Sleep-disordered Breathing Measures Research Articles

Longitudinally assessed maternal sleep position, measures of breathing during sleep, and fetal growth in high-risk pregnancies.

Subjective recall of supine sleep during pregnancy has been linked to increased risk of stillbirth, but longitudinal, objective data are lacking. We aimed to examine how sleep position and breathing parameters change throughout pregnancy, and investigated associations between maternal supine sleep, assessed objectively in early and late gestation, and fetal growth velocity in high-risk women. Women with singleton pregnancies and body mass index (BMI) ≥27 kg/m2 underwent level-III sleep apnea testing. Sleep position was assessed by accelerometry. We derived percentiles of estimated fetal weight and birthweight using FetalGPSR software, then calculated growth velocity as change in percentile/week between the second-trimester anatomy scan and birth. In total, 446 women were included, with N = 126 in the longitudinal sleep pattern analysis and N = 83 in the fetal growth analysis. Sleep-onset position and predominant sleep position were significantly correlated in both early (p = 0.001) and late (p < 0.01) pregnancy. However, supine going-to-bed position predicted predominant supine sleep in only 47% of women. Between early and late pregnancy there was a reduction in predominant supine sleepers (51.6% to 30.2%). Percent of sleep spent supine and oxygen desaturation index, in the third trimester, were significantly associated after BMI adjustment (B = 0.018, p = 0.04). Models did not suggest significant effects of early or late pregnancy supine sleep on growth velocity (p > 0.05). Going-to-bed position predicts predominant supine sleep in less than half of women with overweight and obesity. Time spent supine throughout pregnancy correlates with measures of sleep-disordered breathing. Maternal sleep position patterns did not affect fetal growth velocity in this high-risk population, but the study was not powered to detect differences.

Novel metrics of sleep-disordered breathing are associated with outcome after ischemic stroke

Objective/backgroundStandard measures of sleep-disordered breathing (SDB) that rely on count data may not sufficiently capture SDB severity or reflect downstream consequences of SDB. We hypothesized that novel metrics derived from pulse rate, oxygen saturation, and nasal pressure would be associated with stroke outcomes. Patients/methodsShortly after ischemic stroke, participants in a population-based study were offered ApneaLink Plus testing. Signal analysis was used to generate 166 metrics from the nasal pressure cannula and finger probe, categorized as: autonomic (based on pulse rate variability), oximetry-derived, nasal pressure-derived, and mixed oxygen and nasal pressure-derived measures. Three-month outcome assessments included functional and cognitive outcomes and stroke recurrence. Tobit regression and Cox proportional hazards models were used to examine associations between each sleep apnea metric and the three outcomes, unadjusted and adjusted for multiple potential confounders. Models were adjusted for multiple comparisons. ResultsOf the 530 participants, the median age was 65 (IQR: 57, 73), 49 % were female, and 64 % were Mexican American. Without covariate adjustment, 23 of 166 variables were associated with functional outcome, 43 were associated with cognitive outcome, and 1 was associated with stroke recurrence. After adjustment, 7 mixed, oximetry, or nasal pressure-based metrics and 1 autonomic metric were associated with functional outcome, but none was associated with cognitive outcome or stroke recurrence. ConclusionsMany novel metrics of SDB were associated with important stroke outcomes, and 8 novel metrics were associated with functional outcome in adjusted models. This raises hypotheses about pathways by which SDB may negatively impact stroke outcomes.

