Sleep-wake behaviors associated with cognitive performance in middle-aged participants of the Hispanic Community Health Study/Study of Latinos.

OBJECTIVES: Many sleep-wake behaviors have been associated with cognition. We examined a panel of sleep-wake/activity characteristics to determine which are most robustly related to having low cognitive performance in midlife. Secondarily, we evaluate the predictive utility of sleep-wake measures to screen for low cognitive performance. METHODS: The outcome was low cognitive performance defined as being >1 standard deviation below average age/sex/education internally normalized composite cognitive performance levels assessed in the Hispanic Community Health Study/Study of Latinos. Analyses included 1006 individuals who had sufficient sleep-wake measurements about 2years later (mean age=54.9, standard deviation= 5.1; 68.82% female). We evaluated associations of 31 sleep-wake variables with low cognitive performance using separate logistic regressions. RESULTS: In individual models, the strongest sleep-wake correlates of low cognitive performance were measures of weaker and unstable 24-hour rhythms; greater 24-hour fragmentation; longer time-in-bed; and lower rhythm amplitude. One standard deviation worse on these sleep-wake factors was associated with ∼20%-30% greater odds of having low cognitive performance. In an internally cross-validated prediction model, the independent correlates of low cognitive performance were: lower Sleep Regularity Index scores; lower pseudo-F statistics (modellability of 24-hour rhythms); lower activity rhythm amplitude; and greater time in bed. Area under the curve was low/moderate (64%) indicating poor predictive utility. CONCLUSION: The strongest sleep-wake behavioral correlates of low cognitive performance were measures of longer time-in-bed and irregular/weak rhythms. These sleep-wake assessments were not useful to identify previous low cognitive performance. Given their potential modifiability, experimental trials could test if targeting midlife time-in-bed and/or irregular rhythms influences cognition.

Sleep Apnea and Hypertension Control among Hispanic/Latino Adults in the United States: Results from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL).

Objectives: Hispanic/Latino adults have a high prevalence of uncontrolled hypertension predisposing them to CVD. We hypothesize that sleep apnea severity is associated with uncontrolled blood pressure (BP) and resistant hypertension in Hispanic/Latino adults. Methods: This was a cross-sectional study of 2,849 Hispanic Community Health Study/Study of Latinos participants with hypertension (i.e., systolic BP ≥130 mm Hg, or diastolic BP ≥80 mm Hg or self-reported antihypertensive medication use) who were taking at least one class of antihypertensive medication. Participants were categorized as having controlled (BP < 130/80 mmHg among those on hypertension treatment) , uncontrolled (BP ≥ 130/80 mmHg using one or two classes of antihypertensive medications), or resistant hypertension (BP ≥ 130/80 mmHg while on ≥ 3 classes of antihypertensive medications or the use of ≥ 4 classes of antihypertensive medications regardless of BP control). Sleep apnea was classified based on the respiratory event index (REI; events/h) as mild (REI ≥ 5 and < 15), moderate-to-severe (REI ≥ 15), or no sleep apnea (REI < 5). Results: In multinomial logistic regression, moderate-to-severe sleep apnea (vs. no sleep apnea) was associated with higher odds of resistant hypertension (Odds Ratio [OR], 2.15; 95% CI, 1.36-3.39 at 4% desaturation and OR 1.68; 95% CI, 1.05-2.67 at 3% desaturation). Neither mild nor moderate-to-severe sleep apnea was associated with uncontrolled hypertension. Conclusion: Among diverse Hispanic/Latino persons, moderate-to-severe but not mild sleep apnea was associated with resistant hypertension. Identification and management of sleep apnea in this population may improve BP control and subsequently prevent adverse cardiovascular outcomes.

Untargeted Metabolome Atlas for Sleep Phenotypes in the Hispanic Community Health Study/Study of Latinos.

Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep phenotypes and blood metabolites. Utilizing data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep phenotypes, grouped in several domains (i.e., sleep disordered breathing (SDB), sleep duration, timing, insomnia symptoms, and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualize and interpret the associations between sleep phenotypes and metabolites. The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, some xenobiotic metabolites were associated with sleep duration and heart rate phenotypes (e.g. 1H-indole-7-acetic acid, 4-allylphenol sulfate), while ketone bodies and fatty acid metabolism metabolites were associated with sleep timing measures (e.g. 3-hydroxybutyrate (BHBA), 3-hydroxyhexanoylcarnitine (1)). Heart rate phenotypes had the overall largest number of detected metabolite associations. Many of these associations were shared with both SDB and with sleep timing phenotypes, while SDB phenotypes shared relatively few metabolite associations with sleep duration measures. A number of metabolites were associated with multiple sleep phenotypes, from a few domains. The amino acids vanillylmandelate (VMA) and 1-carboxyethylisoleucine were associated with the greatest number of sleep phenotypes, from all domains other than insomnia. This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.

