The Epworth sleepiness scale may have more advantages than the multiple sleep latency test in assessing sleepiness in patients with obstructive sleep apnea.

This study aimed to analyze the brain function of severe obstructive sleep apnea patients with various sleepiness assessment methods and explore the brain imaging basis for the differences between these methods. This study included 30 severe obstructive sleep apnea patients and 19 healthy controls. Obstructive sleep apnea patients were divided into a subjective excessive daytime sleepiness group and a subjective non-excessive daytime sleepiness group according to the Epworth sleepiness scale. Moreover, they were divided into an objective excessive daytime sleepiness group and an objective non-excessive daytime sleepiness group according to the multiple sleep latency test. The fractional amplitude of low-frequency fluctuation was used to assess the features of brain function. Compared with healthy controls, participants in the subjective excessive daytime sleepiness group exhibited higher fractional amplitude of low-frequency fluctuation signals in the right thalamus, left cerebellar lobe 6, left putamen, and pallidum. Participants in the objective excessive daytime sleepiness group showed higher fractional amplitude of low-frequency fluctuation signals in the right thalamus and lower fractional amplitude of low-frequency fluctuation signals in the right superior frontal gyrus, the dorsolateral and superior frontal gyrus, and the medial orbital. We concluded that the thalamus may be involved in subjective and objective sleepiness regulation. Functional abnormalities in the putamen and pallidum may be involved in subjective sleepiness, whereas the frontal lobe may be involved in objective sleepiness.

P300/CBP Regulates HIF-1-Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia.

Obstructive sleep apnea (OSA), a widespread breathing disorder, leads to intermittent hypoxia (IH). Patients with OSA and IH-treated rodents exhibit heightened sympathetic nerve activity and hypertension. Previous studies reported transcriptional activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) by HIF-1 (hypoxia-inducible factor-1) contribute to autonomic dysfunction in IH-treated rodents. Lysine acetylation, regulated by KATs (lysine acetyltransferases) and KDACs (lysine deacetylases), activates gene transcription and plays an important role in several physiological and pathological processes. This study tested the hypothesis that acetylation of HIF-1α by p300/CBP (CREB-binding protein) (KAT) activates Nox transcription, leading to sympathetic activation and hypertension. Experiments were performed on pheochromocytoma-12 cells and rats treated with IH. IH increased KAT activity, p300/CBP protein, HIF-1α lysine acetylation, HIF-1 transcription, and HIF-1 binding to the Nox4 gene promoter in pheochromocytoma-12 cells, and these responses were blocked by CTK7A, a selective p300/CBP inhibitor. Plasma norepinephrine (index of sympathetic activation) and blood pressures were elevated in IH-treated rats. These responses were associated with elevated p300/CBP protein, HIF-1α stabilization, transcriptional activation of Nox2 and Nox4 genes, and reactive oxygen species, and all these responses were absent in CTK7A-treated IH rats. These findings suggest lysine acetylation of HIF-1α by p300/CBP is an important contributor to sympathetic excitation and hypertension by IH.

Tandem Mass Tag-Labeled Quantitative Proteome Analyses Identify C1R and A2M as Novel Serum Biomarkers in Pregnant Women with Obstructive Sleep Apnea.

The aim of this study was to identify serum diagnostic biomarkers associated with the severity of obstructive sleep apnea (OSA) during pregnancy. Differentially expressed proteins (DEPs) were identified in the control (C), mild (O), and moderate (MO) OSA groups (n = 3 in each group). Bioinformatics analysis was conducted to identify the underlying functions, pathways, and networks of the proteins. Receiver operating characteristic curves were used to assess the diagnostic value of the identified DEPs. The enzyme-linked immunoassay was performed to detect serum levels of the complement C1r subcomponent (C1R) and alpha-2-macroglobulin (A2M) in 79 pregnant women with OSA (mild OSA [n = 32]; moderate OSA [n = 29], and severe OSA [n = 18]) and 65 healthy pregnant women without OSA. Pearson's correlation analysis was conducted to analyze the correlation between C1R and A2M levels and OSA clinicopathological factors. In total, 141 DEPs, 29 DEPs, and 103 DEPs were identified in the three groups (i.e., the mild OSA vs control group, the moderate OSA vs mild apnea group, and the moderate OSA vs control group, respectively). C1R and A2M were identified as continuously up-regulated proteins, and the levels of C1R and A2M were associated with OSA severity. C1R and A2M were found to be correlated with body mass index, systolic blood pressure, apnea-hypopnea index, oxygen desaturation index, time with saturation below 90%, and lowest SaO2. Adverse maternal and neonatal outcomes were observed in pregnant women with OSA. C1R and A2M have been identified as diagnostic biomarkers and are associated with the severity of OSA during pregnancy.