0820 Integrated Polysomnographic and Sleep Symptom-Based Cluster Subtypes Associated with Incident Atrial Fibrillation

Abstract Introduction While sleep disorders are implicated in atrial fibrillation (AF), the interplay and overlap of these disorders in AF risk remains unclear and a risk stratification challenge. Sleep-based clusters associated with AF can account for this complexity and translate to actionable approaches to identify at-risk patients. We hypothesized discrete phenotypes of symptoms and polysomnography (PSG)-based data differ in relation to incident AF. Methods Cleveland Clinic patients (age&amp;gt;18) who underwent PSG 11/27/2004-12/30/2015 were retrospectively examined. Clusters were identified using latent class analysis of 23 symptoms (e.g. related to sleep disordered breathing (SDB), sleepiness, REM intrusion, NREM parasomnias), Epworth Sleepiness Scale (ESS) score, and 24 measures of SDB and sleep architecture from PSG reports. Outcome was 5-year incident AF. Cox-proportional hazards models were adjusted for age, sex, race, body mass index, cardiovascular disease and risk factors, tobacco use, chronic obstructive pulmonary disease, anti-arrhythmic medication use, and positive airway pressure use. Results The sample included 43,433 patients: age 51.8±14.5, 51.9% (n=22,548) male, 74.4% (n=32,313) White, 7.3% (n=3,151) with baseline AF, and 4.3% (n=1,875) developed 5-year incident AF. Five clusters were identified and ranked by strength of AF association: 1) Hypoxemic (n=3,245): highest %time SaO2&amp;lt; 90% (T90), 2) Apneas+Arousals (n=4,592): most witnessed apneas, highest apnea hypopnea index (AHI), highest arousal index, least hypopneas, 3) Short sleep+NREM (n=6,126): shortest sleep time, longest REM latency, lowest %REM, 4) Hypopneas (n=2,661): most hypopneas, 5) Long sleep+REM (n=26,809): longest sleep time, shortest REM latency, highest %REM. Compared to ‘Long sleep+REM’, ‘Hypoxemic’ had 47% higher AF risk (HR=1.47,95%CI=1.27-1.69), and ‘Hypopneas’ did not differ (HR=1.05,95%CI=0.86-1.28). Conclusion Of five clusters identified, the ‘Hypoxemic’ subtype conferred the strongest AF risk with the highest degree of hypoxemia (highest T90, lowest minimum and mean SaO2), maximum end-tidal CO2, heart rate, and ESS score. Consistent with prior evidence of hypoxemia as an AF driver and cardiovascular risk of the sleepy phenotype, this constellation of symptoms and physiologic alterations illustrates risk in the clinical setting, providing potential value as a risk prediction tool. Future investigation should focus on external validation of these findings. Support (if any) Cleveland Clinic Neurological Institute Center for Outcomes Research &amp; Evaluation Pilot Grant, Transformative Research Resource Development Award

0834 Association of Sleep Disordered Breathing and Hemodynamics of World Symposium on Pulmonary Hypertension Groups in PVDOMICS Cohort

Abstract Introduction As sleep disordered breathing(SDB)-related pathophysiology of intermittent hypoxia, autonomic dysfunction and intrathoracic pressure alterations, etc. likely exerts differential influences across World Symposium on Pulmonary Hypertension(WSPH) groups that have yet to be characterized , we postulate differing SDB-pulmonary hemodynamics relationships across these groups. Methods Pulmonary Vascular Disease Phenomics(PVDOMICS-NCT02980887), a multicenter cohort study, included patients with mean pulmonary artery pressure(mPAP) on right heart catheterization(RHC) ≥ 25mmHg and home sleep apnea testing(HSAT) within 6 weeks of RHC. SDB measures included apnea-hypopnea index(AHI, 3% desaturation hypopnea definition used) and % recording time&amp;lt; 90% SpO2(TRT&amp;lt; 90%). Pulmonary hemodynamic indices included:mPAP, mean pulmonary capillary wedge pressure(PCWP), right atrial mean pressure(RAP). Linear regression models(beta coefficients±standard error) were constructed to assess sleep indices and RHC measurements with adjustment for age, sex, race, body-mass index(BMI), PH medication and supplemental oxygen use; PH group interaction was analyzed. Results We included 424 participants with available data in the final analytic sample. Groups 2 and 3 were older(65.6±11.9, 64.2±10.8 years, respectively) and Group 5 had the highest % males(71.4%). Group 2 had highest BMI: 34.3±9.2kg/m2 and Group 5 lowest: 28.7±6.4k g/m2. SDB(AHI≥5), was most prevalent in Group 2(71.4%) and least in Group 4(42.9%). TRT&amp;lt; 90% was highest in Group 1(37.0%, [P25=2.2, P75=87.3]) followed by Group 4(35.7% [5.3,82.9]) and lowest in Group 2(6.4% [0.61,41.8]). AHI and RAP association differed across groups, p=0.027 and was strongest in Group 2; per 5-unit increase in AHI, RAP increased by 0.75mmHg (estimate=0.75, standard error[0.15,1.36],p=0.015). TRT&amp;lt; 90% and mPAP had significant cross-group differences, p=0.004. TRT&amp;lt; 90% was associated with mPAP in Groups 1 and 4:per 5-unit increase in TRT&amp;lt; 90%, mPAP increased by 2mmHg(2.10,[1.52,2.68],p&amp;lt; 0.001) and 1.4mmHg(1.40,[0.07,2.73],p=0.039) respectively. Other associations were not significant. Conclusion SDB prevalence differs across WSPH groups and was highest in Group 2 PH. Findings suggest that AHI and TRT&amp;lt; 90%SaO2 differentially contribute to the pathogenesis in PH groups; with AHI associating with RAP, especially in Group 2 PH, and TRT&amp;lt; 90%SaO2 with mPAP in Groups 1 and 4 PH, perhaps via hypoxia-induced pulmonary vasoconstriction and remodeling. Support (if any) Funding: U01 HL125218, U01 HL125205, U01 HL125212, U01 HL125208, U01 HL125175, U01 HL125215, and U01 HL125177 and the Pulmonary Hypertension Association.