A comparison of caregiver-reported snoring and objective snoring in children from urban neighborhoods.

OBJECTIVE: Sleep Disordered Breathing (SDB) is both prevalent and under-recognized in pediatric minority populations. Recognition of SDB is often triggered by symptoms of caregiver-reported snoring. However, the validity and utility of caregiver reports likely vary across populations. Our objective is to assess the association between caregiver-reported snoring and objectively recorded snoring in a low-income urban community and explore factors associated with agreement between objective and subjective snoring. METHODS: 169 6 to 12 year old participants underwent at-home sleep studies with a WatchPAT device as part of the Environmental Assessment of Sleep in Youth (EASY) cohort study. Differences in subjective snoring, objective snoring, and concordance between subjective and objective snoring based on socioeconomic and clinical characteristics were assessed. RESULTS: The sample had a high proportion of non-white (78.9 %) and low income (39.6 %) children. Caregivers reported snoring for 20.7 % of the children and snoring was measured objectively for 21.9 %. Of those with objective snoring, only 29.7 % were identified as snorers by caregiver report (sensitivity: 0.30; specificity: 0.82). Primary Spanish language and co-sleeping were associated with increased caregiver reported snoring, and allergy was associated with increased objective snoring. Older child age and normal range BMI percentile were associated with higher concordance between caregiver and objective snoring. CONCLUSIONS: Among a community-based, predominantly minority sample, caregiver-reported snoring resulted in under-estimation of prevalence of objectively assessed snoring. Reliance on caregiver report may poorly identify children with snoring or SDB in clinical practice.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Pioneering a Multi-Phase Framework to Harmonize Self-Reported Sleep Data Across Cohorts.

STUDY OBJECTIVES: Harmonizing and aggregating data across studies enable pooled analyses that support external validation and enhance replicability and generalizability. However, the multidimensional nature of sleep poses challenges for data harmonization and aggregation. Here we describe and implement our process for harmonizing self-reported sleep data. METHODS: We established a multi-phase framework to harmonize self-reported sleep data: (1) compile items; (2) group items into domains; (3) harmonize items; and (4) evaluate harmonizability. We applied this process to produce a pooled multi-cohort sample of five United States cohorts plus a separate yet fully harmonized sample from Rotterdam, Netherlands. Sleep and sociodemographic data are described and compared to demonstrate the utility of harmonization and aggregation. RESULTS: We collected 190 unique self-reported sleep items and grouped them into 15 conceptual domains. Using these domains as guiderails, we developed 14 harmonized items measuring aspects of Satisfaction, Alertness/Sleepiness, Timing, Efficiency, Duration, Insomnia, and Sleep Apnea. External raters determined that 13 of these 14 items had moderate-to-high harmonizability. Alertness/Sleepiness items had lower harmonizability, while continuous, quantitative items (e.g., timing, total sleep time, efficiency) had higher harmonizability. Descriptive statistics identified features that are more consistent (e.g., wake-up time, duration) and more heterogeneous (e.g., time in bed, bedtime) across samples. CONCLUSIONS: Our process can guide researchers and cohort stewards towards effective sleep harmonization and provides a foundation for further methodological development in this expanding field. Broader national and international initiatives promoting common data elements across cohorts are needed to enhance future harmonization and aggregation efforts.

Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies.

BACKGROUND: Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. METHODS: In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. FINDINGS: For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. INTERPRETATION: With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. FUNDING: US National Institutes of Health.

Aircraft noise exposure and body mass index among female participants in two Nurses' Health Study prospective cohorts living around 90 airports in the United States.

