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Arousal Threshold Modifies the Effect of CPAP on Executive Function Among Individuals with Obstructive Sleep Apnea., Background: Obstructive Sleep Apnea (OSA) is associated with neurocognitive dysfunction. However, randomized trials evaluating the effects of continuous positive airway pressure (CPAP) on neurocognition in those without dementia do not show a benefit. We thus aimed to assess whether arousal threshold (ArTH) modifies the effect of CPAP on neurocognitive function., Methods: We performed a secondary analysis of a randomized, sham-controlled trial, Apnea Positive Pressure Long-term Efficacy Study. ArTH was estimated from polysomnography using a translatable method (Sands et al ., SLEEP 2018). Neurocognitive outcomes included the Sustained Working Memory Test-Overall-Mid-Day score (SWMT-OMD, executive function, primary outcome), with the Pathfinder Number Test - total time (attention) and Buschke Selective Reminding Test - sum recall (learning and memory) as secondary outcomes. Generalized linear modeling assessed whether the effect of CPAP was modified by baseline ArTH (treatment-by-ArTH interaction). 833 participants with OSA, [apnea-hypopnea index (AHI) ≥10 events/h], available ArTH, and outcomes were analyzed (CPAP n=437, Sham n=396)., Results: For executive function, the effect of CPAP treatment was modified by ArTH (p-interaction=0.042). Specifically, for every 1 sd increase in ArTH, the SWMT-OMD score improved by 0.10 95% CI (0.01, 0.18) in active compared to sham CPAP at 6 months; At ArTH 1 sd above the mean SWMT-OMD improvements were nearly three times that in those with average ArTH (0.139 [0.018, 0.261] versus 0.053 [-0.034, 0.140] respectively. No effect modification was observed for attention (p=0.311) or learning and memory (p=0.744)., Conclusion: In OSA, a higher ArTH is associated with greater improvements in executive function following CPAP therapy., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

The prevalence of obstructive sleep apnea (OSA) is on the rise, driven by various factors including more sensitive diagnostic criteria, increased awareness, enhanced technology through at-home testing enabling easy and cost-effective diagnosis, and a growing incidence of comorbid conditions such as obesity. Treating symptomatic patients with OSA syndrome to enhance quality of life remains a cornerstone approach. However, there is a lack of consensus regarding treatment to improve cardiovascular disease (CVD) outcomes, particularly in light of overall negative results from several randomized controlled trials (RCT) indicating no benefit of positive airway pressure (PAP) therapy on primary and secondary CVD events. These RCTs were limited by suboptimal PAP adherence, use of composite CVD outcomes, and limited diversity and generalizability to Sleep Clinic patients. As such, this workshop assembled clinical experts, as well as researchers in basic and translational science, epidemiology, clinical trials, and population health to discuss the current state, and future research directions to guide personalized therapeutic strategies and future research directions in OSA. There was overall consensus among workshop participants that OSA represents a heterogeneous disease with variable endotypes and phenotypes, and heterogeneous responses to treatment. Future research should prioritize employing multi-modal therapeutic approaches within innovative and adaptive trial designs, focusing on specific subgroups of OSA patients hypothesized to benefit from a CVD perspective. Future work should also be inclusive of diverse populations and consider the life-course of OSA to better comprehend treatment strategies that can address the disproportionate impact of OSA on racially minoritized groups. Further, a more holistic approach to sleep must be adopted to include broader assessments of symptoms, sleep duration, and comorbid sleep and circadian disorders. Finally, it is imperative to establish a sleep research consortium dedicated to collecting raw data and biospecimens categorized by OSA subtypes. This will facilitate mechanistic determinations, foster collaborative research, and help bolster the pipeline of early-career researchers.

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx)., Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors., Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min)., Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion., Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated., Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (β, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min)., Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered., Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

OSA is diagnosed and managed by a metric called the apnea-hypopnea index (AHI). The AHI quantifies the number of respiratory events (apnea or hypopnea), disregarding important information on the characteristics and physiologic consequences of respiratory events, including degrees of ventilatory deficit and associated hypoxemia, cardiac autonomic response, and cortical activity. The oversimplification of the disorder by the AHI is considered one of the reasons for divergent findings on the associations of OSA and cardiovascular disease (CVD) in observational and randomized controlled trial studies. Prospective observational cohort studies have demonstrated strong associations of OSA with several cardiovascular diseases, and randomized controlled trials of CPAP intervention have not been able to detect a benefit of CPAP to reduce the risk of CVD. Over the last several years, novel methodologies have been proposed to better quantify the magnitude of OSA-related breathing disturbance and its physiologic consequences. As a result, stronger associations with cardiovascular and neurocognitive outcomes have been observed. In this review, we focus on the methods that capture polysomnographic heterogeneity of OSA., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. A. reports grant support from Somnifix and serves as a consultant for Somnifix, Respicardia, Eli Lilly, Inspire, Cerebra, and Apnimed. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. A. A.’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. A. W. works as a consultant for Apnimed, Nox, Inspire, and Somnifix International LLC. He has received grants from Sanofi and Somnifix. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies for sleep apnea. A. W.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. None declared (G. L., Y. K.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Obstructive sleep apnea (OSA) is associated with cognitive impairment; however, the underlying mechanisms remain incompletely understood. OSA is characterized by periods of interrupted ventilation ("ventilatory burden (VB)"), leading to hypoxemia ("hypoxic burden (HB)") and/or arousal ("arousal burden (AB)") from sleep. While hypoxemia is considered a key mechanism underlying white matter injury, its measurement has been limited. In our primary analysis, we assessed the association of HB, a quantitative measure of hypoxemia, with white matter hyperintensity volume (WMH v ), a marker of small vessel disease, and compared with that of VB and AB (quantitative measures of ventilatory deficit and arousals)., Methods: Data from participants in the Multi-Ethnic Study of Atherosclerosis with full polysomnograms (PSG) and brain MRI were analyzed. HB was defined as the total area under the oxygen desaturation curve per hour of sleep, while VB was defined as the event-specific area under the ventilation signal and AB was defined as the normalized cumulative duration of all arousals. The primary outcome was WMH v , with other MRI measures considered secondary outcomes., Results: The analysis included PSGs from 587 participants (age: 65.5±8.2 years). In the fully adjusted model, each 1 standard deviation (SD) increase in HB was associated with a 0.09 SD increase in WMH v (p=0.023), after adjusting for demographics, study site, and comorbidities. In contrast, VB, AB, and conventional OSA measures were not associated with outcomes., Conclusions: Hypoxic burden was associated with white matter hyperintensity volume in a racially/ethnically diverse cohort of older individuals with a high prevalence of OSA., (© 2024 American Academy of Sleep Medicine.)