0449 Unbiased Examination of Metabolomic Signatures in Sleep Disordered Breathing and Group 1 PAH in the (PVDOMICS) Cohort

Abstract Introduction Metabolic alterations have been identified as a novel driver of pulmonary arterial hypertension (PAH) pathogenesis. Sleep disordered breathing (SDB), characterized by intermittent hypoxemic episodes, has also been implicated in PAH, particularly when associated with more profound degrees of hypoxia, and metabolic dysfunction. We hypothesize to observe in SDB and PAH in humans a similar pattern of metabolic alterations as previously described in animal models of PAH. Methods Pulmonary Vascular Disease Phenomics (PVDOMICS,NCT02980887), a multicenter study, was designed in part to elucidate molecular signatures in PH. We analyzed data from Group 1 PAH participants who underwent home sleep apnea testing with circulating plasma metabolomic measures (Metabolon). We conducted an unbiased analysis of SDB measures: apnea-hypopnea index (AHI, 3% oxygen desaturation hypopnea definition) and % recording time&amp;lt; 90% SpO2 (TRT&amp;lt; 90%), with metabolites (954 after qc filtering) using a flexible and robust semi-parametric proportional hazards model adjusted for age, sex, body mass index (BMI), diabetes mellitus (DM), race and study site. Metabolites with False discovery rate (FDR) adjusted p-values &amp;lt; 0.1 were called significant. Closed-set testing with the Simes method and Metabolon provided annotations (90 sets) was used to test metabolite sets. Results The cohort (n=175) was 72% female, 81% White and 16% DM with (1st Quartile/Median/3rd Quartile) Age: 42/54/63 years, BMI: 24.6/29.1/34.1 kg/m2, AHI: 0.9/4.3/12.6 and TRT&amp;lt; 90%: 2.3/37/87.4. 21 metabolites showed significant association with TRT&amp;lt; 90% (8 with positive direction/13 negative) and 0 with AHI. Among metabolite sets, Pregnenolone steroids had the strongest association with TRT&amp;lt; 90% (6 members; adjusted p=0.038; True Discovery Proportion (TDP)=0.33) followed by Fatty Acid Metabolism (Acyl Choline) (7 members; adjusted p-value=0.046; TDP=0.71) and Polyamine Metabolism (7 members; adjusted p-value p=0.054; TDP=0.14). Conclusion Three primary metabolite pathways were associated with sleep-related hypoxia in Group 1 PAH. Polyamine metabolism and fatty acid metabolism changes have previously been observed in a rat PAH model, consistent with our findings. Findings specific to metabolic biomarkers in SDB and PAH are novel and may lead to insights that broaden our understanding of PAH pathobiology and potential therapeutic targets. Support (if any)

An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling

Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Women’s Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health Study/Study of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.

Visceral adiposity is related to insulin sensitivity and inflammation in adolescents with obesity and mild sleep disordered breathing.

To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO2; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO2; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). Subjects (55% female) were mean (SD) 14.4 (2.1)years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2h insulin and 1h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO2 nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

0713 Longitudinal Sleep Position Patterns and Breathing Parameters in Pregnancy

Abstract Introduction Supine sleep position during pregnancy has been linked to increased risk of stillbirth in retrospective studies. However, existing literature is largely cross-sectional and limited by recall bias and self-reporting of sleep position. This study aims to use objectively-measured sleep position to quantify sleep position change between trimesters and its influence on maternal respiratory health. Methods This study is a secondary analysis of data from a study investigating maternal sleep, among women with singleton pregnancies and overweight or obesity. Each participant underwent level III sleep apnea monitoring using Noxturnal T3 devices (Nox Medical, Georgia, US), in the first (0-12 weeks) and third (29-40 weeks) trimester of pregnancy. Using accelerometry, the software differentiated 5 positions including supine, right lateral, left lateral, prone, and upright. The studies were scored using AASM 2012 recommended criteria. The first non-upright position was recorded as going-to-bed position. The number of sleep position changes was calculated using only positions that lasted ≥30 seconds. Results A total of 126 women were included. Mean BMI was 34.00±5.14 and mean age was 30.46±5.40 years. Mean number of position changes was similar in early (14.19±7.82) vs. late (14.58±8.25) pregnancy. There was a significant correlation between sleep onset position and predominant sleep position in both early (p=0.001) and late (p&amp;lt;0.01) pregnancy. However, supine going-to-bed position predicted predominant supine sleep in only 47% of women. There was a significant change in sleep position between early and late pregnancy (p=0.04) with a reduction in supine sleep (51.6% to 30.2%) and an increase in left lateral sleep (24.6% to 37.3%). Only in the third trimester, there was a significant positive correlation between time spent supine and oxygen desaturation index (r=0.22, p=0.01), and a trend toward positive correlation with respiratory event index (r=0.15, p=0.08). Conclusion Going-to-bed position predicts predominant sleep position in less than half of women with overweight and obesity. Time spent supine in late pregnancy correlates with measures of sleep-disordered breathing. More prospective studies are needed to evaluate the potential for sleep position changes over time as a potentially modifiable risk factor for maternal and neonatal health outcomes. Support (If Any) R01HL130702, R01HD078515, SRA grant

