenas com a massa gorda e com a leptina (R=-0,35; P=0,006). Conclusão. Independente da presença da AOS, pacientes com SMet apresentam diminuição da eficiência cardiorrespiratória. Os níveis elevados de leptina pode ser uma das explicações para essa diminuição nesses pacientes
Introduction. Low aerobic capacity is an important marker of poor prognosis and a strong predictor of risk of death in patients referred for cardiopulmonary exercise testing (CPET) for clinical reasons. The oxygen uptake efficiency slopes (OUES), a new cardiorespiratory efficiency index, has been used as a submaximal marker during CPET. Recent studies suggest that leptin may play an important role in regulating respiration, and consequently, increased levels of leptin may be related to decreased OUES. However, the impact of metabolic syndrome (MetS) and obstructive sleep apnea (OSA) in the OUES is unknown. Objective. To investigate the OUES in MetS patients with or without OSA. Methods. We studied 73 patients with MetS (ATP-III), allocated into two groups according to apnea/hypopnea index (AHI), assessed by nocturnal polysomnography: MetS+OSA (AHI >= 15 events/hour, n=38, 49±1 years, 33±0.6 kg/m2) and MetS-OSA (AHI < 15 events/hour, n=35, 46±1 years, 32±0.6 kg/m2). A healthy control group (CG, n=20, 47±1 years, 26.1±0.8 kg/m2), matched for age and gender, was also studied. The patients performed the following evaluations: polysomnography; Laboratory tests (glycemia, triglycerides, total cholesterol and fractions, leptin and C-reactive protein); Anthropometric measurements (height, body weight, body mass index, waist circumference); Body composition by bioimpedance; Blood pressure measurements; and CPET. Results. Both MetS groups had impairment in weight, body mass index, and MetS risk factors (waist circumference, glycemia, triglycerides, HDL-c and systolic and diastolic blood pressure, P < 0.05) compared with CG. MetS+OSA and MetS-OSA groups presented lower values of peak oxygen consumption (VO2peak, 22.2±0.7, 21.7±0.9 and 28.0±1.1 ml/kg/min, respectively; Interaction; P < 0.001) compared to CG. In the same way, MetS groups had lowest: VO2 at anaerobic threshold (VO2LA), ratio of VO2 and workload (deltaVO2/deltaW) and OUES (25.3±0.8, 25.0±0.9 and 31.1±1.2, Interaction; P < 0.001) compared with CG. In further analyzes, OUES correlated only with fat mass and leptin (R =-0.35, P =0.006). Conclusion. Regardless of the presence of OSA, MetS patients present decreased cardiorespiratory efficiency. Elevated levels of leptin may be one of the explanations for this decrease in these patients

L’objectif de ce travail de thèse était d’évaluer le bénéfice d’une activité physique régulière sur le syndrome d’apnées-hypopnées obstructives du sommeil (SAHOS). Pour répondre à notre objectif, cinq études ont été conduites pendant cette thèse et seront présentées au cours de ce manuscrit. Ces études se sont déroulées dans deux contextes de pratique distincts : un contexte associatif au sein de la Fédération Française d’Éducation Physique et de Gymnastique Volontaire (FFEPGV) et un contexte hospitalier au sein de l’Unité de réhabilitation cardio-respiratoire du CHU de Saint-Etienne. Notre étude principale, l’étude EXESAS, a évalué le bénéfice d’un programme d’activité physique pratiqué au sein de la FFEPGV (programme NeuroGyV™) dans une étude contrôlée randomisée incluant 96 patients avec un SAHOS modéré et âgés de 40 à 80 ans. Nous avons montré que neuf mois de ce programme, incluant trois heures d’activité physique par semaine, permettait de « guérir » 58% des patients du groupe exercice alors que seulement 20% des patients du groupe contrôle ayant bénéficié de conseils diététiques et de recommandations de bonne pratique en activité physique étaient considérés comme guéris (index d’apnées-hypopnées [IAH] < 15 évènements/heure). A l’issue du programme, les patients du groupe exercice amélioraient également leur qualité de vie et réduisaient leur somnolence. Au-delà de l’amélioration de l’IAH, nous avons mis en évidence une augmentation de la consommation maximale d’oxygène, suggérant une réduction du risque cardiovasculaire. L’étude EXESAS s’est par ailleurs intéressée à l’effet du programme NeuroGyV™ sur l’activité du système nerveux autonome (SNA) mesurée par la variabilité de fréquence cardiaque (VFC). Il a été montré que l’activité du SNA était préservée chez les patients SAHOS ayant bénéficié du programme d’activité physique. En revanche, le groupe contrôle présentait quant à lui une charge hypoxémique plus importante et une variabilité de fréquence cardiaque diminuée, suggérant que le SAHOS et le risque cardiovasculaire associé s’aggravaient spontanément en l’absence d’une activité physique régulière. Le screening de l’étude EXESAS a permis de réaliser un abstract sur le choix du questionnaire de dépistage du SAHOS le plus pertinent en population générale. Nous avons alors montré que le questionnaire STOP-BANG avait une meilleure sensibilité que le questionnaire de Berlin et qu’il devrait être privilégié en dépistage clinique même si sa spécificité reste faible.Enfin, nos travaux de recherche en réhabilitation cardiaque ont permis de confirmer le bénéfice du réentrainement à l’effort sur la sévérité du SAHOS et le rééquilibrage du SNA chez des patients coronariens. Par contre, les résultats préliminaires de l’étude RICAOS ont révélé que le renforcement des muscles inspiratoires chez les patients coronariens souffrant d’un SAHOS modéré n’apportait pas de bénéfice supplémentaire par rapport à un programme de réhabilitation cardiaque classique.En conclusion, l’activité physique régulière réduit efficacement la sévérité du SAHOS chez des patients avec ou sans antécédents cardiaques. Les résultats des différentes études conduites au cours de cette thèse suggèrent que l’activité physique régulière devrait être considérée comme une pierre angulaire dans la prévention et dans la prise en charge des formes légères et modérées. De futurs études devraient être conduites afin d’explorer plus en détail les mécanismes physiologiques sous-jacents et déterminer quels patients doivent bénéficier en priorité de cette alternative thérapeutique
