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Methadone, a widely-prescribed medication for chronic pain and opioid addiction, is associated with respiratory depression and increased predisposition for torsades de pointes, a potentially fatal arrhythmia. Most methadone-related deaths occur during sleep. The objective of this study was to determine whether methadone’s arrhythmogenic effects increase during sleep, with a focus on cardiac repolarization instability using QT variability index (QTVI), a measure shown to predict arrhythmias and mortality. Sleep study data of 24 patients on chronic methadone therapy referred to a tertiary clinic for overnight polysomnography were compared with two matched groups not on methadone: 24 patients referred for overnight polysomnography to the same clinic (Clinic group), and 24 volunteers who had overnight polysomnography at home (Community group). Despite similar values for heart rate, heart rate variability, corrected QT interval, QTVI and oxygen saturation (SpO(2)) when awake, patients on methadone had larger QTVI (p=0.015 vs Clinic, p1000 premature beats per median sleep period), a precursor for torsades de pointes, was uncommon but more frequent in patients on methadone (p=0.039). This study demonstrates that chronic methadone use is associated with increased cardiac repolarization instability. Methadone’s pro-arrhythmic impact may be mediated by sleep-related hypoxemia which could explain the increased nocturnal mortality associated with this opioid.

Objectives Postprandial hyperglycemia is common in type 2 diabetes even in those with acceptable glycemic control and conveys an increased risk of cardiovascular morbidity and mortality. Although obstructive sleep apnea (OSA) has been associated with altered glucose metabolism, data regarding its association with postprandial hyperglycemia in type 2 diabetes are limited. Thus, the current study sought to characterize the association between OSA and postprandial hyperglycemia in adults with type 2 diabetes. Methods A cross-sectional study of adults with type 2 diabetes was conducted. Home sleep testing was used to assess OSA severity as determined by the oxygen desaturation index (ODI). Self-monitoring of blood glucose (SMBG) was performed before and 2-h after breakfast, lunch, and dinner for three days. The association between OSA and glucose levels before and after each meal was examined using multivariable logistic regression. Results The study sample consisted of 195 adults with 52% being men. OSA severity, as assessed by ODI quartiles, was associated with higher postprandial glucose values after dinner but not after breakfast or lunch. The adjusted odds ratios (95% confidence intervals) for a higher post-dinner glucose level for four ODI quartiles were 1.00 (Reference), 2.16 (0.96, 4.87), 2.23 (1.03, 4.83), and 2.58 (1.18, 5.94). Stratified analyses showed that this association was present in men but not women. Conclusions Increasing OSA severity is associated with postprandial hyperglycemia in type 2 diabetes and may contribute to impaired glycemic control. Future studies examining the impact of OSA treatment on glucose metabolism should consider meal-related glycemic excursions as a potential outcome.

Background Sleep-disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. However, data on whether SDB alters the metabolism of free fatty acids (FFAs) are lacking. Research Question The primary objective of the current study was to characterize alterations in FFA metabolism across the spectrum of SDB severity. Study Design and Methods The study sample included 118 participants with and without SDB who underwent full-montage polysomnography, the frequently sampled IV glucose tolerance test (FSIGTT), and body composition measurements including determination of percent body fat. Parameters of lipolysis suppression, time to FFA nadir, and FFA rebound after an IV glucose challenge were derived using a mathematical model. Multivariable regression analyses were used to characterize the independent associations between SDB severity and parameters of FFA metabolism. Results SDB severity, as assessed by the apnea-hypopnea index, was associated with adipocyte insulin resistance, a decrease in the glucose- and insulin-mediated suppression of lipolysis, a longer duration to reach a nadir in FFA levels during the FSIGTT, and a sluggish rebound in FFA levels after suppression. Severity of SDB-related hypoxemia was independently associated with adipocyte insulin resistance and the time to reach the FFA nadir during the FSIGTT. Finally, a higher percentage of stage N3 sleep was positively associated with greater suppression of lipolysis and a faster rebound in the FFA levels during the FSIGTT. Interpretation Independent of adiposity, SDB is associated with impairments in FFA metabolism, which may contribute to the development of glucose intolerance and type 2 diabetes in SDB.

Background Lung to finger circulation time (LFCT) measured from sleep studies may represent a novel physiologic marker for cardiovascular risk in patients with sleep disordered breathing (SDB). We hypothesized that sleep study-derived LFCT would improve risk classification of markers of subclinical cardiovascular disease. Methods We included participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep cohort with moderate-severe SDB (apnea hypopnea index [AHI] ≥ 15/hr) (N = 598). Results Those with average LFCT above the median (19.4 s) (vs. shorter LFCT) tended to be older, more obese and male. In multivariable analysis, no significant associations were found between average LFCT and subclinical cardiovascular markers including coronary artery calcium, carotid intima-media thickness or left ventricular hypertrophy. However, there was modest improvement in risk classification of coronary artery calcification as compared with AHI alone when average LFCT was added to AHI (C statistics 0.53 vs. 0.62, p = 0.0066). Conclusions In conclusion, LFCT may be a useful addition to conventional SDB metrics to improve cardiovascular risk assessment.

Summary We introduce a multilevel functional Beta model to quantify the blood glucose levels measured by continuous glucose monitors for multiple days in study participants with type 2 diabetes mellitus. The model estimates the subject-specific marginal quantiles, quantifies the within- and between-subject variability, and produces interpretable parameters of blood glucose dynamics as a function of time from the actigraphy-estimated sleep onset. Results are validated via simulations and by studying the association between the estimated model parameters and hemoglobin A1c, the gold standard for assessing glucose control in diabetes.

