Exosomes regulate SIRT3-related autophagy by delivering miR-421 to regulate macrophage polarization and participate in OSA-related NAFLD.

PURPOSE: To analyze the role of and mechanism underlying obstructive sleep apnea (OSA)-derived exosomes in inducing non-alcoholic fatty liver (NAFLD). METHODS: The role of OSA-derived exosomes was analyzed in inducing hepatocyte fat accumulation in mice models both in vivo and in vitro. RESULTS: OSA-derived exosomes caused fat accumulation and macrophage activation in the liver tissue. These exosomes promoted fat accumulation; steatosis was more noticeable in the presence of macrophages. Macrophages could internalize OSA-derived exosomes, which promoted macrophage polarization to the M1 type. Moreover, it inhibited sirtuin-3 (SIRT3)/AMP-activated protein kinase (AMPK) and autophagy and promoted the activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes. The use of 3-methyladenine (3-MA) to inhibit autophagy blocked NLRP3 inflammasome activation and inhibited the M1 polarization of macrophages. miR-421 targeting inhibited SIRT3 protein expression in the macrophages. miR-421 was significantly increased in OSA-derived exosomes. Additionally, miR-421 levels were increased in OSA + NAFLD mice- and patient-derived exosomes. In the liver tissues of OSA and OSA + NAFLD mice, miR-421 displayed similar co-localization with the macrophages. Intermittent hypoxia-induced hepatocytes deliver miR-421 to the macrophages via exosomes to inhibit SIRT3, thereby participating in macrophage M1 polarization. After OSA and NAFLD modeling in miR-421-/- mice, liver steatosis and M1 polarization were significantly reduced. Additionally, in the case of miR-421 knockout, the inhibitory effects of OSA-derived exosomes on SIRT3 and autophagy were significantly alleviated. Furthermore, their effects on liver steatosis and macrophage M1 polarization were significantly reduced. CONCLUSIONS: OSA promotes the delivery of miR-421 from the hepatocytes to macrophages. Additionally, it promotes M1 polarization by regulating the SIRT3/AMPK-autophagy pathway, thereby causing NAFLD.

Association of obstructive sleep apnea symptoms with all-cause mortality and cause-specific mortality in adults with or without diabetes: A cohort study based on the NHANES.

BACKGROUND: The association between obstructive sleep apnea syndrome (OSAS) and mortality has not been extensively researched among individuals with varying diabetic status. This study aimed to compare the relationship of OSAS with all-cause and cause-specific mortality in US individuals with or without diabetes based on data from the National Health and Nutrition Examination Survey (NHANES). METHODS: The study included participants from the NHANES 2005-2008 and 2015-2018 cycles with follow-up information. OSAS data (OSAS.MAP10) was estimated from the questionnaire. Hazard ratios (HRs) and the 95% confidence interval (CI) of OSAS for mortality were calculated by Cox regression analysis in populations with different diabetes status. The relationships between OSAS and mortality risk were examined using survival curves and restricted cubic spline curves. RESULTS: A total of 13 761 participants with 7.68 ± 0.042 follow-up years were included. In the nondiabetic group, OSAS.MAP10 was positively associated with all-cause, cardiovascular, and cancer mortality. In individuals with prediabetes, OSAS.MAP10 was positively related to all-cause mortality (HR 1.11 [95% CI: 1.03-1.20]) and cardiovascular mortality (HR 1.17 [95% CI: 1.03-1.33]). The relationship between OSAS.MAP10 and the risk of all-cause mortality and cancer mortality exhibited L-shaped curves in diabetes patients (both with nonlinear p values <.01). Further threshold effect analysis revealed that OSAS was positively related to death risk when OSAS.MAP10 exceeded the threshold scores. CONCLUSION: The relationship between OSAS and mortality differed among participants with or without diabetes. Individualized clinical treatment plans should be developed in clinical practice to reduce the risk of death for patients with different metabolic conditions.

Outcomes of coronary artery bypass grafting (CABG) in patients with OSA-COPD overlap syndrome versus COPD alone: an analysis of US Nationwide Inpatient Sample.