The main purpose of this thesis was to assess the benefit of regular physical activity on obstructive sleep apnea (OSA). A total of five studies were conducted during this thesis and will be presented during this manuscript. These studies took place in two different practice settings: a community setting within the French Federation of Physical Education and Voluntary Gymnastics (FFEPGV) and an in-hospital setting into the Cardiopulmonary Rehabilitation Unit of the University Hospital of Saint-Etienne.Our main study, EXESAS, evaluated the benefit of a community physical activity program practiced within the FFEPGV (NeuroGyV™ program) in a randomized controlled trial including 96 patients aged from 40 to 80 years with moderate OSA. We demonstrated that nine months of NeuroGyV™ program, including three hours of physical activity per week, could "cure" (apnea-hypopnea index [IAH] <15 events/hour) 58% of patients in the exercise group while only 20% of patients in the control group who received dietary advice and physical activity recommendations were considered cured. At the end of the program, patients in the exercise group also improved their quality of life and reduced their sleepiness. Beyond the improvement of the AHI, we demonstrated an increase in the maximum oxygen consumption during exercise test, suggesting a cardiovascular risk reduction.The EXESAS study also investigated the effect of the NeuroGyV™ program on autonomic nervous system (ANS) activity as measured by heart rate variability (HRV). We showed that ANS activity is preserved in OSA patients who benefited from the physical activity program. In contrast, patients in the control group had a greater hypoxemic load and decreased heart rate variability, suggesting that OSA and the associated cardiovascular risk worsened spontaneously in absence of regular physical activity.The screening of the EXESAS study led to an abstract on the choice of the most relevant OSA screening questionnaire in the general population. We showed that the STOP-BANG questionnaire had a better sensitivity than the Berlin and thus STOP-BANG questionnaire should be preferred in clinical screening even if its specificity remains low.Finally, our trial in cardiac rehabilitation confirmed the benefit of exercise training on OSA severity and on the rebalancing of ANS in coronary arterial disease (CAD) patients. Yet, preliminary results from the RICAOS study showed that inspiratory muscles training in CAD patients with moderate OSA do not provide additional benefits over a standard cardiac rehabilitation program.In conclusion, regular physical activity effectively reduces the severity of OSA in patients with or without a history of heart disease. The results of the five studies conducted during this thesis suggest that regular physical activity should be considered as a cornerstone in the prevention and management of mild and moderate forms.Future studies should be conducted to explore in more detail the underlying physiological mechanisms and determine which patients should better benefit from this therapeutic alternative as a matter of priority

Orientadores: Roberto José Maria Covolan, Rickson Coelho Mesquita
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Física Gleb Wataghin
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Resumo: A atividade cerebral envolve uma complexa rede de processos neurofisiológicos cuja demanda energética requer constante aporte de glicose e oxigênio, supridos através da microcirculação sanguínea cerebral. Variações na circulação sanguínea cerebral decorrentes de ativação neuronal podem ser detectadas e registradas através da técnica óptica denominada NIRS (near infrared spectroscopy). Neste trabalho, desenvolvemos estudos sobre a aplicabilidade da técnica NIRS sob três diferentes abordagens, envolvendo indivíduos saudáveis e portadores de uma condição patológica específica. Os estudos com indivíduos saudáveis foram focados na aplicabilidade da técnica NIRS para investigar alterações hemodinâmicas associadas à estimulação do córtex visual e à realização de exercício físico. No caso envolvendo condição patológica, investigamos a aplicabilidade clínica desta mesma técnica para avaliar a perfusão cerebral de pacientes com estenose carotídea. Nos estudos sobre estimulação do córtex visual, buscou-se estabelecer uma relação entre a frequência do estímulo apresentado ao voluntário e parâmetros obtidos das curvas hemodinâmicas. Nos experimentos associados a exercícios físicos, ciclistas semiprofissionais e indivíduos fisicamente ativos realizaram testes em bicicletas simulando tipos específicos de provas, envolvendo tarefas abertas (teste progressivo) e fechadas (teste contra relógio em uma prova de 4Km), em diferentes condições (controle, ingestão de placebo ou cafeína), buscando caracterizar diferenças em aspectos da hemodinâmica cerebral a elas associadas. Por fim, nos experimentos envolvendo indivíduos com estenose carotídea, foram realizadas medidas de NIRS, durante a realização de testes de apneia com duração de 30 segundos, buscando estabelecer a aplicabilidade da técnica na avaliação clínica deste tipo de patologia. Para cada uma dessas abordagens, foram estabelecidos parâmetros associados às respostas hemodinâmicas obtidas através de tarefas e estímulos específicos, que permitiram caracterizar e quantificar os processos fisiológicos envolvidos em cada tipo de experimento, demonstrando assim a aplicabilidade da técnica NIRS para o estudo da atividade cerebral sob as condições experimentais em questão
Abstract: Brain activity involves a complex network of neurophysiological processes whose energy demand requires constant supply of glucose and oxygen which is provided by the cerebral microcirculation. Changes in cerebral blood flow due to neuronal activation can be detected and recorded by the optical technique called NIRS (near infrared spectroscopy). In this work, we developed studies on the applicability of the NIRS technique under three different approaches, involving healthy subjects and patients with a specific pathological condition. Studies in healthy subjects were focused on the applicability of the NIRS technique to investigate hemodynamic changes associated with stimulation of the visual cortex and the performance of physical exercise. In the case involving pathological condition, we investigated the clinical applicability of this same technique to evaluate cerebral perfusion in patients with carotid stenosis. In studies of stimulation of the visual cortex, we sought to establish a relationship between the frequency of the stimulus presented to volunteer and parameters obtained from the hemodynamic curves. In the experiments associated with exercise, semi-professional cyclists and physically active subjects performed tasks on bicycles simulating specific types of tests, involving open tasks (progressive test) and closed (a 4km test against the clock), under different conditions (control, placebo or caffeine intake), seeking to characterize differences in aspects of cerebral hemodynamics associated with them. Finally, in experiments involving individuals with carotid stenosis, NIRS measurements were carried out during apnea tests lasting 30 seconds, from which we sought to establish the applicability of the technique in the clinical evaluation of this type of pathology. For each of these approaches, parameters associated with the hemodynamic responses obtained by stimulation of specific tasks allowed to characterize and quantify the physiological processes involved in each type of experiment, thus demonstrating the applicability of the NIRS technique to the study of brain activity under the experimental conditions in question