Rationale: Sleep-disordered breathing (SDB) occurring primarily during rapid eye movement (REM) sleep is a common clinical problem. The natural history of REM-related SDB and the associated cardiovascular sequelae of disease progression remain to be determined. Objectives: The objective of the current study was to describe the natural history of REM-related SDB, ascertain predictors of progression, and determine whether the evolution of REM-related SDB into non-REM (NREM) sleep is associated with incident cardiovascular events. Methods: Participants from the Sleep Heart Health Study with a baseline NREM apnea–hypopnea index (NREM-AHI) of

Background:People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV–) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.Methods:We studied 1123 men (589 HIV+ and 534 HIV–) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1–quartile 3]: 78.3 [66.3–83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Results:Mean (SD) age was 60.1 (11.9) years among HIV– and 54.2 (11.2) years among HIV+ participants (PConclusions:HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV– men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

BackgroundMechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden.MethodsThis cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010–2013. Sleep depth was assessed using the ‘OR product’, a continuous measure of arousability. Airflow limitation was assessed by duty cycle (Ti/Tt) and % of breaths with flow limitation, and hypoxia by ‘hypoxic burden’. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances.ResultsThe sample had a mean age of 68.4 years and apnoea–hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications.ConclusionsHigher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.

Background Data on the prevalence and correlates of restless legs syndrome (RLS) in people with HIV are limited. This study sought to determine the prevalence of RLS, associated clinical correlates, and characterize sleep-related differences in men with and without HIV. Methods Sleep-related data were collected in men who have sex with men participating in the Multicenter AIDS Cohort Study (MACS). Demographic, health behaviors, HIV status, comorbidities, and serological data were obtained from the MACS visit coinciding with sleep assessments. Participants completed questionnaires, home polysomnography, and wrist actigraphy. RLS status was determined with the Cambridge-Hopkins RLS questionnaire. RLS prevalence was compared in men with and without HIV. Multinomial logistic regression was used to examine correlates of RLS among all participants and men with HIV alone. Sleep-related differences were examined in men with and without HIV by RLS status. Results The sample consisted of 942 men (56% HIV+; mean age 57 years; 69% white). The prevalence of definite RLS was comparable in men with and without HIV (9.1% vs 8.7%). In multinomial regression, HIV status was not associated with RLS prevalence. However, white race, anemia, depression, and antidepressant use were each independently associated with RLS. HIV disease duration was also associated with RLS. Men with HIV and RLS reported poorer sleep quality, greater sleepiness, and had worse objective sleep efficiency/fragmentation than men without HIV/RLS. Conclusions The prevalence of RLS in men with and without HIV was similar. Screening for RLS may be considered among people with HIV with insomnia and with long-standing disease.

Glucose and free fatty acids (FFA) are essential nutrients that are both partly regulated by insulin. Impaired insulin secretion and insulin resistance are hallmarks of aberrant glucose disposal, and type 2 diabetes (T2DM). In the current study, a novel model of FFA kinetics is proposed to estimate the role insulin action on FFA lipolysis and oxidation allowing estimation of adipose tissue insulin sensitivity (SIFFA). Twenty-five normal volunteers were recruited for the current study. To participate, volunteers had to be less than 40 years of age and have a body mass index (BMI) < 30 kg/m2, and be free of medical comorbidity. The proposed model of FFA kinetics was used to analyze the data derived from the insulin-modified FSIGT. Mean fractional standard deviations of the parameter estimates were all less than 20%. Standardized residuals of the fit of the model to the FFA temporal data were randomly distributed, with only one estimated point lying outside the 2-standard deviation range, suggesting an acceptable fit of the model to the FFA data. The current study describes a novel one-compartment non-linear model of FFA kinetics during an FSIGT that provides an FFA metabolism insulin sensitivity parameter (SIFFA). Furthermore, the models suggest a new role of glucose as the modulator of FFA disposal. Estimates of SIFFA confirmed previous findings that FFA metabolism is more sensitive to changes in insulin than glucose metabolism. Novel derived indices of insulin sensitivity of FFA (SIFFA) were correlated with minimal model indices. These associations suggest a cooperative rather than competitive interplay between the two primary nutrients (glucose and FFA) and allude to the FFA acting as the buffer, such that glucose homeostasis is maintained.

Background: Intermittent hypoxemia (IH), a pathognomonic component of obstructive sleep apnea (OSA), has been independently associated with development of glucose intolerance, insulin resistance, and type 2 diabetes. L-type calcium channel blockers (CCB) influence glucose homeostasis including insulin sensitivity and secretion. To date, the potential impact of the combined effects of L-type CCB and IH on fasting glycemia and glucose tolerance have not been examined. The objective of this study was to determine whether CCB alters glucose metabolism in a murine model of IH. Methods: Adult male C57BL6/J mice (age 19-week-old) were exposed to IH using an automated system with specially-modified cages that oscillated FiO2from 21% to 5.5% at a target rate of 60 events/h during a 12 h (7am – 7pm) light cycle to simulate severe OSA for 5 days. The L-type CCB, nifedipine, or vehicle (polyethleneglycol-400) were administered at a dose of 20mg/kg/day via subcutaneous osmotic pumps (Alzet model 2001). Mice were exposed to IH or intermittent air (IA) with four resulting groups: IA-vehicle (n=12), IH-vehicle (n=16), IA–nifedipine (n=10), and IH–nifedipine (n=13). Fasting glucose, intraperitoneal glucose tolerance test, and insulin levels were obtained after exposures. Results: In the absence of a L-type CCB, IH increased fasting (105.1 vs. 71.2 mg/dL; p

Rationale: Dietary patterns may alter immune responses and increase asthma risk or affect lung function. Objectives: To examine whether a proinflammatory diet (assessed by the energy-adjusted Dietary Inflammatory Index [E-DII]) or high dietary quality (assessed by the Alternative Healthy Eating Index [AHEI-2010]) are associated with current asthma, current asthma symptoms, and lung function in Hispanic adults. Methods: This was a cross-sectional study of 12,687 adults aged 18 to 76 years who participated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The E-DII and AHEI-2010 were calculated based on two 24-hour dietary recalls. Logistic or linear regression was used for the multivariable analysis of E-DII or AHEI-2010 scores and current asthma, asthma symptoms, and lung function measures, adjusting for age, sex, annual household income, study center, Hispanic/Latino background, smoking status, and other covariates. Results: A higher E-DII score was associated with current asthma (odds ratio [OR] for quartile 4 vs. 1, 1.35; 95% confidence interval [CI], 0.97–1.90) and asthma symptoms (OR for quartile 4 vs. 1, 1.42; 95% CI, 1.12–1.81). The AHEI-2010 score was not associated with current asthma or asthma symptoms. Among adults without asthma, a higher E-DII score was associated with lower forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC), and a higher AHEI-2010 score was associated with higher FEV(1) and FVC. Conclusions: Our findings suggest that a proinflammatory diet increases the risk of asthma and asthma symptoms in Hispanic adults. An antiinflammatory diet (indicated by a lower E-DII or a higher AHEI-2010 score) may positively influence lung function in Hispanic adults without asthma.