BACKGROUND: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) are associated with unfavorable outcomes following coronary artery bypass grafting (CABG). The purpose of this study was to compare in-hospital outcomes of patients with COPD alone versus OSA-COPD overlap after CABG. METHODS: Data of adults ≥ 18 years old with COPD who received elective CABG between 2005 and 2018 were extracted from the US Nationwide Inpatient Sample (NIS). Patients were divided into two groups: with OSA-COPD overlap and COPD alone. Propensity score matching (PSM) was employed to balance the between-group characteristics. Logistic and linear regression analyses determined the associations between study variables and inpatient outcomes. RESULTS: After PSM, data of 2,439 patients with OSA-COPD overlap and 9,756 with COPD alone were analyzed. After adjustment, OSA-COPD overlap was associated with a significantly increased risk of overall postoperative complications (adjusted odd ratio [aOR] = 1.12, 95% confidence interval [CI]: 95% CI: 1.01-1.24), respiratory failure/prolonged mechanical ventilation (aOR = 1.27, 95%CI: 1.14-1.41), and non-routine discharge (aOR = 1.16, 95%CI: 1.03-1.29), and AKI (aOR = 1.14, 95% CI: 1.00-1.29). Patients with OSA-COPD overlap had a lower risk of in-hospital mortality (adjusted odd ratio [aOR] = 0.53, 95% CI: 0.35-0.81) than those with COPD only. Pneumonia or postoperative atrial fibrillation (AF) risks were not significantly different between the 2 groups. Stratified analyses revealed that, compared to COPD alone, OSA-COPD overlap was associated with increased respiratory failure/prolonged mechanical ventilation risks among patients ≥ 60 years, and both obese and non-obese subgroups. In addition, OSA-COPD overlap was associated with increased risk of AKI among the older and obese subgroups. CONCLUSION: In US adults who undergo CABG, compared to COPD alone, those with OSA-COPD are at higher risks of non-routine discharge, AKI, and respiratory failure/prolonged mechanical ventilation, but a lower in-hospital mortality. No increased risk of AF was noted.

Sleep duration time and human papillomavirus infection risk: The U-shaped relationship revealed by NHANES data.

PURPOSE: This study aims to investigate the relationship between sleep factors (sleep duration time [SDT] and obstructive sleep apnea [OSA]) and human papillomavirus (HPV)/high-risk HPV(HR-HPV) infection, utilizing data from the National Health and Nutrition Examination Survey (NHANES). METHODS: We conducted a cross-sectional analysis using NHANES data, focusing on SDT and OSA's association with HPV/HR-HPV infection. The primary statistical methods included weighted multivariate linear regression and logistic regression to assess the association between SDT, OSA, and HPV/HR-HPV infection. The study employed restricted cubic splines (RCS) for evaluating potential non-linear relationships between SDT and HPV/HR-HPV infection. Subgroup analyses were conducted. Interaction terms were used to examine the heterogeneity in associations across different subgroups. RESULTS: The study identified a U-shaped relationship between SDT and HPV infection. Specifically, 7 hours of sleep was associated with the lowest risk of HPV infection. In comparison, SDT less than 7 hours resulted in a 26.3% higher risk of HPV infection (Odds Ratio [OR] = 1.26, 95% Confidence Interval [CI]: 1.029, 1.549), and more than 9 hours of sleep showed a 57.4% increased risk (OR = 1.574, 95% CI: 1.116, 2.220). The relationship between SDT and HR-HPV infection was significant in the first two models, but not in the fully adjusted model. No significant interaction was found between sleep duration and other covariates. There was no association between OSA and HPV/HR-HPV infection. CONCLUSION: The study underscores the complex relationship between sleep duration and HPV infection risk, suggesting both very short and very long sleep durations may increase HPV infection likelihood. The findings highlight the need for further research to explore the biological mechanisms underpinning this association and to consider broader population groups and more precise sleep assessment methods in future studies.

A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options.

Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.