Central sleep apnea (CSA) is commonly encountered among patients with sleep-disordered breathing, however its clinical consequences are less well-characterized. We therefore convened an expert panel to discuss the common presentations of CSA, as well as challenges and knowledge gaps in the diagnosis and management of CSA. The panel identified several key research priorities essential for advancing our understanding of the disorder. Within the diagnostic realm, panel members discussed the utility of multi-night assessments, and importance of the development and validation of novel metrics and automated assessments for differentiating central versus obstructive hypopneas, such that their impact on clinical outcomes and management may be better evaluated. The panel also discussed the current therapeutic landscape for the management of CSA and agreed that therapies should primarily aim to alleviate sleep-related symptoms, after optimizing treatment to address the underlying cause. Most importantly, the panel concluded that there is a need to further investigate the clinical consequences of CSA, as well as the implications of therapy on clinical outcomes, particularly among those who are asymptomatic. Future research should focus on endo-phenotyping central events for a better mechanistic understanding of the disease, validating novel diagnostic methods for implementation in routine clinical practice, as well as the use of combination therapy and comparative effectiveness trials in elucidating the most efficacious interventions for managing CSA., (© 2024 American Academy of Sleep Medicine.)

Objective: The efficacy of hypoglossal nerve stimulation (HGNS) therapy is limited by obstruction of the oropharyngeal lateral walls (OLWs). Our objective was to investigate the effect of palatine tonsillectomy on HGNS efficacy in obstructive sleep apnea (OSA) patients with OLW collapse., Study Design: Case-control study of patients with moderate-to-severe OSA, complete-or-partial OLW collapse, and small tonsils (1 - 2+). Concomitant palatine tonsillectomy and HGNS (HGNS+T) were compared against a control group of patients who underwent HGNS alone., Setting: Single academic institution., Methods: Study outcomes were measures of HGNS efficacy defined as a %reduction in apnea-hypopnea index (AHI) (primary) and successful treatment response (50% AHI reduction to <15/h, logistic regression), respectively. Regression analyses quantified the additional effect of tonsillectomy (HGNS+T vs HGNS alone, independent variable) on HGNS efficacy. Analyses were adjusted for OLW collapse severity (complete vs partial), tonsil size, age, sex, body mass index, and baseline AHI., Results: Nineteen patients underwent HGNS+T and had follow-up sleep testing for the current analysis. The control group (HGNS alone) consisted of 78 patients. Baseline demographics and OSA severity were similar between the groups, except HGNS+T group had increased prevalence of complete OLW collapse. Linear regression demonstrated that adding tonsillectomy resulted in an additional 22.9% [7.5, 35.2] reduction in AHI [95% confidence interval, CI] (P = .006), and 8.6 [1.7,43.4] (P = .010) greater odds [95% CI] of a successful treatment response with HGNS., Conclusion: Compared to historically poorer outcomes of HGNS in patients with OLW collapse, these early results suggest combining tonsillectomy with HGNS may represent a promising strategy to improve success rates., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Rationale: Moderate-severe obstructive sleep apnea (OSA) (apnea-hypopnea index [AHI], >15 events/h) disturbs sleep through frequent bouts of apnea and is associated with daytime sleepiness. However, many individuals without moderate-severe OSA (i.e., AHI <15 events/h) also report sleepiness. Objectives: To test the hypothesis that sleepiness in the AHI <15 events/h group is a consequence of substantial flow limitation in the absence of overt reductions in airflow (i.e., apnea/hypopnea). Methods: A total of 1,886 participants from the MESA sleep cohort were analyzed for frequency of flow limitation from polysomnogram-recorded nasal airflow signal. Excessive daytime sleepiness (EDS) was defined by an Epworth Sleepiness Scale score ⩾11. Covariate-adjusted logistic regression assessed the association between EDS (binary dependent variable) and frequency of flow limitation (continuous) in individuals with an AHI <15 events/h. Results: A total of 772 individuals with an AHI <15 events/h were included in the primary analysis. Flow limitation was associated with EDS (odds ratio, 2.04; 95% confidence interval, 1.17-3.54; per 2-standard deviation increase in flow limitation frequency) after adjusting for age, sex, body mass index, race/ethnicity, and sleep duration. This effect size did not appreciably change after also adjusting for AHI. Conclusions: In individuals with an AHI <15 events/h, increasing flow limitation frequency by 2 standard deviations is associated with a twofold increase in the risk of EDS. Future studies should investigate addressing flow limitation in low-AHI individuals as a potential mechanism for ameliorating sleepiness.

Surgical interventions, like barbed reposition pharyngoplasty (BRP), are a valuable alternative for patients with obstructive sleep apnea (OSA) who are unable to tolerate continuous positive airway pressure (CPAP). However, predicting surgical success remains challenging, partly due to the contribution of non-anatomical factors. Therefore, combined medical treatment with acetazolamide, known to stabilize respiratory drive, may lead to superior surgical results. This double-blind, parallel-group randomized controlled trial evaluates the efficacy of acetazolamide as an add-on therapy to BRP in OSA. A total of 26 patients with moderate to severe OSA undergoing BRP were randomized to receive either acetazolamide or placebo post-surgery for 16 weeks. The group who was treated with BRP in combination with acetazolamide showed a reduction in AHI of 69.4%, significantly surpassing the 32.7% reduction of the BRP + placebo group ( p < 0.01). The sleep apnea-specific hypoxic burden also decreased significantly in the group who was treated with BRP + acetazolamide ( p < 0.01), but not in the group receiving BRP + placebo ( p = 0.28). Based on these results, acetazolamide as an add-on therapy following BRP surgery shows promise in improving outcomes for OSA patients, addressing both anatomical and non-anatomical factors.