Rationale: Obstructive sleep apnea (OSA) during REM sleep is a common disorder. Data on whether OSA that occurs predominantly during REM sleep is associated with health outcomes are limited. Objectives: The present study examined the association between OSA during REM sleep and a composite cardiovascular endpoint in a community sample with and without prevalent cardiovascular disease. Methods: Full-montage home polysomnography was conducted as part of the Sleep Heart Health Study. The study cohort was followed for an average of 9.5 years, during which time cardiovascular events were assessed. Only participants with a non-REM apnea–hypopnea index (AHI) of less than 5 events/h were included. A composite cardiovascular endpoint was determined as the occurrence of nonfatal or fatal events, including myocardial infarction, coronary artery revascularization, congestive heart failure, and stroke. Proportional hazards regression was used to derive the adjusted hazards ratios for the composite cardiovascular endpoint. Measurements and Main Results: The sample consisted of 3,265 subjects with a non-REM AHI of less than 5.0 events/h. Using a REM AHI of less than 5.0 events/h as the reference group (n = 1,758), the adjusted hazards ratios for the composite cardiovascular endpoint in those with severe REM OSA (≥30 events/h; n = 180) was 1.35 (95% confidence interval, 0.98–1.85). Stratified analyses demonstrated that the association was most notable in those with prevalent cardiovascular disease and severe OSA during REM sleep with an adjusted hazards ratio of 2.56 (95% confidence interval, 1.46–4.47). Conclusions: Severe OSA that occurs primarily during REM sleep is associated with higher incidence of a composite cardiovascular endpoint, but in only those with prevalent cardiovascular disease.

Population-based studies showing the negative impact of type 2 diabetes (T2D) on lung function are overviewed. Among the well-recognized pathophysiological mechanisms, the metabolic pathways related to insulin resistance (IR), low-grade chronic inflammation, leptin resistance, microvascular damage, and autonomic neuropathy are emphasized. Histopathological changes are exposed, and findings reported from experimental models are clearly differentiated from those described in humans. The accelerated decline in pulmonary function that appears in patients with cystic fibrosis (CF) with related abnormalities of glucose tolerance and diabetes is considered as an example to further investigate the relationship between T2D and the lung. Furthermore, a possible causal link between antihyperglycemic therapies and pulmonary function is examined. T2D similarly affects breathing during sleep, becoming an independent risk factor for higher rates of sleep apnea, leading to nocturnal hypoxemia and daytime sleepiness. Therefore, the impact of T2D on sleep breathing and its influence on sleep architecture is analyzed. Finally, the effect of improving some pathophysiological mechanisms, primarily IR and inflammation, as well as the optimization of blood glucose control on sleep breathing is evaluated. In summary, the lung should be considered by those providing care for people with diabetes and raise the central issue of whether the normalization of glucose levels can improve pulmonary function and ameliorate sleep-disordered breathing. Therefore, patients with T2D should be considered a vulnerable group for pulmonary dysfunction. However, further research aimed at elucidating how to screen for the lung impairment in the population with diabetes in a cost-effective manner is needed.

Background Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality. Objectives The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to-severe sleep apnea. Methods Eligible patients hospitalized with HF and moderate-to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6-min walk distance) at 6 months. Results 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p Conclusions In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874 )

Introduction Obstructive sleep apnea (OSA) is associated with increased glucose intolerance and insulin resistance, and commonly coexists with type 2 diabetes mellitus (T2DM). Research suggests an independent association between these two conditions. However, more research into the role of T2DM in the development of OSA, or vice versa, is needed. Methods Leveraging data from 139 participants with T2DM from the Sleep AHEAD cohort and 5,085 participants without T2DM from the Sleep Heart Health Study (SHHS), we conducted two complementary propensity score (PS) subclassification analyses to estimate the effect of T2DM on the oxygen desaturation index (ODI), both at baseline and over 4-5 years of follow-up. PS models included age, sex, race, body mass index, neck circumference, waist circumference, total cholesterol, HDL cholesterol, triglycerides, Epworth Sleepiness Scale, and comorbid hypertension or cardiovascular disease. Models evaluating ODI progression also included baseline ODI. Results The PS subclassification analysis identified 109 participants with T2DM and 480 without T2DM, balanced with respect to baseline covariates, for evaluation of the effect of T2DM on baseline ODI. On average, those with T2DM had a 9 events/hour greater ODI compared to those without (24.3 [20.8, 27.9] vs. 15.3 [13.6, 16.9] events/hour; p Conclusion Using two robust PS subclassification designs to minimize selection bias, we evaluated the effect of T2DM on baseline ODI and ODI progression in adults with OSA after 4-5 years. Those with T2DM had more severe baseline ODI, but there were no meaningful differences in ODI progression. Results further our understanding of the association between these coexisting conditions. Support NIH grant HL070301