A risk prediction nomogram for resistant hypertension in patients with obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) are liable to have resistant hypertension (RH) associated with unfavorable cardiovascular events. It is of necessity to predict OSA patients who are susceptible to resistant hypertension. Hence, we conducted a retrospective study based on the clinical records of OSA patients admitted to Yixing Hospital Affiliated to Jiangsu University from January 2018 to December 2022. According to different time periods, patients diagnosed between January 2018 and December 2021 were included in the training set (n = 539) for modeling, and those diagnosed between January 2022 and December 2022 were enrolled into the validation set (n = 259) for further assessment. The incidence of RH in the training set and external validation set was comparable (P = 0.396). The related clinical data of patients enrolled were collected and analyzed through univariate analysis and least absolute shrinkage and selection operator (LASSO) logistic regression analysis to identify independent risk factors and construct a nomogram. Finally, five variables were confirmed as independent risk factors for OSA patients with RH, including smoking, heart disease, neck circumference, AHI and T90. The nomogram established on the basis of variables above was shown to have good discrimination and calibration in both the training set and validation set. Decision curve analysis indicated that the nomogram was useful for a majority of OSA patients. Therefore, our nomogram might be useful to identify OSA patients at high risk of developing RH and facilitate the individualized management of OSA patients in clinical practice.

A pilot observation using ultrasonography and vowel articulation to investigate the influence of suspected obstructive sleep apnea on upper airway.

Failure to employ suitable measures before administering full anesthesia to patients with obstructive sleep apnea (OSA) who are undergoing surgery may lead to developing complications after surgery. Therefore, it is very important to screen OSA before performing a surgery, which is currently done by subjective questionnaires such as STOP-Bang, Berlin scores. These questionnaires have 10-36% specificity in detecting sleep apnea, along with no information given on anatomy of upper airway, which is important for intubation. To address these challenges, we performed a pilot study to understand the utility of ultrasonography and vowel articulation in screening OSA. Our objective was to investigate the influence of OSA risk factors in vowel articulation through ultrasonography and acoustic features analysis. To accomplish this, we recruited 18 individuals with no risk of OSA and 13 individuals with high risk of OSA and asked them to utter vowels, such as /a/ (as in "Sah"), /e/ (as in "See"). An expert ultra-sonographer measured the parasagittal anterior-posterior (PAP) and transverse diameter of the upper airway. From the recorded vowel sounds, we extracted 106 features, including power, pitch, formant, and Mel frequency cepstral coefficients (MFCC). We analyzed the variation of the PAP diameters and vowel features from "See: /i/" to "Sah /a/" between control and OSA groups by two-way repeated measures ANOVA. We found that, there was a variation of upper airway diameter from "See" to "Sah" was significantly smaller in OSA group than control group (OSA: ∆12.8 ± 5.3 mm vs. control: ∆22.5 ± 3.9 mm OSA, p < 0.01). Moreover, we found several vowel features showed the exact same or opposite trend as PAP diameter variation, which led us to build a machine learning model to estimate PAP diameter from vowel features. We found a correlation coefficient of 0.75 between the estimated and measured PAP diameter after applying four estimation models and combining their output with a random forest model, which showed the feasibility of using acoustic features of vowel sounds to monitor upper airway diameter. Overall, this study has proven the concept that ultrasonography and vowel sounds analysis may be useful as an easily accessible imaging tool of upper airway.

The causal relationship between depression and obstructive sleep apnea: A bidirectional Mendelian randomization study.

OBJECTIVE: Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR). METHODS: Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators. RESULTS: The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (ORivw = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (ORivw = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (ORivw = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (ORivw = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA. CONCLUSION: These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA.

Changes in the nasopharyngeal and oropharyngeal microbiota in pediatric obstructive sleep apnea before and after surgery: a prospective study.

OBJECTIVE: To explore the changes and potential mechanisms of microbiome in different parts of the upper airway in the development of pediatric OSA and observe the impact of surgical intervention on oral microbiome for pediatric OSA. METHODS: Before adeno-tonsillectomy, we collected throat swab samples from different parts of the oropharynx and nasopharynx of 30 OSA patients and 10 non-OSA patients and collected throat swab samples from the oropharynx of the above patients one month after the adeno-tonsillectomy. The 16 S rRNA V3-V4 region was sequenced to identify the microbial communities. The correlation analysis was conducted based on clinical characteristics. RESULTS: There was a significant difference of alpha diversity in different parts of the upper airway of pediatric OSA, but this difference was not found in children with non-OSA. Beta diversity was significantly different between non-OSA and pediatric OSA. At the genus level, the composition of flora in different parts is different between non-OSA and pediatric OSA. The correlation analysis revealed that the relative abundance of Neisseria was significantly correlated with obstructive apnea hypopnea index. Furthermore, the functional prediction revealed that pathways related to cell proliferation and material metabolism were significantly different between non-OSA and pediatric OSA. Besides, the adeno-tonsillectomy has minimal impact on oral microbiota composition in short term. CONCLUSION: The changes in upper airway microbiome are highly associated with pediatric OSA. The relative abundance of some bacteria was significantly different between OSA and non-OSA. These bacteria have the potential to become new diagnostic and early warning biomarkers.

