Jodi H. Barnet

Increased Prevalence of Sleep-Disordered Breathing in Adults

Sleep-disordered breathing is a common disorder with a range of harmful sequelae. Obesity is a strong causal factor for sleep-disordered breathing, and because of the ongoing obesity epidemic, previous estimates of sleep-disordered breathing prevalence require updating. We estimated the prevalence of sleep-disordered breathing in the United States for the periods of 1988-1994 and 2007-2010 using data from the Wisconsin Sleep Cohort Study, an ongoing community-based study that was established in 1988 with participants randomly selected from an employed population of Wisconsin adults. A total of 1,520 participants who were 30-70 years of age had baseline polysomnography studies to assess the presence of sleep-disordered breathing. Participants were invited for repeat studies at 4-year intervals. The prevalence of sleep-disordered breathing was modeled as a function of age, sex, and body mass index, and estimates were extrapolated to US body mass index distributions estimated using data from the National Health and Nutrition Examination Survey. The current prevalence estimates of moderate to severe sleep-disordered breathing (apnea-hypopnea index, measured as events/hour, ≥15) are 10% (95% confidence interval (CI): 7, 12) among 30-49-year-old men; 17% (95% CI: 15, 21) among 50-70-year-old men; 3% (95% CI: 2, 4) among 30-49-year-old women; and 9% (95% CI: 7, 11) among 50-70 year-old women. These estimated prevalence rates represent substantial increases over the last 2 decades (relative increases of between 14% and 55% depending on the subgroup).

Association Between Asthma and Risk of Developing Obstructive Sleep Apnea

IMPORTANCE Obstructive sleep apnea (OSA) is more common among patients with asthma; whether asthma is associated with the development of OSA is unknown. OBJECTIVE To examine the prospective relationship of asthma with incident OSA. DESIGN, SETTING, AND PARTICIPANTS Population-based prospective epidemiologic study (the Wisconsin Sleep Cohort Study) beginning in 1988. Adult participants were recruited from a random sample of Wisconsin state employees to attend overnight polysomnography studies at 4-year intervals. Asthma and covariate information were assessed during polysomnography studies through March 2013. Eligible participants were identified as free of OSA (apnea-hypopnea index [AHI] of <5 events/h and not treated) by 2 baseline polysomnography studies. There were 1105 4-year follow-up intervals provided by 547 participants (52% women; mean [SD] baseline age, 50 [8] years). EXPOSURES Questionnaire-assessed presence and duration of self-reported physician-diagnosed asthma. MAIN OUTCOMES AND MEASURES The associations of presence and duration of asthma with 4-year incidences of both OSA (AHI of ≥5 or positive airway pressure treatment) and OSA concomitant with habitual daytime sleepiness were estimated using repeated-measures Poisson regression, adjusting for confounders. RESULTS Twenty-two of 81 participants (27% [95% CI, 17%-37%]) with asthma experienced incident OSA over their first observed 4-year follow-up interval compared with 75 of 466 participants (16% [95% CI, 13%-19%]) without asthma. Using all 4-year intervals, participants with asthma experienced 45 cases of incident OSA during 167 4-year intervals (27% [95% CI, 20%-34%]) and participants without asthma experienced 160 cases of incident OSA during 938 4-year intervals (17% [95% CI, 15%-19%]); the corresponding adjusted relative risk (RR) was 1.39 (95% CI, 1.06-1.82), controlling for sex, age, baseline and change in body mass index, and other factors. Asthma was also associated with new-onset OSA with habitual sleepiness (RR, 2.72 [95% CI, 1.26-5.89], P = .045). Asthma duration was related to both incident OSA (RR, 1.07 per 5-year increment in asthma duration [95% CI, 1.02-1.13], P = .01) and incident OSA with habitual sleepiness (RR, 1.18 [95% CI, 1.07-1.31], P = .02). CONCLUSIONS AND RELEVANCE Asthma was associated with an increased risk of new-onset OSA. Studies investigating the mechanisms underlying this association and the value of periodic OSA evaluation in patients with asthma are warranted.

