Pathophysiology Of Obstructive Sleep Apnea Research Articles

Obstructive sleep apnea phenotypes in men based on characteristics of respiratory events during polysomnography.

The upper airway (UA) anatomical collapsibility, UA muscle responsiveness, breathing control, and/or arousability are important contributing factors for obstructive sleep apnea (OSA). Differences in clinical manifestations of OSA are believed to reflect interactions among these factors. We aimed to classify OSA patients into subgroups based on polysomnographic (PSG) variables using cluster analysis and assess each subgroup's characteristics. Men with moderate or severe OSA and without any concomitant heart or psychosomatic disease were recruited. A hierarchical cluster analysis was performed using variables including fraction of apnea, respiratory event duration, minimum oxygen saturation, arousal rate before termination, and frequency of respiratory events in the supine position. The impact of sleep stages or body position on PSG variables was also evaluated in each cluster. A total of 210 men (mean age, 50.0years, mean body mass index, 27.4kg/m2) were studied. The three subgroups that emerged from the analysis were defined as follows: cluster 1 (high fraction of apnea and severe desaturation (20%)), cluster 2 (high fraction of apnea and long event duration (31%)), and cluster 3 (low fraction of apnea (49%)). There were differences in the body mass index and apnea type between the three clusters. Sleep stages and/or body position affected PSG variables in each cluster. Patients with OSA could be divided into three distinct subgroups based on PSG variables. This clustering may be used for assessing the pathophysiology of OSA to tailor individual treatment other than continuous positive airway pressure therapy.

Craniofacial and upper airway profile assessment in North Indian patients with obstructive sleep apnea.

Introduction:Upper airway imaging can often identify the anatomical risk factors for sleep apnea and provide sufficient insight into the pathophysiology of obstructive sleep apnea (OSA).Materials and Methods:We conducted a case–control, observational study at a tertiary care hospital in North India. All cases and controls underwent lateral cephalometry and magnetic resonance imaging (MRI) for craniofacial and upper airway evaluation. Only the cases had polysomnography testing for confirmation of OSA and assessing the severity of disease.Results:Forty cases and an equal number of matched controls were recruited. On X-ray cephalometry, it was observed that the cases had a significantly larger hyoid mandibular distance and soft palate length; and shorter mandibular length. The MRI cephalometric variables were significantly different, the soft palate length, tongue length, and submental fat were longer while the retropalatal and retroglossal distance was shorter amongst the cases. A statistically significant positive correlation was found between the cephalometric parameters and the indices of severity of OSA. An increased hyoid mandibular distance and soft palate length, and a decrease in the lower anterior facial height were found to be predictive of severe OSA (Apnea–Hypopnea Index –>30/h). An increased hyoid mandibular distance, soft palate length, and the tongue length and a reduced mandibular length were found to be predictive of need for continuous positive airway pressure (CPAP) pressures of ≥15 cm H2O. There were significant differences between the cephalometric parameters of the Indian OSA patients and patients from other ethnicities reported in the literature.Conclusions:OSA patients had a significantly smaller upper airway compared to age-, sex-, and body mass index-matched controls and cephalometric variables correlated with the indices of OSA severity. The cephalometric assessment was also predictive of severe OSA and the need for higher pressures of CPAP. This indicates the important role of upper airway anatomy in the pathogenesis of OSA.

Chapter 22 - Clinical neurophysiology of apnea

Understanding the clinical neurophysiology of apnea generation encompasses discussion of the neuroanatomic aspects of central respiratory rhythm and pattern generation, including the central respiratory control networks, central and peripheral chemoreceptors, mechanisms of respiratory muscles, and sleep state dependent differences. Anatomical and functional links to apnea also involve central respiratory motor output recruited from the hypoglossal nerve, which has led to novel treatments for obstructive sleep apnea. Autonomic fluctuations occur in relation to sleep-wake and sleep states (i.e., REM vs NREM sleep), with both parasympathetic and sympathetic contributions. Finally, our understanding of the pathophysiology of obstructive sleep apnea now includes concepts of critical closing pressure of the upper airway, increased loop gain as reflected by high responsiveness to external perturbations, inadequate responsiveness of upper airway muscle recruitment, and reductions in arousal threshold leading to ventilatory instability. In turn, these concepts have led to the development of novel therapies such as hypoglossal nerve stimulation and targeting key culprit physiologic mechanisms specific to the individual.