Doutorado
Física
Doutor em Ciências

Le syndrome d'apnée obstructive du sommeil (SAOS), est une maladie chronique qui se caractérise par des interruptions répétées de la respiration durant le sommeil en raison de la fermeture temporaire des voies aériennes supérieures. L'hypoxie intermittente chronique (HI) résultante de cette fermeture transitoire des voies aériennes supérieures, constitue l’une des conséquences majeures du SAOS, et elle est la responsable de la plupart des complications liées à cette pathologie, dont nous citons: l’hypertension artérielle, l’infarctus de myocarde et plus généralement le remodelage cardiovasculaire.D’autre part, l’entrainement physique intensif(EI)est bien connu d’avoir des bénéfices sur le système cardiovasculaire, d’où nous avons poser l’hypothèse que l’EI peut inverser les effets délétères de l’HI sur la réactivité et le remodelage vasculaire ainsi que sur la signalisation calcique intracellulaire dans les cellules musculaires.Pour répondre à cette question, nous avons choisi le rat comme modèle animal, pour étudier l’effet potentiel de l'EI dans la prévention et l’inversion des effets délétères de (HI) en termes de réactivité et signalisation calcique dans les tissues musculaires.Des rats ont été exposés durant 21 jours à l’hypoxie intermittente dans des cages spécialement équipées pour maintenir un flux d’air alternant entre 21% et 5% de PO2 dans les cages contenant les rats hypoxique et a 21% de PO2 dans les cages contenant les rats contrôles. Durant les deux dernières semaines d’exposition à l’HI, un groupe des rats hypoxiques et un des rats normoxiques ont subi des sessions d'EI en courant sur un tapis roulant avec une vitesse allant de 16m/min jusqu'à 30 m/min.Les paramètres physiologiques ont été mesurés (Pression artérielle, fréquence cardiaque, hématocrites), l’aorte a été prélevé pour étudier la réactivité vasculaire, les cellules musculaires lisses de l’aorte ont été ensuite prélevés et cultivées pour étudier la signalisation calcique par microscopie à EPIfluorescence. Finalement les gènes codant pour les médiateurs de la signalisation calcique : RyR1, RyR2 RyR3, (ryanodine receptors), TRPV4 (transient receptor potential channel), SERCA1, SERCA2 (Sarco/Endoplasmic Reticulum Ca2+ -ATPase) et IP3R1 (Inositol 1,4,5-Trisphosphate Receptor) dans différentes tissues vasculaires et squelettiques ont été étudiés au niveau moléculaire par Q-PCR et Western Blot.Nos résultats montrent que l'HI induit une augmentation significative de pression artérielle et de l’hématocrite et une diminution dans la relaxation de l'aorte induite par l'acétylcholine pré contractée par la phénylnephrine. Ceci est conforme à notre observation selon laquelle HI augmente le niveau de calcium intracellulaire dans le muscle lisse aortique cultivé. D'autre part, l'EI induit une diminution significative de l’hématocrite et de la vasoconstriction aortique induite par la phénylnephrine et l'endothélie-1, conformément à l'observation que l'EI réduit la différence HI-N dans la réponse calcique. A l’échelle moléculaire, HI induit une augmentation significative de l'expression de RyR1, RyR2, RyR3, SERCA1, SERCA2, TRPV4 et IP3R1 au niveau de l'ARNm dans les tissus de tous les groupes, avec une plus grande quantité de RyR1,RyR2,et RyR3 dans les tissus HI des muscles lisses (principalement dans l'aorte thoracique et abdominale) et le SERCA1 (9 fois plus haut dans les tissus IH) et le SERCA2 (10 fois plus élevé dans les tissus HI) dans les muscles squelette (Gastrocnemius, plantaris et soléus). De plus, HI induit une augmentation significative de RYR1, RYR2 et TRPV4 au niveau protéique dans l'aorte thoracique et abdominale; et l'EI réduit la différence d'expression entre les animaux N et IH.Nos résultats suggèrent que l'EI représente un traitement prometteur non pharmacologique ou complémentaire pour limiter les complications cardio-vasculaires induites par l’HI et le remodelage musculaire chez les patients atteints de SAOS
Obstructive sleep apnea syndrome (OSAS) is a chronic disease characterized by repeated interruptions of breathing during sleep due to the temporary closure of the upper airway. Its prevalence increases with the increasing in prevalence of obesity, especially in developed countries.Chronic intermittent hypoxia (IH) resulting from this transient closure of the upper airway is one of the major consequences of OSAS and is responsible of most of the complications related to this pathology, including hypertension, myocardial infarction, atherosclerosis and more generally cardiovascular remodeling.On the other hand, intensive physical training(IT) is well known to have benefits on cardiovascular system, thus we hypothesize that physical training can reverse the deleterious effects of IH on reactivity and vascular remodeling as well as intracellular calcium signaling in muscle cells.To answer this question, we chose the rat as an animal model to study the potential effect of IT in the prevention and reversal of deleterious (IH) effects in terms of reactivity and calcium signaling in muscle tissue.Rats were exposed for 21 days to intermittent hypoxia and housed in cages specially equipped to maintain an airflow alternating between 21% and 5% PO2 in cages containing hypoxic rats and 21% PO2 in cages containing the control rats. During the last two weeks of exposure to IH, a group of hypoxic rats and one of the normoxic rats underwent IT sessions on a treadmill at a speed of 16m / min to 30m / min.Physiological parameters were measured (blood pressure, heart rate, hematocrit), the aorta was removed to study the vascular reactivity, then vascular smooth muscle cells were removed and cultured to study calcium signaling by EPIfluorescence microscopy. Finally, the genes coding for the key mediators of the calcium signaling: RyR1, RyR2 RyR3, (ryanodine receptors), TRPV4 (transient receptor potential channel), SERCA1, SERCA2 (Sarco / Endoplasmic Reticulum Ca2 + -ATPase) and IP3R1 , 5-Trisphosphate Receptor) in various vascular and skeletal tissues were studied at the molecular level as mRNA by Q-PCR or as protein by Western Blot.Our results show that IH induces a significant increase in blood pressure and hematocrit and a decrease in acetylcholine-induced aortic relaxation pre-contracted with phenylnephrine. This was consistent with our observation that HI increases the level of intracellular calcium in cultured aortic smooth muscle. On the other hand, IT induced a significant decrease in hematocrit and aortic vasoconstriction induced by phenylnephrine and endothelial-1, consistant with the observation that IT reduces the IH-N difference in the calcium response. On the molecular scale, IH induces a significant increase in the expression of RyR1, RyR2, RyR3, SERCA1, SERCA2, TRPV4 and IP3R1 at the mRNA level in the tissues of all groups with a greater amount of RyR1,RyR2,& RyR3 higher in IH tissue of smooth muscles (mainly in the thoracic and abdominal aorta) and SERCA1 (9-fold higher in IH tissues) and SERCA2 (10-fold higher in IH tissues) in the skeletal muscles (Gastrocnemius, plantaris and soléus). In addition, IH induces a significant increase in RYR1, RYR2 and TRPV4 at the protein level in the thoracic and abdominal aorta; And IT reduces the difference in expression between animals N and IH.Our results suggest that IT is a promising, non-pharmacological or complementary treatment for limiting cardiovascular complications induced by IH and muscle remodeling in patients with OSAS

碩士
臺灣大學
物理治療學研究所
98
Background and purpose: Obstructive sleep apnea syndrome (OSAS) is characterized by repeated episodes of upper airway obstruction during sleep. Recent studies have found evidence of airway inflammation in patients with OSAS. Individuals with chronic airway inflammation are at higher risk for exercise-induced bronchoconstriction (EIB) during exercise. The main purpose of this study was to evaluate EIB during exercise challenge test in patients with severe OSAS. The effect of a 3-month continuous positive airway pressure (CPAP) therapy on EIB was also explored. Methods: Twenty-two patients with severe OSAS and 9 control subjects matched for age, gender, and body mass index (BMI) were recruited from sleep clinic. All participants came to the laboratory on 2 separate days. On the 1st visit, baseline pulmonary function test (PFT) and airway inflammation assessed by induced sputum were performed. On the 2nd visit, an exercise challenge was performed using standard testing protocol and post-exercise forced expiratory volume in one second (FEV1) were measured at 2.5, 5, 10, 15, 20, and 30 minutes. For patients with severe OSAS, all measurements were repeated after a 3-month CPAP therapy. Results: The FEV1/FVC ratio (p＜0.01) and FEF25-75 (p=0.03) were significantly lower in the OSAS group than those in the control group. None of the subjects in the OSAS group demonstrated EIB attack after exercise challenge test. The percentages of macrophage in the induced sputum were significantly lower in the OSAS group both at baseline and post-exercise (p=0.03). Compared with baseline, the percentages of bronchial epithelial cells were significantly higher after exercise challenge test in both groups. The percentage of neutrophil at baseline was negatively correlated with the maximal FEV1 drop post exercise challenge test. Conclusions: The study confirmed airway inflammation exists in patients with severe OSAS. Although no EIB attack was found in patients with OSAS in this study, the correlation between airway inflammation and FEV1 changes post exercise challenge test suggests that the degree of airway inflammation plays a role in how airways would respond to exercise.

L’argomento della tesi era di testare l’ipotesi generale che vede al termine della fase II, il termine della fase di steady state dei parametri cardiovascolari che coincide con il punto di rottura fisiologico dell’apnea (Lin et al, 1974). Questa ipotesi è stata analizzata attraverso due esperimenti presenti in questa tesi di dottorato. Ognuno di essi ha analizzato l’ipotesi generale attraverso diverse metodologie sperimentali. Il primo esperimento testato ricercava la riduzione della durata della fase II e fase III mediante lo svolgimento dell’apnea in esercizio utilizzando un carico di 30 W al cicloergometro, incrementando il metabolismo del soggetto. Ci attendevamo di trovare valori cardiovascolari simili alla fine della fase II sia in esercizio che a riposo e simili caratteristiche anche durante la fase III. Il secondo esperimento era di prolungare la durata della fase II e della fase III quando l’apnea era preceduta dalla respirazione per un tempo prolungato di ossigeno puro. In questo caso ci attendevamo di vedere al termine della fase II dei valori simili a livello cardiovascolare trovate a esercizio ed a riposo e con simili caratteristiche anche in fase III.
The aim of this thesis was to test the general hypothesis, that the end of phase II, i.e. the breaking of the steady state for cardiovascular variables, may coincide with the physiological breaking point of apnoea (Lin et al, 1974). This hypothesis was investigated by means of two, interrelated studies. Each of these studies analysed an experimental consequence of the general hypothesis, the one opposite with respect to the other. The first experimental consequence to be tested was that the duration of phase II and phase III would be shorter when apnoeas are carried out during light exercise than at rest because of the increase in metabolic rate in the former case. Of course, we expected to find the same values for cardiovascular variables at end of phase II at exercise as at rest, with similar characteristics during phase III. The testing of this hypothesis is the object of the first article, which is currently under revision at the European Journal of Applied Physiology. The second experimental consequence to be tested was that the duration of phase II and phase III would be longer when apnoeas are carried out when pure oxygen is breathed before apnoea instead of air, because of the increase in oxygen stores in the former case. Of course, we expected to find the same values for cardiovascular variables at end of phase II at exercise as at rest, with similar characteristics during phase III. The testing of this hypothesis is the object of the second article, which is currently under preparation.