Background: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b)., Methods: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and pre-eclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and infant birthweight., Results: Of 1939 participants with flow limitation data at both time-points (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m -2 ), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h -1 ). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM., Conclusions: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy., Competing Interests: Conflict of interest: A. Azarbarzin receives personal fees as a consultant for Somnifix, Apnimed, LinguaFlex, Respicardia and Inspire, and receives grant support from Somnifix. A. Wellman has financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnoea; his interests are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict of interest policies; A. Wellman also consults for Apnimed, Nox Medical, Inspire, Somnifix, Mosanna and Takeda, and has received grants from Somnifix and Sanofi. P.C. Zee receives personal fees as a consultant from Eisai, Jazz, Idorsia, Harmony Bioscience, Sleep Number and CVS Caremark. S. Redline received personal fees from Jazz Pharma, Eli Lilly and Apnimed. S.A. Sands receives personal fees as a consultant for Nox Medical, Merck, Apnimed, Respicardia, Inspire, Lilly, LinguaFlex and Forepont outside the submitted work, and receives grant support from Apnimed, ProSomnus and Dynaflex for unrelated studies. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: In patients with obstructive sleep apnea (OSA), novel metrics such as hypoxic burden (HB) and sleep apnea-specific pulse-rate response (ΔHR) may better correlate with cardiovascular diseases (CVD) than the apnea-hypopnea index (AHI). This manuscript aims to assess the correlation between ΔHR and HB with subclinical atherosclerosis in patients with OSA, testing the hypothesis that elevated ΔHR and HB are associated with subclinical atherosclerosis development., Methods: In a prospective study, individuals aged 20-65 years with suspected OSA without known comorbidities were consecutively recruited and defined as OSA (AHI≥5events/h) or healthy controls. Using bilateral carotid ultrasonography, common carotid intima-media thickness (CIMT) was assessed and the identification of at least one atheromatous plaque defined the presence of subclinical atherosclerosis. ΔHR, and HB were derived from pulse-oximetry., Results: We studied 296 patients of age 45±10 years old, of whom 28% were women, and with a BMI of 30.3±5.3kg/m 2 . Overall, 245 had OSA and 51 were healthy controls. After controlling for confounding variables higher ΔHR but not HB, was associated with higher CIMT (p=0.006) and higher time spent with oxygen saturation below 90% (T90) was associated with an increase in carotid atheroma plaques (p=0.032). When stratifying OSA based on HB tertiles, we observed that within tertile 2 of HB, an increase in ΔHR was associated with larger CIMT (p=0.017)., Conclusion: A higher ΔHR is associated with an increase in CIMT among adult patients with OSA. This study suggests that ΔHR could be a biomarker of risk for CVD in patients with OSA., (Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment., Methods: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure., Results: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity., Conclusions: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site of collapse using overnight polysomnography., Methods: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, n=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (n=22) versus absence (n=128) of CCCp (partial collapse and concurrent tongue base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue base or epiglottis collapse. External validation was performed on a separate dataset (n total =466)., Results: CCCp was characterised by greater scoopiness (β=1.5±0.6 per 2sd, multivariable estimate±se) and skewness (β=11.4±2.4) compared with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 1.5-12.4) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue base and epiglottis collapse characteristics. External validation confirmed model prediction., Conclusions: The current study provides a means to recognise patients with likely CCCp or other DISE-based site of collapse categories using routine polysomnography. Since site of collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions., Competing Interests: Conflict of interest: S. Op de Beeck reports grants and travel support from Research Foundation Flanders (FWO). D. Vena receives personal fees as a consultant for Inspire Medical Systems. A. Azarbarzin receives personal fees as a consultant for Somnifix, ZOLL Respicardia, Eli Lilly and Apnimed, and receives grant support from Somnifix, American Heart Association and American Academy of Sleep Medicine; in addition, A. Azarbarzin reports receipt of equipment from Philips Respironics, and the following patents: System and method for endo-phenotyping and risk stratifying obstructive sleep apnea, and Method, non-transitory computer readable medium and apparatus for arousal intensity scoring. P. Huyett is an education consultant for Inspire Medical Systems, and reports grants from Inspire Medical Systems and Nyxoah. J. Verbraecken reports grants and fees from SomnoMed, AstraZeneca, AirLiquide, Atos Medical, Vivisol, Mediq Tefa, Medidis, Micromed OSG, Bioprojet, Desitin, Epilog, Idorsia, Nightbalance, Inspire Medical Systems, Heinen and Löwenstein, Ectosense, Philips, ProSomnus, ResMed, Sefam, SD Worx, SOS Oxygène, Tilman, Total Care, Vlaamse Gemeenschap, Vlerick and ZOLL Itamar, and consultancy for Bioprojet, Idorsia and Epilog. A. Wellman works as a consultant for Apnimed, Somnifix, Inspire, Mosana, Takeda and Nox, and has received grants from the National Institutes of Health, Somnifix and Sanofi; in addition, A. Wellman has a financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnoea, and holds a patent on flow shape analysis to detect the site of airway collapse. O.M. Vanderveken reports research support at Antwerp University Hospital outside the submitted work from ProSomnus, SomnoMed, Philips, Inspire Medical Systems, Nyxoah, Med-El and Cochlear, lecture honoraria from SomnoMed and Inspire Medical Systems, and consultancy for SomnoMed, Inspire Medical Systems and GlaxoSmithKline. S.A. Sands has served as a consultant for Apnimed, Nox Medical, Eli Lilly, Merck, LinguaFlex, Respicardia, Forepont and Inspire Medical, received grant support from Apnimed, ProSomnus, and Dynaflex, received royalties from the licensing of IP for pharmacological therapy for OSA, unrelated to the current study, lecture honoraria from Tufts University, and equipment from Nox Medical; his industry interactions are actively managed by his institution and has the following patents: Co-inventor on a patent for a combination pharmacological therapy therapy and Co-inventor on a patent OSA phenotyping using wearable technology. The remaining authors have not potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Weight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity., Methods: SURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m 2 ) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction., Results: The primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes., Conclusion: SURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology., Trial Registration: ClinicalTrials.gov, NCT05412004., Competing Interests: Declaration of competing interest AM is funded by the National Institutes of Health (NIH) and has received income related to medical education from Eli Lilly and Company, Jazz Pharmaceuticals, LivaNova, and Zoll Medical; ResMed provided a philanthropic donation to the employer of AM (University of California San Diego). TW has served as a consultant/advisory board member from the Alkermes Orexin Advisory Board, Bayer AG, Eli Lilly and Company, and the Idorsia Alliance for Sleep; and has received royalty fees for use of the FOSQ from Alkermes, Axsome Therapeutics, Bayer AG, Bioprojet Deutschland GmbH, Eli Lilly and Company, Harmony Biosciences, Ignis Therapeutics (Shanghai) Ltd., Inspire Medical Systems, IQVIA Technologies, Jazz Pharmaceuticals, LivaNova, Nyxoah, Philips Respironics, ResMed, Signant Health, Signifier Medical Technologies, Stratevi, Syneos Health, Vallis Bioscience, and Verily Life Sciences. RG has served as a consultant for Apnimed and Eli Lilly and Company. IF has served as a consultant for Eli Lilly and Company, Idorsia, ResMed, and Stada Arzneimittel AG; has served as a speaker for Hennig and Idorsia; and has received research grants from Löwenstein Medical and ResMed. SR has received grants from the NIH during the conduct of the study; has received grants and personal fees from Jazz Pharmaceuticals, personal fees from Eli Lilly and Company, and personal fees from Apnimed outside the submitted work; and is the first incumbent of an endowed professorship donated to the Harvard Medical School by Dr. Farrell (the founder and Board Chairman of ResMed) through a charitable remainder trust instrument, with annual support equivalent to the endowment payout provided to the Harvard Medical School during Dr. Farrell's lifetime by ResMed through an irrevocable gift agreement. AA has received grant funding from the American Academy of Sleep Medicine Foundation and NIH; receives grant support from SomniFix; and serves as a consultant for Apnimed, Eli Lilly and Company, Respicardia, and SomniFix. Apnimed is developing pharmacological treatments for OSA. SAS has received grant funding from the NIH; has received grant support from Apnimed, DynaFlex, and ProSomnus; and serves as a consultant for Apnimed, Eli Lilly and Company, Forepont, Inspire Medical Systems, LinguaFlex, Nox Medical, and Respicardia. The interests of AA and SS were reviewed by Brigham and Women's Hospital and Mass General Brigham in accordance with their institutional policies. RJS reports grant and/or research support from ResMed, Inspire, and CryOSA, royalties from UpToDate and Merck Manual, research consulting for Eli Lilly and Company, and is on the Medical Advisory Board for eXciteOSA and Sleep Evolution. JB, SC, JPD, and MCB are employees and shareholders of Eli Lilly and Company., (Copyright © 2023. Published by Elsevier Inc.)