OBJECTIVE: Aircraft noise exposure is linked to cardiovascular disease risk. One understudied candidate pathway is obesity. This study investigates the association between aircraft noise and obesity among female participants in two prospective Nurses' Health Study (NHS and NHSII) cohorts. METHODS: Aircraft day-night average sound levels (DNL) were estimated at participant residential addresses from modeled 1 dB (dB) noise contours above 44 dB for 90 United States (U.S.) airports in 5-year intervals 1995-2010. Biennial surveys (1994-2017) provided information on body mass index (BMI; dichotomized, categorical) and other individual characteristics. Change in BMI from age 18 (BMI18; tertiles) was also calculated. Aircraft noise exposures were dichotomized (45, 55 dB), categorized (<45, 45-54, ≥55 dB) or continuous for exposure ≥45 dB. Multivariable multinomial logistic regression using generalized estimating equations were adjusted for individual characteristics and neighborhood socioeconomic status, greenness, population density, and environmental noise. Effect modification was assessed by U.S. Census region, climate boundary, airline hub type, hearing loss, and smoking status. RESULTS: At baseline, the 74,848 female participants averaged 50.1 years old, with 83.0%, 14.8%, and 2.2% exposed to <45, 45-54, and ≥55 dB of aircraft noise, respectively. In fully adjusted models, exposure ≥55 dB was associated with 11% higher odds (95% confidence interval [95%CI]: -1%, 24%) of BMIs ≥30.0, and 15% higher odds (95%CI: 3%, 29%) of membership in the highest tertile of BMI18 (ΔBMI 6.7 to 71.6). Less-pronounced associations were observed for the 2nd tertile of BMI18 (ΔBMI 2.9 to 6.6) and BMI 25.0-29.9 as well as exposures ≥45 versus <45 dB. There was evidence of DNL-BMI trends (ptrends ≤ 0.02). Stronger associations were observed among participants living in the West, arid climate areas, and among former smokers. DISCUSSION: In two nationwide cohorts of female nurses, higher aircraft noise exposure was associated with higher BMI, adding evidence to an aircraft noise-obesity-disease pathway.

A sociodemographic index identifies non-biological sex-related effects on insomnia in the Hispanic Community Health Study/Study of Latinos.

Background: Sex differences are related to both biological factors and the gendered environment. To untangle sex-related effects on health and disease it is important to model sex-related differences better. Methods: Data came from the baseline visit of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a longitudinal cohort study following 16,415 individuals recruited at baseline from four study sites: Bronx NY, Miami FL, San Diego CA, and Chicago IL. We applied LASSO penalized logistic regression of male versus female sex over sociodemographic, acculturation, and psychological factors jointly. Two "gendered indices", GISE and GIPSE, summarizing the sociodemographic environment (GISE, primary) and psychosocial and sociodemographic environment (GIPSE, secondary) associated with sex, were calculated by summing these variables, weighted by their regression coefficients. We examined the association of these indices with insomnia derived from self-reported symptoms assessed via the Women Health Initiative Insomnia Rating Scale (WHIIRS), a phenotype with strong sex differences, in sex-adjusted and sex-stratified analyses. All analyses were adjusted for age, Hispanic/Latino background, and study center. Results: The distribution of GISE and GIPSE differed by sex with higher values in male individuals, even when constructing and validating them on separate, independent, subsets of HCHS/SOL individuals. In an association model with insomnia, male sex was associated with lower likelihood of insomnia (odds ratio (OR)=0.60, 95% CI (0.53, 0.67)). Including GISE in the model, the association was slightly weaker (OR=0.63, 95% CI (0.56, 0.70)), and weaker when including instead GIPSE in the association model (OR=0.78, 95% CI (0.69, 0.88)). Higher values of GISE and of GIPSE, more common in male sex, were associated with lower likelihood of insomnia, in analyses adjusted for sex (per 1 standard deviation of the index, GISE OR= 0.92, 95% CI (0.87, 0.99), GIPSE OR=0.65, 95% CI (0.61, 0.70)). Conclusions: New measures such as GISE and GIPSE capture sex-related differences beyond binary sex and have the potential to better model and inform research studies of health. However, such indices do not account for gender identity and may not well capture the environment experienced by intersex and non-binary persons.

The National Sleep Research Resource: making data findable, accessible, interoperable, reusable and promoting sleep science.

This paper presents a comprehensive overview of the National Sleep Research Resource (NSRR), a National Heart Lung and Blood Institute-supported repository developed to share data from clinical studies focused on the evaluation of sleep disorders. The NSRR addresses challenges presented by the heterogeneity of sleep-related data, leveraging innovative strategies to optimize the quality and accessibility of available datasets. It provides authorized users with secure centralized access to a large quantity of sleep-related data including polysomnography, actigraphy, demographics, patient-reported outcomes, and other data. In developing the NSRR, we have implemented data processing protocols that ensure de-identification and compliance with FAIR (Findable, Accessible, Interoperable, Reusable) principles. Heterogeneity stemming from intrinsic variation in the collection, annotation, definition, and interpretation of data has proven to be one of the primary obstacles to efficient sharing of datasets. Approaches employed by the NSRR to address this heterogeneity include (1) development of standardized sleep terminologies utilizing a compositional coding scheme, (2) specification of comprehensive metadata, (3) harmonization of commonly used variables, and (3) computational tools developed to standardize signal processing. We have also leveraged external resources to engineer a domain-specific approach to data harmonization. We describe the scope of data within the NSRR, its role in promoting sleep and circadian research through data sharing, and harmonization of large datasets and analytical tools. Finally, we identify opportunities for approaches for the field of sleep medicine to further support data standardization and sharing.