A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women

BACKGROUND a small number of reports exist on the cognitive effects of soy isoflavones, the findings from which are mixed. Isoflavone efficacy is dependent upon conversion of glycosides contained in soy foods and supplements to the biologically active aglycons. Of particular interest is the production of the metabolite, equol, which is dependent upon intestinal microflora and an integrous digestive system, both being altered by age and age-associated conditions. Unfortunately, few studies enrolled adults over the age of 70, and none included older men. OBJECTIVE we examined safety, feasibility and cognitive efficacy of soy isoflavone administration in older nondemented men and women (age 62-89 years). DESIGN AND METHODS in this randomised, placebo-controlled, double-blind pilot study, subjects ingested either 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets for 6 months. RESULTS active and placebo-treated subjects exhibited a comparable side-effect profile. Plasma levels of genistein and daidzein (P < 0.001), but not equol, increased with isoflavone administration. While similar at baseline, the two groups differed across 6 months of treatment on 8 of 11 cognitive tests administered. Isoflavone-treated subjects improved on tests of visual-spatial memory (P < 0.01) and construction (P = 0.01), verbal fluency (P < 0.01) and speeded dexterity (P = 0.04). Placebo-treated participants were faster than isoflavone-treated subjects on two tests of executive function (P < 0.05). CONCLUSIONS these data suggest that administration of 100 mg/day of isoflavones was well tolerated. Plasma genistein and daidzein levels, but not equol, increased with isoflavone administration. Finally, data support the potential cognitive effects of soy isoflavones in older adults.

Narcolepsy and Predictors of Positive MSLTs in the Wisconsin Sleep Cohort

STUDY OBJECTIVES To study whether positive multiple sleep latency tests (MSLTs, mean sleep latency [MSL] ≤ 8 minutes, ≥ 2 sleep onset REM sleep periods [SOREMPs]) and/or nocturnal SOREMP (REM sleep latency ≤ 15 minutes during nocturnal polysomonography [NPSG]) are stable traits and can reflect incipient narcolepsy. DESIGN AND SETTING Cross-sectional and longitudinal investigation of the Wisconsin Sleep Cohort Study. PARTICIPANTS Adults (44% females, 30-81 years) underwent NPSG (n = 4,866 in 1,518 subjects), and clinical MSLT (n = 1,135), with 823 having a repeat NPSG-MSLT at 4-year intervals, totaling 1725 NPSG with MSLT studies. Data were analyzed using linear mixed-effects models, and the stability of positive MSLTs was explored using κ statistics. MEASUREMENTS AND RESULTS Prevalence of a nocturnal SOREMP on a NPSG, of ≥ 2 SOREMPs on the MSLT, of MSL ≤ 8 minutes on the MSLT, and of a positive MSLT (MSL ≤ 8 minutes plus ≥ 2 SOREMPs) were 0.35%, 7.0%, 22%, and 3.4%, respectively. Correlates of a positive MSLT were shift work (OR = 7.8, P = 0.0001) and short sleep (OR = 1.51/h, P = 0.04). Test-retest for these parameters was poor, with κ < 0.2 (n.s.) after excluding shift workers and short sleepers. Excluding shift-work, short sleep, and subjects with negative MSLTs, we found one undiagnosed subject with possible cataplexy (≥ 1/month) and a NPSG SOREMPs; one subject previously diagnosed with narcolepsy without cataplexy with 2 NPSG SOREMPs and a positive MSLT, and two subjects with 2 independently positive MSLTs (66% human leukocyte antigen [HLA] positive). The proportions for narcolepsy with and without cataplexy were 0.07% (95% CI: 0.02-0.37%) and 0.20% (95% CI: 0.07-0.58%), respectively. CONCLUSIONS The diagnostic value of multiple sleep latency tests is strongly altered by shift work and to a lesser extent by chronic sleep deprivation. The prevalence of narcolepsy without cataplexy may be 3-fold higher than that of narcolepsy-cataplexy.

Exercise is associated with a reduced incidence of sleep-disordered breathing

BACKGROUND The effect of exercise on sleep-disordered breathing is unknown. While diet and weight loss have been shown to reduce the severity of sleep-disordered breathing, it is unclear whether exercise has an independent effect. METHODS A population-based longitudinal epidemiologic study of adults measured the association between exercise and incidence and severity of sleep-disordered breathing. Hours of weekly exercise were assessed by 2 mailed surveys (1988 and 2000). Sleep-disordered breathing was assessed by 18-channel in-laboratory polysomnography at baseline and at follow-up. RESULTS Associations were modeled using linear and logistic regression, adjusting for body mass index, age, sex, and other covariates. Hours of exercise were associated with reduced incidence of mild (odds ratio 0.76, P=.011) and moderate (odds ratio 0.67, P=.002) sleep-disordered breathing. A decrease in exercise duration also was associated with worsening sleep-disordered breathing, as measured by the apnea-hypopnea index (β=2.368, P=.048). Adjustment for body mass index attenuated these effects. CONCLUSIONS Exercise is associated with a reduced incidence of mild and moderate sleep-disordered breathing, and decreasing exercise is associated with worsening of sleep-disordered breathing. The effect of exercise on sleep-disordered breathing appears to be largely, but perhaps not entirely, mediated by changes in body habitus.