Access to abstract permanently restricted to Ball State community only
Access to thesis permanently restricted to Ball State community only
School of Physical Education, Sport, and Exercise Science

Access to abstract permanently restricted to Ball State community only
Access to thesis permanently restricted to Ball State community only
School of Physical Education, Sport, and Exercise Science

碩士
長庚大學
護理學研究所
95
This qusai-experimental study used one group pretest-post-test design is aimed to study the effect of stair stepping exercise in patients with obstructive sleep apnea syndrome (OSAS). Patients meet the following criteria were invited to participate in this study: being diagnosed with AHI (Apnea-hyponea index)>15/hr and ODI (oxygen desaturation index)>10/hr by Polysomnography, aged 19 or older. Fourteen patients with OSAS treated in the outpatient department of Chang Gung Medical Center were recruited over a period of 8 months. Each patient performed stair stepping exercise daily for eight weeks at home. Cardiopulmonary endurance assessed by three minutes step test and bicycle exercise testing, sleep condition assessed by Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Polysomnography, and symptom assessed by a symptom list and Modified Borg Scale were recorded just prior to the stair stepping exercise at Day 1 as baseline, at the end of the fourth week, and at the end of the eighth week. Scores after stair stepping exercise indicated that Cardiopulmonary index measured by three minutes step test, HRexp and HRrest measured by bicycle exercise testing were singnificantly improved (p= .009, p= .01, p< .03 respectively); sleep condition measured by Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index were singnificantly improved (p< .02, p< .03 respectively) after adjustment for covariates (time, age, sex, BMI, and smoking pack-year). Differences in the effect of stair stepping exercise for other outcome variables were either minimal or not statistically significant. Stair stepping exercise appears to have better cardiopulmonary endurance and sleep condition to patients with OSAS.

Access to abstract permanently restricted to Ball State community only
Access to thesis permanently restricted to Ball State community only
School of Physical Education, Sport, and Exercise Science

碩士
長庚大學
護理學研究所
96
This twelve months prospective randomized control study is aimed to study the effect of stair stepping exercise training on cardiopulmonary endurance and sleep condition in patients with obstructive sleep apnea syndrome (OSAS). Patients meet the following criteria will be invited to participate in this study: being diagnosed with AHI (Apnea-hyponea index)＞15/hr and ODI (oxygen desaturation index)＞10/hr by Polysomnography, aged 19 or older. In this study, 27 patients with OSAS from the outpatient department of Chang Gung Medical Center were recruited over a period of 9 weeks. Patients were randomly assigned to receive stair stepping in addition to nursing education and standard care, or nursing education and standard care alone. Stair stepping exercises performed at home daily for eight weeks. Outcome measures include sleep condition: Polysomnography, daytime sleepiness measured by Epworth sleepiness scale, Pittsburgh sleep quality index , cardiopulmonary endurance condition: cardiorespiratory fitness index, rating of perceived exertion, six-minute walking distance test, rate of perceived exertion; symptom scale and cytokines examination. Data were analyzed using descriptive statistics and Multiple Linear Regression of Generalized Estimating Equation (GEE). Results of this study showed that after adjustment for the effect of sex, age and body mass, AHI (p=0.02), Epworth Sleepiness Scale (p=0.01), cardiorespiratory fitness index (p=0.004), rating of perceived exertion(p=0.007), and snoring and sleep deprivation of symptoms scale (p< .001) were significantly improved. Differences in the effect of stair stepping exercise for other outcome variables were either minimal or not statistically significant. Eight weeks of stair stepping exercise training could be useful in improving sleep condition and increasing cardiopulmonary endurance on patients with OSAS.

Le sommeil, de par ses fonctions récupératrices, est essentiel à la vie. Pour autant, la modification du mode de vie et des comportements, tant sédentaires que nutritionnels, sont à l’origine d’une altération du sommeil, conduisant ensemble à des situations d’obésité. Cet excès pondéral s’accompagne fréquemment d’un syndrome d’apnées obstructives du sommeil (SAOS). Lorsque ces deux pathologies sont présentes, les troubles métaboliques s’aggravent et sont à l’origine d’une inflammation de bas grade. A notre connaissance, aucune étude ne s’est intéressée aux bénéfices d’un reconditionnement à l’exercice physique combiné à une modification des habitudes alimentaires, en dehors de ceux induits par la perte de poids, sur ces différents paramètres. L’objectif de ce travail de thèse a donc été, à partir d’une étude ancillaire, d’évaluer le sommeil d’adolescents obèses par polysomnographie (PSG) par comparaison à celui de sujets normo-pondérés. Dans l’étude principale, les effets d’un programme de 9 mois (reconditionnement à l’exercice, activités physiques adaptées, rééquilibre alimentaire) ont été évalués sur l’architecture et la durée du sommeil, le SAOS, les différents facteurs biologiques (inflammatoires, hormonaux, profils glucidique et lipidique) et sur les adaptations physiologiques à l’exercice musculaire, afin de mieux comprendre l’implication de l’endurance aérobie et des troubles du sommeil sur la santé cardio-métabolique. Trente-deux adolescents obèses (âge : 14,6 ans, z-score d’IMC= 4 ,7) ont été recrutés. Toutes les variables ont été analysées en pré et post-intervention. Les résultats montrent une durée de sommeil réduite chez les jeunes obèses avec un SAOS, diagnostiqué chez 58% d’entre eux, malgré une architecture du sommeil satisfaisante. En post-intervention, une perte de poids de 11 kg et une amélioration des paramètres d’adaptation à l’exercice maximal (PMA, VE, VO2pic…) ont été rapportées chez tous les sujets, que le SAOS soit encore, ou non, présent. En effet, ce syndrome s’est normalisé chez 46% d’entre eux. Par ailleurs, grâce à l’intervention, le sommeil s’est amélioré (qualité et quantité). Enfin, la protéine C-réactive basale du groupe SAOS, dont les valeurs atteignaient 11mg/l à l’admission, a considérablement diminué, accompagnée d’une baisse de la leptinémie et d’une hausse de l’adiponectinémie, pouvant expliquer le moindre risque cardio-métabolique. Nos résultats démontrent qu’à l’admission, l’inflammation est liée à l’obésité, alors qu’en post-intervention, sa baisse s’explique par l’augmentation de l’endurance aérobie, et ceci indépendamment du sexe, du poids, de la durée de sommeil et du SAOS. Bien que ce dernier n’ait pas été normalisé chez tous les sujets, sa prévention par l’exercice physique ainsi que celle des troubles métaboliques observés dans ces deux pathologies devrait faire partie intégrante de la prise en charge des jeunes obèses en vue d’atténuer le risque de morbi-mortalité cardiovasculaire à l’âge adulte