Background: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB)., Methods: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB., Results: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP., Conclusions: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB., Competing Interests: Disclosures A. Azarbarzin receives grant support from Somnifix and serves as a consultant for Somnifix, Respicardia, Eli Lilly, and Apnimed; Apnimed is a developing pharmacological treatment for obstructive sleep apnea. A. Azarbarzin’s interests were reviewed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their institutional policies. S. Sands receives personal fees as a consultant for Nox Medical, Apnimed, Merck, and Inspire outside the submitted work, and he has received grant support from Apnimed, Prosomnus, and Dynaflex. A. Wellman works as a consultant for Apnimed, Somnifix, Inspire, and Nox Medical. He has received grants from Somnifix and Regeneron. He has a financial interest in Apnimed, a company developing pharmacological therapies for sleep apnea. His interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. C. Schmickl reports income from consulting for Verily outside the submitted work. A. Malhotra is funded by the National Institutes of Health. He reports income related to medical education from Livanova, Eli Lilly, Jazz, and Zoll. ResMed provided a philanthropic donation to University of California San Diego. S. Redline received consulting fees from Eli Lilly, Inc, and Jazz Pharma and has consulted for Apnimed, Inc. D.J. Gottlieb has served on scientific advisory boards for Signifier Medical Technologies, Inc, and Wesper, Inc, and as a consultant to Powell-Mansfield, Inc, and Apnimed, Inc, and has received research support from ResMed, Inc. The other authors report no conflicts.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HB ev ) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHR ev ), vasoconstriction (vasoconstriction burden [VCB ev ] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HB ev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HB ev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHR ev , VCB ev , and β-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Background: Impaired daytime vigilance is an important consequence of OSA, but several studies have reported no association between objective measurements of vigilance and the apnea-hypopnea index (AHI). Notably, the AHI does not quantify the degree of flow limitation, that is, the extent to which ventilation fails to meet intended ventilation (ventilatory drive)., Research Question: Is flow limitation during sleep associated with daytime vigilance in OSA?, Study Design and Methods: Nine hundred ninety-eight participants with suspected OSA completed a 10-min psychomotor vigilance task (PVT) before same-night in-laboratory polysomnography. Flow limitation frequency (percent of flow-limited breaths) during sleep was quantified using airflow shapes (eg, fluttering and scooping) from nasal pressure airflow. Multivariable regression assessed the association between flow limitation frequency and the number of lapses (response times > 500 ms, primary outcome), adjusting for age, sex, BMI, total sleep time, depression, and smoking status., Results: Increased flow limitation frequency was associated with decreased vigilance: a 1-SD (35.3%) increase was associated with 2.1 additional PVT lapses (95% CI, 0.7-3.7; P = .003). This magnitude was similar to that for age, where a 1-SD increase (13.5 years) was associated with 1.9 additional lapses. Results were similar after adjusting for AHI, hypoxemia severity, and arousal severity. The AHI was not associated with PVT lapses (P = .20). In secondary exploratory analysis, flow limitation frequency was associated with mean response speed (P = .012), median response time (P = .029), fastest 10% response time (P = .041), slowest 10% response time (P = .018), and slowest 10% response speed (P = .005)., Interpretation: Increased flow limitation during sleep was associated with decreased daytime vigilance in individuals with suspected OSA, independent of the AHI. Flow limitation may complement standard clinical metrics in identifying individuals whose vigilance impairment most likely is explained by OSA., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. T. has received royalties related to Bittium BrainStatus EEG outside the submitted work. S. A. S. has received personal fees as a consultant for Nox Medical, Merck, Apnimed, Respicardia, Inspire Medical Systems, Eli Lilly, LinguaFlex, and Forepont outside the submitted work; receives grant support from Apnimed, Prosomnus, and Dynaflex for unrelated studies; and holds patents on phenotyping from wearable technology and sleep apnea pharmacotherapy through his institution’s Innovation department. His industry interactions are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict of interest policies. P. I. T. has received honoraria from the University of Sydney, the University of Adelaide, and Flinders University outside the submitted work. Outside the submitted work, A. A. has received a grant from Somnifix; consulting fees from Apnimed, Somnifix, LinguaFlex, Respicardia, Eli Lilly, and Inspire; honoraria from the American Academy of Orofacial Pain for a lecture; honoraria from University of Alberta for a grant review; equipment loaned from Philips Respironics; and has a patent pending for phenotyping sleep apnea using wearables. None declared (E. S., T. L., S. K., T. G., D. L. M., B. D.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is associated with pregnanolone and progesterone-related sulfated metabolites. SDB PC2, characterized by short respiratory event length and self-reported restless sleep, enriched in young adults, is associated with sphingomyelins. Metabolite risk scores (MRSs), representing metabolite signatures associated with the two SDB PCs, are associated with 6-year incident hypertension and diabetes. These MRSs have the potential to serve as biomarkers for SDB, guiding risk stratification and treatment decisions., (© 2024. The Author(s).)