Association of Sleep-Related Hypoxia With Risk of COVID-19 Hospitalizations and Mortality in a Large Integrated Health System

The influence of sleep-disordered breathing (SDB) and sleep-related hypoxemia in SARS-CoV-2 viral infection and COVID-19 outcomes remains unknown. Controversy exists regarding whether to continue treatment for SDB with positive airway pressure given concern for aerosolization with limited data to inform professional society recommendations. To investigate the association of SDB (identified via polysomnogram) and sleep-related hypoxia with (1) SARS-CoV-2 positivity and (2) World Health Organization (WHO)-designated COVID-19 clinical outcomes while accounting for confounding including obesity, underlying cardiopulmonary disease, cancer, and smoking history. This case-control study was conducted within the Cleveland Clinic Health System (Ohio and Florida) and included all patients who were tested for COVID-19 between March 8 and November 30, 2020, and who had an available sleep study record. Sleep indices and SARS-CoV-2 positivity were assessed with overlap propensity score weighting, and COVID-19 clinical outcomes were assessed using the institutional registry. Sleep study-identified SDB (defined by frequency of apneas and hypopneas using the Apnea-Hypopnea Index [AHI]) and sleep-related hypoxemia (percentage of total sleep time at <90% oxygen saturation [TST <90]). Outcomes were SARS-CoV-2 infection and WHO-designated COVID-19 clinical outcomes (hospitalization, use of supplemental oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, and death). Of 350 710 individuals tested for SARS-CoV-2, 5402 (mean [SD] age, 56.4 [14.5] years; 3005 women [55.6%]) had a prior sleep study, of whom 1935 (35.8%) tested positive for SARS-CoV-2. Of the 5402 participants, 1696 were Black (31.4%), 3259 were White (60.3%), and 822 were of other race or ethnicity (15.2%). Patients who were positive vs negative for SARS-CoV-2 had a higher AHI score (median, 16.2 events/h [IQR, 6.1-39.5 events/h] vs 13.6 events/h [IQR, 5.5-33.6 events/h]; P < .001) and increased TST <90 (median, 1.8% sleep time [IQR, 0.10%-12.8% sleep time] vs 1.4% sleep time [IQR, 0.10%-10.8% sleep time]; P = .02). After overlap propensity score-weighted logistic regression, no SDB measures were associated with SARS-CoV-2 positivity. Median TST <90 was associated with the WHO-designated COVID-19 ordinal clinical outcome scale (adjusted odds ratio, 1.39; 95% CI, 1.10-1.74; P = .005). Time-to-event analyses showed sleep-related hypoxia associated with a 31% higher rate of hospitalization and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.08-1.57; P = .005). In this case-control study, SDB and sleep-related hypoxia were not associated with increased SARS-CoV-2 positivity; however, once patients were infected with SARS-CoV-2, sleep-related hypoxia was an associated risk factor for detrimental COVID-19 outcomes.

Impact of nasal dilator strips on measures of sleep-disordered breathing in pregnancy.

Women with sleep-disordered breathing (SDB) in pregnancy are at a greater risk of developing serious adverse perinatal outcomes. However, the pathogenesis of SDB in pregnancy is poorly understood. As nasal congestion is common in pregnancy, nasal obstruction may contribute to SDB in this population. This study aims to assess the impact of nasal dilator strips (NDS) on measures of SDB and their potential for use as a placebo condition. Pregnant women ≥ 18 years old, body mass index ≥ 27 kg/m2, and habitual snoring were enrolled. Participants completed 2 consecutive level III home sleep apnea tests and used NDS during the second test. Objective measures including respiratory event index and pulse transit time drop index, a measure of increased arterial stiffness, were compared across tests. Subjective assessments of participants' perceived impact of NDS use was also obtained. 54 women, 59% White, 60% in the third trimester were enrolled. Median time between the 2 studies was 1 day (interquartile range [IQR] 4). There was no significant change between the night without NDS use and the night with NDS use in respiratory event index (5.30 [IQR 6.20] vs 4.80 [IQR 6.78], P = .8) or pulse transit time drop index (6.8 [IQR 13.3] vs 6.6 [IQR 15.8], P = .360). Subjective measures of sleep did not differ between the 2 nights. Despite the high prevalence of pregnancy-associated rhinitis, NDS do not have a significant impact on measures of SDB. Results from this study support the use of NDS as an appropriate placebo in prenatal clinical trials. Maxwell M, Sanapo L, Monteiro K, etal. Impact of nasal dilator strips on measures of sleep-disordered breathing in pregnancy. J Clin Sleep Med. 2022;18(2):477-483.

