Telemedicine management of obstructive sleep apnea disorder in China: a randomized, controlled, non-inferiority trial.

PURPOSE: Previous studies assessed different components of telemedicine management pathway for OSA instead of the whole pathway. This randomized, controlled, and non-inferiority trial aimed to assess whether telemedicine management is clinically inferior to in-person care in China. METHODS: Adults suspected of OSA were randomized to telemedicine (web-based questionnaires, self-administered home sleep apnea test [HSAT], automatically adjusting positive airway pressure [APAP], and video-conference visits) or in-person management (paper questionnaires, in-person HSAT set-up, APAP, and face-to-face visits). Participants with an apnea-hypopnea index (AHI) ≥ 15 events/hour received APAP for 3 months. The non-inferiority analysis was based on the change in Functional Outcomes of Sleep Questionnaire (FOSQ) score and APAP adherence. Cost-effectiveness analysis was performed. RESULTS: In the modified intent-to-treat analysis set (n = 111 telemedicine, 111 in-person), FOSQ scores improved 1.73 (95% confidence interval [CI], 1.31-2.14) points with telemedicine and 2.05 (1.64-2.46) points with in-person care. The lower bound of the one-sided 95% non-inferiority CI for the difference in change between groups of - 0.812 was larger than the non-inferiority threshold of - 1. APAP adherence at 3 months was 243.3 (223.1-263.5) minutes/night for telemedicine and 241.6 (221.3-261.8) minutes/night for in-person care. The lower bound of the one-sided 95% non-inferiority CI of - 22.2 min/night was higher than the non-inferiority delta of - 45 min/night. Telemedicine had lower total costs than in-person management (CNY 1482.7 ± 377.2 vs. 1912.6 ± 681.3; p < 0.0001), driven by patient costs, but no significant difference in QALYs. CONCLUSIONS: Functional outcomes and adherence were not clinically inferior in patients managed by a comprehensive telemedicine approach compared to those receiving in-person care in China. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn , Registration number ChiCTR2000030546. Retrospectively registered on March 06, 2020.

Physiologic and anatomic determinants of hyoid motion during drug-induced sleep endoscopy.

PURPOSE: To examine factors accounting for differences in hyoid motion during obstructive breathing events amongst obstructive sleep apnea (OSA) patients. METHODS: This was a prospective cohort study from June 2022 to October 2022. Patients with OSA undergoing evaluation for PAP alternative therapies with drug-induced sleep endoscopy with positive airway pressure titration (DISE-PAP). All patients underwent DISE-PAP and concurrent hyoid-focused ultrasound. DISE-PAP enabled measurement of airway physiology (flow, respiratory effort) and airway collapsibility (pharyngeal opening pressure, PhOP). Hyoid-ultrasound enabled hyoid bone movement during obstructive breathing. Respiratory effort was measured using a retro-epiglottic pressure-sensitive catheter. Hyoid position was measured using a standardized, awake, CT protocol. Regression analyses adjusted for age, race, sex, and BMI were performed to associate indices of respiratory effort and CT data with hyoid motion. RESULTS: On average, the 26 patients in this cohort were older (63.9 ± 10.5 years), male (69%), overweight (29.6 ± 3.99 kg/m2), and with moderate-to-severe OSA (26.8 ± 10.4 events/hour). Greater respiratory effort was associated with increased hyoid motion (ß [95% CI] = 0.034 [0.016,0.052], standardized ß = 0.261,p = 0.0003). Higher hyoid position was associated with greater hyoid displacement (ß [95% CI] = -0.20 [-0.38,-0.01], Standardized ß = -0.57, p = 0.036). CONCLUSION: Our data demonstrate that greater respiratory effort, higher hyoid position, and higher airway collapsibility, but not airflow, are associated with greater hyoid motion during obstructive breathing in DISE. These findings suggest that downward hyoid movement represents a compensatory response to upper airway obstruction. Further studies should investigate the vectors of hyoid motion to better understand its role in sleep-related airway collapse.