STUDY OBJECTIVES: Self-reported sleepiness is common in patients with obstructive sleep apnea (OSA) and is being increasingly recognized as an effect modifier of the association between OSA and cardiovascular outcomes. However, data on whether sleepiness modifies the association between OSA and glycemic outcomes are lacking. The current study sought to characterize the association between glycemic control and sleepiness in people with OSA and type 2 diabetes. METHODS: Adults with non-insulin requiring type 2 diabetes and undiagnosed moderate to severe OSA were recruited from the community. Demographic data, Epworth Sleepiness Scale (ESS), hemoglobin A1c (HbA1c), as well a type III home sleep test were obtained. The association between self-reported sleepiness and glycemic control was examined using quantile regression. RESULTS: The study cohort included 311 participants with 56% of the sample being men. Stratified analyses by sex demonstrated that self-reported sleepiness was associated with a higher HbA1c level, but this association was present only in men with a body mass index (BMI) < 35 kg/m(2). Mean HbA1c levels were higher by 0.57% (95% confidence interval: 0.11, 1.02) in men with an ESS ≥ 11 compared to men with an ESS < 11. No such association was observed in men with a BMI ≥ 35 kg/m(2) or in women of any BMI category. CONCLUSIONS: The association between self-reported sleepiness and glycemic control in people with type 2 diabetes and moderate to severe OSA varies a function of BMI and sex. The noted differences in association should be considered when assessing possible treatment effects of therapy for OSA on metabolic outcomes. CITATION: Aurora RN, Punjabi NM. Obstructive sleep apnea, sleepiness, and glycemic control in type 2 diabetes. J Clin Sleep Med. 2019;15(5):749–755.

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity‐related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross‐sectional linear regression of individual‐level data from participants in MESA (Multi‐Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1 H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1 H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid‐lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P =4.88×10 −20 –1.16×10 −3 ). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched‐chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P =1.90×10 −35 –8.46×10 −7 ), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community‐based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

The Hyperglycemic Profiles in Obstructive Sleep Apnea (HYPNOS) randomized clinical trial was conducted in adults with type 2 diabetes and moderate-to-severe obstructive sleep apnea (OSA) to determine whether treatment with positive airway pressure (PAP) therapy is associated with improvements in glycemic measures. Participants were randomly assigned to PAP therapy with lifestyle counseling or lifestyle counseling alone. While observational and experimental evidence indicate that intermittent hypoxemia and recurrent arousals in OSA may alter glucose metabolism and worsen glycemic measures, the effect of treating OSA with PAP therapy on these measures in type 2 diabetes is uncertain. Adequately powered randomized clinical trials have yet to be performed to demonstrate whether PAP therapy for OSA in patients with type 2 diabetes can improve glycemic measures. The HYPNOS trial was designed to determine whether PAP therapy for OSA in patients with type 2 diabetes over 3 months leads to improvements in glycemic measures including glycemic variability (standard deviation) based on Dexcom G4 Platinum continuous glucose monitoring. Secondary objectives were to assess the effects of PAP therapy for OSA on measures of: (1) glycemic variability based on Abbott Freestyle Pro Libre continuous glucose monitoring; (2) point-of-care hemoglobin A1c (HbA1c); (3) degree of post-prandial hyperglycemia as determined by 7-point self-monitoring of blood glucose; (4) clinic and ambulatory blood pressure; and (5) endothelial function. The HYPNOS trial was designed to address gaps in our understanding of the effects of PAP therapy on glucose metabolism in adults with type 2 diabetes and moderate-to-severe OSA. Trial Registration: ClinicalTrials.gov Identifier NCT02454153

Importance Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA. Observations The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events. Conclusions and Relevance OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.

STUDY OBJECTIVES: To examine the associations of sleep measures with hemoglobin A1c (HbA1c) among individuals with and without type 2 diabetes. METHODS: Data were from 2049 Multi-Ethnic Study of Atherosclerosis participants taking part in a sleep ancillary study. Cross-sectional linear regression models examined associations of actigraphy estimates of sleep (sleep duration, variability, and maintenance efficiency) and polysomnography measures (obstructive sleep apnea [OSA] and hypoxemia) with HbA1c, stratified by diabetes status. Primary models were adjusted for demographics, lifestyle behaviors, and obesity. RESULTS: Among individuals with diabetes (20 per cent population), those who slept

OBJECTIVE: The study aimed to examine the association based on objective estimates of sleep duration and quality and aortic stiffness while accounting for the potential confounding effect of SDB. METHOD: Participants were part of the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep study. Sleep duration and quality were assessed by 7-day wrist actigraphy, SDB by home polysomnography, and aortic stiffness by magnetic resonance imaging (MRI)-based aortic pulse wave velocity (aPWV), ascending and descending aorta distensibility (AAD and DAD). Aortic stiffness of participants with ‘normal’ sleep duration (6–8 hours) were compared with those of ‘short’ (8 hours) adjusting for common cardiovascular risk factors and apnea hypopnea index (AHI). RESULTS: The sample consisted of 908 participants (mean age 68.4±9.1 years, 55.3% female). There was a significant linear trend of increased aPWV across short (n=252), normal (n=552), and long sleep durations (n=104) (p for trend=0.008). Multivariable analysis showed that people with short sleep duration had 0.94 m/s lower aPWV (95% CI: −1.54, −0.35), compared with those with normal sleep duration. CONCLUSION: In this ethnically diverse community cohort, habitual short sleep duration as estimated by actigraphy was associated with lower aortic stiffness.

Background Patients with heart failure and sleep apnea are at increased risk for developing arrhythmias. Whether treatment of sleep apnea reduces arrhythmias is unknown. Objective The purpose of this study was to determine whether adaptive servo-ventilation (ASV) with optimal medical therapy (OMT) reduces atrial fibrillation (AF) and/or ventricular tachycardia/ventricular fibrillation (VT/VF) burden compared to OMT alone. Methods We conducted a prospective substudy of patients with pacemakers/defibrillators in the Cardiovascular Improvements with Minute Ventilation-Targeted ASV Therapy in Heart Failure (CAT-HF) trial. Change in arrhythmia burden was compared using a mixed model analysis to account for multiple measurements per patient. Results Among 35 randomized patients eligible and analyzed (19 ASV, 16 OMT only) in the AF cohort, mean age was 64 ± 12 years, 23% were women (n = 8), 49% had previous AF (n = 17), 89% had reduced ejection fraction (n = 31), and mean apnea hypopnea index was 41 ± 17 events per hour. Baseline characteristics were similar between groups. Change in AF burden from baseline to follow-up was –15.8% ± 36.5% with ASV vs +23.7% ± 36.2% with OMT (P = .034). There was no significant change in the AF cohort in the mean number of VT/VF events: +3.3 ± 14.9 events with ASV vs –0.3 ± 7.3 events with OMT (P = .58). Five subjects had appropriate therapies for VT/VF in the ASV arm vs 6 subjects in the OMT arm. Conclusion This study provides proof of concept that treatment of sleep apnea with ASV leads to reduction in AF burden compared with OMT alone, without an increase in VT/VF events. This hypothesis should be tested in a large outcomes trial.