Obstructive sleep apnoea in obesity: A review.

Obstructive sleep apnea is a common comorbidity that occurs in individuals with obesity. It classically manifests with excessive daytime sleepiness, resulting in reduced quality of life, workplace productivity, and an increased risk of motor vehicle accidents. Weight gain plays an important role in its pathogenesis through worsening upper airway collapsibility, and current treatment options are targeted towards mechanically overcoming upper airway obstruction and weight loss. Continuous positive airway pressure therapy remains the most widely prescribed treatment for obstructive sleep apnea but poor tolerance is a common barrier to effective treatment. Sustainable weight loss is an important treatment option but can be difficult to achieve without bariatric surgery. The recent advances in incretin-based pharmacotherapies represent a promising avenue not only in achieving long-term weight loss but also in treating obstructive sleep apnoea and alleviating the burden of its symptoms and comorbidities.

Risk of Sarcopenia and Osteoporosis in Elderly Male Patients with Obstructive Sleep Apnea Syndrome: A Multicenter Study.

The aim of this study was to assess the risk of sarcopenia and osteoporosis in elderly patients with obstructive sleep apnea syndrome (OSAS). We recruited both OSAS patients and non-OSAS subjects from multiple centers and evaluated their skeletal muscle index (SMI), bone mineral density (BMD), and inflammatory factors. All participants underwent polysomnography (PSG) testing, handgrip strength testing, chest CT, and dual-energy x-ray BMD testing. Based on the PSG diagnosis results, the participants were divided into a control group and an OSAS group. The analysis results revealed a higher incidence of sarcopenia in the OSAS group (χ2 = 22.367; P = 0.000) and osteoporosis (χ2 = 11.730a; P = 0.001). There were statistically significant differences in BMI (P = 0.000), grip strength (P = 0.000), SMI (P = 0.000), bone density (P = 0.000) and vitamin D (P = 0.000). The independent sample t test results showed that there was no statistical difference between IL-6 (P = 0.247) and CRP (P = 0.246). Considering the potential impact of body weight on the observed indicators, we employed covariance analysis to calculate the modified P value for each observation indicator. The findings demonstrated that the grip strength, IL-6, and CRP levels in the OSAS group were significantly higher compared to the control group. Conversely, the SMI, bone density, and Vitamin D levels were found to be significantly lower in the OSAS group than in the control group. These results suggest a higher likelihood of sarcopenia and osteoporosis among OSAS patients. Further studies should be conducted in larger study populations.

Chronic intermittent hypoxia-induced hypertension: the impact of sex hormones.

Obstructive sleep apnea, a common form of sleep-disordered breathing, is characterized by intermittent cessations of breathing that reduce blood oxygen levels and contribute to the development of hypertension. Hypertension is a major complication of obstructive sleep apnea that elevates the risk of end-organ damage. Premenopausal women have a lower prevalence of obstructive sleep apnea and cardiovascular disease than men and postmenopausal women, suggesting that sex hormones play a role in the pathophysiology of sleep apnea-related hypertension. The lack of protection in men and postmenopausal women implicates estrogen and progesterone as protective agents but testosterone as a permissive agent in sleep apnea-induced hypertension. A better understanding of how sex hormones contribute to the pathophysiology of sleep apnea-induced hypertension is important for future research and possible hormone-based interventions. The effect of sex on the pathophysiology of sleep apnea and associated intermittent hypoxia-induced hypertension is of important consideration in the screening, diagnosis, and treatment of the disease and its cardiovascular complications. This review summarizes our current understanding of the impact of sex hormones on blood pressure regulation in sleep apnea with a focus on sex differences.

DAHOS Study: Efficacy of dapagliflozin in treating heart failure with reduced ejection fraction and obstructive sleep apnea syndrome - A 3-month, multicenter, randomized controlled clinical trial.