Sleep, through its restorative functions, is essential for life. However, lifestyle modifications, sedentary and unhealthy feeding behaviors trigger sleep curtailment and sleep disruption, leading together to weight gain. Obesity is usually associated with obstructive sleep apnea (OSA), and these two diseases both induce metabolic dysfunctions and low-grade systemic inflammation. To the best of our knowledge, no study has assessed the effects of exercise reconditioning and modified food habits on these parameters. The purpose of this work was to assess and compare, from an ancillary study, polysomnographic variables between obese adolescents and normal-weight (NW) controls. In the main study, the effects of a 9-month program (exercise reconditioning, adapted physical activities and modified food habits) on sleep architecture, sleep duration, OSA, biological factors (inflammatory, hormonal, carbohydrates and lipid profiles) and physiological adaptations at exercise were assessed, in order to a better understanding of the roles of cardiorespiratory fitness and sleep disorders on cardio-metabolic health. Thirty-two obese adolescents (age: 14.6 years, BMI z-score: 4.7) were recruited. Every parameters were assessed at admission and post-intervention. Short sleep duration and a high prevalence of OSA (58%) were observed at admission in obese adolescents despite a satisfying sleep architecture, compared with NW controls. Post-intervention, weight loss (11kg) and improved parameters of physiological adaptations at exercise (MAP, VE, VO2peak) were found in every subject and OSA was normalized in 46% of them. Sleep quantity and sleep quality were improved. Decreased C-reactive protein (6.78 vs 10.98 mg/l) and leptin concentrations, and increased adiponectin levels were found, and cardio-metabolic risk (CMR) was decreased. At admission, obesity explains by itself the systemic inflammation whereas the decrease in inflammation, post-intervention, is explained by enhanced cardiorespiratory fitness related to fat-free mass, after controlling for sex, weight loss, change in sleep duration and OSA. Prevention of OSA and metabolic dysfunctions by chronic exercise should be an integral part of the obesity management in youths in order to decrease the risk of cardiovascular morbi-mortality in adulthood

Introduction Sympathetic–parasympathetic interaction plays a critical role in the evolution and outcome of many cardiovascular disorders. It is well established that the sympathetic activation has an arrhythmogenic potential, contrariwise the vagal activation has an opposite effect. These findings are summarised in the generic concept of the “autonomic balance”, which generate the common perception that the loss of autonomic balance is a potentially proarrhythmic condition, and therapeutic strategies that aim at modulating the autonomic nervous system might increase the cardiac electrical stability. Several tools have been proposed to investigate the activity of the autonomic nervous system, and the analysis of the arterial baroreflex is considered an indirect measure of the cardiac vagal activity. In fact the spontaneous baroreflex sensitivity (BRS) is viewed as an index of the rise in the cardiac vagal efferent activity in response to an increase in arterial blood pressure. BRS has been assessed in a variety of conditions and with a variety of experimental techniques, focusing mostly on the cardiac-chronotropic efferent branch. Healthy subjects and several cardiovascular diseases have been extensively investigated by the analysis of baroreflexes with either a closed-loop and/or an open-loop approach. The latter allows computation of the characteristic parameters of the baroreflex curve, i.e. the centring point, the operating point, and the maximal gain. This approach can be applied only in steady state conditions, at rest and during exercise, since it make use of external factors (mechanical or pharmacological) to modify the operating range and to construct the responding range, in terms of heart rate (HR) or arterial blood pressure (BP) responses. Contrariwise, the closed-loop approach analyses the relationship between HR and BP to define the sensitivity of the baroreflex close to the operating point, which could be displaced toward the “threshold” of the baroreflex curves in some conditions, i.e. during exercise. In closed-loop condition, Bertinieri and colleagues (1988) proposed the so-called sequence method which they applied in steady state condition. In practice, they computed the mean slope of several BRS sequences, of at least three beats, in which the R-R interval (RRi) of the ECG varied consensually to BP, regardless of the direction. Recently, this method was applied also in unsteady state conditions (Adami et al., 2013, Bringard et al., 2017; Fagoni et al., 2015; Sivieri et al. 2015); the only a-priori assumption behind the sequence method is that each heart beat has a biunivocal effect on the following beat: no upper limit was imposed to the length of baroreflex sequences (minimum three beats). Moreover, the BRS analysis was applied to estimate the prognosis in patients affected by cardiovascular diseases (Head, 1995; Korner et al., 1974; La Rovere et al., 1998, 2008, 2011). Autonomic output is different in health and disease and the BRS can be used to analyse these differences in several conditions. Thus, the purpose of this project was to perform a closed-loop baroreflex analysis, under different dynamic conditions (rest, exercise, apnoeas), in healthy subjects and in patients affected by mild arterial hypertension. The closed-loop approach was used to this aim, in order to deeply investigate the dynamics of the arterial baroreflex in the following unsteady state conditions: i) at exercise onset and ii) during apnoeas, in healthy volunteers; iii) during exercise, comparing healthy subjects and hypertensive patients. Commonly, the sequence method is computed starting from the R-R interval (RRi) of the ECG, and the systolic blood pressure (SAP). In literature, both HR and RRi are used to calculate BRS, even though RRi is the reciprocal of HR, and these two parameters provided two different information. To clarify this challenging point, a further detailed paper will be proposed to discuss this topic. In this thesis, we decided to use the relationship between HR and MAP to compute BRS. While HR has been an a-priori choice, the use of MAP was a