A composite sleep and pulmonary phenotype predicting hypertension.

BackgroundMultiple aspects of sleep and Sleep Disordered Breathing (SDB) have been linked to hypertension. However, the standard measure of SDB, the Apnoea Hypopnea Index (AHI), has not identified patients likely to experience large improvements in blood pressure with SDB treatment.MethodsTo use machine learning to select sleep and pulmonary measures associated with hypertension development when considered jointly, we applied feature screening followed by Elastic Net penalized regression in association with incident hypertension using a wide array of polysomnography measures, and lung function, derived for the Sleep Heart Health Study (SHHS).FindingsAt baseline, n=860 SHHS individuals with complete data were age 61 years, on average. Of these, 291 developed hypertension ~5 years later. A combination of pulmonary function and 18 sleep phenotypes predicted incident hypertension (OR=1.43, 95% confidence interval [1.14, 1.80] per 1 standard deviation (SD) of the phenotype), while the apnoea-hypopnea index (AHI) had low evidence of association with incident hypertension (OR =1.13, 95% confidence interval [0.97, 1.33] per 1 SD). In a generalization analysis in 923 individuals from the Multi-Ethnic Study of Atherosclerosis, aged 65 on average with 615 individuals with hypertension, the new phenotype was cross-sectionally associated with hypertension (OR=1.26, 95% CI [1.10, 1.45]).InterpretationA unique combination of sleep and pulmonary function measures better predicts hypertension compared to the AHI. The composite measure included indices capturing apnoea and hypopnea event durations, with shorter event lengths associated with increased risk of hypertension.FundingThis research was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by National Center for Advancing Translational Sciences grants UL1-TR- 000040, UL1-TR-001079, and UL1-TR-001420. The MESA Sleep ancillary study was supported by NHLBI grant HL-56984. Pulmonary phenotyping in MESA was funded by NHLBI grants R01-HL077612 and R01-HL093081. This work was supported by NHLBI grant R35HL135818 to Susan Redline.

Sleep Disordered Breathing Measures in Early Pregnancy Are Associated with Depressive Symptoms in Late Pregnancy.

Sleep disordered breathing (SDB) and depression are both common complications of pregnancy and increase risk for adverse maternal and neonatal outcomes. SDB precedes onset of depression in non-pregnant adults; however, the longitudinal relationship has not been studied in pregnancy. The present research examined temporal associations between SDB and depressive symptoms in 175 pregnant women at risk for SDB (based on frequent snoring and obesity), but without an apnea hypopnea index of ≥5 events per hour at enrollment. Women completed a self-report assessments of depressive symptoms using PHQ-9 and in-home level III sleep apnea monitoring at approximately 12- and 32-weeks’ gestation. We also assessed the risk for SDB using the Berlin Questionnaire in early pregnancy. Results revealed that measures of SDB in early pregnancy as assessed by in-home sleep study, but not by self-reported SDB, predicted elevated depressive symptoms in late pregnancy. SDB in late pregnancy was not associated with depressive symptoms. To conclude, these findings suggest that SDB may increase the risk for elevated depressive symptoms as pregnancy progresses.

Association of lipoprotein levels with sleep apnea: role of autonomic dysfunction.

Objectives. Although multiple mechanisms, including autonomic dysfunction, seem to link sleep-disordered breathing (SDB) with dyslipidemia in animal studies, the data in clinical studies are limited. The aim of this study was to explore the association of lipoprotein levels with SDB measures in healthy habitual snorers. We supposed that autonomic dysfunction is the linking mechanism.Methods. We enrolled 110 previously healthy subjects with complaints of habitual snoring. To assess SDB, polysomnography was performed. Blood samples for the analysis of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) were obtained in a fasting condition after the polysomnography. Baroreflex sensitivity (BRS) was used to assess the autonomic dysfunction.Results. In stepwise multiple linear regression analysis, minimal nocturnal blood oxygen saturation (beta=-0.240, p=0.020) and neck circumference (beta=0.224, p=0.03) were the only significant contributors in model predicting TG. SDB measures were not identified as significant contributors in models predicting TC, LDL, and HDL. We failed to find any significant difference in BRS in SDB subjects when compared according to the presence or absence of hypercholesterolemia/ hypertriglyceridemia. In SDB subjects, the area under the curve in a receiver operating curve to predict hypercholesterolemia and hypertriglyceridemia by BRS was 0.468 (95% CI: 0.328-0.608) and 0.425 (95% CI: 0.304-0.546), respectively.Conclusions. Our results suggest that minimal nocturnal blood oxygen saturation is significant contributor in model predicting TG. No significant decrease in BRS was found in SDB subjects with hypercholesterolemia and hypertriglyceridemia. In SDB subjects, the role of autonomic dys-function in the development of dyslipidemia remains controversial.

Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy

BackgroundSleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment.MethodsIn two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses.FindingsTwenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT).InterpretationLow oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

0869 Slow Wave Sleep Is Associated With Decreased Risk Of Gestational Diabetes Mellitus

Abstract Introduction Pregnancy is associated with disrupted slow-wave sleep (SWS) and a high prevalence of sleep disordered breathing (SDB), which may further exacerbate the decrease of deep sleep. Reduced slow wave sleep may impair glucose homeostasis, contributing to Gestational Diabetes Mellitus (GDM). Studies investigating EEG markers of deep and light sleep, and their associations with SDB and GDM are lacking. In this study, we measured associations of EEG Delta-power with objective SDB measures assessed in late-pregnancy to determine if changes in these bands are associated with GDM risk. Methods 74 women (24-36 weeks pregnancy) underwent overnight polysomnography. Spectral profiles for Delta relative power were created for NREM and REM sleep after removing epochs with movements or muscle artifacts. The association of Delta power with SDB, assessed by the Apnea Hypopnea-Index (AHI) and AHI-based SDB severity (none, mild, moderate, severe) was tested by multivariate linear regression including demographic variables with bivariate correlations (p&amp;lt;0.2) versus Delta-power. Conditional-regression was used to explore relationships between Delta-power and GDM, controlling for covariates. Results Obstructive Sleep Apnea (OSA, AHI&amp;gt;5) was present in 14% of subjects (8 GDM-cases and 3 controls). In bivariate analyses, AHI, AHI-severity categories and OSA were associated with Delta-power in NREM (all p&amp;lt;0.2) and AHI was associated with Delta relative-power in REM (p=0.18). However, these associations did not remain significant after adjusting for covariates. Delta relative-power in NREM was significantly associated with decreased risk of GDM (OR:0.50, 95%CI-0.25,0.91), but, in REM sleep, was not associated with GDM risk (OR:1.25, 95%CI-0.79,1.97). Conclusion These analyses failed to demonstrate an association between OSA or OSA severity and EEG Delta power. However, lower levels of SWS, characterized by low Delta power were associated with increased GDM risk. Support NIH-R00-NR013187

Severe obstructive sleep apnea in patients with chronic obstructive pulmonary disease is associated with an increased prevalence of mild cognitive impairment

BackgroundChronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are associated with mild cognitive impairment (MCI). However, this association is unclear. This study aimed to assess the prevalence of MCI in patients with overlap syndrome, determine whether OSA increases the risk of MCI in patients with COPD, and investigate the potential mechanisms for this association. MethodsParticipants with stable Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2–4 COPD and complaints of snoring in 2016–2018 were enrolled in this cross-sectional observational study. All were free of asthma, acute left-sided congestive heart failure, unstable coronary heart disease, uncontrolled hypertension, diabetes, encephalitis, and epilepsy. They underwent pulmonary function tests and overnight polysomnography and completed the Montreal Cognitive Assessment (MoCA). MCI was defined by an MoCA score of <23, while OSA was defined by an apnea-hypopnea index (AHI) of ≥15 per hour. The association between MCI, demographics, and comorbidities was tested by logistic regression analysis with adjustment for confounders. Sleep-disordered breathing measures were investigated as potential mechanisms underlying this relationship. ResultsMCI was significantly more common in patients with overlap syndrome than in those with COPD (40.6% [43/106] vs 24.6% [42/171]). After adjustment, severe OSA was an independent contributor to MCI (odds ratio, OR 2.27; 95% confidence interval, CI 1.12–4.62). Increased percent of night-time spent with oxygen saturation <90% (TSat90) was associated with increased odds of MCI (odds ratio 4.75, 95% CI 2.73–11.13). ConclusionsMCI is more prevalent in overlap syndrome than in COPD. OSA may contribute to MCI in COPD. The mechanism may involve TSat90.

Associations between symptoms of sleep-disordered breathing and maternal sleep patterns with late stillbirth: Findings from an individual participant data meta-analysis.

Sleep-disordered breathing (SDB) affects up to one third of women during late pregnancy and is associated with adverse pregnancy outcomes, including hypertension, diabetes, impaired fetal growth, and preterm birth. However, it is unclear if SDB is associated with late stillbirth (≥28 weeks' gestation). The aim of this study was to investigate the relationship between self-reported symptoms of SDB and late stillbirth. Data were obtained from five case-control studies (cases 851, controls 2257) from New Zealand (2 studies), Australia, the United Kingdom, and an international study. This was a secondary analysis of an individual participant data meta-analysis that investigated maternal going-to-sleep position and late stillbirth, with a one-stage approach stratified by study and site. Inclusion criteria: singleton, non-anomalous pregnancy, ≥28 weeks' gestation. Sleep data ('any' snoring, habitual snoring ≥3 nights per week, the Berlin Questionnaire [BQ], sleep quality, sleep duration, restless sleep, daytime sleepiness, and daytime naps) were collected by self-report for the month before stillbirth. Multivariable analysis adjusted for known major risk factors for stillbirth, including maternal age, body mass index (BMI kg/m2), ethnicity, parity, education, marital status, pre-existing hypertension and diabetes, smoking, recreational drug use, baby birthweight centile, fetal movement, supine going-to-sleep position, getting up to use the toilet, measures of SDB and maternal sleep patterns significant in univariable analysis (habitual snoring, the BQ, sleep duration, restless sleep, and daytime naps). Registration number: PROSPERO, CRD42017047703. In the last month, a positive BQ (adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 1.02-2.04), sleep duration >9 hours (aOR 1.82, 95% CI 1.14-2.90), daily daytime naps (aOR 1.52, 95% CI 1.02-2.28) and restless sleep greater than average (aOR 0.62, 95% CI 0.44-0.88) were independently related to the odds of late stillbirth. 'Any' snoring, habitual snoring, sleep quality, daytime sleepiness, and a positive BQ excluding the BMI criterion, were not associated. A positive BQ, long sleep duration >9 hours, and daily daytime naps last month were associated with increased odds of late stillbirth, while sleep that is more restless than average was associated with reduced odds. Pregnant women may be reassured that the commonly reported restless sleep of late pregnancy may be physiological and associated with a reduced risk of late stillbirth.

High Levels of Peripheral Vasoconstriction Detected By Polysomnography Predict More Acute Severe Pain Episodes in Children with Sickle Cell Anemia

Sickle cell anemia (SCA) is genetic disease associated with chronic hemolysis and severe vaso-occlusive pain. Triggers for vaso-occlusive pain include both extreme temperatures (hot and cold), and stress. Our prior work demonstrates that anticipatory pain, experimental pain, experimental mental stress, and cold exposure cause significant global vasoconstriction in SCA and vasoconstriction responses differ among subjects.Anything that decreases microvascular flow will increase the likelihood that the red blood cells will not escape the microvasculature before deoxyhemoglobin S (HbS) polymerizes, leading to vaso-occlusion. However, this theoretical model has not been proven at a macro scale in patients. We showed that hypoxia induced in SCA subjects causes loss of parasympathetic modulation of heart rate but not decreased microvascular flow. Consistent with this, a prospective cohort study of SCA subjects showed no significant association between low mean nocturnal SpO2 and the incidence of VOC. However, surges in sympathetic activity accompany transient arousals and respiratory events during sleep, and lead to varying levels of peripheral vasoconstriction. In a prospective NIH funded cohort study of children with SCA, we tested the hypothesis that children with SCA and high levels when compared to low levels of intrinsic microvascular vasoreactivity (based on vasoconstriction events detected by polysomnography (PSG)) have a higher incidence rate of severe vaso-occlusive pain that requires hospitalization within 6 months of the PSG. We analyzed the time-series of R-R intervals (RRI) derived from the electrocardiogram and beat-to-beat amplitudes of finger photoplethysmography reflecting peripheral blood flow (PPGa) derived from the scored PSGs and clinical records of 212 children, who participated in the multi-center prospective SCA cohort study reported by Willen et al. (Am J Hematol 2018; 93:478-485). Vasoconstriction events were detected by applying an algorithm that found reductions in PPGa from local baseline that exceeded a threshold level of change. The changes in RRI from the pre-vasoconstriction baseline were also computed (Fig 1). The duration, average magnitude (Mvasoc) and area under the curve of PPGa were extracted from each significant vasoconstriction. The median values of these compact descriptors were taken to represent the nocturnal vasoconstriction characteristics of each participant. A participant was classified to be in the high- or low-pain event category if they were hospitalized for severe pain at least two times or less than 2 times within a 1-year window from 6 months before to 6 months after the PSG, respectively. Multiple logistic regression analysis was applied, using pain category as the outcome variable, and vasoconstriction descriptors, arousal index, obstructive apnea-hypopnea index, age, sex and hemoglobin level as predictor variables. Pain category was strongly associated with magnitude of vasoconstriction (Mvasoc; p=0.0058), with larger Mvasoc predicting high-pain, after accounting for age, sex and hemoglobin level (Hgb). Figure 2 displays the adjusted Mvasoc (mean ± SE) in the high-pain and low/no-pain groups. Mvasoc was strongly correlated with arousal index (p=0.0073). However, none of the traditional measures of sleep-disordered breathing, including arousal index, were associated with pain category. Age was the only other predictor of severe pain. These findings, showing that propensity for a high degree of microvascular vasoconstriction is associated with the temporal relationship of severe pain requiring hospitalization, validate on a macro scale the model that increased microvascular transit time promotes entrapment of sickled red blood cells, elevating the risk of severe vaso-occlusive pain. Our data reveals for the first time, a mechanistic link between the patient's symptoms and the triggering of transition from steady state to acute severe pain. The fact that individuals have intrinsic vasoreactivity phenotypes, that can be identified by analysis of the photoplethysmogram, provides yet another factor in acute vaso-occlusive pain. Autonomic balance and vasoreactivity likely contribute to known variability of the incidence rate of severe pain and represent another plausible target for therapeutic intervention. Disclosures Coates: apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study.