Large-arterial stiffness is recognized as a subclinical marker of cardiovascular disease (CVD). Self-reported short and long habitual sleep duration has been implicated in increased arterial stiffness. However, studies that use objective assessments of sleep duration while accounting for confounding effects of sleep apnea are scarce. We examined the association between habitual sleep duration, as assessed by actigraphy, and magnetic resonance imaging (MRI)- based aortic stiffness, controlling for other CV risk factors including sleep apnea. Method: We included participants in the Multi-Ethnic Study of Atherosclerosis who had undergone MRI assessment of aortic distensibility and a sleep study. Sleep duration was assessed by wrist actigraphy for 7-days and aortic stiffness by aortic pulse wave velocity (aPWV), ascending aorta distensibility (AAD), and descending aorta distensibility (DAD) using MRI. Multiple linear regressions were used to evaluate the association between sleep duration (defined as: short:< 6 hours, normal: 6-8 hours, and long: > 8 hours) and aPWV, AAD, or DAD, adjusting for demographic, life style factors, common cardiovascular risk, and apnea-hypopnea index. Results: The sample consisted of 908 participants (Mean age 68.4±9.1 years, 55.3% women). There was a significant linear trend of increased aPWV across short, normal, and long sleep durations (8.4 ± 3.6 vs. 8.7 ± 4.2 vs. 9.9 ± 4.9, respectively, p=0.008). In multivariable model, participants with short sleep duration (n=252), had average 0.87 m/s (95% CI: -1.47, -.27) lower PWV and 0.23 mmHg -1 (95% CI: .01, .45) higher DAD, compared with those with normal sleep duration (n=552). No significant difference in PWV or DAD was found between those with normal and long sleep duration. No associations were noted between sleep duration and AAD. Sleep duration had no significant interactions with age, gender or race. Conclusion: This study shows that short sleep duration, as assessed by actigraphy, is significantly associated with low aortic stiffness measured by MRI in a large community-based cohort. Future studies on the association between sleep duration and aortic stiffness are warranted to confirm these findings and elucidate potential underlying mechanisms.

STUDY OBJECTIVE To characterize the association among apnea-hypopnea indices (AHIs) determined using three common metrics for defining hypopnea, and to develop a model to calibrate between these AHIs. DESIGN Cross-sectional analysis of Sleep Heart Health Study Data. SETTING Community-based. PARTICIPANTS There were 6,441 men and women age 40 y or older. MEASUREMENT AND RESULTS Three separate AHIs have been calculated, using all apneas (defined as a decrease in airflow greater than 90% from baseline for ≥ 10 sec) plus hypopneas (defined as a decrease in airflow or chest wall or abdominal excursion greater than 30% from baseline, but not meeting apnea definitions) associated with either: (1) a 4% or greater fall in oxyhemoglobin saturation-AHI4; (2) a 3% or greater fall in oxyhemoglobin saturation-AHI3; or (3) a 3% or greater fall in oxyhemoglobin saturation or an event-related arousal-AHI3a. Median values were 5.4, 9.7, and 13.4 for AHI4, AHI3, and AHI3a, respectively (P < 0.0001). Penalized spline regression models were used to compare AHI values across the three metrics and to calculate prediction intervals. Comparison of regression models demonstrates divergence in AHI scores among the three methods at low AHI values and gradual convergence at higher levels of AHI. CONCLUSIONS The three methods of scoring hypopneas yielded significantly different estimates of the apnea-hypopnea index (AHI), although the relative difference is reduced in severe disease. The regression models presented will enable clinicians and researchers to more appropriately compare AHI values obtained using differing metrics for hypopnea.

No data exist as to the role of ethnicity in the associations between obstructive sleep apnea (OSA), sleep duration, and metabolic dysfunction.To examine links between OSA, objectively measured habitual sleep duration, and fasting glucose in U.S. ethnic groups.The Multi-Ethnic Study of Atherosclerosis is a multisite community-based study that conducted polysomnography and wrist actigraphy. In 2,151 subjects (1,839 in fully adjusted models), the apnea-hypopnea index was used to classify OSA as none (0-4.9/h), mild (5-14.9/h), or moderate to severe (≥15/h). Actigraphic sleep duration was classified as short (≤5 h/night), intermediate (5 and8 h/night), or long (≥8 h/night). Subjects were classified as having normal fasting glucose (100 mg/dl and no hypoglycemic medication use) or abnormal fasting glucose (≥100 mg/dl and/or hypoglycemic medication use).The sample was 45.8% male, age 68.5 ± 9.2 (mean ± SD) years, and 27.3% African American, 37.2% white, 11.8% Chinese, and 23.8% Hispanic. The prevalence of abnormal fasting glucose was 40.2%. Relative to subjects without apnea, moderate-to-severe OSA was significantly associated with abnormal fasting glucose in African Americans (odds ratio, 2.14; 95% confidence interval, 1.12-4.08) and white participants (odds ratio, 2.85; 95% confidence interval, 1.20-6.75), but not among Chinese or Hispanic subjects, after adjusting for site, age, sex, waist circumference, and sleep duration (P = 0.06 for ethnicity-by-OSA severity interaction). In contrast, sleep duration was not significantly associated with abnormal fasting glucose after considering the influence of OSA.This large multiethnic study confirmed previous reports of an independent association between OSA and metabolic dysfunction, and suggested that this association may vary by ethnicity.