BACKGROUND: The recent discovery of new therapeutic approaches to heart failure with reduced ejection fraction (HFrEF), including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as well as improved treatment of co-morbidities has provided much needed help to HFrEF. In addition, dapagliflozin, one of the SGLT-2 inhibitors, serves as a promising candidate in treating obstructive sleep apnea (OSA) of HFrEF patients due to its likely mechanism of countering the pathophysiology of OSA of HFrEF. METHODS: This 3-month multicenter, prospective, randomized controlled trial enrolled participants with left ventricular ejection fraction (LVEF) less than 40% and apnea-hypopnea index (AHI) greater than 15. Participants were randomized into two groups: the treatment group received optimized heart failure treatment and standard-dose dapagliflozin, while the control group only received optimized heart failure treatment. The primary endpoint was the difference in AHI before and after treatment between the two groups. Secondary endpoints included oxygen desaturation index (ODI), minimum oxygen saturation, longest apnea duration, inflammatory factors (CRP, IL-6), quality of life score, and LVEF. RESULTS: A total of 107 patients were included in the final analysis. AHI, LVEF and other baseline data were similar for the dapagliflozin and control groups. After 12 weeks of dapagliflozin treatment, the dapagliflozin group showed significant improvements in sleep parameters including AHI, HI, longest pause time, ODI, time spent with SpO2 < 90%, and average SpO2. Meanwhile, the control group showed no significant changes in sleep parameters, but did demonstrate significant improvements in left ventricular end-diastolic diameter, LVEF, and NT-proBNP levels at 12 weeks. In the experimental group, BMI was significantly reduced, and there were improvements in ESS score, MLHFQ score, and EQ-5D-3L score, as well as significant reductions in CRP and IL-6 levels, while the CRP and IL-6 levels were not improved in the control group. The decrease in LVEF was more significant in the experimental group compared to the control group. There were no significant differences in the magnitude of the decreases between the two groups. CONCLUSIONS: Dapagliflozin may be an effective treatment for heart failure complicated with OSA, and could be considered as a potential new treatment for OSA. (Trial registration  www.chictr.org.cn , ChiCTR2100049834. Registered 10 August 2021).

Secondhand Smoke Exposure Measured in Urinary Cotinine Levels and Severity of Pediatric Sleep Apnea.

Importance: Exposure to secondhand smoke has been associated with numerous health problems in children, including obstructive sleep apnea. Secondhand smoke exposure may be a risk factor for increased pediatric sleep apnea severity. Objectives: To assess the association of secondhand smoke exposure (SHSe), quantified by urinary cotinine levels, with severity of obstructive sleep apnea (OSA) in children. Design, Setting, and Participants: This was a prospective cohort trial including pediatric patients from 3 to 16 years of age with sleep-disordered breathing who underwent a polysomnogram at a tertiary-level children's hospital in the US in either March 2014 to October 2016 or March 2020 to March 2021. Urine specimens were analyzed for cotinine, an important metabolite of nicotine. Each child's caregiver completed a validated SHSe questionnaire. Data were analyzed from February to June 2023. Exposure: OSA and secondhand smoke. Main Outcome and Measures: SHSe and severity of pediatric OSA, quantified by urinary cotinine levels and obstructive apnea hypopnea index (AHI) scores. Secondary outcomes were association of urinary cotinine levels with nadir oxygen saturation, sleep-related quality of life measured by the OSA-18 questionnaire, and caregiver-reported smoking habits (collected through a questionnaire). Results: The study included 116 patients with a median (IQR) age of 6 (5-9) years, among whom 51 (45%) had obesity. The median (IQR) AHI was 3.0 (1.2-8.0), with 28 children (30.0%) having severe disease (AHI >10). Thirty-four children (29.0%) were found to have a positive result for urine cotinine screening, with a mean (SD) level of 11.7 (9.4) ng/mL. The percentage of children with SHSe was less than anticipated. There was no association identified between urinary cotinine levels and either AHI (ρ = -0.04; 95% CI, -0.22 to 0.15) or nadir oxygen saturation (ρ = -0.07; 95% CI, -0.26 to 0.11). Furthermore, SHSe was not associated with the presence of severe OSA (odds ratio, 0.70; 95% CI, 0.26 to 1.90). Children whose caregivers reported indoor SHSe were more likely to have a detectable urinary cotinine level (odds ratio, 20.3; 95% CI, 6.67 to 61.8). Conclusions and Relevance: This cohort study did not identify any clinically meaningful association between SHSe, quantified by urinary cotinine level, and pediatric OSA severity. Future research with a larger number of children with SHSe is needed to confirm these findings and determine whether SHSe affects OSA treatment outcomes in children.

CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization.

BACKGROUND: Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease. METHODS: Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed. FINDINGS: Patients with OSA (n = 189; 84% men; age 66 ± 8 years, BMI 28 ± 3.5 kg/m2, AHI 41 ± 23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n = 91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n = 98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes. INTERPRETATION: Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA. FUNDING: National Institutes of Health/National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.

Effects of metformin on glucose metabolism and mitochondrial function in patients with obstructive sleep apnea: A pilot randomized trial.

Obstructive sleep apnea (OSA) is associated with increased risk for diabetes, and standard treatment with positive airway pressure (PAP) device shows inconsistent effects on glucose metabolism. Metformin is known to treat and prevent diabetes, but its effects on skeletal muscle mitochondrial function are not completely understood. Here, we evaluate the effects of metformin on glucose metabolism and skeletal muscle mitochondrial function in patients with OSA. Sixteen adults with obesity (50.9 ± 6.7 years, BMI: 36.5 ± 2.9 kg/m2 ) and moderate-to-severe OSA were provided with PAP treatment and randomized to 3 months of placebo (n = 8) or metformin (n = 8) treatment in a double-blind parallel-group design. Whole body glucose metabolism was determined by oral glucose tolerance test. A skeletal muscle biopsy was obtained to evaluate mitochondrial respiratory capacity and expression of proteins related to mitochondrial dynamics and energy metabolism. Whole body insulin-sensitivity (Matsuda index) did not change in metformin or placebo treated groups. However, metformin treatment prevented increases in insulin release relative to placebo during follow-up. Insulin area under the curve (AUC) and insulin to glucose AUC ratio increased in placebo but remained unchanged with metformin. Furthermore, metformin treatment improved skeletal muscle mitochondrial respiratory capacity and dynamics relative to placebo. Metformin treatment prevented the decline in whole body glucose homeostasis and skeletal muscle mitochondrial function in patients with moderate to severe OSA. Patients with OSA may benefit from the addition of metformin to prevent diabetes.

Incremental values of AOPP, IL-6, and GDF15 for identifying arteriosclerosis in patients with obstructive sleep apnea.

BACKGROUND: The objective of this study was to determine the independent and incremental values of advanced oxidative protein product (AOPP), interleukin 6 (IL-6), and growth differentiation factor 15 (GDF15) in identifying arteriosclerosis in patients with obstructive sleep apnea (OSA). METHODS: A total of 104 individuals diagnosed with OSA by polysomnography were recruited in our study. Arteriosclerosis was defined by measuring the ultrafast pulse wave velocity of the carotid artery. Peripheral venous blood samples were collected to analyze the levels of AOPP, IL-6, and GDF15 utilizing commercially available enzyme-linked immunosorbent assays. RESULTS: Compared to OSA patients without arteriosclerosis, those with arteriosclerosis exhibited significantly higher levels of AOPP, IL-6, and GDF15. GDF15 remained significantly associated with arteriosclerosis even after accounting for clinical factors such as age, gender, body mass index, systolic blood pressure, fasting blood glucose, smoking, and the apnea-hypoxia index (AHI). GDF15 demonstrated the largest area under the curve (AUC) for identifying arteriosclerosis in OSA patients (AUC, 0.85 [0.77-0.94]). The logistic regression model, combining clinical factors and AHI, was enhanced by the inclusion of AOPP and IL-6 (Chi-square = 25.06), and even further improved when GDF15 was added (Chi-square = 50.74). The integrated discrimination index increased by 0.06 to 0.16 when GDF15 was added to the models including clinical factors, AOPP, and IL-6. CONCLUSIONS: This study verified the independent and incremental value of GDF15 in identifying arteriosclerosis in OSA patients, surpassing clinical risk factors and other serum biomarkers such as AOPP and IL-6.

Genetic variant in TNF-α gene and its plasma level in relation to obstructive sleep apnoea in the Pakistani population.