Association of sleep-disordered breathing with total healthcare costs and utilization in older men: the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study.

To determine the associations of sleep-disordered breathing (SDB) with subsequent healthcare costs and utilization including inpatient and post-acute care facility stays among community-dwelling older men. Participants were 1,316 men (mean age 76.1 [SD = 5.7] years) in the Outcomes of Sleep Disorders in Older Men (MrOS sleep) study (from December 2003 to March 2005), who were enrolled in a Medicare Fee-For-Service plan. Primary SDB measures including apnea hypopnea index (AHI) and oxygen desaturation index (ODI) were collected using in-home level 2 polysomnography. Incident healthcare costs and utilization were determined from claims data in the subsequent 3-year period post-MrOS sleep visit. Five hundred and twenty-nine (40.2%) men had at least one hospitalization in the 3-year period. Compared with those without sleep apnea (AHI < 5/hour), men with moderate to severe sleep apnea (AHI ≥ 15/hour) had a higher odds of all-cause hospitalization (odds ratio [OR] adjusted for age and site 1.43, 95% confidence interval [CI]: 1.07-1.90). This association was slightly attenuated after further adjustment for traditional prognostic factors including education, body mass index, comorbid medical conditions, and health status (OR = 1.36; 95% CI: 1.01-1.83). Similar associations were observed for ODI. However, measures of SDB were not related to subsequent healthcare costs (total or outpatient) or odds of post-acute skilled nursing facility stay. Older men with SDB have an increased risk of hospitalization, not entirely explained by the greater prevalence of comorbid conditions, but not higher subsequent total healthcare costs. These findings indicate a need to evaluate the impact of SDB treatment on subsequent healthcare utilization.

Sleep and neuropsychological performance in HIV+ subjects on efavirenz-based therapy and response to switch in therapy

The antiretroviral drug efavirenz (EFV) has been linked to disordered sleep and cognitive abnormalities. We examined sleep and cognitive function and subsequent changes following switch to an alternative integrase inhibitor-based regimen. Thirty-two HIV-infected individuals on EFV, emtricitabine, and tenofovir (EFV/FTC/TDF) without traditional risk factors for obstructive sleep apnea (OSA) were randomized 2:1 to switch to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) or to continue EFV/FTC/TDF therapy for 12 weeks. Overnight polysomnography and standardized sleep and neuropsychological assessments were performed at baseline and at 12 weeks. No significant differences in change over 12 weeks were noted between the two arms in any sleep or neuropsychological test parameter. At entry, however, the rate of sleep disordered breathing (SDB) was substantially higher in study subjects compared to published age-matched norms and resulted in a high assessed OSA rate of 59.4%. Respiratory Disturbance Index (RDI), a measure of SDB, correlated with age- and education-adjusted global neuropsychological Z-score (NPZ) (r = −0.35, p = 0.05). Sleep Maintenance Efficiency, Wake after Sleep Onset, REM Sleep and RDI correlated with domain-specific NPZ for learning and memory (all p-values ≤ 0.05). Among HIV-infected individuals on EFV-based therapy and without traditional risk factors for OSA, sleep and neuropsychological abnormalities do not readily reverse after discontinuation of EFV. High baseline rates of SDB and abnormalities in sleep architecture exist in this population correlating with neuropsychological impairment. The role of HIV immuno-virologic or lifestyle factors as contributing etiologies should be explored. OSA may be an under-recognized etiology for cognitive dysfunction during chronic HIV.