Rationale: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone., Methods: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index., Results: Although AtoOxy lowered AHI by 49 (33, 62)% baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)% baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)% baseline , primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)% baseline ) and acetazolamide (+37 (5, 58)% baseline ), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)% baseline ). Arousal index was also modestly reduced with each intervention (11% baseline -16% baseline ). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy., Conclusions: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms., Trial Registration Number: NCT03892772., Competing Interests: Competing interests: The combination intervention under investigation in the current study was protected by a patent ('Combination pharmacological interventions for multiple mechanisms of obstructive sleep apnoea', WO-2021091902-A1, Sands co-inventor) licensed to Apnimed from the Brigham and Women’s Hospital. SS has received grant funding from Apnimed, Prosomnus and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire, Eli Lilly, Merck, Forepont, LinguaFlex, Achaemenid. He is also co-inventor on a patent related to wearable oximetry technology. He has received royalties from licensed intellectual property. AA served as a consultant for Somnifix, Respicardia and Apnimed; SS and AA’s industry interactions are managed by the Brigham and Women’s Hospital. SJ and GH has received equipment to support research projects from Resmed, Philips Respironics and Air Liquide Healthcare. BE has received grant funding from Apnimed and Incannex, and received personal fees from Signifier Medical outside the current work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Randomized trials have shown inconsistent cardiovascular benefits from obstructive sleep apnea (OSA) therapy. Intermittent hypoxemia can increase both sympathetic nerve activity and loop gain ("ventilatory instability"), which may thus herald cardiovascular treatment benefit. Objectives: To test the hypothesis that loop gain predicts changes in 24-hour mean blood pressure (MBP) in response to OSA therapy and compare its predictive value against that of other novel biomarkers. Methods: The HeartBEAT (Heart Biomarker Evaluation in Apnea Treatment) trial assessed the effect of 12 weeks of continuous positive airway pressure (CPAP) versus oxygen versus control on 24-hour MBP. We measured loop gain and hypoxic burden from sleep tests and identified subjects with a sleepy phenotype using cluster analysis. Associations between biomarkers and 24-h MBP were assessed in the CPAP/oxygen arms using linear regression models adjusting for various covariates. Secondary outcomes and predictors were analyzed similarly. Results: We included 93 and 94 participants in the CPAP and oxygen arms, respectively. Overall, changes in 24-hour MBP were small, but interindividual variability was substantial (mean [standard deviation], -2 [8] and 1 [8] mm Hg in the CPAP and oxygen arms, respectively). Higher loop gain was significantly associated with greater reductions in 24-hour MBP independent of covariates in the CPAP arm (-1.5 to -1.9 mm Hg per 1-standard-deviation increase in loop gain; P  ⩽ 0.03) but not in the oxygen arm. Other biomarkers were not associated with improved cardiovascular outcomes. Conclusions: To our knowledge, this is the first study suggesting that loop gain predicts blood pressure response to CPAP therapy. Eventually, loop gain estimates may facilitate patient selection for research and clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT01086800).

Rationale: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Background: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP)., Methods: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h -1 ) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h -1 ). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level., Results: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship., Conclusion: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis., Competing Interests: Conflict of interest: M.Á. Martinez-Garcia received grants from VitalAire and Philips, Spain, and serves as a consultant for ResMed Inc., Australia, companies that develop products related to sleep apnoea. L. Messineo received a consultancy fee from Apnimed. A. Wellman works as a consultant for Apnimed, SomniFix and Nox, and has received grants from SomniFix and Sanofi; A. Wellman has a financial interest in Apnimed, a company developing pharmacological therapies for sleep apnoea. His interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. S. Redline received grant support and consulting fees from Jazz Pharmaceuticals, and consulting fees from Apnimed and Lilly Pharma. S. Sands receives personal fees as a consultant for Nox Medical and Merck, outside the submitted work, and receives grant support from Apnimed and ProSomnus. F. Barbé received a research grant from ResMed Inc., Australia, a company that develops products related to sleep apnoea. A. Azarbarzin reports grant support from SomniFix and serves as a consultant for SomniFix, Respicardia, Eli Lilly and Apnimed. Apnimed is developing pharmacological treatments for obstructive sleep apnoea. A. Azarbarzin's interests were reviewed by Brigham and Women's Hospital and Mass General Brigham in accordance with their institutional policies. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Rationale: Recent studies have shown that sleep apnea-specific intermittent hypoxemia quantified by the hypoxic burden (HB) predicted cardiovascular disease (CVD)-related mortality in community-based and clinical cohorts. Calculation of HB is based on manual scoring of hypopneas and apneas, which is time-consuming and prone to interscorer variability. Objective: To validate a novel method to quantify the HB that is based on automatically scored desaturations. Methods: The sample included 5,655 middle-aged or older adults from the Sleep Heart Health Study (52.8% women; age, 63.2 ± 11.3 yr). The original HB method was based on a subject-specific search window obtained from an ensemble average of oxygen saturation signals (as measured by pulse oximetry) and synchronized with respect to the termination of scored respiratory events. In this study, however, the search window was obtained from ensemble average of oxygen saturation signals that synchronized with respect to the minimum of all automatically identified desaturations (⩾2% and other thresholds, including 3% and 4%, in sensitivity analyses). The time interval between the two maxima around the minimum saturation was defined as the search window. The oximetry-derived HB (HB Oxi ) was defined as the total area under all desaturation curves (restricted by the search window) divided by the total sleep time. Logistic and Cox regression models assessed the adjusted odds ratio (aOR)/hazard ratio of excessive daytime sleepiness (EDS), hypertension (HTN), and CVD mortality per 1-standard deviation increase in HB Oxi after adjusting for several covariates and confounders. Results: The Spearman's rank correlation between HB (median [interquartile range], 34.4 [18.4-59.8] % min/h) and HB Oxi (median [interquartile range], 34.5 [21.6-53.8] % min/h) was 0.81 ( P  < 0.001). Similar to HB, HB Oxi was significantly associated with EDS (aOR [95% confidence interval (CI)], 1.17 [1.09-1.26] per standard deviation), HTN (aOR [95% CI], 1.13 [1.05-1.21]), and CVD mortality (adjusted hazard ratio [95% CI], 1.15 [1.01-1.30]) in fully adjusted models. Conclusions: The HB Oxi was highly correlated with the HB based on manually scored apneas and hypopneas and was associated with EDS, HTN, and CVD mortality with similar effect sizes as previously reported. This method could be incorporated into wearable technology that accurately records oxygen saturation signals.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R  = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, β drive :β pressure ; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half ( n  = 22 of 42) exhibited drive-dominant responses (i.e., β drive :β pressure  > 2:1), and one-quarter ( n  = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., β drive :β pressure  < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] % baseline /standard deviation of β drive :β pressure ; P  = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Obstructive sleep apnoea (OSA), characterized by recurrent periods of upper airway obstruction and intermittent hypoxaemia, is prevalent in patients with cardiovascular disease (CVD), and is therefore important to consider in the prevention and management of CVD. Observational studies indicate that OSA is a risk factor for incident hypertension, poorly controlled blood pressure, stroke, myocardial infarction, heart failure, cardiac arrhythmias, sudden cardiac death and all-cause death. However, clinical trials have not provided consistent evidence that treatment with continuous positive airway pressure (CPAP) improves cardiovascular outcomes. These overall null findings might be explained by limitations in trial design and low levels of adherence to CPAP. Studies have also been limited by the failure to consider OSA as a heterogeneous disorder that consists of multiple subtypes resulting from variable contributions from anatomical, physiological, inflammatory and obesity-related risk factors, and resulting in different physiological disturbances. Novel markers of sleep apnoea-associated hypoxic burden and cardiac autonomic response have emerged as predictors of OSA-related susceptibility to adverse health outcomes and treatment response. In this Review, we summarize our understanding of the shared risk factors and causal links between OSA and CVD and emerging knowledge on the heterogeneity of OSA. We discuss the varied mechanistic pathways that result in CVD that also vary across subgroups of OSA, as well as the potential role of new biomarkers for CVD risk stratification., (© 2023. Springer Nature Limited.)