consequence of the typology of experiments we carried out. The beginning of physical activity is accomplished by the sudden change in the total peripheral resistances (TPR), which predominantly acts on DAP; this modification affects more MAP than SAP, thus the former parameter was chosen to define the BRS. First study: baroreflex at exercise onset This first experiment analysed the dynamics of baroreflex resetting at exercise onset. Baroreflex resetting is generally studied at steady state, by means of open-loop procedures, and it was demonstrated that during exercise the operating point is displaced upward and rightward with respect to rest, and its maximal gain is invariant (Rowell et al. 1996; DiCarlo and Bishop 2001; Raven et al. 2002; Raven et al. 2006; Raven 2008; Fadel and Raven 2012; Mitchell 2013). Notwithstanding, the dynamics of baroreflex displacement from rest to exercise was never described so far. We aimed at investigating the temporal components of the mechanisms that intervene in determining baroreflex resetting during transient. Ten healthy volunteers took parts in the experiments. They performed three repetition of a 50 W exercise on a cycle ergometer, lasting seven minutes, in supine and upright position; the different posture was used to have an a-priori displacement the BRS operating point (Schwartz et al., 2013) even at rest. HR was continuously recorded, on single beat basis, by electrocardiography. Arterial pressure was continuously recorded by a non-invasive finger pressure cuff. From pulse pressure profiles, we determined cardiac output (CO) by Modelflow, and we computed MAP; TPR was derived as the ratio between the former two parameters. We performed the closed-loop analysis of HR vs MAP relationship at rest before starting the exercise (BRS computed as the average of the mean slopes of all analysed sequences of each single subject, over one minute), during the transient (HR vs MAP relationship), and during exercise (BRS over one minute steady state recording). At exercise onset, HR was higher than in quiet rest. As exercise started, MAP fell to a minimum (MAPmin) of about 73 mmHg in both posture, while HR increased. The initial HR versus MAP relationship was linear, with flatter slope than resting baroreflex sensitivity, in both postures. TPR fell and CO increased. After MAPmin, both HR and MAP increased toward exercise steady state, with further CO increase. The sensitivity of baroreflex during steady state at exercise resulted lower than at rest, in both posture, and invariant compared to the beginning of exercise. These results suggest that, at exercise onset, the falling of MAP was corrected by a HR reduction along a baroreflex curve; the sensitivity of the baroreflex changed immediately during the transient, with lower sensitivity than at rest, and then BRS remained unchanged during the exercise steady state. After reaching MAPmin, the baroreflex resetting took place, yet with a delay after the beginning of exercise. Thus, the baroreflex resetting starts after the exercise onset, but the sensitivity of the baroreflex changes immediately, and this process is compatible with the central command hypothesis. However, the central command theory may not explain the resetting process, that lasted one minute upright, but not supine (it took more time), compatibly with a possible role of increasing sympathetic stimulation of the sinus node during exercise (Fagraeus and Linnarsson, 1976; Orizio et al., 1988). Second study: baroreflex in apnoea. The cardiovascular response to apnoea is characterised by three phases (Fagoni et al., 2015, 2017; Perini et al., 2008; Sivieri et al., 2015). The first dynamic phase (φ1) of the cardiovascular response to apnoea is characterised by a sudden drop in MAP, accompanied by an increase HR (Costalat et al, 2015; Fagoni et al., 2015; Perini et al, 2008, 2010; Sivieri et al., 2015). It was interpreted as a baroreflex attempt at correcting a MAP fall due to a reduction in venous return caused by an increase in intrathoracic pressure occurring at elevated lung volumes. The purpose was to perform the analysis of the HR vs MAP relationship during the φ1 of apnoeas performed at lung volumes close to the total lung capacity, at rest and during exercise. Indeed, during exercise apnoeas, the characteristics of φ1 would be different than in resting apnoeas, because the BRS slope at exercise is lower than at rest, and the operating point of the baroreflex should be displaced. We calculated BRS in steady state condition before apnoeas, during phase II (φ2), and we analysed the HR vs MAP relationship during φ1, before and after attainment MAPmin, in resting and exercise apnoeas. Ten healthy divers performed resting and exercise (30 W) apnoeas. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres®, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during steady φ2, before and after the attainment of MAPmin, were computed in both conditions. We also analysed the modification of the prevailing HR and MAP from the first part of φ1, before the MAPmin, and after MAPmin, to investigate if baroreflex resetting took place after attainment of MAPmin. Before the beginning of apnoeas, BRS was lower (p<0.05) during exercise than in resting apnoeas (-1.23 ± 0.23 and -0.87 ± 0.21 b min-1 mmHg-1, respectively). This difference was also reported for the HR vs MAP relationship in all the investigated conditions. In either resting and exercise apnoeas, slopes were lower at the beginning of φ1 (-0.49 ± 0.20 and -0.31 ± 0.08 b min-1 mmHg-1, resting and exercise, respectively), compared to rest, φ2 (-1.12 ± 0.33 and -0.82 ±0.27 b min-1 mmHg-1, resting and exercise, respectively) and after MAPmin (-0.96 ± 0.24 and -0.70± 0.31 b min-1 mmHg-1, resting and exercise, respectively). The prevailing HR and MAP at the beginning of apnoeas resulted different compared to after attainment of MAPmin, then both HR and MAP increased consensually to attain new levels: whereas at rest both HR and MAP increased, during exercise MAP was displaced upward and rightward, whilst the HR remained unchanged. The novelty of this study is that during the dynamic phase of apnoeas, the HR vs MAP relationship showed a baroreflex dynamic characterized by a sudden modification in the sensitivity compared to rest and to the steady phase II. After the attainment of MAPmin, a parallel rise in HR and MAP took place, which we interpreted as due to baroreflex resetting. Indeed, the prevailing HR and MAP resulted shifted upward and rightward during exercise compared to rest. During exercise, this process caused an increase in MAP after MAPmin, compared to before MAPmin, with an invariant HR: the prevailing sympathetic output during exercise might affects much more the vasomotor component of the cardiovascular responses compared to