Different components of excessive daytime sleepiness and the change with positive airway pressure treatment in patients with obstructive sleep apnea: Results from the Icelandic Sleep Apnea Cohort (ISAC).

Excessive daytime sleepiness includes both an inability to stay awake during the day and a general feeling of sleepiness. We describe different dimensions of daytime sleepiness in adults with moderate-severe obstructive sleep apnea (OSA) before and after 2 years of positive airway pressure (PAP) treatment. Using the Epworth Sleepiness Scale (score >10 defined as "risk of dozing") and Basic Nordic Sleep Questionnaire (feeling sleepy ≥3 times/week defined as "feeling sleepy"), participants were categorised into sleepiness phenotypes labelled non-sleepy, risk of dozing only, feeling sleepy only, or both symptoms. Participants repeated baseline assessments and PAP adherence was evaluated after 2 years. PAP-adherent subjects with sleepiness symptoms at both baseline and follow-up were considered persistently sleepy. Of the 810 participants, 722 (89%) returned for follow-up. At baseline, 17.7% were non-sleepy, 7.7% were at risk of dozing only, 24.7% were feeling sleepy only, and 49.9% had both symptoms. PAP adherence did not differ by baseline sleepiness phenotype. Patients with risk of dozing demonstrated greater PAP benefits for sleepiness symptoms than non-sleepy and feeling sleepy only phenotypes. Using these phenotypes, 42.3% of PAP users had persistent sleepiness; they had less severe OSA (p < 0.001), more persistent OSA symptoms and more often had symptoms of insomnia than patients in whom sleepiness resolved. Our present results, therefore, suggest that measuring the risk of dozing and the feeling of sleepiness reflect different sleepiness components and may respond differently to PAP. Patients feeling sleepy without risk of dozing may need more thorough evaluation for factors contributing to sleepiness before initiating treatment.

Effect of Weight Loss on Upper Airway Anatomy and the Apnea-Hypopnea Index. The Importance of Tongue Fat.

Rationale: Obesity is the primary risk factor for obstructive sleep apnea (OSA). Tongue fat is increased in obese persons with OSA, and may explain the relationship between obesity and OSA. Weight loss improves OSA, but the mechanism is unknown.Objectives: To determine the effect of weight loss on upper airway anatomy in subjects with obesity and OSA. We hypothesized that weight loss would decrease soft tissue volumes and tongue fat, and that these changes would correlate with reductions in apnea-hypopnea index (AHI).Methods: A total of 67 individuals with obesity and OSA (AHI ≥ 10 events/h) underwent a sleep study and upper airway and abdominal magnetic resonance imaging before and after a weight loss intervention (intensive lifestyle modification or bariatric surgery). Airway sizes and soft tissue, tongue fat, and abdominal fat volumes were quantified. Associations between weight loss and changes in these structures, and relationships to AHI changes, were examined.Measurements and Main Results: Weight loss was significantly associated with reductions in tongue fat and pterygoid and total lateral wall volumes. Reductions in tongue fat were strongly correlated with reductions in AHI (Pearson's rho = 0.62, P < 0.0001); results remained after controlling for weight loss (Pearson's rho = 0.36, P = 0.014). Reduction in tongue fat volume was the primary upper airway mediator of the relationship between weight loss and AHI improvement.Conclusions: Weight loss reduced volumes of several upper airway soft tissues in subjects with obesity and OSA. Improved AHI with weight loss was mediated by reductions in tongue fat. New treatments that reduce tongue fat should be considered for patients with OSA.

Changes in sleepiness and 24-h blood pressure following 4 months of CPAP treatment are not mediated by ICAM-1.