Study Objectives: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI] ≥3%Only ) vs events with arousals but no desaturation (AHI ArOnly ) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts., Methods: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI ≥3%Only and AHI ArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease., Results: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI ≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHI ArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years ( P < .0001)., Conclusions: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea., Citation: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med . 2023;19(8):1475-1484., (© 2023 American Academy of Sleep Medicine.)

Rationale: Obstructive sleep apnea (OSA) has been hypothesized to be a risk factor in interstitial lung disease (ILD) and is associated with radiological markers that may represent the earlier stages of ILD. Prior studies have been limited by their cross-sectional design and potential confounding by body habitus. Objectives: To test the hypothesis that OSA severity is associated with more high-attenuation areas (HAAs) on computed tomography and worse lung function over time among older community-dwelling adults. Methods: We used data from participants in the MESA (Multi-Ethnic Study of Atherosclerosis) who had apnea-hypopnea index (AHI) measured from polysomnography (2010-2013), high attenuation areas (HAAs, -600 to -250 Hounsfield units, n  = 784), assessments from exams 5 (2010-2012) and 6 (2016-2018) full-lung computed tomography scans, and spirometry assessments ( n  = 677). Linear mixed-effects models with random intercept were used to examine associations of OSA severity (i.e., AHI and hypoxic burden) with changes in HAAs, total lung volumes, and forced vital capacity (FVC) between exams 5 and 6. Potential confounders were adjusted for in the model, including age, sex, smoking history, height, and weight. Results: Among those with a higher AHI there were more men and a higher body mass index. Participants with AHI ⩾ 15 events/h and in the highest hypoxic burden quartile each had increases in HAAs of 11.30% (95% confidence interval [CI], 3.74-19.35%) and 9.85% (95% CI, 1.40-19.01%) per 10 years, respectively. There was a more rapid decline in total lung volumes imaged and FVC among those with AHI ⩾ 15 events/h of 220.2 ml (95% CI, 47.8-392.5 ml) and 3.63% (95% CI, 0.43-6.83%) per 10 years, respectively. Conclusions: A greater burden of hypoxia related to obstructive events during sleep was associated with increased lung densities over time and a more rapid decline in lung volumes regardless of body habitus. Our findings suggest OSA may be a contributing factor in the early stages of ILD.

Study Objectives: The American Academy of Sleep Medicine recommends scoring hypopneas in adults when there is a ≥ 3% oxygen desaturation or when the event is associated with an arousal. However, there is no rule regarding the duration of the interval between the event termination and the associated arousal. The purpose of this study is to explore the timing between arousals and sleep-disordered breathing (SDB) events., Methods: We analyzed cortical arousals (> 1.6 million) and SDB events (> 350,000 apneas and > 1.9 million hypopneas) from 11,400 manually scored polysomnography recordings. Only arousals that started within ±30 seconds from the end of SDB events were included. We used the 2 local minimums on either side of the arousal distribution as the start/end times for the distribution and to define which arousals are associated with SDB events. Finally, we calculated arousal probability near the end of SDB events., Results: Cortical arousals with start times that fell within the 2 minimums were considered to be associated with SDB events. Using this definition, we found that 90% of apnea-associated arousals started no earlier than 4 seconds before and no later than 9 seconds after the end of apneas. Similarly, 90% of hypopnea-associated arousals started no earlier than 6 seconds before and no later than 14 seconds after the end of hypopneas, with the peak of the distribution coinciding with event end time. Arousal probability was highest during the first 10 seconds after the end of the event and was higher for longer events., Conclusions: Our results suggest that 90% of SDB-associated arousals start no earlier than 6 seconds before and no later than 14 seconds after the end of the respiratory events., Citation: Zitting K-M, Lockyer BJ, Azarbarzin A, et al. Association of cortical arousals with sleep-disordered breathing events. J Clin Sleep Med . 2023;19(5):899-912., (© 2023 American Academy of Sleep Medicine.)

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N  = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m 2 [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

The combination of noradrenergic (reboxetine) plus antimuscarinic (oxybutynin) drugs (reb-oxy) reduced obstructive sleep apnea (OSA) severity but no data are available on its effects on cardiac autonomic modulation. We sought to evaluate the impact of 1-week reb-oxy treatment on cardiovascular autonomic control in OSA patients. OSA patients were randomized to a double-blind, crossover trial comparing 4 mg reboxetine plus 5 mg oxybutynin to a placebo for OSA treatment. Heart rate (HR) variability (HRV), ambulatory blood pressure (BP) monitoring (ABPM) over 24 h baseline and after treatment were performed. Baroreflex sensitivity was tested over beat-to-beat BP recordings. 16 subjects with (median [interquartile range]) age 57 [51-61] years and body mass index 30 [26-36]kg/m 2 completed the study. The median nocturnal HR was 65 [60-69] bpm at baseline and increased to 69 [64-77] bpm on reb-oxy vs 66 [59-70] bpm on placebo (p = 0.02). The mean 24 h HR from ABPM was not different among treatment groups. Reb-oxy administration was not associated with any modification in HRV or BP. Reb-oxy increased the baroreflex sensitivity and did not induce orthostatic hypotension. In conclusion, administration of reb-oxy did not induce clinically relevant sympathetic overactivity over 1-week and, together with a reduction in OSA severity, it improved the baroreflex function., (© 2023. The Author(s).)

Study Objectives: Polysomnograms (PSGs) collect a plethora of physiologic signals across the night. However, few of these PSG data are incorporated into standard reports, and hence, ultimately, under-utilized in clinical decision making. Recently, there has been substantial interest regarding novel alternative PSG metrics that may help to predict obstructive sleep apnea (OSA)-related outcomes better than standard PSG metrics such as the apnea-hypopnea index. We systematically review the recent literature for studies that examined the use of alternative PSG metrics in the context of OSA and their association with health outcomes., Methods: We systematically searched EMBASE, MEDLINE, and the Cochrane Database of Systematic Reviews for studies published between 2000 and 2022 for those that reported alternative metrics derived from PSG in adults and related them to OSA-related outcomes., Results: Of the 186 initial studies identified by the original search, data from 31 studies were ultimately included in the final analysis. Numerous metrics were identified that were significantly related to a broad range of outcomes. We categorized the outcomes into 2 main subgroups: (1) cardiovascular/metabolic outcomes and mortality and (2) cognitive function- and vigilance-related outcomes. Four general categories of alternative metrics were identified based on signals analyzed: autonomic/hemodynamic metrics, electroencephalographic metrics, oximetric metrics, and respiratory event-related metrics., Conclusions: We have summarized the current landscape of literature for alternative PSG metrics relating to risk prediction in OSA. Although promising, further prospective observational studies are needed to verify findings from other cohorts, and to assess the clinical utility of these metrics., Citation: Hajipour M, Baumann B, Azarbarzin A, et al. Association of alternative polysomnographic features with patient outcomes in obstructive sleep apnea: a systematic review. J Clin Sleep Med . 2023;19(2):225-242., (© 2023 American Academy of Sleep Medicine.)