The Importance of Posture and Gravity in the Pathophysiology of Obstructive Sleep Apnea "Because of an Elephantiasis Case with Sleep Disordered Breathing"

The objective of drafting this case report is to delineate the relationship between elephantiasis disease rarely encountered in clinical practice and sleep disordered breathing, to try to understand how this specific condition influences the quality of sleep, to review the mechanisms for Obstructive Sleep Apnea Syndrome which is the most common sleep disordered breathing seen and to underline its importance once again.

Pathophysiology of Obstructive Sleep Apnea (OSA) - Blood Cells' Reactive Oxygen Species and Inflammation Prevent Polycythemia

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia, causes cardiovascular, metabolic, neurocognitive and cancer complications. Hypoxia expands the red cell mass by stimulating erythropoietin (EPO) production; yet in our analysis of 527 OSA patients, <1% had OSA-related polycythemia (Gangaraju et al Blood 2016 128:2444). Typical hypoxia-induced red blood cells (RBCs) mass normalized upon return to normoxia by neocytolysis i.e. preferential destruction of young hypoxia-born RBCs. In an animal model, we demonstrated that neocytolysis is caused by excessive generation of reactive oxygen species (ROS) from increase of mitochondrial retention and accumulation of ROS. ROS increase resulted from decreased antioxidant enzyme catalase mediated by hypoxia-induced miR-21. We hypothesized that polycythemia in OSA was prevented by neocytolysis.It is also well-known that OSA induces systemic inflammation markers including C-reactive protein, IL-6, TNF-α, IL-8, and NF-κb. Inflammation participates in the control of the number of RBCs by inducing hepcidin, the principal regulator of iron metabolism. Increased hepcidin suppresses erythropoiesis by inhibiting iron release from macrophages. Based on this evidence, we also hypothesized that the absence of polycythemia in OSA might be caused by an independent contribution of inflammation-mediated suppression of erythropoiesis.We studied OSA patients before and after treatment with continuous positive airway pressure (CPAP). Increased erythropoiesis was evidenced by increased EPO and reticulocytosis. EPO levels correlated with time spent below sPO2 89 %, indicating that severe OSA patients had more augmented erythropoiesis. However, hematocrit levels were normal. Hemolysis was detected in some but not all OSA patients by end tidal carbon monoxide (a product from heme catabolism). After CPAP treatment, these changes diminished but hematocrits did not change. Conditions favoring neocytolysis were confirmed by increased ROS from expanded reticulocytes' mitochondria which correlated with time spent below sPO2 89 %. Downregulated catalase resulting from increased miR-21 was also detected. Also these changes normalized with CPAP. These results indicate that hemolysis of hypoxia-born RBCs prevents OSA patients from becoming polycythemic. Increased ROS was not only found in reticulocytes but also in leukocytes; these also normalized with CPAP.Expression of inflammatory markers (NFKB1, TNF, and IL6) in granulocytes was higher in OSA compared to controls and normalized by CPAP; these levels correlated with apnea-hypopnea Index (AHI). OSA patients had higher hepcidin levels, correlating with inflammatory marker levels and inversely correlated with EPO. Iron and transferrin saturation levels were lower in OSA compared to controls, inversely correlating with high hepcidin levels. These data indicated that besides neocytolysis, coexistent suppression of erythropoiesis by inflammation contributed to the lack of polycythemia in OSA.In OSA, inflammation mediated increase of ROS in leukocytes is a known causative factor of cardiovascular disease. We now report increase of both ROS and inflammatory markers in leukocytes.We conclude that the absence of polycythemia in OSA is the result of hemolysis via neocytolysis and inflammation-mediated suppression of erythropoiesis. Increased ROS in blood cells and systemic inflammation from OSA-constitute mechanisms likely contributing to the pathophysiology of OSA. DisclosuresGanz:Vifor: Consultancy; Ablynx: Consultancy; Keryx Pharma: Consultancy, Research Funding; Silarus Pharma: Consultancy, Equity Ownership; La Jolla Pharma: Consultancy, Patents & Royalties: Patent licensed to La Jolla Pharma by UCLA; Akebia: Consultancy, Research Funding; Intrinsic LifeScience: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy.