the cardiac one, resulting in higher TPR and lower HR values (Fagoni et al., 2015; Sivieri et al., 2015) Third study: baroreflex in hypertensive patients. The BRS in hypertensive patients is impaired (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978), and the modification in BRS is associated with worst outcome in cardiovascular patients (La Rovere et al., 1998, 2008, 2011; Osculati et al., 1990). Studies concerning the implantation of continuous baroreflex stimulators as a tool to diminish central sympathetic outflow (Mohaupt et al., 2007) and the introduction of catheter-based renal selective denervation for resistant hypertension show a significantly reduction in blood pressure (DiBona and Esler, 2010; Esler, 2011; Schlaich et al., 2009). These data suggest that the overall cardiovascular regulation in hypertensive patients may be different from normal, and the analysis of the dynamics of the baroreflex response to exercise might be different from healthy subjects. We aimed at investigating the steady-state and the dynamics of the HR vs MAP relationship in response to exercise in patients affected by essential hypertension compared to age-matched healthy controls, carried out in supine and upright postures, at two different workloads, 50 and 75W. Ten patients affected by grade I or II of arterial hypertension were age-matched with ten healthy controls. HR and MAP were recorded on a beat-by-beat basis by means of an electrocardiography and the Portapres®, respectively. The resulting slopes of the linear regression line of the HR versus MAP relationship, at rest, during the transient and at steady state during exercise, were computed in supine and upright position. Data were compared between patients and healthy volunteers, between positions, and among the different phases before and during exercises. BRS resulted steeper in controls than in hypertensive patients (supine -1.43 ± 0.19 and -1.16 ± 0.33 b min-1 mmHg-1 for controls and hypertensive patients, respectively; upright -1.22 ± 0.2 and -0.99 ± 0.19 b min-1 mmHg-1 for controls and hypertensive patients, respectively), as well as the linear relationship between HR and MAP at the beginning of exercise at 50 W, in both positions, resulted higher in controls than in patients. In supine position controls showed higher slopes at rest than at the beginning and during exercise. In controls and hypertensive patients, at the beginning of exercise at 75 W the slopes were lower in upright than supine. These data showed a trend characterised by a reduced baroreflex sensitivity in all conditions with sympathetic hyperactivity: hypertension versus control, exercise versus rest, and upright versus supine. Moreover, several slopes resulted lower at the beginning of exercise and during steady state exercise compare to rest, confirming previous findings. It is noteworthy that during the transient at 75 W the baroreflex response was absent in several patients in supine position, probably due to sympathetic overactivity which limited the MAP fall demonstrated at the exercise onset because of the sudden drastic fall in TPR (Elstad et al., 2009; Faisal et al., 2010; Lador et al., 2006, 2008; Wieling et al., 1996). Conclusion The analysis of the relationship between HR and MAP by means of the closed-loop approach is a non-invasive method that can be easily applied in health and disease, and it can be used as an indirect measure of the autonomic nervous system activity. The reported results on the patterns of baroreflex changes in dynamic states suggested that the baroreflex resetting started after the beginning of exercise, but the modification of the sensitivity was almost immediate, as soon as the MAP fell and the baroreflex activity tried to counteract by increasing the HR. After the attainment of the MAPmin, which might be considered a trigger MAP value, the resetting phase took place. The change in slope at exercise onset might be attributed to the sudden vagal withdrawal, and compatibly more with the central command theory. Contrariwise, the resetting process may well be mediated by other neural mechanisms (Raven et al., 2006), and it is possible that the activation of the sympathetic efferent branch of the autonomic nervous system plays a role in the phase of the exercise transient after attainment MAPmin (Lador et al., 2006). At the same time, apnoea provided interesting information about the baroreflex function, since the first phase is characterized by dynamic and deep modifications in MAP, sustained for several beats, counteracted by adjustments in HR. In exercise apnoeas BRS was lower than resting apnoeas, in all the investigated conditions. In φ1, rapid cardiovascular adjustments affect the baroreflex responses with different pattern before and after MAPmin, showing higher values of the HR vs MAP slopes after the attainment of MAPmin compared to the onset of φ1. The baroreflex sensitivity restored immediately after reaching the MAPmin in φ1, indeed BRS in φ2 was similar to the one computed at the beginning of apnoea. Finally, the prevailing HR and MAP points during exercise apnoeas were displaced rightward and upward compared to resting apnoeas. During φ2, HR decreased, and the TPR increased, thus a modification in the autonomic output can occur, with a dissociation between heart (characterised by predominant vagal activity) and vascular system (with predominant sympathetic activity), that may explain why these modifications did not affect the baroreflex sensitivity during φ2 apnoeas. In the hypertension study, patients presented a reduced baroreflex gain, in agreement with previous findings (Bristow et al., 1969; Head, 1995; Korner et al., 1974; Mancia et al., 1978). The baroreflex sensitivity, in healthy and hypertensive subjects, changed immediately at the exercise onset, in both positions, and remained unchanged during the steady state of light-mild exercises: the baroreflex resetting acted in the same manner in healthy and hypertensive patients, but with a reduced gain in the latter compared to the former. The closed-loop approach allows the analysis of the BRS in several conditions, such as rest, exercise, apnoea and in pathologies (hypertension, orthostatic intolerance, dysautonomic diseases). BRS could be a useful tool, i.e. to assess improvements after rehabilitation in neurological as well as in cardiorespiratory diseases, or after prolonged bed rest, in healthy volunteers and in patients after prolonged hospital stay. The application of this technique might be used to monitor the efficacy of the undertaken treatment, whether behavioural or pharmacological. Thus, the modification in BRS might be considered as a mirror of cardiovascular adjustments following a different stimulation of the two branches of the autonomic nervous system, in health and disease.