We examined cross-sectional and longitudinal associations between neighborhood socioeconomic status, social cohesion and safety and features of the diurnal cortisol curve including: area under the curve (AUC), wake-to-bed slope, wake-up, cortisol awakening response (CAR, wake-up to 30 minutes post-awakening), early decline (30 minutes to 2 hours post-awakening) and late decline (2 hours post-awakening to bed time). In cross-sectional analyses, higher neighborhood poverty was associated with a flatter early decline and a flatter wake-to-bed slope. Higher social cohesion and safety were associated with higher wake-up cortisol, steeper early decline and steeper wake-to-bed slope. Over 5 years, wake-up cortisol increased, CAR, early decline, late decline and wake-to-bed slope became flatter and AUC became larger. Higher poverty was associated with less pronounced increases in wake-up and AUC, while higher social cohesion was associated with greater increases in wake-up and AUC. Adverse neighborhood environments were cross-sectionally associated with flatter cortisol profiles, but associations with changes in cortisol were weak and not in the expected direction.

The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-based studies. We prospectively (2000–2011) investigated the associations of physician-diagnosed sleep apnea (PDSA), which is considered more severe sleep apnea, and self-reported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in white, black, and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease at baseline (2000–2002). Cox proportional hazards models were used to assess the associations, with adjustment for socioeconomic status, traditional vascular disease risk factors, race/ethnicity, body mass index, diabetes, chronic kidney disease, alcohol intake, and lipid-lowering therapy. Out of 4,395 respondents to a sleep questionnaire administered in MESA, 181 reported PDSA, 1,086 reported HS, and 3,128 reported neither HS nor PDSA (unaffected). Over an average 8.5-year follow-up period, 212 AF events were identified. As compared with unaffected participants, PDSA was associated with incident AF in the multivariable analysis, but HS was not (PDSA: hazard ratio = 1.76, 95% confidence interval: 1.03, 3.02; HS: hazard ratio = 1.02, 95% confidence interval: 0.72, 1.44). PDSA, a marker of more severe sleep apnea, was associated with higher risk of incident AF in this analysis of MESA data.

Study objective Blood pressure (BP) may be adversely affected by a variety of sleep disturbances, including sleep fragmentation, hypoxemia, respiratory disturbances, and periodic limb movements. We aim to identify which polysomnography indices are most strongly and consistently associated with systolic and diastolic blood pressure (SBP, DBP) levels in a population-based sample. Design Cross-sectional analysis of data from 2,040 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent polysomnography at MESA Exam 5 in 2011-2013. Setting Multisite cohort study. Participants Participants were mean age 68 y (54% females; 28% African American, 24% Hispanic, 11% Chinese). Measurements Thirty-two candidate polysomnography predictors were identified representing the domains of breathing disturbance frequency, hypoxemia, sleep architecture, and periodic limb movements. Cluster analysis was used for variable reduction. Statistical models, adjusted for potential confounders, were derived using stepwise regression. Final models were selected using cross-validation techniques. Results The apnea-hypopnea index (AHI) defined using a 4% desaturation hypopnea criterion (AHI4P) was most consistently associated with SBP level. The AHI and periodic limb movement index (associated with arousals; PLMIA) were significantly associated with DBP. Estimated adjusted differences in SBP and DBP levels between an individual with no sleep apnea (AHI4P = 0) and one with moderately severe sleep apnea (AHI4P = 30) were 2.2 mm Hg and 1.1 mm Hg, respectively. Each 10-unit increase in the PLMIA was associated with an increase in DBP of 1.2 mm Hg. Conclusion Our results support the use of a currently recommended apnea-hypopnea index definition as a marker of blood pressure risk and indicate that measurement of limb movements with arousals is also independently associated with diastolic blood pressure.

We sought to quantify the association between slow-wave (stage N3) sleep and hypertension in a large cohort of middle-aged men and women. Data from 1850 participants free of baseline hypertension from the Sleep Heart Health Study were analyzed. The primary exposure was percentage of N3 sleep on baseline in-home polysomnography and the primary outcome was incident hypertension, defined as systolic blood pressure ≥ 140 mm Hg, diastolic blood pressure ≥ 90 mm Hg, and/or use of any blood pressure lowering medications at follow-up. Multivariable logistic regression models were adjusted for study site, age, sex, race, waist circumference, tobacco use, alcohol use, apnea–hypopnea index, nocturnal oxygen desaturation, sleep duration, sleep efficiency, and arousal index. Mean age was 59.4 ± 10.1 years and 55.5% were female. The mean baseline systolic and diastolic blood pressure was 118.8 and 70.6 mm Hg, respectively. Approximately 30% of the sample developed hypertension during a mean follow-up of 5.3 years. In the multi-adjusted model, participants in quartiles 1 (

Background Sleep apnea is an underdiagnosed condition in patients with heart failure. Efficient identification of sleep apnea is needed, as treatment may improve heart failure–related outcomes. Currently, use of portable sleep monitoring in hospitalized patients and those at risk for central sleep apnea is discouraged. This study examined whether portable sleep monitoring with respiratory polygraphy can accurately diagnose sleep apnea in patients hospitalized with decompensated heart failure. Methods Hospitalized patients with decompensated heart failure underwent concurrent respiratory polygraphy and polysomnography. Both recordings were scored for obstructive and central disordered breathing events in a blinded fashion, using standard criteria, and the apnea-hypopnea index (AHI) was determined. Pearson’s correlation coefficients and Bland-Altman plots were used to examine the concordance among the overall, obstructive, and central AHI values derived by respiratory polygraphy and polysomnography. Results The sample consisted of 53 patients (47% women) with a mean age of 59.0 years. The correlation coefficient for the overall AHI from the two diagnostic methods was 0.94 (95% CI, 0.89-0.96). The average difference in AHI between the two methods was 3.6 events/h. Analyses of the central and obstructive AHI values showed strong concordance between the two methods, with correlation coefficients of 0.98 (95% CI, 0.96-0.99) and 0.91 (95% CI, 0.84-0.95), respectively. Complete agreement in the classification of sleep apnea severity between the two methods was seen in 89% of the sample. Conclusions Portable sleep monitoring can accurately diagnose sleep apnea in hospitalized patients with heart failure and may promote early initiation of treatment.