OBJECTIVE: To assess the link between tumour necrosis factor-alpha -308 guanine/adenine polymorphism and tumour necrosis factor-alpha plasma levels in relation to obstructive sleep apnoea. METHODS: The cross-sectional study was conducted from December 2018 to March 2021 at the sleep clinic of Dow University Hospital, Karachi, on obstructive sleep apnoea patients and healthy controls. Epworth Sleep Scale score was used to determine daytime sleepiness, while full-night polysomnography was carried out for obstructive sleep apnoea confirmation and categorisation according to severity. Blood sample collection was followed by deoxyribonucleic acid extraction and plasma tumour necrosis factor-alpha measurement using enzyme-linked immunosorbent assay. Genotype distribution and allelic frequency were assessed. Data was analysed using SPSS 20. RESULTS: Out of the 225 subjects, with a mean age of 47.68±9.88 years, 132 (58.7%) were males, and 93 (41.3%) were females. Among them, 150 (66.7%) were patients, and 75 (33.3%) were controls. Heterozygous tumour necrosis factor-alpha -308 guanine/adenine genotypes were significantly higher among the patients (p<0.05). Minor allele - 308 adenine showed an association with obstructive sleep apnoea, its severity, higher tumour necrosis factor-alpha levels, neck circumference, excessive daytime sleepiness and the presence of hypertension (p<0.05). CONCLUSIONS: Tumour necrosis factor-alpha -308 adenine allele and higher tumour necrosis factor-alpha levels were found to be linked with obstructive sleep apnoea. The polymorphism also showed an association with hypertension in obstructive sleep apnoea patients.

Prevalence of Obstructive Sleep Apnea in Head and Neck Squamous Cell Carcinoma Patients before and after Treatment.

Background and Objectives: Obstructive sleep apnea (OSA) is common not only in the general population but even more so in patients with tumors of the head and neck region. Untreated, it leads to reduced quality of life, increased daytime sleepiness, and other comorbidities. The aim of this study was to determine the difference in the occurrence of OSA in the patient population with head and neck tumors compared with the general population as represented by the Trend cohort of the Study of Health in Pomerania (SHIP), and to assess the influence of tumor treatment. Materials and Methods: Between July 2018 and December 2021, preoperative polysomnography was conducted in 47 patients with histologically confirmed squamous cell carcinoma in the oropharynx, hypopharynx, or larynx. A follow-up polysomnography was performed in 23 patients 2-11 months after completing treatment. The collected data were correlated with tumor treatment and tumor size. Results: Of the included patients, 43 were male and 4 were female. Age ranged from 54 to 90 years. The pretherapeutic measurement found no significant difference in the prevalence of a pathologically elevated apnea-hypopnea index (AHI) in our patients compared with the SHIP Trend cohort. In the follow-up measurement after completion of treartment, a significant deterioration in AHI was observed. Initially, 70% of patients had an AHI > 5; after therapy, this increased to 87% (p = 0.008). The effect was particularly pronounced in the group of patients with advanced tumor stages who had received primary chemoradiation. Conclusions: OSA is a relevant condition in patients with head and neck cancer. Tumor treatment can lead to an increased occurrence of sleep-related breathing disorders, especially in patients with advanced tumor stages undergoing primary chemoradiation. Additional studies are necessary to better understand the exact mechanism involved.

A novel presentation of diaphragmatic flutter in a patient with obstructive sleep apnea and recurrent cerebellar hemangioblastoma.

We report a unique case of diaphragmatic flutter in a patient with obstructive sleep apnea who had no respiratory symptoms related to flutter and a history of recurrent cerebellar hemangioblastoma. The flutter was detected during a routine follow-up monitoring through the built-in software of the positive airway pressure device; the flow and pressure curves showed abnormal and curious oscillations. The ultrasound confirmed the diagnosis and ruled out other causes of abnormal diaphragmatic movements. This case report contributes to the scientific literature by presenting a novel case of diaphragmatic flutter associated with recurrent cerebellar hemangioblastoma. It also emphasizes the need for more research on the pathophysiology and treatment of this rare condition. CITATION: Ciorba C, Espinoza Perez JA, Alfonso Imizcoz M, Errasti Viader J, Cebollero Rivas P, De Vito EL. A novel presentation of diaphragmatic flutter in a patient with obstructive sleep apnea and recurrent cerebellar hemangioblastoma. J Clin Sleep Med. 2024;20(2):313-317.