OBJECTIVE: Continuous positive airway pressure (CPAP) therapy reduces circulating intercellular adhesion molecule 1 (ICAM-1) in adults with obstructive sleep apnea (OSA). ICAM-1 levels may affect the daytime sleepiness and elevated blood pressure associated with OSA. We evaluated the association of changes from baseline in ICAM-1 with changes of objective and subjective measures of sleepiness, as well as 24-h ambulatory blood pressure monitoring (ABPM) measures, following 4 months of CPAP treatment. METHODS: The study sample included adults with newly diagnosed OSA. Plasma ICAM-1, 24-h ABPM, Epworth Sleepiness Scale (ESS), and psychomotor vigilance task (PVT) were obtained at baseline and following adequate CPAP treatment. The associations between changes in natural log ICAM-1 and changes in the number of lapses on PVT, ESS score, and 24-h mean arterial blood pressure (MAP) were assessed using multivariate regression models, controlling for a priori baseline covariates of age, sex, BMI, race, site, smoking status, physical activity, anti-hypertensive medications, AHI, and daily hours of CPAP use. RESULTS: Among 140 adults (83% men), mean (± SD) body mass index (BMI) was 31.5 ± 4.2 kg/m2, and apnea-hyopnea index (AHI) was 36.8 ± 15.3 events/h. Sleepiness measures, although not ICAM-1 or ABPM measures, improved significantly following CPAP treatment. We observed no statistically significant associations between the change in ICAM-1 and changes in sleepiness, MAP, or other ABPM measures. CONCLUSION: Changes in ICAM-1 levels were not related to changes in sleepiness or ABPM following CPAP treatment of adults with OSA. Future work should explore whether or not other biomarkers may have a role in mediating these treatment outcomes in adults with OSA.

RNA-seq analysis of galaninergic neurons from ventrolateral preoptic nucleus identifies expression changes between sleep and wake.

BACKGROUND: Previous studies show that galanin neurons in ventrolateral preoptic nucleus (VLPO-Gal) are essential for sleep regulation. Here, we explored the transcriptional regulation of the VLPO-Gal neurons in sleep by comparing their transcriptional responses between sleeping mice and those kept awake, sacrificed at the same diurnal time. RESULTS: RNA-sequencing (RNA-seq) analysis was performed on eGFP(+) galanin neurons isolated using laser captured microdissection (LCM) from VLPO. Expression of Gal was assessed in our LCM eGFP(+) neurons via real time qPCR and showed marked enrichment when compared to LCM eGFP(-) cells and to bulk VLPO samples. Gene set enrichment analysis utilizing data from a recent single-cell RNA-seq study of the preoptic area demonstrated that our VLPO-Gal samples were highly enriched with galanin-expressing inhibitory neurons, but not galanin-expressing excitatory neurons. A total of 263 genes were differentially expressed between sleep and wake in VLPO-Gal neurons. When comparing differentially expressed genes in VLPO-Gal neurons to differentially expressed genes in a wake-active neuronal region (the medial prefrontal cortex), evidence indicates that both systemic and cell-specific mechanisms contribute to the transcriptional regulation in VLPO-Gal neurons. In both wake-active and sleep-active neurons, ER stress pathways are activated by wake and cold-inducible RNA-binding proteins are activated by sleep. In contrast, expression of DNA repair genes is increased in VLPO-Gal during wakefulness, but increased in wake-active cells during sleep. CONCLUSION: Our study identified transcriptomic responses of the galanin neurons in the ventrolateral preoptic nucleus during sleep and sleep deprivation. Data indicate that VLPO contains mainly sleep-active inhibitory galaninergic neurons. The VLPO galanin neurons show responses to sleep and wake similar to wake-active regions, indicating these responses, such as ER stress and cold-inducible RNA-binding proteins, are systemic affecting all neuronal populations. Region-specific differences in sleep/wake responses were also identified, in particular DNA repair. Our study expands knowledge about the transcriptional response of a distinct group of neurons essential for sleep.

Impact of a nurse-led limited risk factor modification program on arrhythmia outcomes in patients with atrial fibrillation undergoing catheter ablation.