The shifting relationship between weight and pediatric obstructive sleep apnea: A historical review.

For more than a century, pediatric obstructive sleep apnea (OSA) was associated with failure to thrive. However, that association has faded over the last few decades. A 21st century child with OSA is much more likely to be overweight than underweight. This raises the question: Has pediatric OSA changed over time, or has the rise of childhood obesity in the United States created a new, separate disease? This literature review explores the historical shift in the relationship between weight and OSA, and the associated changes in treatment. We demonstrate a clear transition in the prevalence of failure to thrive and obesity in the OSA literature in the mid-2000s. What is less clear is whether these two clinical phenotypes should be considered two distinct diseases, or whether subtle differences in one set of pathophysiologic pathways-adenotonsillar hypertrophy, altered inflammation, and increased energy expenditure-can lead to divergent metabolic outcomes. More research is needed to fully elucidate the pathophysiology of OSA in children with obesity. We may need new and different treatments for obesity-associated OSA as adenotonsillectomy-which is effective at reversing failure to thrive in OSA-is not as effective at treating OSA in children with obesity. One option is drug-induced sleep endoscopy, which could personalize and improve surgical treatment of OSA. There is some evidence that therapies used for OSA in adults (e.g., weight loss and positive airway pressure) are also helpful for overweight/obese children with OSA. Laryngoscope, 129:2414-2419, 2019.

Does Rapid Eye Movement Sleep Aggravate Obstructive Sleep Apnea?

Objectives.To investigate the apnea-hypopnea index (AHI) according to the sleep stage in more detail after control of posture.Methods.Patients who underwent nocturnal polysomnography between December 2007 and July 2018 were retrospectively evaluated. Inclusion criteria were as follows: age >18 years, sleep efficacy >80%, and patients who underwent polysomnography only in the supine position (100% of the time). Patients were classified into different groups according to the methods: the first, rapid eye movement (REM)-dominant group (AHIREM/AHINREM >2), non-rapid eye movement (NREM)-dominant group (AHINREM/AHIREM >2), and non-dominant group; and the second, light sleep group (AHIN1N2>AHISWS) and slow wave sleep (SWS) group (AHISWS>AHIN1N2).Results.A total of 234 patients (mean age, 47.4±13.9 years) were included in the study. There were 108 patients (46.2%) in the REM-dominant group, 88 (37.6%) in the non-dominant group, and 38 (16.2%) in the NREM-dominant group. The AHI was significantly higher in the NREM-dominant group than in the REM-dominant group (32.9±22.9 events/hr vs. 18.3±9.5 events/hr, respectively). There were improvements in the AHI from stage 1 to SWS in NREM sleep with the highest level in REM sleep. A higher AHISWS than AHIN1N2 was found in 16 of 234 patients (6.8%); however, there were no significant predictors of these unexpected results except AHI.Conclusion.Our results demonstrated the highest AHI during REM sleep stage in total participants after control of posture. However, there were 16.2% of patients showed NREM-dominant pattern (AHINREM/AHIREM >2) and 6.8% of patients showed higher AHISWS than AHIN1N2. Therefore, each group might have a different pathophysiology of obstructive sleep apnea (OSA), and we need to consider this point when we treat the patients with OSA.

Correlation of changes in the red blood cell distribution width with the response to continuous positive airway pressure in patients with obstructive sleep apnea

