Search

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: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P

Rationale: Acetazolamide, eszopiclone, and venlafaxine may target different underlying mechanisms of obstructive sleep apnea (OSA) and individually may partially reduce OSA severity in select patients. We tested whether acetazolamide plus eszopiclone (DualRx) reduces OSA severity. We further explored whether the addition of venlafaxine (TripleRx) alleviates OSA in patients who do not fully respond to DualRx. Methods: In this double-blind crossover trial, 20 patients with OSA underwent baseline polysomnography followed by DualRx/placebo phases in random order. Subsequently, 18 patients underwent an open-label TripleRx phase. Each phase lasted 3 days and concluded with polysomnography. The primary outcome was the placebo-adjusted change in apnea–hypopnea index during supine, non–rapid eye movement sleep (AHINREM,supine) from baseline to DualRx. Secondary outcomes included other OSA metrics, sleep parameters, and select clinical outcomes (blood pressure, symptoms, and vigilance). Results: Participants were on average middle aged, overweight, and relatively diverse (20% women, 60% non-White), with severe OSA (median [interquartile range] AHINREM,supine, 32.8 [20 to 48.8] events/h). Compared with placebo, DualRx was well tolerated and improved AHINREM,supine (−13.8 [−24.1 to −5.2] events/h or −45% [−77% to −14%]; PWilcoxon = 0.003), overall AHI, hypoxic burden, and sleep architecture (P < 0.05) but not the selected clinical outcomes. TripleRx did not provide a clear benefit relative to DualRx, although some measures of OSA-related hypoxemia improved more substantially. There were no serious side effects. Conclusions: Short-term use of dual-drug therapy with DualRx substantially reduced OSA severity. Adding venlafaxine did not generally reduce OSA severity but may be beneficial for some patients. Longer term studies are needed to assess effects on clinically important outcomes. Clinical trial registered with (NCT 04639193). [ABSTRACT FROM AUTHOR]

There are multiple mechanisms underlying obstructive sleep apnea (OSA) development. However, how classic OSA risk factors such as body mass index (BMI) and sex portend to OSA development has not been fully described. Thus we sought to evaluate how obesity leads to OSA and assess how these mechanisms differ between men and women. The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the University of California, San Diego, sleep clinic between January 2017 and December 2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced the apnea-hypopnea index (AHI) using OSA pathophysiological traits as mediators, adjusting for age, race, and ethnicity. We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese [body mass index (BMI) > 30 kg/m2]. BMI was significantly associated with AHI in both women and men. In men, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (βstandardized = 0.124), a reduction in circulatory delay (βstandardized = 0.063), and an increase in arousal threshold (βstandardized = 0.029; Pboot-strapped,all < 0.05). In women, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (βstandardized = 0.05) and circulatory delay (βstandardized = 0.037; Pboot-strapped,all < 0.05). BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (higher AHI), while the relationship between arousal threshold and OSA is likely complex. NEW & NOTEWORTHY: Our data provide important insights into obesity-related obstructive sleep apnea (OSA) pathogenesis, thereby validating, and extending, prior research findings. This is the largest sample size study to examine the relationships between obesity and gender on OSA pathogenesis. The influence of obesity on sleep apnea severity is mediated by different mechanistic traits (endotypes). [ABSTRACT FROM AUTHOR]

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 (119 events/h per 11 kg/m2 [2 SD]), male sex (113 events/h vs. female), older age (17 events/h per 20 yr), and Chinese ancestry (15 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (10.40 SD) and greater loop gain (10.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (10.86 SD) and reduced compensation (20.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (10.37 SD) and greater loop gain (10.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (10.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (20.30 SD) and elevated loop gain (10.29 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. [ABSTRACT FROM AUTHOR]