BACKGROUND: We have previously demonstrated the feasibility of a nurse-led risk factor modification (RFM) program for improving weight loss and obstructive sleep apnea (OSA) care among patients with atrial fibrillation (AF). OBJECTIVE: We now report its impact on arrhythmia outcomes in a subgroup of patients undergoing catheter ablation. METHODS: Participating patients with obesity and/or need for OSA management (high risk per Berlin Questionnaire or untreated OSA) underwent in-person consultation and monthly telephone calls with the nurse for up to 1 year. Arrhythmias were assessed by office ECGs and ≥2 wearable monitors. Outcomes, defined as Arrhythmia control (0-6 self-terminating recurrences, with ≤1 cardioversion for nonparoxysmal AF) and Freedom from arrhythmias (no recurrences on or off antiarrhythmic drugs), were compared at 1 year between patients undergoing catheter ablation who enrolled and declined RFM. RESULTS: Between 1 November 2016 and 1 April 2018, 195 patients enrolled and 196 declined RFM (body mass index, 35.1 ± 6.7 vs 34.3 ± 6.3 kg/m2 ; 50% vs 50% paroxysmal AF; P = NS). At 1 year, enrolled patients demonstrated significant weight loss (4.7% ± 5.3% vs 0.3% ± 4.4% in declined patients; P < .0001) and improved OSA care (78% [n = 43] of patients diagnosed with OSA began treatment). However, outcomes were similar between enrolled and declined patients undergoing ablation (arrhythmia control in 80% [n = 48] vs 79% [n = 38]; freedom from arrhythmia in 58% [n = 35] vs 71% [n = 34]; P = NS). CONCLUSION: Despite improving weight loss and OSA care, our nurse-led RFM program did not impact 1-year arrhythmia outcomes in patients with AF undergoing catheter ablation.

Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes.

Rationale: Symptom subtypes have been described in clinical and population samples of patients with obstructive sleep apnea (OSA). It is unclear whether these subtypes have different cardiovascular consequences.Objectives: To characterize OSA symptom subtypes and assess their association with prevalent and incident cardiovascular disease in the Sleep Heart Health Study.Methods: Data from 1,207 patients with OSA (apnea-hypopnea index ≥ 15 events/h) were used to evaluate the existence of symptom subtypes using latent class analysis. Associations between subtypes and prevalence of overall cardiovascular disease and its components (coronary heart disease, heart failure, and stroke) were assessed using logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether subtypes were associated with incident events, including cardiovascular mortality.Measurements and Main Results: Four symptom subtypes were identified (disturbed sleep [12.2%], minimally symptomatic [32.6%], excessively sleepy [16.7%], and moderately sleepy [38.5%]), similar to prior studies. In adjusted models, although no significant associations with prevalent cardiovascular disease were found, the excessively sleepy subtype was associated with more than threefold increased risk of prevalent heart failure compared with each of the other subtypes. Symptom subtype was also associated with incident cardiovascular disease (P < 0.001), coronary heart disease (P = 0.015), and heart failure (P = 0.018), with the excessively sleepy again demonstrating increased risk (hazard ratios, 1.7-2.4) compared with other subtypes. When compared with individuals without OSA (apnea-hypopnea index < 5), significantly increased risk for prevalent and incident cardiovascular events was observed mostly for patients in the excessively sleepy subtype.Conclusions: OSA symptom subtypes are reproducible and associated with cardiovascular risk, providing important evidence of their clinical relevance.

Dynamic Upper Airway Imaging during Wakefulness in Obese Subjects with and without Sleep Apnea.

RATIONALE: Obesity is a major risk factor for obstructive sleep apnea. Although greater dimensional changes in the upper airway during wake respiration have been noted in patients with apnea compared with control subjects, whether these differences remain in the presence of obesity is unknown. OBJECTIVES: To evaluate upper airway anatomic characteristics and airway compliance (distensibility) in obese subjects with obstructive sleep apnea compared with obese control subjects. METHODS: Dynamic magnetic resonance imaging was performed in 157 obese subjects with apnea and 46 obese control subjects during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal). Differences in measurements between subjects with apnea and control subjects, and correlations with apnea-hypopnea index among subjects with apnea, were examined. MEASUREMENTS AND MAIN RESULTS: Measurements included airway areas and linear dimensions. Subject-specific coefficients of variation were calculated to examine variability in airway size. Controlling for covariates, the retropalatal area during respiration was significantly smaller in subjects with apnea than control subjects, based on the average (P = 0.003), maximum (P = 0.004), and minimum (P = 0.001) airway area. Airway narrowing was observed in anteroposterior and lateral dimensions (adjusted P < 0.05). Results were similar in an age, sex, and body mass index-matched subsample. There were significant correlations between apnea-hypopnea index and dynamic measures of airway caliber in the retropalatal and retroglossal regions among subjects with apnea. CONCLUSIONS: Upper airway caliber during respiration was significantly narrower in obese subjects with apnea than obese control subjects in the retropalatal region. These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of obstructive sleep apnea in obese subjects.