Conventional measures of obstructive sleep apnea (OSA) severity, such as the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) are commonly used to quantify OSA severity and guide therapeutical decision-making processes. However, it is widely recognized that both AHI and ODI have important limitations and novel physiologically-informed metrics are needed to better capture the severity of OSA and characterize its physiological consequences, particularly the severity of recurrent nocturnal hypoxemia, ensuing the respiratory events. According to recent studies, the sleep apnea-specific "hypoxic burden (HB)", defined as the sum of individual areas under the oxygen desaturation curve, has shown some promise in identifying high risk individuals with OSA. In addition to the frequency of respiratory events, HB capture the depth and duration of OSA-related hypoxemia that may prove to be important disease characterizing features, not captured by the conventional "frequency-based" metrics, such as AHI and ODI. In this "perspective" paper the methods to quantify the HB, its characteristics, associations with health outcomes, and its limitations will be discussed., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Rationale: A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO 2 -mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing the arousal threshold in OSA and subsequently reducing OSA severity. Objectives: We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes). Methods: A total of 18 OSA participants were studied in a randomized, double-blind, crossover study. Patients received a single dose of placebo or pimavanserin 34 mg 4 hours before in-lab polysomnography. Airflow was measured with an oronasal mask attached to a pneumotachograph, and ventilatory drive was recorded with an intraesophageal electromyography catheter. Results are presented as mean or median changes (Δ) and 95% confidence intervals (CIs). Results: Pimavanserin did not increase the arousal threshold, nor did it decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ[confidence interval (CI)], 39.5 [95%CI, -1.2 to 80.1] min). In an exploratory analysis, a subgroup of seven patients who had a 10% or more increase in arousal threshold on pimavanserin exhibited a decrease in AHI 4 (hypopneas associated with 4% desaturation) (Δ[CI], 5.6 [95%CI, 3.6-11.1] events/h) and hypoxic burden (Δ[CI], 22.3 [95%CI, 6.6-32.3] %min/h). Conclusions: A single dose of pimavanserin did not have a significant effect on arousal threshold or OSA severity. However, in a post hoc analysis, a subset of patients who exhibited an increase in arousal threshold on pimavanserin showed a small decrease in OSA severity. Thus, if the arousal threshold could be increased with pimavanserin, perhaps with longer dosing to reach higher drug blood concentrations, then the desired effect on OSA severity might be achievable. Clinical trial registered with ClinicalTrials.gov (NCT04538755).

Background and Objective: The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes., Methods: Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per V MIN and arousal threshold) were derived from validated algorithms., Results: Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised V MIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %V EUPNOEA , mean [CI], p = 0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %V EUPNOEA , p = 0.038). In post hoc analysis, 6/6 patients with milder collapsibility (V MIN  > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia., Conclusion: While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals., (© 2022 Asian Pacific Society of Respirology.)

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; n CPAP  = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). n control  < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) ( Measurements and Main Results:  < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P  < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) ( P  < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P  = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.arbres.2022.08.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal, (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Study Objectives: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h)., Methods: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping., Results: Within-night repeatability for traits ranged from R = 0.62-0.79 and improved to R = 0.69-0.83 when recommended amounts of data were available (20-35 7-min windows, available in 94%-98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79-0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30-0.61) and improved (R = 0.36-0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3., Conclusions: Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies., Clinical Trial Information: The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h ( P  = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm ( P  < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea.

Background: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements., Methods: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models)., Results: On average, ventilatory drive fell (rather than rose) during events (-20 (-42 to 3)% baseline , median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (-17 (-20 to -14)%/drive) and EMGgg (-3.5 (-3.8 to -3.3)% max /drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100% eupnoea ); associations were concentrated in patients with drive-dependent OSA (ie, flow: -37 (-40 to -34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure-without tidal volume correction-falsely suggested rising drive during events ( classic model)., Conclusions: In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention., Competing Interests: Competing interests: SS received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical and Merck. DPW is a distinguished scientist with Apnimed and a consultant for RBNC Therateutics, Philips Respironics, Cryosa and Cerebra Health. AA serves as consultant for Somnifix and Apnimed and receives grant support from Somnifix. AW works as a consultant for Apnimed, Nox, Inspire and Somnifix and has received grants from Sanofi and Somnifix. LT-M works as medical director at Apnimed. AW and LT-M have a financial interest in Apnimed Inc, a company developing pharmacological therapies for sleep apnoea; their interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: Obstructive sleep apnea has major health consequences but is challenging to treat. For many therapies, efficacy is determined by the severity of underlying pharyngeal collapsibility, yet there is no accepted clinical means to measure it. Here, we provide insight into which polysomnographic surrogate measures of collapsibility are valid, applicable across the population, and predictive of therapeutic outcomes., Methods: Seven promising polysomnography-derived surrogate collapsibility candidates were evaluated: Vpassive (flow at eupneic ventilatory drive), Vmin (ventilation at nadir drive), event depth (depth of the average respiratory event), oxygen desaturation slope and mean oxygen desaturation (events-related averages), Fhypopneas (fraction of events scored as hypopneas), and apnea index. Evaluation included (1) validation by comparison to physiological gold-standard collapsibility values (critical closing pressure, Pcrit), (2) capacity to detect increased collapsibility with older age, male sex, and obesity in a large community-based cohort (Multi-Ethnic Study of Atherosclerosis, MESA), and (3) prediction of treatment efficacy (oral appliances and pharmacological pharyngeal muscle stimulation using atomoxetine-plus-oxybutynin)., Results: Pcrit was significantly correlated with Vmin (r = -0.54), event depth (r = 0.49), Vpassive (r = -0.38), Fhypopneas (r = -0.46), and apnea index (r = -0.46; all p < .01) but not others. All measures detected greater collapsibility with male sex, age, and obesity, except Fhypopneas and apnea index which were not associated with obesity. Fhypopneas and apnea index were associated with oral appliance and atomoxetine-plus-oxybutynin efficacy (both p < .05)., Conclusions: Among several candidates, event depth, Fhypopneas, and apnea index were identified as preferred pharyngeal collapsibility surrogates for use in the clinical arena., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Obstructive sleep apnoea (OSA) episode related blood pressure (BP) surge may mediate the association of OSA with cardiovascular disease. However, BP is not measured during a clinical sleep study., Method: We tested the feasibility of incorporating the Caretaker physiological monitor, which utilizes a novel continuous beat-to-beat (b-b) BP monitoring technology, into polysomnography (PSG) and aimed to characterize BP surges related to obstructive respiratory events. B-b BP was concurrently collected and merged with PSG data on a posthoc basis. We compared BP surge between mean respiratory (apnoea, hypopnea and desaturation-alone events) and nonrespiratory events (spontaneous or leg movement-related arousals). We examined the association of the degree of oxygen desaturation with BP surge in a given respiratory event combining all events. A total of 17 consecutive patients (12 men, mean 52 years old, nine diagnostic and eight split-night PSGs) undergoing clinically indicated PSG were included after excluding one patient with poor signal quality due to excessive movement., Results: Caretaker was well tolerated. Mean respiratory BP surge ranged from 5 to 19 mmHg [Median (IQR) = 13.9 (9.5--16.2)]. Mean BP surge between the respiratory and nonrespiratory events was similar [13.8 (4.5) vs. 14.9 (5.3) mmHg, P = 0.13]. Accounting for the count distribution of desaturation/BP surge data pair events, there was a linear correlation between the degree of oxygen desaturation and BP surge (R = 0.57, P < 0.001). In eight patients undergoing split-night sleep studies, the number of BP surge events (≥10 mmHg/h) decreased during continuous positive airway pressure in all but one patient., Conclusion: We demonstrated highly variable OSA-related BP surge patterns using the Caretaker's b-b BP monitoring technology that has the potential to be integrated into sleep studies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1 ) withdrawal of neural ventilatory drive or 2 ) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness ). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P  < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P  < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