Motivations: The purpose of this research is to develop adaptive nonparametric statistical methods for 2 × 2 cross over designs with repeated measures. Methods: The statistics and their asymptotic distributions are established for testing: (1) the equality for carry-over effects; (2) direct treatment effect when carry-over effects are equal; (3) equality of carry-over effect over time; (4) equality of direct treatment effect over time when carry-over effect over time is equal; (5) the average response for carry-over effects; and (6) the average response for direct treatment effects when average response for carry-over effects are equal. Findings: The methods are applied to the slopes of systolic and diastolic pressures in the study regarding to sleep apnea severity. Implications: Using the sleep apnea severity study as an example, we show that adaptive procedures had advantage of detecting the significance of test while the ranks-only based methods by Johnson and Grender (1993) failed to detect such significant result. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnoea (OSA) is associated with neurocognitive dysfunction. However, randomised 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 randomised, sham-controlled trial (Apnea Positive Pressure Long-term Efficacy Study (APPLES); ClinicalTrials.gov: NCT00051363). ArTH was estimated from polysomnography using a translatable method. Neurocognitive outcomes included the Sustained Working Memory Test-Overall Mid-Day (SWMT-OMD) score (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. Generalised linear modelling assessed whether the effect of CPAP was modified by baseline ArTH (treatment×ArTH interaction). 833 participants with OSA (apnoea-hypopnoea index ≥10 events·h -1 ), available ArTH and outcomes were analysed (active CPAP n=437 and sham CPAP n=396)., Results: For executive function, the effect of CPAP treatment was modified by ArTH (p interaction =0.042). Specifically, for every 1sd increase in ArTH, the SWMT-OMD score improved by 0.091 (95% CI 0.003-0.178) in active compared to sham CPAP at 6 months; at ArTH 1sd above the mean, SWMT-OMD improvements were nearly three times that in those with average ArTH (0.139 (95% CI 0.018-0.261) versus 0.053 (95% CI -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., Competing Interests: Conflicts of interest: A.V. Zinchuk works as a consultant for Restful Robotics Inc. and receives grant support from ResMedco. C.A. Kushida works as a consultant for Cerebra Health, Vivos Therapeutics, Restful Robotics, Koko Home Inc., Eisai, Asleep, Oxama Medical, SoundHealth Inc., Samsung and Genentech. A. Wellman works as a consultant for Apnimed, Nox Medical, Inspire and Somnifix, has received grants from Sanofi and Somnifix, and has a financial interest in Apnimed Corp., a company developing pharmacological therapies for sleep apnoea; A. Wellman's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. A. Azarbarzin reports grant support from Somnifix, and serves as a consultant for Somnifix, Respicardia, Inspire, Eli Lilly, Cerebra 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. A.W. Varga works as a consultant for Jazz Pharmaceuticals. S.A. Sands works as a consultant for Apnimed, Eli Lilly, Forepont, Merck, Nox Medical and Respicardia, and receives grant support from Apnimed, Prosomnus and Dynaflex. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2025. For reproduction rights and permissions contact permissions@ersnet.org.)

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.)

We present an approach to quantifying nocturnal blood pressure (BP) variations that are elicited by sleep disordered breathing (SDB). A sample-by-sample aggregation of the dynamic BP variations during normal breathing and BP oscillations prompted by apnea episodes is performed. This approach facilitates visualization and analysis of BP oscillations. Preliminary results from analysis of a full night study of 7 SDB subjects (5 Male 2 Female, 52±5.6 yrs., Body Mass Index 36.4±7.4 kg/m 2 , Apnea-Hypopnea Index 69.1±26.8) are presented. Aggregate trajectory and quantitative values for changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) concomitant with obstructive apnea episodes are presented. The results show 19.4 mmHg (15.3%) surge in SBP and 9.4 mmHg (13.6%) surge in DBP compared to their respective values during normal breathing (p<0.05). Further, the peak of the surge in SBP and DBP occurred about 9s and 7s, respectively, post the end of apnea events. The return of SBP and DBP to baseline values displays a decaying oscillatory pattern.

Monitoring apnea-induced cerebral blood flow oscillations is of importance for assessing apnea patient brain health. Using an autoregressive moving average model, peak and trough values of cerebral blood flow were estimated from a concurrently recorded forehead photoplethysmography signal. Preliminary testing of the method in 7 subjects (4 F, 32±4 yrs., BMI 24.57±3.87 kg/m 2 ) using a breath hold paradigm for simulating apnea shows that maximum mean and standard deviation of the prediction error is -1.10±8.49 cm/s and the maximum root mean squared of the error is 8.92 cm/s.

Monitoring apnea-induced cerebral blood flow (CBF) oscillations is of importance for assessing apnea patient brain health. Blood pressure (BP) oscillations during apnea can induce oscillations in CBF. Preliminary results of testing an Auto Regressive Moving Average model relating nocturnal CBP oscillations to nocturnal BP variations in 8 obstructive sleep apnea subjects (3 F, 55±8 yrs., BMI 34.2±7.85 kg/m 2 ) showed that largest mean and standard deviation of the CBF estimation errors was 4.49±7.57 cm/s and maximum root mean squared of the errors was 8.80 cm/s. Hence, reasonable accuracy in estimating CBF from BP during sleep apnea events was observed.