Serum ferritin and obstructive sleep apnea-epidemiological study.

PURPOSE: Ferritin is an intracellular iron storage protein and a marker of inflammation. Studies have shown that subjects with obstructive sleep apnea (OSA) have higher levels of circulating pro-inflammatory cytokines, but little is known about the association between ferritin and OSA. The aims of the study were to evaluate serum ferritin (S-Ferritin) levels in OSA patients compared to levels in the general population and also examine the effect of obesity level and treatment with positive airway pressure (PAP) on S-Ferritin levels. METHODS: The OSA subjects (n = 796) were part of the Icelandic Sleep Apnea Cohort. The control subjects (n = 637) were randomly chosen Icelanders who participated in an epidemiological study. Propensity score (PS) methodologies were employed to minimize selection bias and strengthen causal inferences when comparing non-randomized groups. S-Ferritin levels were measured and all participants answered the same detailed questionnaire about sleep and health. Only OSA patients underwent a sleep study and were re-invited for a 2-year follow-up. RESULTS: S-Ferritin levels were significantly higher in OSA males than controls (213.3 vs. 197.3 µg/L, p = 0.007). However, after adjusting for confounders and using our PS methodology, no significant difference was found. S-Ferritin levels were not correlated with severity of OSA, obesity level, or clinical symptoms. Also, no significant change in S-Ferritin levels was found with 2 years of PAP treatment. CONCLUSIONS: S-Ferritin levels are comparable in OSA patients and controls and do not change consistently with obesity level or PAP treatment in our sample.

The obstructive sleep apnoea syndrome in adolescents.

BACKGROUND: The obstructive sleep apnoea syndrome (OSAS) results from a combination of structural and neuromotor factors; however, the relative contributions of these factors have not been studied during the important developmental phase of adolescence. We hypothesised that adenotonsillar volume (ATV), nasopharyngeal airway volume (NPAV), upper airway critical closing pressure (Pcrit) in the hypotonic and activated neuromotor states, upper airway electromyographic response to subatmospheric pressure and the ventilatory response to CO2 during sleep would be major predictors of OSAS risk. METHODS: 42 obese adolescents with OSAS and 37 weight-matched controls underwent upper airway MRI, measurements of Pcrit, genioglossal electromyography and ventilatory response to CO2 during wakefulness and sleep. RESULTS: ATV, NPAV, activated and hypotonic Pcrit, genioglossal electromyography and ventilatory response to CO2 during sleep were all associated with OSAS risk. Multivariate models adjusted for age, gender, body mass index and race indicated that ATV, NPAV and activated Pcrit each independently affected apnoea risk in adolescents; genioglossal electromyography was independently associated in a reduced sample. There was significant interaction between NPAV and activated Pcrit (p=0.021), with activated Pcrit more strongly associated with OSAS in adolescents with larger NPAVs and NPAV more strongly associated with OSAS in adolescents with more negative activated closing pressure. CONCLUSIONS: OSAS in adolescents is mediated by a combination of anatomic (ATV, NPAV) and neuromotor factors (activated Pcrit). This may have important implications for the management of OSAS in adolescents.

Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents.