Background: The recent discovery that a combination of noradrenergic and antimuscarinic drugs improved upper airway muscle function during sleep and reduced OSA severity has revitalized interest in pharmacologic therapies for OSA., Research Question: Would 1 week of reboxetine plus oxybutynin (Reb-Oxy) be effective on OSA severity?, Study Design and Methods: A randomized, placebo-controlled, double-blind, crossover trial was performed comparing 4 mg reboxetine plus 5 mg oxybutynin (Reb-Oxy) vs placebo in patients with OSA. After a baseline in-laboratory polysomnogram (PSG), patients underwent PSGs after 7 nights of Reb-Oxy and 7 nights of placebo to compare apnea-hypopnea index (AHI), which was the primary outcome. Response rate was based on the percentage of subjects with a ≥ 50% reduction in AHI from baseline. Secondary outcomes included Epworth Sleepiness Scale (ESS) score and psychomotor vigilance test (PVT) values. Home oximetry evaluated overnight oxygen desaturation index (ODI) throughout treatment., Results: Sixteen subjects aged 57 [51-61] years (median [interquartile range]) with a BMI of 30 [26-36] kg/m 2 completed the study. Reb-Oxy lowered AHI from 49 [35-57] events per hour at baseline to 18 [13-21] events per hour (59% median reduction) compared with 39 [29-48] events per hour (6% median reduction) with placebo (P < .001). Response rate for Reb-Oxy was 81% vs 13% for placebo (P < .001). Although ESS scores were not significantly lowered, PVT median reaction time decreased from 250 [239-312] ms at baseline to 223 [172-244] ms on Reb-Oxy vs 264 [217-284] ms on placebo (P < .001). Home oximetry illustrated acute and sustained improvement in the oxygen desaturation index on Reb-Oxy vs placebo., Interpretation: The administration of Reb-Oxy greatly decreased OSA severity and increased vigilance. These results highlight potential possibilities for pharmacologic treatment of OSA., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04449133; URL: www.clinicaltrials.gov., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Objectives: The presence of flow limitation during sleep is associated with adverse health consequences independent of obstructive sleep apnea (OSA) severity (apnea-hypopnea index, AHI), but remains extremely challenging to quantify. Here we present a unique library and an accompanying automated method that we apply to investigate flow limitation during sleep., Methods: A library of 117,871 breaths (N = 40 participants) were visually classified (certain flow limitation, possible flow limitation, normal) using airflow shape and physiological signals (ventilatory drive per intra-esophageal diaphragm EMG). An ordinal regression model was developed to quantify flow limitation certainty using flow-shape features (e.g. flattening, scooping); breath-by-breath agreement (Cohen's ƙ); and overnight flow limitation frequency (R2, %breaths in certain or possible categories during sleep) were compared against visual scoring. Subsequent application examined flow limitation frequency during arousals and stable breathing, and associations with ventilatory drive., Results: The model (23 features) assessed flow limitation with good agreement (breath-by-breath ƙ = 0.572, p < 0.001) and minimal error (overnight flow limitation frequency R2 = 0.86, error = 7.2%). Flow limitation frequency was largely independent of AHI (R2 = 0.16) and varied widely within individuals with OSA (74[32-95]%breaths, mean[range], AHI > 15/h, N = 22). Flow limitation was unexpectedly frequent but variable during arousals (40[5-85]%breaths) and stable breathing (58[12-91]%breaths), and was associated with elevated ventilatory drive (R2 = 0.26-0.29; R2 < 0.01 AHI v. drive)., Conclusions: Our method enables quantification of flow limitation frequency, a key aspect of obstructive sleep-disordered breathing that is independent of the AHI and often unavailable. Flow limitation frequency varies widely between individuals, is prevalent during arousals and stable breathing, and reveals elevated ventilatory drive. Clinical trial registration: The current observational physiology study does not qualify as a clinical trial., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pulse arrival time (PAT) is commonly used to estimate blood pressure response. We hypothesised that PAT response to obstructive respiratory events would be associated with increased cardiovascular risk in people with obstructive sleep apnoea., Methods: PAT, defined as the time interval between electrocardiography R wave and pulse arrival by photoplethysmography, was measured in the Multi-Ethnic Study of Atherosclerosis Sleep study participants. The PAT response to apnoeas/hypopnoeas was defined as the area under the PAT waveform following respiratory events. Cardiovascular outcomes included markers of subclinical cardiovascular disease (CVD): left ventricular mass, carotid plaque burden score and coronary artery calcification (CAC) (cross-sectional) and incident composite CVD events (prospective). Multivariable logistic and Cox proportional hazard regressions were performed., Results: A total of 1407 participants (mean age 68.4 years, female 47.5%) were included. Higher PAT response (per 1 SD increase) was associated with higher left ventricular mass (5.7 g/m 2 higher in fourth vs first quartile, p<0.007), higher carotid plaque burden score (0.37 higher in fourth vs first quartile, p=0.02) and trended to greater odds of CAC (1.44, 95% CI 0.98 to 2.15, p=0.06). A total of 65 incident CVD events were observed over the mean of 4.1 (2.6) years follow-up period. Higher PAT response was associated with increased future CVD events (HR: 1.20, 95% CI 1.02 to 1.42, p=0.03)., Conclusion: PAT is independently associated with markers of subclinical CVD and incident CVD events. Respiratory-related PAT response is a novel and promising polysomnography metric with cardiovascular implications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)