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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 – 60.5; BMI range = 19.0 – 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 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.

Background and Purpose: Little is known about influences of obstructive sleep apnea syndrome (OSAS) on dietary intake and body composition. The purpose of this study was to evaluate dietary status, body fat distribution and leptin in overweight young men with and without OSAS in comparison to published values for normal weight counterparts. Methods: Groups were comprised of 24 sedentary overweight young men with and without OSAS, who had a body mass index (BMI) greater than 25 kg/m². Serum leptin concentration was measured in the 24 subjects using radioimmunoassay, while OSAS assessment was done using nighttime home somnography. Analysis of 4-day diet recalls was performed using Nutritionist Pro (First DataBank, Inc., San Bruno, CA). A Healthy Eating Index (HEI) score was calculated for the 24 overweight subjects. Results: There were no differences between the two overweight groups for total fat mass, central abdominal fat, BMI, waist circumference, leptin, or the HEI. The HEI was not predictive of overall OSAS severity; however, BMI was moderately related to OSAS severity (r = 0.39; p=0.05). The normal weight group did have a 50% higher report of carbohydrate intake, and consumed on average, 500 more kilocalories per day. The normal weight group consumed 50% less sodium, and 50% more Vitamin's C and E including a 13% increase in the HEI. Conclusions: Regulation of eating behavior and related influences on diet composition may be affected by a number of neurohormonal disturbances associated with OSAS and/or obesity, itself. Further research is needed to quantify these possible differences on dietary status and the underlying mechanism involved. / Master of 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 syndrome (OSAS) is a complex disorder characterized by repetitive bouts of upper airway collapse during sleep, causing subsequent intermittent hypoxia, hypercapnia, and fragmented sleep and is also associated with significant morbidity including daytime sleepiness, hypertension, and elevated cardiovascular risk. OSAS affects at least 4% of men and 2% of women; unfortunately, it is estimated that 80% to 90% of adults with OSAS remain undiagnosed. Both clinical characteristics and complex genetic and environmental interactions have made it difficult to understand OSAS disease etiology and identifying patients at risk is still elusive. A pattern of gene expression in cells or tissues related to a disease state for OSAS would provide beneficial information to be most effective in screening or diagnosing this disease. Objectives: The objectives of this study were to: 1) map out the study design and bench assay strategies by which to investigate this issue; 2) find out if there are specific differences in the global gene expression profiles of adult females with OSAS compared to those without OSAS, under conditions in which subjects were clinically similar (BMI, diabetes, cardiovascular disease, etc.); and 3) assess the protein expression differences that could potentially be linked via well-established molecular pathways associated with any differences found in global gene expression profiles in the presence and absence of OSAS. Methods: Subjects were overweight premenopausal Caucasian women with untreated OSAS (n=6; age = 40.7 ± 3.4; BMI = 49.04 ± 6.97; apnea-hypopnea index = 27.3 ± 16.02), and control subjects (n=10) (age = 38.2 ± 7.6; BMI = 47.94 ± 6.15; apnea-hypopnea index < 5), and matched for other clinical characteristics (diabetes, cardiovascular disease status, medications, etc.) recruited from either Carilion Clinic Pulmonary/Sleep Medicine or Carilion Clinic Bariatric Surgery practices. Subjects provided a fasting blood sample in which the monocytes were isolated from whole blood. The RNA was extracted from the monocytes, assessed for purity and quantity, frozen and shipped to collaborators at Dana-Farber Cancer Institute and hybridized to Affymetrix whole human genome chips on a gene chip. The initial computational evaluation and interpretation generated the hypothesis. Two-step quantitative real time polymerase chain reaction (qPCR) was performed to verify the results from the microarray analysis. The laminin enzyme immunoassay (EIA), and cellular adhesion assays were performed to determine if genomic changes resulted in proteomic and phenotypic assessments. Results: OSAS subjects had nine aberrantly regulated genes, of which three genes (LAMC-1, CDC42, and TACSTD2) showed a pattern in segregation between OSAS and controls subjects based on expression patterns. In addition, qPCR indicated a 2.1 fold increase in LAMC-1 and a 1.1 fold increase CDC42 expression unique to the tissue samples of patients with OSAS. Though the serum laminin EIA did not differ between groups, a statistically significant increase in peripheral blood mononuclear cells (PBMC) cellular adhesion in OSAS patients versus control subjects was found. The OSAS subjects had a well cell count of 9.27 ± 1.54 cells vs. controls 5.75 ± 0.78 cells (p Ë‚ 0.05), which is relative to the 103 cells/field that were plated. Conclusions: Cells isolated from women with moderate-severe OSAS show an abnormality in cellular adhesion, a process driven in part by the gene LAMC-1, which was also aberrantly expressed in these subjects. This suggests that inflammation may be linked to the pathogenesis of OSAS. This pilot study has provided the framework and preliminary data needed to propose a larger study with extramural research funding. / Ph. D.

An electronically-controlled positive-displacement bellows-type air pump has been developed in the Bio-medical Engineering Laboratory for the treatment of adult Sleep Apnea Syndrome (SAS). An electronically-controlled positive-displacement pump has been employed in order to eliminate the pressure regulator and accompanying noise of present therapeutic devices. The positive-displacement pump is found to quietly and effectively provide the required airway pressures for the treatment of adult Sleep Apnea Syndrome. New developments in the reduction of the size and noise levels of current therapeutic devices, however, preclude mass production of the bellows-type pump because of its size disadvantage. The custom nasal mask and exhalation valve, control system, pressure-monitoring alarm system, and the controlled humidifier of the positive-displacement pump should be incorporated within the present fanâ type Nasal Continuous Positive Airway Pressure (NCPAP) system to provide quieter, more comfortable, and safer NCPAP therapy. Before the design and development of the positive displacement NCPAP pump is detailed in this thesis, however, the problem of adult Sleep Apnea Syndrome is introduced, available therapies are investigated, and the current NCPAP therapy system is examined. / Master of Science