RATIONALE: Structural risk factors for obstructive sleep apnea syndrome (OSAS) in adolescents have not been well characterized. Because many adolescents with OSAS are obese, we hypothesized that the anatomic OSAS risk factors would be more similar to those in adults than those in children. OBJECTIVES: To investigate the anatomic risk factors in adolescents with OSAS compared with obese and lean control subjects using magnetic resonance imaging (MRI). METHODS: Three groups of adolescents (age range: 12-16 yr) underwent MRI: obese individuals with OSAS (n = 49), obese control subjects (n = 38), and lean control subjects (n = 50). MEASUREMENTS AND MAIN RESULTS: We studied 137 subjects and found that (1) obese adolescents with OSAS had increased adenotonsillar tissue compared with obese and lean control subjects; (2) obese OSAS adolescents had a smaller nasopharyngeal airway than control subjects; (3) the size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between subjects with OSAS and obese control subjects; (4) although there were no major craniofacial abnormalities in most of the adolescents with OSAS, the ratio of soft tissue to craniofacial space surrounding the airway was increased; and (5) there were sex differences in the pattern of lymphoid proliferation. CONCLUSIONS: Increased size of the pharyngeal lymphoid tissue, rather than enlargement of the upper airway soft tissue structures, is the primary anatomic risk factor for OSAS in obese adolescents. These results are important for clinical decision making and suggest that adenotonsillectomy should be considered as the initial treatment for OSAS in obese adolescents, a group that has poor continuous positive airway pressure adherence and difficulty in achieving weight loss.

Alzheimer disease susceptibility loci: evidence for a protein network under natural selection.

Recent genome-wide association studies have identified a number of susceptibility loci for Alzheimer disease (AD). To understand the functional consequences and potential interactions of the associated loci, we explored large-scale data sets interrogating the human genome for evidence of positive natural selection. Our findings provide significant evidence for signatures of recent positive selection acting on several haplotypes carrying AD susceptibility alleles; interestingly, the genes found in these selected haplotypes can be assembled, independently, into a molecular complex via a protein-protein interaction (PPI) network approach. These results suggest a possible coevolution of genes encoding physically-interacting proteins that underlie AD susceptibility and are coexpressed in different tissues. In particular, PICALM, BIN1, CD2AP, and EPHA1 are interconnected through multiple interacting proteins and appear to have coordinated evidence of selection in the same human population, suggesting that they may be involved in the execution of a shared molecular function. This observation may be AD-specific, as the 12 loci associated with Parkinson disease do not demonstrate excess evidence of natural selection. The context for selection is probably unrelated to AD itself; it is likely that these genes interact in another context, such as in immune cells, where we observe cis-regulatory effects at several of the selected AD loci.

Effects of obesity on the association between long-term sleep apnea treatment and changes in interleukin-6 levels: the Icelandic Sleep Apnea Cohort.

The aim of this study was to evaluate changes in interleukin (IL)-6 and soluble IL-6 receptor levels in obstructive sleep apnea patients and assess the role of positive airway pressure treatment and obesity on these changes. A total of 309 newly diagnosed subjects with sleep apnea from the Icelandic Sleep Apnea Cohort were referred for treatment and reassessed at a 2-year follow-up. Full treatment was defined objectively as use ≥ 4 h day(-1) and ≥ 20 days month(-1). At the 2-year follow-up, there were 177 full users, 44 partial users and 88 non-users. The mean change in biomarker levels from baseline to the 2-year follow-up was assessed in a primary model that included adjustment for baseline biomarker levels, baseline body mass index and change in body mass index, as well as after adjustment for numerous relevant covariates. No significant overall difference in IL-6 level change was found among full, partial and non-users. However, in severely obese patients (body mass index ≥ 35), a significant increase in IL-6 levels during the 2-year period was found in partial and non-users, compared to no change in full users. Results were attenuated in a smaller propensity score matched subsample, although similar trends were observed. No differences were found in soluble IL-6 receptor levels between full users and non-users, after adjustment for confounders. In conclusion, among untreated obese sleep apnea patients, IL-6 levels increase substantially during 2 years, while adherence to positive airway pressure treatment may prevent further increases in this inflammatory biomarker.