Background Sleep-disordered breathing (SDB), including central and obstructive sleep apnea, is a marker of poor prognosis in heart failure (HF) and may worsen cardiac dysfunction over time. Treatment of SDB with adaptive servoventilation (ASV) may reverse pathologic cardiac remodeling in HF patients. Methods The Cardiovascular Improvements with Minute Ventilation-targeted Adaptive Servo-Ventilation Therapy in Heart Failure (CAT-HF) trial randomized patients with acute decompensated HF and confirmed SDB to either optimal medical therapy (OMT) or treatment with ASV and OMT. Patients with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) were included. Echocardiograms, performed at baseline and 6 months, assessed cardiac size and function and evaluated cardiac remodeling over time. The CAT-HF trial was stopped early in response to the SERVE-HF trial, which found increased mortality among HFrEF patients with central sleep apnea treated with ASV. Results Of the 126 patients enrolled prior to trial cessation, 95 had both baseline and 6-month echocardiograms (77 HFrEF and 18 HFpEF). Among HFrEF patients, both treatment arms demonstrated a significant increase in EF: +4.3% in the ASV group (.0004) and +4.6% in OMT alone (P = .007) and a significant decrease in LV end-systolic volume index: −9.4 mL/m2 in the ASV group (P = .01) and −8.6 mL/m2 in OMT alone (P = .003). Reductions in left atrial (LA) volume and E/e’ were greater in the ASV arm, whereas patients receiving OMT alone demonstrated more improvement in right ventricular function. HFpEF patients treated with ASV also had a decrease in LA size that was greater than those receiving OMT alone. Although there were significant intragroup changes within the ASV + OMT and OMT-alone groups, there were no significant intergroup differences at 6 months. Conclusions Significant reverse LV remodeling was seen among HFrEF patients with SDB regardless of treatment allocation. Substantial reductions in LA volume among HFrEF and HFpEF patients receiving ASV suggest that ASV treatment may also improve diastolic function and warrant further investigation.

Background Reduced lung function is associated with clinical outcomes such as cardiovascular disease. However, little is known about its association with incident end-stage renal disease (ESRD) and chronic kidney disease (CKD). Study Design Prospective cohort study. Setting & Participants 14,946 participants aged 45 to 64 years at baseline (1987-1989) in the Atherosclerosis Risk in Communities (ARIC) Study (45.0% men and 25.2% black), with follow-up through 2012. Predictors Race- and sex-specific quartiles of percent-predicted forced vital capacity (FVC) and the proportion of forced expiratory volume in 1 second of expiration to FVC (FEV 1 /FVC) at baseline determined with spirometry. Outcomes Incident ESRD (defined here as renal replacement therapy or death due to CKD) as the primary outcome and incident CKD (defined here as ESRD, ≥25% decline in estimated glomerular filtration rate to a level 2 , or CKD-related hospitalizations/deaths) as the secondary outcome. Results During a median follow-up of 23.6 years, 526 (3.5%) participants developed ESRD. After adjusting for potential confounders, the cause-specific HR of incident ESRD for the lowest (vs highest) quartile was 1.72 (95% CI, 1.31-2.26) for percent-predicted FVC and 1.33 (95% CI, 1.03-1.73) for FEV 1 /FVC. Compared to a high-normal lung function pattern, a mixed pattern (ie, percent-predicted FVC 1 /FVC 1 /FVC≥70%; 4.8% of participants) at 2.03 (95% CI, 1.47-2.81), obstructive pattern (ie, percent-predicted FVC≥80% and FEV 1 /FVC 1 /FVC≥70%, or percent-predicted FVC≥80% and FEV 1 /FVC 70%- Limitations Limited number of participants with moderate/severe lung dysfunction and spirometry only at baseline. Conclusions Reduced lung function, particularly lower percent-predicted FVC, is independently associated with CKD progression. Our findings suggest a potential pathophysiologic contribution of reduced lung function to the development of CKD and a need for monitoring kidney function in persons with reduced lung function.

Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia.

Rationale: Obstructive sleep apnea (OSA) is associated with cardiovascular morbidity and mortality, although the underlying mechanisms are not well understood. Objectives: We aimed to determine whether more severe OSA, measured by the Respiratory Disturbance Index (RDI), is associated with subclinical myocardial injury and increased myocardial wall stress. Methods: A total of 1,645 participants (62.5 ± 5.5 yr and 54% women) free of coronary heart disease and heart failure and participating in both the Atherosclerosis Risk in the Communities and the Sleep Heart Health Studies underwent overnight polysomnography and measurement of high-sensitivity troponin T (hs-TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Measurements and Main Results: OSA severity was defined using conventional clinical categories: none (RDI ≤ 5), mild (RDI 5–15), moderate (RDI 15–30), and severe (RDI > 30). Hs-TnT, but not NT-proBNP, was associated with OSA after adjusting for 17 potential confounders (P = 0.02). Over a median of 12.4 (interquartile range, 11.6–13.1) years follow-up, hs-TnT was related to risk of death or incident heart failure in all OSA categories (P ≤ 0.05 in each category). Conclusions: In middle-aged to older individuals, OSA severity is independently associated with higher levels of hs-TnT, suggesting that subclinical myocardial injury may play a role in the association between OSA and risk of heart failure. OSA was not associated with NT-proBNP levels after adjusting for multiple possible confounders.

Objectives Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. Interventions C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Results Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Conclusions Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism.

Chitotriosidase (ChT) is secreted by chronically activated macrophages in Gaucher's disease. We hypothesize that circulating levels of ChT are altered with normal aging, reflecting age-related chronic macrophage activation. Potential sources that might contribute to altered levels were assessed by measuring systemic levels of ChT are α-naphthyl acetate esterase, a macrophage lysosomal enzyme; granulocyte-macrophage colony-stimulating factor (GM-CSF), which stimulates neutrophilic granule release of ChT; interleukin-6 (IL-6); and neopterin, a macrophage activation marker.Serum was obtained from 315 healthy participants whose age ranged from 18 to 92 years. Anthropometric measures included percent body fat and body mass index. ChT and α-naphthyl acetate esterase levels were measured by enzyme activity assays. GM-CSF, IL-6, and neopterin concentrations were measured by commercial enzyme-linked immunosorbent assays. Serum marker values were statistically analyzed using nonparametric tests.Six percent of the participants had undetectable ChT levels. A positive association with age was observed for ChT and IL-6, whereas a negative correlation with age was seen for α-naphthyl acetate esterase and GM-CSF. ChT values were not associated with α-naphthyl acetate esterase or GM-CSF levels. ChT was independently associated with IL-6 and neopterin levels, but statistical significance was attenuated when controlled for age.The data are consistent with increased serum ChT activity not arising from altered macrophage lysosomal enzyme trafficking or GM-CSF-stimulated release of neutrophil granule stores. The association of ChT with age remains significant after controlling for neopterin and IL-6 changes with age, suggesting that ChT levels reflect a macrophage state distinct from acute macrophage activation or inflammatory state.

BACKGROUND: No consensus on definitions of prediabetes exists among international organisations. Analysis of associations with different definitions and clinical complications can inform the comparative value of different prediabetes definitions. We compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions. METHODS: We did a prospective cohort study of participants in the ARIC study who did not have diagnosed diabetes and who attended visit 2 (1990-92; n=10 844) and who attended visit 4 (1996-98; n=7194). ARIC participants were enrolled from four communities across the USA. Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6-6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1-6·9 mmol/L), HbA1c (ADA HbA1c cutoff 5·7-6·4% [39-46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0-6·4% [42-46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8-11·0 mmol/L). FINDINGS: Prediabetes defined using the ADA fasting glucose concentration cutoff (prevalence 4112 [38%] of 10 844 people; 95% CI 37·0-38·8) was the most sensitive for major clinical outcomes, whereas using the ADA HbA1c cutoff (2027 [19%] of 10 884 people; 18·0-19·4) and IEC HbA1c cutoff (970 [9%] of 10 844 people; 8·4-9·5), and the WHO fasting glucose concentration cutoff (1213 [11%] of 10 844 people; 10·6-11·8) were more specific. After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p INTERPRETATION: Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall. FUNDING: US National Institutes of Health.

In this paper, we first critically appraise the epidemiologic literature examining the association of restless legs syndrome (RLS) with cardiovascular disease (CVD) and then consider whether lessons learned from the study of cardiovascular consequences of other sleep disorders might inform a research agenda to examine the potential mechanisms of cardiovascular morbidity of RLS. Cross-sectional and longitudinal studies are both mixed as to whether there is a meaningful association of RLS and CVD. On the other hand, numerous cross-sectional and longitudinal observational studies have shown a strong association of obstructive sleep apnea (OSA) with CVD risk. Each of the potential mediating mechanisms in OSA may also be assessed in RLS, including 1) neural mechanisms such as increased central sympathetic outflow, impaired baroreflex function, diminished heart rate and blood pressure variability, and increased chemoreflex sensitivity, 2) metabolic mechanisms such as glucose intolerance and reduced insulin sensitivity/diabetes as a result of sleep disturbance in RLS, 3) oxidative stress, 4) systemic or vascular inflammatory mechanisms, and 5) vascular mechanisms including impaired endothelial functioning, increased aortic stiffness, hypothalamic-pituitary axis activation or renin-angiotensin-aldosterone activation. Three known characteristics of RLS may contribute to these specific mechanisms of increased cardiovascular risk: 1) periodic limb movements of sleep, which are associated with large increases in heart rate and blood pressure, 2) sleep fragmentation and sleep deprivation, which are known to produce adverse consequences for neural, metabolic, oxidative, inflammatory, and vascular systems, and 3) iron deficiency, which is an emerging risk for cardiovascular disease. Future research priorities include additional epidemiologic studies which characterize multiple CVD risk factors, case-control studies which examine known markers of cardiovascular risk, and small clinical trials which assess the effects of RLS treatment on intermediate physiological markers such as sympathetic activity or baroreflex control, measures of vascular stiffness and reactivity, or measures of insulin sensitivity and glucose tolerance.

Introduction Obstructive sleep apnea (OSA) is associated with impaired health-related quality of life (HRQL). Treatment with continuous positive airway pressure (CPAP) has variable impacts on HRQL, and this may be influenced by patient's tolerance of therapy. The objective is to determine the impact of nocturnal supplemental oxygen (NSO) and CPAP on HRQL compared with healthy lifestyle education (HLSE) in individuals with OSA. Methods Patients with coronary heart disease (CHD) or at least 3 major CHD risk factors with apnea-hypopnea index of 15 to 50 events/h were randomized to CPAP, NSO, or HLSE. Health-related quality of life was assessed using the Short-Form 36, and depression was assessed with Patient Health Questionnaire-9 at baseline and 12 weeks. The treatment effect on HRQL change scores through 12 weeks was assessed using multivariable models adjusting for study site, presence of CHD at baseline, race, and baseline HRQL. Results A total of 318 patients were randomized to 1 of 3 treatment arms with 1:1:1 ratio and 94% completed baseline and follow-up HRQL instruments. Mean Short-Form 36 scores were similar at baseline in all 3 groups ranging from 41.8±12 to 51.6±12 in various domains. In multivariable models, the CPAP group noted a significantly greater improvement than NSO in mental health (+2.33, 95% CI 0.34-4.31, P =.02) and mental composite score (+2.40, 95% CI 0.40-4.41, P =.02). Conversely, the CPAP group noted less improvement than NSO in physical function (−2.68, 95% CI −4.66 to −0.70, P =.008) and physical composite score (−2.17, 95% CI −3.82 to −0.51, P =.01). Compared with HLSE, vitality and Patient Health Questionnaire-9 improved with CPAP but not with NSO. Significant interactions were noted between treatment effects with larger differences in black and sleepy patients. Conclusion These data support the use of CPAP for improving vitality, sleepiness, mental health, social functioning, and depressive symptoms in patients with OSA and established CHD or risk factors. Nocturnal supplemental oxygen may have beneficial effects on perceived physical functioning.