It is recently found that the red blood cell distribution width (RDW) is independently associated with cardiovascular disease in patients with obstructive sleep apnea (OSA).The goal of this study is to investigate the correlation of RDW with the severity of OSA and whether RDW could be used to monitor the response to continuous positive airway pressure (CPAP) therapy in OSA patients. The study enrolled 70 participants. Control group (n = 24) consisted of patients with normal polysomnography and OSA group (n = 46) comprised patients with OSA of varying severity. RDW was measured before polysomnography in both groups. In addition, RDW was measured in the OSA group following 3 months of CPAP therapy. The RDW was significantly higher in the OSA group (p < 0.001), and this difference remained after adjusting for age and body mass index (p = 0.001). The RDW was approximately twofold greater in the OSA group (OR 2.126, 95% confidence interval 1.32–3.41; p = 0.002). On univariate analysis, the RDW was significantly correlated with hypoxia parameters, which was persistent with multivariate analysis. Furthermore, CPAP therapy reduced RDW (p = 0.002), and the change in the severity of 3% ODI by CPAP was correlated with the change in the RDW (r = 0.416, p = 0.013). The high RDW may be related to the pathophysiology of OSA. The high RDW in OSA may be associated with hypoxia. Therefore, treating OSA with CPAP could improve the RDW.

Catestatin serum levels are increased in male patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a complex sleep disorder associated with autonomic and sympathetic dysregulation. To the contrary, catestatin, an endogenous pleiotropic peptide cleaved from chromogranin A, is known for its inhibitory effects on catecholamine release and sympathetic activity. The aims of the study were to determine catestatin serum levels among male OSA patients compared to healthy control subjects and to explore associations of catestatin with anthropometric, polysomnographic, and lipid profile parameters. Seventy-eight male OSA patients aged 50.3 ± 8.8years and 51 age/sex/BMI-matched control subjects aged 50.4 ± 7.8years were enrolled in the study. Catestatin serum levels were determined by an enzyme-linked immunosorbent assay (ELISA). Catestatin serum levels were significantly higher among OSA patients compared to control subjects (2.9 ± 1.2 vs. 1.5 ± 1.1ng/mL, p < 0.001). Serum catestatin levels significantly correlated with apnea-hypopnea index (AHI) among non-obese OSA subjects (r = 0.466, p = 0.016; β = 0.448, p = 0.026), while in whole OSA population, catestatin levels significantly correlated with neck circumference (r = 0.318, p < 0.001; β = 0.384, p < 0.001) and high-density lipoprotein (HDL) cholesterol (r = - 0.320, p < 0.001; β = - 0.344, p < 0.001). In multivariate-adjusted regression model, serum catestatin was significant and independent predictor of OSA status (OR 4.98, 95% CI 2.17-11.47, p < 0.001). Catestatin serum levels are significantly increased in male OSA population and positively correlate with disease severity in non-obese patients. OSA status is independently predicted by catestatin levels; however, this finding is restricted to patients with moderate-to-severe disease. Further studies are necessary to elucidate the mechanistic role of catestatin in the complex pathophysiology of OSA.

Syndrome ‘Z’: A Predictor of Angiographic Severity of Coronary Artery Disease in Patients of Acute Coronary Syndrome

Owing to the growing evidence that the pathophysiology of obstructive sleep apnoea (OSA) and metabolic syndrome (MS) overlap considerably and both adversely impact cardiovascular health, we hypothesised that the presence of OSA with MS additively and adversely affect the severity of coronary artery disease (CAD). Exploration and understanding of this may have direct implications for the development of targeted, preventive strategies for CAD. Thus, this prospective study was aimed to determine the prevalence of 'Syndrome Z' in patients of MS who present with an acute coronary event and to correlate it with the angiographic severity of CAD in these patients. The present study was a single centre, cross sectional study conducted in a university teaching hospital. In a span of 6 months, 922 patients with acute coronary syndromes (ACS) were screened for the study. Among these, 861 patients had no evidence of MS. The remaining 61 patients who were diagnosed to have MS were then subjected to an overnight sleep study. Only 58 had good sleep data so were included for further analysis. Angiographic parameters in terms of number of vessels involved and culprit lesions were noted and correlated with presence and absence of OSA and also with its severity based on the Apnoea/Hypopnoea Index (AHI). The prevalence of OSA positivity in patients with MS who presented with ACS was 34.5% (n=20). Most of the patients in the OSA negative group (78.9%, n=30) had disease limited to only one vessel while in the OSA positive group only a minority (15%, n=3) of patients had their disease limited to a single vessel (p=0.001). The number of lesions in the culprit vessel was also significantly less in the OSA negative group compared to the OSA positive group. While in the OSA negative group 68.4% (n=26) patients had a solitary lesion, followed by two and three lesions in 15.8% (n=6) of the patients each, multiple lesions were more common in OSA positive patients, involving 80% of cases (45.0%, n=9 with two lesions; 35.0%, n=7 with three lesions; only 20%, n=4 had a solitary lesion). Prevalence of 'Syndrome Z' is high in patients having MS presenting with ACS and it correlates with the angiographic severity of CAD.