Adverse Pregnancy Outcomes and Pharyngeal Flow Limitation during Sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

RATIONALE: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. OBJECTIVE: To determine whether a novel objective measure of flow limitation identifies an increased risk of preeclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be. 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 preeclampsia, 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 (age: 27.0±5.4 yr [mean±sd], BMI: 27.7±6.1 kg·m-2), 5.8% developed preeclampsia, 12.7% developed HDP, and 4.5% developed GDM. Greater flow limitation was associated with increased preeclampsia risk: adjusted Odds Ratio (OR) 2.49, 95% Confidence Interval [1.69, 3.69], per 2SD increase in severity. Findings persisted in women without sleep apnea (apnea-hypopnea index <5 events·hr-1). Flow limitation was associated with HDP (OR: 1.77 [1.33, 2.38]) and reduced infant birthweight (83.7 [31.8, 135.6] g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of preeclampsia, HDP, and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial.

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/m2) 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.

Group-based sleep trajectories in children and adolescents: A systematic review.

Sleep is crucial for health and development. Evidence indicates that sleep changes over time and distinct subgroups may experience different longitudinal patterns. This study systematically reviewed the studies that used latent trajectory modeling to investigate sleep trajectories of children and adolescents aged 0-18 years, and summarized the associated determinants and health-related outcomes. We searched PubMed, Embase, CENTRAL, PsycINFO, and Web of Science, identifying 46 articles that met our criteria. To ensure the reliability of the review, only studies rated as good or fair in terms of methodological quality were included, resulting in a total of 36 articles. Group-based trajectories were identified on several sleep dimensions (i.e., sleep duration, general and specific sleep problems, and bed-sharing behavior) and three or four trajectories were reported in most studies. There was a convergence trend across sleep duration trajectories during the first six years of life. Studies on specific sleep problem (i.e., insomnia, night-waking, and sleep-onset difficulties) typically identified two trajectories: consistent, minimal symptoms or chronic yet fluctuating symptoms. Lower socioeconomic status, maternal depression, and night feeding behaviors were the most frequently reported determinants of sleep trajectories. Membership in a group with certain adverse patterns (e.g., persistent short sleep duration) was associated with increased risks of multiple negative health-related conditions, such as obesity, compromised immunity, neurological problems, substance use, or internalizing/externalizing symptoms. Generally, there is potential to improve the quality of studies in this field. Causality is hard to be inferred within the current body of literature. Future studies could emphasize early life sleep, incorporate more assessment timepoints, use objective measures, and employ experimental design to better understand changes of and mechanisms behind the various sleep trajectories and guide targeted interventions for at-risk subpopulations.

Flow Limitation Is Associated with Excessive Daytime Sleepiness in Individuals without Moderate or Severe Obstructive Sleep Apnea.

Rationale: Moderate-Severe Obstructive Sleep Apnea (OSA, AHI>15) disturbs sleep through frequent bouts of apnea and is associated with daytime sleepiness. However, many individuals without moderate-severe OSA (i.e., AHI<15) also report sleepiness. Objective: To test the hypothesis that sleepiness in the AHI<15 group is a consequence of substantial flow limitation, in the absence of overt reductions in airflow (i.e., apnea/hypopnea). Methods: N=1886 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 Epworth Sleepiness Scale ≥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. Results: N=772 individuals with an AHI<15 were included in primary analysis. Flow limitation was associated with EDS (odds ratio of 2.04, CI95% [1.17-3.54], per 2 standard deviation (2SD) increase in flow limitation frequency) after adjusting for age, sex, BMI, race/ethnicity, and sleep duration. This effect size did not appreciably change after additionally adjusting for AHI. Conclusions: In individuals with an AHI<15, increasing flow limitation frequency by 2SD is associated with a 2-fold increase in risk of EDS. Future studies should investigate addressing flow limitation in low AHI individuals as a potential mechanism for ameliorating sleepiness.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

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.

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

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

Metabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development.

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.