ALTERED CONTROL OF BREATHING IN A RAT MODEL OF ALLERGIC LOWER AIRWAY INFLAMMATION.

Obstructive sleep apnea (OSA) is highly prevalent in patients with asthma. Asthma, dose-dependently to its duration, promotes incident OSA, suggesting that asthma plays a role in OSA pathogenesis. We hypothesized that asthma-related inflammation alters breathing control mechanisms, specifically the carotid chemoreflex. Accordingly, we measured hypoxic ventilatory responses (HRV) in awake, unrestrained, ovalbumin (OVA)-sensitized Brown Norway rats and compared them with responses in sham-sensitized (SALINE) controls. To differentiate the role of allergic inflammation from bronchoconstriction, we repeated HVR after administration of formoterol, a long-acting bronchodilator. Blood and bronchoalveolar lavage (BAL) fluid were collected for quantification of inflammatory cytokines. The rise in ventilatory equivalent for O2 evoked by acute exposure to hypoxia was augmented following sensitization by OVA, whereas it remained stable after SALINE. This augmentation was driven by increased breathing frequency with no change in tidal volume. Tachypneic hyperventilation in normoxia was also observed with OVA. Neither the increased HVR nor excessive normoxic ventilation was affected by formoterol, suggesting that they were not secondary to lung mechanical constraints. Higher levels of inflammatory cytokines were observed in BAL fluid and serum of OVA vs. SALINE. In OVA, serum interleukin-5 correlated with change (baseline to post-sensitization) in ventilatory response to severe hypoxia (FIO2, 0.09). These observations are consistent with inflammation-induced enhancement of carotid chemoreflex function, i.e. increased controller gain, and they suggest a possible role for asthma-related allergic inflammation in the ventilatory instability known to promote upper airway collapse and sleep apnea in humans.

Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is associated with the progression of cardiovascular diseases, arrhythmias, and sudden cardiac death (SCD). However, the acute impacts of OSA and its consequences on heart function are not yet fully elucidated. We hypothesized that desaturation events acutely destabilize ventricular repolarization, and the presence of accompanying arousals magnifies this destabilization. Ventricular repolarization lability measures, comprising heart rate corrected QT (QTc), short-time-variability of QT (STVQT), and QT variability index (QTVI), were calculated before, during, and after 20,955 desaturations from lead II electrocardiography signals of 492 patients with suspected OSA (52% men). Variations in repolarization parameters were assessed during and after desaturations, both with and without accompanying arousals, and groupwise comparisons were performed based on desaturation duration and depth. Regression analyses were used to investigate the influence of confounding factors, comorbidities, and medications. The standard deviation (SD) of QT, mean QTc, SDQTc, and STVQT increased significantly (P < 0.01), whereas QTVI decreased (P < 0.01) during and after desaturations. The changes in SDQT, mean QTc, SDQTc, and QTVI were significantly amplified (P < 0.01) in the presence of accompanying arousals. Desaturation depth was an independent predictor of increased SDQTc (ß = 0.405, P < 0.01), STVQT (ß = 0.151, P < 0.01), and QTVI (ß = 0.009, P < 0.01) during desaturation. Desaturations cause acute changes in ventricular repolarization, with deeper desaturations and accompanying arousals independently contributing to increased ventricular repolarization lability. This may partially explain the increased risk of arrhythmias and SCD in patients with OSA, especially when the OSA phenotype includes high hypoxic load and fragmented sleep.NEW & NOTEWORTHY Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.

Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM. METHODS: A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR. RESULTS: Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation. CONCLUSIONS: HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.

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.

Evaluation and Management of Resistant Hypertension: Core Curriculum 2024.

Resistant hypertension is defined as blood pressure above goal despite confirmed adherence to 3 first-line antihypertensive agents or when blood pressure is controlled with 4 or more medications at maximal or maximally tolerated doses. In addition to meeting these criteria, identifying patients with true resistant hypertension requires both accurate in-office blood pressure measurement as well as excluding white coat effects through out-of-office blood pressure measurements. Patients with resistant hypertension are at higher risk for adverse cardiovascular events and are more likely to have a potentially treatable secondary cause contributing to their hypertension. Effective treatment of resistant hypertension includes ongoing lifestyle modifications and collaboration with patients to detect and address barriers to optimal medication adherence. Pharmacologic treatment should prioritize optimizing first-line, once daily, longer acting medications followed by the stepwise addition of second-, third-, and fourth-line agents as tolerated. Physicians should systematically evaluate for and address any underlying secondary causes. A coordinated, multidisciplinary team approach including clinicians with experience in treating resistant hypertension is essential. New treatment options, including both pharmacologic and device-based therapies, have recently been approved, and more are in the pipeline; their optimal role in the management of resistant hypertension is an area of ongoing research.

The prevalence of obstructive sleep apnea syndrome after COVID-19 infection.

Obstructive sleep apnea is a well-known risk factor regarding the severity of COVID-19 infection. However, to date, relatively little research performed on the prevalence of obstructive sleep apnea in COVID-19 survivors. The purpose of this study was to investigate the risk of obstructive sleep apnea after COVID-19 infection. This study was based on data collected from the US Collaborative Network in TriNetX. From January 1, 2020 to June 30, 2022, participants who underwent the SARS-CoV-2 test were included in the study. Based on their positive or negative results of the COVID-19 test results (the polymerase chain reaction [PCR] test), we divided the study population into two groups. The duration of follow-up began when the PCR test was administered and continued for 12 months. Hazard ratios (HRs) and 95% confidence intervals (CIs) for newly recorded COVID-19 positive subjects for obstructive sleep apnea were calculated using the Cox proportional hazards model and compared to those without COVID-19 infection. Subgroup analyses were performed for the age, sex, and race, groups. The COVID-19 group was associated with an increased risk of obstructive sleep apnea, at both 3 months of follow-up (HR: 1.51, 95% CI: 1.48-1.54), and 1 year of follow-up (HR: 1.57, 95% CI: 1.55-1.60). Kaplan-Meier curves regarding the risk of obstructive sleep apnea revealed a significant difference of probability between the two cohorts in the follow-up periods of 3 months and 1 year (Log-Rank test, p < 0.001). The risks of obstructive sleep apnea among COVID-19 patients were significant in the less than 65 year of age group (HR: 1.50, 95% CI: 1.47-1.52), as well as in the group older than or equal to 65 years (HR:1.69, 95% CI: 1.64-1.73). Furthermore, the risks of obstructive sleep apnea were evident in both the male and female COVID-19 groups. Compared to the control group, the risks of obstructive sleep apnea in the COVID-19 participants increased in the subgroups of White (HR: 1.62, 95% CI: 1.59-1.64), Blacks/African Americans (HR: 1.50, 95% CI: 1.45-1.55), Asian (HR: 1.46, 95% CI: 1.32-1.62) and American Indian/Alaska Native (HR: 1.36, 95% CI: 1.07-1.74). In conclusion, the incidence of new diagnosis obstructive sleep apnea could be substantially higher after COVID-19 infection than non-COVID-19 comparison group. Physicians should evaluate obstructive sleep apnea in patients after COVID-19 infection to help prevent future long-term adverse effects from occurring in the future, including cardiovascular and neurovascular disease.

Sensitivity, Specificity, and Cutoff Identifying Optic Atrophy by Macular Ganglion Cell Layer Volume in Syndromic Craniosynostosis.

PURPOSE: To determine the sensitivity, specificity, and cutoff of macular ganglion cell layer (GCL) volume consistent with optic atrophy in children with syndromic craniosynostosis and to investigate factors independently associated with reduction in GCL volume. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients with syndromic craniosynostosis evaluated at Boston Children's Hospital (2010-2022) with reliable macular OCT scans. METHODS: The latest ophthalmic examination that included OCT macula scans was identified. Age at examination, sex, ethnicity, best-corrected logarithm of the minimum angle of resolution (logMAR) visual acuity, cycloplegic refraction, and funduscopic optic nerve appearance were recorded in addition to history of primary or recurrent elevation in intracranial pressure (ICP), Chiari malformation, and obstructive sleep apnea (OSA). Spectral-domain OCT software quantified segmentation of macula retinal layers and was checked manually. MAIN OUTCOME MEASURES: The primary outcome was determining sensitivity, specificity, and optimal cutoff of GCL volume consistent with optic atrophy. The secondary outcome was determining whether previously elevated ICP, OSA, Chiari malformation, craniosynostosis diagnosis, logMAR visual acuity, age, or sex were independently associated with lower GCL volume. RESULTS: Median age at examination was 11.9 years (interquartile range, 8.5-14.8 years). Fifty-eight of 61 patients (112 eyes) had reliable macula scans, 74% were female, and syndromes represented were Apert (n = 14), Crouzon (n = 17), Muenke (n = 6), Pfeiffer (n = 6), and Saethre-Chotzen (n = 15). Optimal cutoff identifying optic atrophy was a GCL volume < 1.02 mm3 with a sensitivity of 83% and specificity of 77%. Univariate analysis demonstrated that significantly lower macular GCL volume was associated with optic atrophy on fundus examination (P < 0.001), Apert syndrome (P < 0.001), history of elevated ICP (P = 0.015), Chiari malformation (P = 0.001), OSA (P < 0.001), male sex (P = 0.027), and worse logMAR visual acuity (P < 0.001). Multivariable median regression analysis confirmed that only OSA (P = 0.005), optic atrophy on fundus examination (P = 0.003), and worse logMAR visual acuity (P = 0.042) were independently associated with lower GCL volume. CONCLUSIONS: Surveillance for optic atrophy by GCL volume may be useful in a population where cognitive skills can limit acquisition of other key ophthalmic measures. It is noteworthy that OSA is also associated with lower GLC volume in this population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Pooled prevalences of obstructive sleep apnea and heart failure: a systematic review and meta-analysis.

Obstructive sleep apnea (OSA) is a disease with intermittent hypoxemia during sleep. It has been shown that OSA is related to several cardiovascular diseases including heart failure. Both OSA and heart failure have a close association bidirectionally. This study aimed to estimate the pooled prevalence of OSA in patients with heart failure as well as pooled prevalence of heart failure in patients with OSA. This was a systematic review with a meta-analysis. The inclusion criteria were observational or epidemiological studies conducted in adult patients with heart failure to evaluate the prevalence of OSA and patients with OSA to evaluate the prevalence of heart failure. The outcomes of this study were prevalence of OSA in patients with heart failure and prevalence of heart failure in patients with OSA. Four databases were used for systematic searching including PubMed, Science Direct, Scopus, and CINAHL Plus. Manual searches for related studies were also conducted. Proportion meta-analyses using a random-effects model were conducted to identify pooled proportion (prevalence) of heart failure in patients with OSA and vice versa. Among 3,941 articles from the four databases met the study criteria. Thirty-three studies showed the prevalence of OSA in patients with heart failure, while thirteen studies presented the prevalence of heart failure in patients with OSA. The prevalence of OSA in patients with heart failure was 38.4% (95% CI 31.9 to 45.2; I2 of 96.1%). Using a diagnostic criterion of OSA of more than 10 events/hr had the highest prevalence of OSA in patients with heart failure at 53.4% (95% CI 42.0 to 64.5). The highest prevalence of OSA in patients with heart failure was 60.1% (95% CI 51.4 to 68.3) in a report from India. The pooled prevalence of heart failure in patients with OSA was 12.8% (95% CI 8.1 to 19.5; I2 of 94.6%). The prevalence in Romania was highest at 22.6% (95% CI 20.4 to 24.9). The pooled prevalence of OSA in patients with heart failure was higher than the pooled prevalence of heart failure in patients with OSA. The pooled prevalence rates of these associations varied among the diagnostic criteria of OSA and countries.

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study.

BACKGROUND: Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. METHODS: A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS: Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. CONCLUSIONS: The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Non-Linear Association between Obstructive Sleep Apnea Risk and Lipid Profile: Data from the 2015-2018 National Health and Nutrition Examination Survey.

Background: The relationship between the multivariable apnea prediction (MAP) index and lipid levels was examined using a cross-sectional and retrospective study of National Health and Nutrition Examination Surveys (2015-2018). A total of 3195 participants with MAP scores were included in the analysis. Methods: The MAP index, an algorithm leveraging sleep apnea symptom frequency, body mass index (BMI), age, and sex, estimates the risk of obstructive sleep apnea (OSA). We investigated the associations between the MAP index and lipid profiles-specifically, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) -using weighted linear regression and restricted cubic splines (RCS) analysis. Additionally, mediation analysis was conducted to explore the potential mediating role of physical activity on the link between OSA risk, hyperlipidemia, and cardiovascular mortality. Results: A non-linear relationship was observed between OSA severity and lipid profiles, including elevated levels of TC, increased LDL-C, higher TG, and decreased HDL-C (All p for non-linearity < 0.05). The findings remained consistent across the stratified sensitivity analyses. Furthermore, physical activity served as a mediator in the association between the MAP index and both hyperlipidemia and cardiovascular mortality, accounting for 16.6% and 16.7% of the indirect effects, respectively. Conclusions: Participants at high risk for OSA demonstrated an increased prevalence of dyslipidemia. Additionally, engagement in physical activity was shown to have beneficial effects on lipid metabolism.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Identification of key genes in chronic intermittent hypoxia-induced lung cancer progression based on transcriptome sequencing.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of lung cancer mortality. Nevertheless, little is known about the underlying molecular mechanisms. This research aimed to investigate differentially expressed genes (DEGs) and explore their function in Lewis lung carcinoma (LLC)-bearing mice exposed to chronic intermittent hypoxia (CIH) by transcriptome sequencing. METHODS: Lung cancer tissues in LLC-bearing mice exposed to CIH or normoxia were subjected for transcriptome sequencing to examine DEGs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to explore the function of DEGs. To evaluate the prognostic value of DEGs, the Kaplan-Meier survival analysis in combination with Cox proportional hazard model were applied based on The Cancer Genome Atlas. RESULTS: A total of 388 genes with 207 up-regulated and 181 down-regulated genes were differentially expressed between the CIH and normoxia control groups. Bioinformatics analysis revealed that the DEGs were related to various signaling pathways such as chemokine signaling pathway, IL-17 signaling pathway, TGF-ß signaling pathway, transcriptional misregulation in cancer, natural killer cell mediated cytotoxicity, PPAR signaling pathway. In addition, the DEGs including APOL1, ETFB, KLK8, PPP1R3G, PRL, SPTA1, PLA2G3, PCP4L1, NINJ2, MIR186, and KLRG1 were proven to be significantly correlated with poorer overall survival in lung adenocarcinoma. CONCLUSIONS: CIH caused a significant change of gene expression profiling in LLC-bearing mice. The DEGs were found to be involved in various physiological and pathological processes and correlated with poorer prognosis in lung cancer.

The Role of Sleep in Cardiovascular Disease.

PURPOSE OF REVIEW: Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD. RECENT FINDINGS: Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health. There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.

Molecular mechanisms of postoperative atrial fibrillation in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) promotes atrial remodeling and fibrosis, providing a substrate for atrial fibrillation (AF). Herein, we investigate the pathophysiological mechanisms of AF in association with OSA in a cohort of cardiac surgery patients. A prospective study including patients undergoing cardiac surgery. Biomarkers reflective of AF pathophysiology (interleukin [IL-6], C-reactive protein [CRP], von Willebrand factor [vWF], N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity Troponin T [hs-TnT], and Galectin-3 [Gal-3]) was assessed by functional or immunological assays. miRNAs involved in AF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Using atrial tissue samples, fibrosis was assessed by Masson's trichrome. Connexin 40 and 43 (Cx40; Cx43) were evaluated by immunolabeling. Fifty-six patients (15 with OSA and 41 non-OSA) were included in this hypothesis-generating pilot study. OSA group had a higher incidence of postoperative AF (POAF) (46.7% vs. 19.5%; p = .042), presented an increased risk of POAF (OR 3.61, 95% CI 1.01-12.92), and had significantly higher baseline levels of NT-proBNP (p = .044), vWF (p = .049), Gal-3 (p = .009), IL-6 (p = .002), and CRP (p = .003). This group presented lower levels of miR-21 and miR-208 (both p < .05). Also, lower Cx40 levels in POAF and/or OSA patients (50.0% vs. 81.8%, p = .033) were found. The presence of interstitial fibrosis (according to myocardial collagen by Masson's trichrome) was raised in OSA patients (86.7% vs. 53.7%, p = .024). Several biomarkers and miRNAs involved in inflammation and fibrosis were dysregulated in OSA patients, which together with a higher degree of interstitial fibrosis, altered miRNA, and Cxs expression predisposes to the development of a substrate that increases the AF risk.

Cytosolic Escape of Mitochondrial DNA Triggers cGAS-STING Pathway-Dependent Neuronal PANoptosis in Response to Intermittent Hypoxia.

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), characterized by neuronal cell death and neurocognitive impairment. We focus on the accumulated mitochondrial DNA (mtDNA) in the cytosol, which acts as a damage-associated molecular pattern (DAMP) and activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a known trigger for immune responses and neuronal death in degenerative diseases. However, the specific role and mechanism of the mtDNA-cGAS-STING axis in IH-induced neural damage remain largely unexplored. Here, we investigated the involvement of PANoptosis, a novel type of programmed cell death linked to cytosolic mtDNA accumulation and the cGAS-STING pathway activation, in neuronal cell death induced by IH. Our study found that PANoptosis occurred in primary cultures of hippocampal neurons and HT22 cell lines exposed to IH. In addition, we discovered that during IH, mtDNA released into the cytoplasm via the mitochondrial permeability transition pore (mPTP) activates the cGAS-STING pathway, exacerbating PANoptosis-associated neuronal death. Pharmacologically inhibiting mPTP opening or depleting mtDNA significantly reduced cGAS-STING pathway activation and PANoptosis in HT22 cells under IH. Moreover, our findings indicated that the cGAS-STING pathway primarily promotes PANoptosis by modulating endoplasmic reticulum (ER) stress. Inhibiting or silencing the cGAS-STING pathway substantially reduced ER stress-mediated neuronal death and PANoptosis, while lentivirus-mediated STING overexpression exacerbated these effects. In summary, our study elucidates that cytosolic escape of mtDNA triggers cGAS-STING pathway-dependent neuronal PANoptosis in response to IH, mainly through regulating ER stress. The discovery of the novel mechanism provides theoretical support for the prevention and treatment of neuronal damage and cognitive impairment in patients with OSA.

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

Exploring the link between vitamin D deficiency and obstructive sleep apnea: A comprehensive review.

Despite the high prevalence and significant health burden of obstructive sleep apnea (OSA), its underlying pathophysiology remains incompletely understood. This comprehensive review explores the emerging connection between vitamin D deficiency and OSA, discusses potential mechanisms underlying this association, and explores the therapeutic implications of these findings. Recent research has consistently highlighted the high incidence of vitamin D deficiency among patients with OSA, which often occurs independently of geographical location. This suggests that factors beyond lack of sunlight exposure may be involved. This review also discusses how reduced vitamin D may be associated with more severe manifestations of OSA. In addition, it explores the potentiality of using vitamin D supplements as a therapeutic strategy for OSA, noting that some studies have found improvements in sleep quality and a reduction in OSA severity. Potential mechanisms are proposed, including the role of vitamin D deficiency in promoting inflammation, oxidative stress, hypoxia, impairing immune function, muscle function, and gene polymorphism of vitamin D receptors, all of which could contribute to the pathogenesis of obstructive sleep apnea. The paper underscores the need for future research to validate these observations, to determine optimal vitamin D supplementation dosage and duration, to explore potential side effects and risks, and to investigate potential interactions with other treatments.