Obstructive Sleep Apnea in Heart Failure: Review of Prevalence, Treatment with Continuous Positive Airway Pressure, and Prognosis.

Obstructive sleep apnea is a sleep-related breathing disorder that has a major impact on cardiovascular function. It has been associated with hypertension, coronary artery disease, cardiac arrhythmias, sudden cardiac death, and heart failure. This review focuses on the relationship between obstructive sleep apnea and heart failure with either reduced or preserved ejection fraction. We discuss the pathophysiology of obstructive sleep apnea, as well as its prevalence, treatment outcomes with continuous positive airway pressure, and prognosis in these 2 distinct types of heart failure. We also identify areas in which further work is needed to improve our understanding of this association in heart failure patients.

Computational model of brain-stem circuit for state-dependent control of hypoglossal motoneurons.

In patients with obstructive sleep apnea (OSA), the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Experimental studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contributes to depression of hypoglossal motoneurons and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. In this new study, we developed a biophysical network model to test the hypothesis that, to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons needs to include excitatory and inhibitory perihypoglossal interneurons that mediate noradrenergic and serotonergic drives to hypoglossal motoneurons. In the model, the state-dependent activation of the hypoglossal motoneurons was in qualitative agreement with in vivo data during simulated rapid eye movement (REM) and non-REM sleep. The model was applied to test the mechanisms of action of noradrenergic and serotonergic drugs during REM sleep as observed in vivo. We conclude that the proposed minimal neuronal circuit is sufficient to explain in vivo data and supports the hypothesis that perihypoglossal interneurons may mediate state-dependent monoaminergic drive to hypoglossal motoneurons. The population of the hypothesized perihypoglossal interneurons may serve as novel targets for pharmacological treatment of OSA. NEW & NOTEWORTHY In vivo studies suggest that during rapid eye movement sleep, withdrawal of noradrenergic and serotonergic drives critically contributes to depression of hypoglossal motoneurons (HMs), which innervate the tongue muscles. By means of a biophysical model, which is consistent with a broad range of empirical data, we demonstrate that the neuronal network controlling the excitability of HMs needs to include excitatory and inhibitory interneurons that mediate noradrenergic and serotonergic drives to HMs.

Complement system activation in obstructive sleep apnea.

The complement system may play a role in the systemic inflammation characterising obstructive sleep apnea; however, this has not been investigated before. We aimed to study the involvement of effector complement elements in obstructive sleep apnea, namely C3a, C5a and SC5b-9. Venous blood was collected in 50 patients with obstructive sleep apnea and 26 control subjects in the evening and the following morning. Plasma complement proteins were analysed with ELISA. Complement factor levels were compared between the two groups and correlated with clinical variables. Plasma C3a concentration was elevated in obstructive sleep apnea both in the evening (84.1 [0-338.5] ng ml-1 ) and in the morning (85.5 [0-247.8] ng ml-1 ) compared with controls (30.3 [0-176.8] ng ml-1 and 36.3 [0-167.1] ng ml-1 , evening and morning, respectively, both p < 0.05). On the contrary, C5a and SC5b-9 levels were comparable between patients and controls at each time point (p > 0.05). There was no change in complement factors from evening to morning in either group (p > 0.05), except for C5a that decreased from evening to morning in obstructive sleep apnea (from 11.6 [1.6-47.4] ng ml-1 to 9.3 [0-46.4] ng ml-1 , p = 0.01). Elevated C3a levels were directly related to obstructive sleep apnea severity, and were significantly associated with male gender, weight, body mass index, hypertension, high C-reactive protein and low high-density lipoprotein cholesterol (p < 0.05). The complement system is activated in obstructive sleep apnea, which is correlated with disease severity. Our findings highlight the potential role of complement system in the pathophysiology of obstructive sleep apnea, thus facilitating further research.

The role of hypoxia-inducible factors in carotid body (patho) physiology.

Hypoxia-inducible factors mediate adaptive responses to reduced O2 availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca2+ levels, which drive increased expression of hypoxia-inducible factor (HIF) 1α and a decrease in the levels of HIF-2α. Intermittent hypoxia increases HIF-1α-dependent expression of Nox2, encoding the pro-oxidant enzyme NADPH oxidase 2, and decreased HIF-2α-dependent expression of Sod2, encoding the anti-oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities. The ROS generated by dysregulated HIF activity in the CB results in oxidation and inhibition of haem oxygenase 2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnoea involves the dysregulation of O2 -regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing.

Association between allergic and nonallergic rhinitis and obstructive sleep apnea.

Allergic rhinitis and nonallergic rhinitis (NAR) are common disorders, which have been considered as potential risk factors for obstructive sleep apnea (OSA). This review summarizes the proposed underlying pathophysiological mechanisms to provide a better understanding of the relationship between these conditions. In adults, allergic rhinitis and NAR may be considered as symptoms potentiating, rather than risk potentiating factors in the pathophysiology of OSA, whereas in children, these are considered to be independent predictors for sleep-disordered breathing (SDB) and failure of adeno-tonsillectomy, the recommended first-line therapy for children with OSA. Current advances suggest IL-6 may be important in regulating the sleep-wake cycle, and serum soluble IL-6 receptor (sIL-6R) levels may reflect the severity of OSA. Elevated Th17/Treg ratio correlates positively with apnea-hypopnea index of OSA patients, and Th17 and Treg imbalances caused by allergic rhinitis and OSA, respectively, may possibly promote each other, leading to further imbalance. Moreover, obesity is a strong risk factor for OSA, and leptin plays an important role in ventilatory function and upper airway obstruction. The variant trigeminocardiac reflex and nasotrigeminal reflex may also be involved in the association between rhinitis and OSA. Allergic rhinitis/NAR and OSA are closely associated, and each condition can be detrimental to the other. Thus, clinicians should pay attention to the potential presence of allergic rhinitis/NAR in OSA patients and vice versa.

Phenotyping the pathophysiology of obstructive sleep apnea using polygraphy/polysomnography: a review of the literature.

Continuous positive airway pressure (CPAP) is the first-line treatment for the majority of patients affected by obstructive sleep apnea syndrome (OSA). However, long-term compliance with CPAP therapy may result limited and alternatives to CPAP therapy are required to address the increasing need to provide tailored therapeutic options. Understanding the pathophysiological traits (PTs) of OSA patients [upper airway (UA) anatomical collapsibility, loop gain (LG), arousal threshold (AT), and UA gain (UAG)] lies at the heart of the customized OSA treatment. However, sleep research laboratories capable to phenotype OSA patients are sparse and the diagnostic procedures time-consuming, costly, and requiring significant expertise. The question arises whether the use of routine clinical polysomnography or nocturnal portable multi-channel monitoring (PSG/PM) can provide sufficient information to characterize the above traits. The aim of the present review is to deduce if the information obtainable from the clinical PSG/PM analysis, independently of the scope and context of the original studies, is clinically useful to define qualitatively the PTs of individual OSA patients. In summary, it is possible to identify four patterns using PSG/PM that are consistent with an altered UA collapsibility, three that are consistent with altered LG, two with altered AT, and three consistent with flow limitation/UA muscle response. Furthermore, some PSG/PM indexes and patterns, useful for the suitable management of OSA patient, have been discussed. The delivery of this clinical approach to phenotype pathophysiological traits will allow patients to benefit in a wider range of sleep services by facilitating tailored therapeutic options.

Role of Leptin in Obstructive Sleep Apnea.

Leptin is a peptide hormone produced mainly in white adipose tissue. It is known to regulate energy homeostasis, inflammation, metabolism, and sympathetic nerve activity. Increasing evidence suggests it has a role in ventilatory function and upper airway obstruction. Leptin levels correlate positively with measurements of adiposity and can potentially provide important insights into the pathophysiology of diseases associated with obesity. Obesity is a strong risk factor for obstructive sleep apnea, a disease characterized by periodic upper airway occlusion during sleep. The neuromuscular activity that maintains upper airway patency during sleep and the anatomy of upper airway are key factors involved in its pathogenesis. Experimental studies using animal models of a low leptin state such as leptin deficiency have shown that leptin regulates sleep architecture, upper airway patency, ventilatory function, and hypercapnic ventilatory response. However, findings from human studies do not consistently support the data from the animal models. The effect of leptin on the pathophysiology of obstructive sleep apnea is being investigated, but the results of studies have been confounded by leptin's diurnal variation and the short-term effects of feeding, adiposity, age, and sex. Improved study design and methods of assessing functional leptin levels, specifically their central versus peripheral effects, will improve understanding of the role of leptin in sleep apnea.

Physiology-Based Modeling May Predict Surgical Treatment Outcome for Obstructive Sleep Apnea.

To test whether the integration of both anatomical and nonanatomical parameters (ventilatory control, arousal threshold, muscle responsiveness) in a physiology-based model will improve the ability to predict outcomes after upper airway surgery for obstructive sleep apnea (OSA). In 31 patients who underwent upper airway surgery for OSA, loop gain and arousal threshold were calculated from preoperative polysomnography (PSG). Three models were compared: (1) a multiple regression based on an extensive list of PSG parameters alone; (2) a multivariate regression using PSG parameters plus PSG-derived estimates of loop gain, arousal threshold, and other trait surrogates; (3) a physiological model incorporating selected variables as surrogates of anatomical and nonanatomical traits important for OSA pathogenesis. Although preoperative loop gain was positively correlated with postoperative apnea-hypopnea index (AHI) (P = .008) and arousal threshold was negatively correlated (P = .011), in both model 1 and 2, the only significant variable was preoperative AHI, which explained 42% of the variance in postoperative AHI. In contrast, the physiological model (model 3), which included AHIREM (anatomy term), fraction of events that were hypopnea (arousal term), the ratio of AHIREM and AHINREM (muscle responsiveness term), loop gain, and central/mixed apnea index (control of breathing terms), was able to explain 61% of the variance in postoperative AHI. Although loop gain and arousal threshold are associated with residual AHI after surgery, only preoperative AHI was predictive using multivariate regression modeling. Instead, incorporating selected surrogates of physiological traits on the basis of OSA pathophysiology created a model that has more association with actual residual AHI. A commentary on this article appears in this issue on page 1023. ClinicalTrials.Gov; Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea; Identifier: NCT02696629; URL: https://clinicaltrials.gov/show/NCT02696629.

Obstructive sleep apnoea and polycystic ovary syndrome: A comprehensive review of clinical interactions and underlying pathophysiology.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple comorbidities including, obesity, insulin resistance and type 2 diabetes, as well as mood disorders and impaired quality of life (QoL). Obstructive sleep apnoea (OSA) is also a common medical condition that is often undiagnosed, particularly in women. OSA is associated with a similar spectrum of comorbidities to that observed in PCOS, including manifestations of the metabolic syndrome and impaired QoL, whilst obesity frequently constitutes a common denominator in the pathophysiology of both OSA and PCOS. Hence, it is not surprising that OSA and PCOS may coexist in women of reproductive age, and the current clinical guidelines on the management of PCOS recommend screening for OSA symptoms in overweight/obese women with PCOS. In this review, we examine the relationship between OSA and PCOS and explore the potential underlying mechanisms that link these two conditions.

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO2 and 3.0 ± 0.2% O2) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO2, O2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea.NEW & NOTEWORTHY Both arousal state and concomitant CO2 levels are known modulators of the effects of intermittent hypoxia on ventilatory neuroplasticity. This is the first study to investigate the effects of combined intermittent hypercapnic hypoxia during sleep in humans. The lack of neuroplastic effects suggests a need for further studies more closely replicating obstructive sleep apnea to determine the pathophysiological relevance of intermittent hypoxia-induced ventilatory neuroplasticity.