Short-term Hormone Therapy with Transdermal Estradiol Improves Cognition for Postmenopausal Women with Alzheimer’s Disease: Results of a Randomized Controlled Trial

We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimers disease (AD). The trial was designed to evaluate the dose-dependent effects of transdermal 17-β estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera©), for 12 months in 43 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result of the Womens Health Initiative (WHI) and anticipated increased attrition, the protocol was modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values < 0.030) and semantic memory (p-values < 0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD.

Obstructive Sleep Apnea Is Associated With Future Subclinical Carotid Artery Disease Thirteen-Year Follow-Up From the Wisconsin Sleep Cohort

Objective— To determine the longitudinal associations between obstructive sleep apnea, carotid artery intima-media thickness (IMT), and plaque. Approach and Results— This is a population-based, prospective cohort study conducted from July, 1989, to November, 2012, on 790 randomly selected Wisconsin residents who completed a mean of 3.5 (range, 1–6) polysomnograms during the study period. Obstructive sleep apnea was characterized by the apnea–hypopnea index (AHI, events/h). Common carotid artery IMT and plaque were assessed by B-mode ultrasound. The mean (SD) time from the first polysomnograms to carotid ultrasound was 13.5 (3.6) years. Multivariable regression models were created to estimate the independent associations of baseline and cumulative obstructive sleep apnea exposure with subsequent carotid IMT and plaque. At baseline, the mean age of participants was 47.6 (7.7) years (55% men, 97% white). AHI was 4.4 (9.0) events/h (range, 0–97); 7% had AHI >15 events/h. Carotid IMT was 0.755 (0.161) mm; 63% had plaque. Adjusting for age, sex, body mass index, systolic blood pressure, smoking, and use of lipid-lowering, antihypertensive, and antidiabetic medications, baseline AHI independently predicted future carotid IMT (&bgr;=0.027 mm/unit log10[AHI+1]; P=0.049), plaque presence (odds ratio, 1.55 [95% confidence intervals, 1.02–2.35]; P=0.041) and plaque score (odds ratio, 1.30 [1.05–1.61]; P=0.018). In cumulative risk factor–adjusted models, AHI independently predicted future carotid plaque presence (P=0.012) and score (P=0.039), but not IMT (P=0.608). Conclusions— Prevalent obstructive sleep apnea is independently associated with increased carotid IMT and plaque more than a decade later, indicating increased future cardiovascular disease risk.Objective— To determine the longitudinal associations between obstructive sleep apnea, carotid artery intima-media thickness (IMT), and plaque. Approach and Results— This is a population-based, prospective cohort study conducted from July, 1989, to November, 2012, on 790 randomly selected Wisconsin residents who completed a mean of 3.5 (range, 1–6) polysomnograms during the study period. Obstructive sleep apnea was characterized by the apnea–hypopnea index (AHI, events/h). Common carotid artery IMT and plaque were assessed by B-mode ultrasound. The mean (SD) time from the first polysomnograms to carotid ultrasound was 13.5 (3.6) years. Multivariable regression models were created to estimate the independent associations of baseline and cumulative obstructive sleep apnea exposure with subsequent carotid IMT and plaque. At baseline, the mean age of participants was 47.6 (7.7) years (55% men, 97% white). AHI was 4.4 (9.0) events/h (range, 0–97); 7% had AHI >15 events/h. Carotid IMT was 0.755 (0.161) mm; 63% had plaque. Adjusting for age, sex, body mass index, systolic blood pressure, smoking, and use of lipid-lowering, antihypertensive, and antidiabetic medications, baseline AHI independently predicted future carotid IMT (β=0.027 mm/unit log10[AHI+1]; P =0.049), plaque presence (odds ratio, 1.55 [95% confidence intervals, 1.02–2.35]; P =0.041) and plaque score (odds ratio, 1.30 [1.05–1.61]; P =0.018). In cumulative risk factor–adjusted models, AHI independently predicted future carotid plaque presence ( P =0.012) and score ( P =0.039), but not IMT ( P =0.608). Conclusions— Prevalent obstructive sleep apnea is independently associated with increased carotid IMT and plaque more than a decade later, indicating increased future cardiovascular disease risk. # Significance {#article-title-30}

Combined effects of sleep disordered breathing and metabolic syndrome on endothelial function: the Wisconsin Sleep Cohort study.

STUDY OBJECTIVES To examine the combined impact of sleep disordered breathing (SDB) and metabolic syndrome (MetS) in endothelial dysfunction. DESIGN Cross-sectional assessment of endothelial function, MetS and SDB status in a population-based sample. SETTING Community-based cohort. PARTICIPANTS Participants (n = 431) from the Wisconsin Sleep Cohort were studied between 2004 and 2007. MetS was defined following the National Cholesterol Education Program criteria. SDB severity was defined by the apnea-hypopnea index ([AHI] events/h of sleep) during overnight polysomnography. Fasting lipids, glucose, and insulin were measured and homeostasis model assessment was calculated to quantify insulin resistance (HOMA-IR). Multivariable linear regression was used to assess associations of brachial artery flow-mediated dilation (FMD) with SDB, MetS, and their interaction. INTERVENTION None. MEASUREMENTS AND RESULTS Participants averaged 60.2 years of age (SD 7.8 years), 44% were female, and 97% Caucasian. MetS was present in 35%; 22% had AHI ≥ 15 events/hour. Of the no-MetS group, 7% had AHI ≥ 15 events/hour. FMD (mean 5.5%; SD 3.5%) was inversely associated with age (r = -0.16, P = 0.001) and mean brachial artery diameter (r = -0.29, P < 0.001). Multivariate linear models adjusted for CVD risk factors showed that the negative association between SDB and FMD was present among subjects with MetS (β FMD(per unit log2(AHI+1)) = -0.55%, P = 0.014), but not among subjects with normal metabolic function (β = 0.13, not significant), P for interaction = 0.011. CONCLUSION Sleep disordered breathing and concurrent metabolic syndrome are synergistically associated with worse endothelial function. Individuals with both of these conditions appear to be at a significantly higher risk for cardiovascular disease complications.

Treatment of Obstructive Sleep Apnea in Young and Middle‐Aged Adults: Effects of Positive Airway Pressure and Compliance on Arterial Stiffness, Endothelial Function, and Cardiac Hemodynamics

Background The cardiovascular effects of positive airway pressure (PAP) therapy in obstructive sleep apnea (OSA) patients are not clear because of confounding by comorbid conditions. Methods and Results Prospective interventional study of PAP therapy and withdrawal. Apnea Hypopnea Index (AHI; events/hour of sleep) was determined from polysomnography. Central aortic blood pressures (BPs), Aortic Augmentation Index (AAIx), and central (PWV c‐f) and peripheral pulse wave (PWV c‐r) velocities were determined by applanation tonometry. Echocardiography and brachial artery reactivity testing were performed at baseline, after 4 and 12 weeks of PAP therapy, and 1 week after PAP withdrawal. The 84 participants were mean (SD) 41.1 (7.6) years old and had 39.8 (24.5) AHI events/hour. After 4 weeks post‐PAP initiation and sustained after 12 weeks, subjects experienced decreases in central systolic BP (P=0.008), diastolic BP, mean BP, AAIx, and PWV c‐r, and brachial artery dilation (all P<0.001), as well as improvements in left ventricular diastolic function and systemic and pulmonary vascular resistance. In adjusted models, PAP use (hours/night) predicted reductions in diastolic BP (β=−0.65 [SE, 0.32] mm Hg/hour; P=0.045), AAIx (β=−0.53 [0.27] %/hour; P=0.049) and PWV c‐r (β=−0.13 [0.05] m·s−1/hour; P=0.007), and improved brachial artery flow‐mediated dilation (β=0.31 [0.14] %/hour use; P=0.015). After 1 week of PAP withdrawal, brachial diameter, diastolic BP, mean BP, AAIx, and heart rate increased (P≤0.05). Conclusions PAP therapy reduces arterial tone and improves endothelial and diastolic function in young to middle‐aged adults. This positive effect is observed after 4 weeks and depends on hours of use, but reverts quickly with PAP withdrawal. Clinical Trial Registration URL: https://clinicaltrials.gov/. Unique identifier: NCT01317329.

Minimal nocturnal oxygen saturation predicts future subclinical carotid atherosclerosis: the Wisconsin sleep cohort.

Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO2) and cardiovascular disease (CVD) risk factors with carotid intima‐media thickness (IMT) and plaques. We used data on 689 Wisconsin sleep cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (SD) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B‐mode ultrasound. Bilateral common, bifurcation and internal carotid artery segments were evaluated for plaque score. Participants (8) were aged 56 years (55% male); 32% had hypertension and mean body mass index (BMI) was 31 (7) kg m2. Mean and minimum nocturnal SaO2 were 95% (2) and 86% (7), respectively. Mean percentage sleep time with SaO2 < 90% was 2% (8). Both mean (odds ratio [OR]: 0.60 lower plaque count per 5% higher mean SaO2, 95% confidence interval [CI]: 0.38–0.96, P = 0.033) and minimum SaO2 (OR: 0.88 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.80–0.97, P = 0.013) predicted carotid plaque score after adjusting for age, sex and BMI. Minimum SaO2 predicted future plaque score after adding adjustment for traditional CVD risk factors (OR: 0.90 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.81–0.99, P = 0.038). Mean SaO2 was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO2 is an independent predictor of future carotid plaque burden. Other nocturnal SaO2 parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors.