Context

Sleep-disordered breathing (SDB), characterized by recurrent arousals from sleep and intermittent hypoxemia, is common among older adults. Cross-sectional studies have linked SDB to poor cognition; however, it remains unclear whether sleep disordered breathing precedes cognitive impairment in older adults.

Objectives

To determine the prospective relationship between sleep disordered breathing and cognitive impairment and to investigate potential mechanisms of this association.

Design, Setting, and Participants

Prospective sleep and cognition study of 298 women without dementia (mean [SD] age: 82.3 [3.2] years) who had overnight polysomnography (PSG) measured between January 2002 and April 2004 in a substudy of the Study of Osteoporotic Fractures. Sleep disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep. Multivariate logistic regression was used to determine the independent association of sleep disordered breathing with risk of mild cognitive impairment or dementia and adjustments were made for age, race, body mass index, education, smoking status, presence of diabetes, presence of hypertension, medication use (antidepressants, benzodiazepines, or non-benzodiazepine anxiolytics), and baseline cognitive scores. Measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship.

Main Outcome Measures

Adjudicated cognitive status (normal, dementia, or mild cognitive impairment [MCI]) based on data collected between November 2006 and September 2008

Results

Compared with the 193 women without sleep disordered breathing, the 105 women (35.2%) with SDB were more likely to develop MCI/dementia (n=60 (31.1%) vs n=47 (44.8%)) even after multivariate adjustment (adjusted OR=1.85, 95% CI 1.11-3.08). Elevated oxygen desaturation index (≥15 events/hour) and high percentage (>7%) of sleep time in apnea or hypopnea, both measures of disordered breathing, were associated with risk of developing MCI/dementia (adjusted OR=1.71, 95% CI 1.04 − 2.83 and adjusted OR=2.04, 95% CI 1.10 − 3.78, respectively). Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment.

Conclusions

Among older women, those with sleep disordered breathing, compared with those without SDB, were associated with an increased risk of developing cognitive impairment.

Objectives

Despite routine use with older adults, the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) have not been adequately validated in older samples, particularly those from diverse racial backgrounds. The objective of this study was to determine the reliability and validity of and to provide normative data for these questionnaires in community-dwelling older women.

Methods

Participants were 306 black and 2,662 white women aged ≥70 from the Study of Osteoporotic Fractures. Participants completed the PSQI and ESS, and provided self-reported assessments of mood, cognition, and functioning, and underwent wrist actigraphy for sleep-wake estimation.

Results

Good internal consistency in both black and white women was demonstrated for the PSQI and ESS. Two PSQI subscales, however, were found to have inadequate reliability (Medications, Daytime Dysfunction). Both the PSQI and ESS were associated with theoretically similar measures in the expected directions. The PSQI also differentiated participants with no reported sleep disorder from those reporting at least one sleep disturbance, such as insomnia, sleep apnea, and restless legs. The ESS only differentiated women reporting no sleep disorder from those reporting insomnia.

Conclusions

In general, findings suggest that the PSQI and ESS are internally consistent, valid measures of self-reported sleep conditions problems in older women. Additional research is required to evaluate the impact of removing the Medications and Daytime Dysfunction PSQI subscales on this measure's internal consistency in older women.

Objectives

The objectives of this study were to 1) compare the strength of associations between sleep duration and BMI in middle childhood, early and late adolescence; 2) determine whether sleep duration in middle childhood predicts BMI in early or late adolescence; 3) examine the consistency of these associations by sex.

Methods

Subjects included 313 children/adolescents aged 8–19 participating in a longitudinal cohort study on sleep and health. Participants were assessed at three time points approximately 4 years apart: ages 8–11, 12–15 and 16–19. BMI z-score (BMIz) was calculated using age and sex normative data from the Centers for Disease Control. Sleep duration was reported by the parent (ages 8–15) or the adolescent (ages 16–19).

Results

Half of the participants were male and 79% were Caucasian. Sleep duration had a negative linear association with BMIz for boys but not girls, and the magnitude of this association decreased with age. Sleep duration at age 8–11 predicted BMIz in early and late adolescence for boys but not girls, and associations were largely attenuated after adjusting for BMIz at age 8–11. The strongest predictor of adolescent BMIz was BMIz at age 8–11 for both boys and girls.

Conclusions

We conclude that the association between sleep duration and BMIz varies by sex and age, with stronger associations in boys and in middle childhood compared to adolescence.

OBJECTIVES

To examine the association of sleep architecture, sleep disordered breathing, and cognition in older men.

DESIGN

A population-based cross-sectional study.

SETTING

6 sites in the United States.

PARTICIPANTS

2,909 community-dwelling men age 67 or older who were not selected on the basis of sleep problems or cognitive impairment.

MEASUREMENTS

Predictors were measured with in-home polysomnography: sleep architecture, nocturnal hypoxemia (any sleep time with SaO2<80%), apnea-hypopnea index (AHI), and arousal index. Cognitive outcomes were measured by the Modified Mini-Mental State Examination (3MS), Trails B test, and the Digit Vigilance Test (DVT).

RESULTS

Analyses adjusted by age, race, education, BMI, lifestyle, comorbidities and medication use show that those who spent less percent of time in rapid eye movement (REM) sleep had worse levels of cognition: compared to the highest quartile (≥23.7%), those in the lowest quartile (<14.8%) took an average of 5.9 seconds longer on the Trails B and 20.1 seconds longer on the DVT. Similarly, increased percent time spent in stage 1 sleep was related to poorer cognitive function. Those in the highest quartile of stage 1 sleep (≥8.6%) had worse cognitive scores on average compared to those in the lowest quartile (<4.0%). Those with nocturnal hypoxemia took longer to complete the DVT by an average of 22.3 seconds compared to those without, but no associations were found with 3MS or Trails B.

CONCLUSION

Spending less percent of time spent in REM sleep, more percent of time spent in stage 1 sleep, and having higher levels of nocturnal hypoxemia were associated with poorer cognition in older men. Further studies are needed to clarify the direction of these associations and to explore potential mechanisms.

With a large percentage of clinical trials still using paper forms as the primary data collection tool, there is much potential for increasing efficiency through web-based data collection systems, especially for large-scale multi-center trials. This paper presents OnWARD, an ontology-driven, secure, rapidly-deployed, web-based framework supporting data capture for large-scale multi-center clinical research. Our approach is developed using the agile methodology to provide a flexible, user-centered dynamic form generator, which can be quickly deployed and customized for any clinical study without the need of deep technical expertise. Because of the flexible framework, the data management system can be extended to accommodate a large variety of data types, including genetic, genomic and proteomic data. In this paper, we demonstrate the initial deployment of OnWARD for a Phase II multi-center clinical trial after a development period of merely three months. The study utilizes 23 clinical report forms containing more than 1500 data points. Preliminary evaluation results show that OnWARD exceeded expectations of the clinical investigators in efficiency, flexibility and ease in setting up.

Background

We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.

Methods

Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.

Results

Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.

Conclusion

PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study.

Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×10−6. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts.

Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis.

Objective

Previous cross-sectional studies have observed alterations in activity rhythms in dementia patients but the direction of causation is unclear. We determined whether circadian activity rhythms measured in community-dwelling older women are prospectively associated with incident dementia or mild cognitive impairment (MCI).

Method

Activity rhythm data were collected from 1,282 healthy community-dwelling women from the Study of Osteoporotic Fractures cohort (mean age 83 years) with wrist actigraphy for a minimum of three 24-hour periods. Each participant completed a neuropsychological test battery and had clinical cognitive status (dementia, MCI, normal) adjudicated by an expert panel approximately 5 years later. All analyses were adjusted for demographics, BMI, functional status, depression, medications, alcohol, caffeine, smoking, health status, and co-morbidities.

Results

After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (Odds ratio[OR]=1.57,95% CI,1.09–2.25) or rhythm robustness (OR=1.57,95%CI,1.10–2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR=1.83,95% CI,1.29–2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51PM) when compared to those with average timing (1:34PM–3:51PM).

Interpretation

Older, healthy women with decreased circadian activity rhythm amplitude and robustness, and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly.

Purpose of review

To provide an update on the connection between obstructive sleep apnea (OSA) and cardiovascular disease.

Recent findings

Large prospective studies have established that OSA is associated with an increased incidence of hypertension and, in men, of coronary disease, stroke, and heart failure. Advances in understanding the pathophysiologic basis for these associations include identification of a role for OSA in inducing abnormalities in hepatic lipid-metabolizing enzymes, endothelial dysfunction, and upregulation of pro-inflammatory and pro-thrombotic mediators. A large body of data implicates OSA as playing a significant role in the occurrence and resistance to treatment of atrial fibrillation. Clinical trials have shown small to modest improvements in blood pressure associated with continuous positive airway pressure (CPAP) use, with smaller or uncontrolled studies suggesting that CPAP may improve cardiovascular outcomes or intermediate markers.

Summary

OSA and cardiovascular disease commonly co-aggregate. Multiple studies indicate that OSA contributes to or exacerbates cardiovascular disease, and thus may be a novel target for cardiovascular risk reduction. While the evidence supports screening and treatment of OSA in patients at risk for cardiovascular disease, it also underscores a need for well powered clinical trials to examine the role of CPAP and other therapies in these populations.

The importance of sleep to health and cardiovascular disease has become increasingly apparent. Sleep disordered breathing (SDB), sleep duration, and sleep architecture may all influence metabolism and neurohormonal systems, yet no prior study has evaluated these sleep characteristics concurrently in relation to incident hypertension. Our objective was to determine if incident hypertension is associated with polysomnography (PSG) measures of SDB, sleep duration, and sleep architecture in older men. Participants were784 community dwelling, ambulatory men ≥65 years (mean age 75.1±4.9 years) from the Outcomes of Sleep Disorders in Older Men Study (MrOs Sleep Study) who did not have hypertension at the time of their in-home PSG sleep studies (2003-2005); and who returned for follow-up (2007-2009). Of 784 older men included in this report, 243 met criteria for incident hypertension after a mean follow-up of 3.4 years. In unadjusted analyses, incident hypertension was associated with increased hypoxemia, increased sleep stages N1 and N2 and decreased stage N3 (slow wave sleep, SWS). After adjustment for age, non-white race, study site, and body mass index, the only sleep index to remain significantly associated with incident HTN was SWS percent (odds ratio for lowest to highest quartile of SWS: 1.83, 95% CI 1.18, 2.85). No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation and indices of SDB. Percentage time in SWS was inversely associated with incident HTN, independent of sleep duration and fragmentation, and SDB. Selective deprivation of SWS may contribute to adverse blood pressure in older men.

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10−5). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10−7 for SBP and 7.52 × 10−7 for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

Background

Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.

Methodology/Principal Findings

We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.

Conclusions/Significance

We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

OBJECTIVES:

The aim of the current study was to compare the objective and subjective effects of continuous positive airway pressure to the use of nasal dilator strips in patients with acromegaly and moderate to severe obstructive sleep apnea.

METHODS:

We studied 12 patients with acromegaly and moderate to severe obstructive sleep apnea (male/females = 8/4, age = 52±8 ys, body mass index = 33.5±4.6 Kg/m2, apnea–hypopnea index = 38±14 events/h) who had been included in a randomized, crossover study to receive three months of treatment with continuous positive airway pressure and nasal dilator strips. All patients were evaluated at study entry and at the end of each treatment by polysomnography, and Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index and treatment satisfaction questionnaires. ClinicalTrials.gov: NCT01265121

RESULTS:

The apnea–hypopnea index values decreased significantly with continuous positive airway pressure treatment but did not change with the use of nasal dilator strips. All of the subjective symptoms improved with both treatments, but these improvements were significantly greater with continuous positive airway pressure than with the nasal dilator strips.

CONCLUSION:

The use of nasal dilator strips had a much smaller effect on the severity of obstructive sleep apnea in patients with acromegaly and moderate to severe obstructive sleep apnea in comparison to the use of continuous positive airway pressure. Moreover, the improvement in several subjective parameters without any significant objective improvement in obstructive sleep apnea resulting from the use of nasal dilator strips is compatible with a placebo effect.

This study examined the association between race/ethnicity and objectively measured sleep characteristics in a large sample of older men. Black men had significantly shorter total sleep time (6.1 hr vs. 6.4 hr), longer sleep latency (28.7 min vs. 21.9 min), lower sleep efficiency (80.6 % vs. 83.4 %), and less slow-wave sleep (4.9 % vs. 8.8 %) than White men, even after controlling for social status, comorbidities, body mass index, and sleep-disordered breathing. Hispanic men slept longer (6.7 hr) at night than Black (6.1 hr) and Asian American men (6.1 hr). This study supports significant variations in sleep characteristics in older men by race/ethnicity.

Objective

To characterize the relationship between insulin sensitivity, assessed by the homeostasis model of insulin (HOMA), and objective measurements of sleep duration in adolescents.

Study design

Cross-sectional analysis from two examinations conducted in the Cleveland Children’s Sleep and Health Cohort (n=387; 43% minorities). Biochemical and anthropometry measurements made in a Clinical Research Unit. Sleep duration measured by actigraphy.

Results

Decreased sleep duration was associated with increased adiposity and minority race. Sleep duration had a quadratic “u-shape” association with HOMA. When adjusted for age, sex, race, preterm status and activity, adolescents who slept 7.75 hours had the lowest predicted HOMA (1.96 [95% CI: 1.82, 2.10]), and adolescents who slept 5.0 hours or 10.5 hours had HOMA indices that were about 20% higher (2.36 [95% CI: 1.94, 2.86] and 2.41 [95% CI: 1.93, 3.01], respectively). After adjusting for adiposity, the association between shorter sleep and HOMA was appreciably attenuated, but the association with longer sleep persisted.

Conclusions

Shorter and longer sleep durations are associated with decreased insulin sensitivity in adolescents. Whereas the association between shorter sleep duration with insulin sensitivity is likely explained by the association between short sleep and obesity, association between longer sleep and insulin sensitivity is independent of obesity.

Objectives

Adolescents are predisposed to short sleep duration and irregular sleep patterns due to certain host characteristics (e.g., age, pubertal status, gender, ethnicity, socioeconomic class, and neighborhood distress) and health-related variables (e.g., ADHD, asthma, birth weight, and BMI). The aim of the current study was to investigate the relationship between such variables and actigraphic measures of sleep duration and variability.

Method

Cross-sectional study of 247 adolescents (48.5% female, 54.3% ethnic minority, mean age of 13.7 years) involved in a larger community-based cohort study.

Results

Significant univariate predictors of sleep duration included gender, minority ethnicity, neighborhood distress, parent income, and BMI. In multivariate models, gender, minority status, and BMI were significantly associated with sleep duration (all p<.05), with girls, non-minority adolescents, and those of a lower BMI obtaining more sleep. Univariate models demonstrated that age, minority ethnicity, neighborhood distress, parent education, parent income, pubertal status, and BMI were significantly related to variability in total sleep time. In the multivariate model, age, minority status, and BMI were significantly related to variability in total sleep time (all p<.05), with younger adolescents, non-minority adolescents, and those of a lower BMI obtaining more regular sleep.

Conclusions

These data show differences in sleep patterns in population sub-groups of adolescents which may be important in understanding pediatric health risk profiles. Subgroups that may particularly benefit from interventions aimed at improving sleep patterns include boys, overweight, and minority adolescents.

Background

Short duration and poor quality of sleep have been associated with increased risks of obesity, cardiovascular disease, diabetes mellitus, and total mortality. However, few studies have investigated their associations with risk of colorectal neoplasia.

Methods

In a screening colonoscopy-based case-control study, the Pittsburg Sleep Quality Index (PSQI) was administered to 1,240 study participants prior to their colonoscopy.

Results

Three hundred and thirty eight (27.3%) of the participants were diagnosed with incident colorectal adenomas. Although there was no appreciable difference in the overall PSQI score between cases and adenoma-free controls (5.32 vs. 5.11; p=0.37), we found a statistically significant association of colorectal adenoma with the PSQI component 3, which corresponds to sleep duration (p=0.02). Cases were more likely to average less than 6 hours of sleep per night (28.9% vs. 22.1% in controls, p=0.01). In multivariate regression analysis adjusted for age, gender, race, smoking, family history of colorectal cancer, and waist-to-hip ratio, individuals averaging less than 6 hours per night had an almost 50% increase in risk of colorectal adenomas (OR=1.47, CI =1.05-2.06, p for trend=0.02) as compared with individuals sleeping at least 7 hours per night. Cases were also more likely to report of being diagnosed with sleep apnea (9.8% vs. 6.5%, p=0.05) and more likely to have worked alternate shifts (54.0% vs. 46.1%, p=0.01), although these differences were not significant in multivariate models.

Conclusions

Shorter duration of sleep significantly increases risk of colorectal adenomas. Our results suggest sleep duration as a novel risk factor for colorectal neoplasia.

Purpose

Sleep-disordered breathing(SDB) may be deleterious to the cardiovascular system and other organs, including the kidney. Although older men are at increased risk for both kidney disease and SDB, it is unknown whether SDB is associated with higher urinary albumin excretion in this population.

Methods

We examined 507 community-dwelling men age ≥67 years(mean 76.0±5.3) enrolled in the MrOS Sleep study who underwent overnight polysomnography and gave a spot urine sample. SDB severity was categorized using the respiratory disturbance index and percent total sleep time <90% oxygen saturation(%time O2<90). Urinary albumin excretion was expressed using the albumin-to-creatinine ratio(ACR).

Results

There was a graded association between respiratory disturbance index and ACR (age and race-adjusted mean ACR=9.35 mg/gCr for respiratory disturbance index≥30 versus 6.72 mg/gCr for respiratory disturbance index<5, p=0.007). This association was attenuated after further adjustment for body mass index(BMI), hypertension and diabetes and no longer reached significance(p=0.129). However, even after adjustment for age, race, BMI, hypertension and diabetes, greater %time O2<90 was associated with higher ACR(10.35 mg/gCr for ≥10%time O2<90 versus 7.45 mg/gCr for <1%time O2<90, p=0.046).

Conclusion

SDB, measured by elevated respiratory disturbance index or nocturnal hypoxemia, was associated with higher ACR. The relationship between respiratory disturbance index and ACR was partially explained by higher BMI and greater prevalence of hypertension and diabetes among men with SDB. However, greater nocturnal hypoxemia was independently associated with higher ACR, suggesting that the hypoxia component of SDB may mediate any detrimental effect of SDB on the kidney.

Background

Periodic limb movements during sleep (PLMS) cause repetitive sympathetic activation and may be associated with increased cardiovascular risk. We hypothesized that PLMS frequency (PLMI) and PLMS arousal frequency (PLMAI) are predictive of incident cardiovascular disease, including coronary heart disease (CHD), peripheral arterial disease (PAD) and cerebrovascular disease (CBD) in an elderly male cohort.

Methods and Results

2,911 men in the observational MrOS sleep study cohort underwent in-home polysomnography with PLMS measurement and were followed four years for the outcomes CHD, CBD, PAD and all-cause cardiovascular disease (cCVD): CHD, CBD or PAD. Cox proportional hazards regression assessed association between PLMI, PLMAI and these outcomes. Models were minimally adjusted for age, clinic and body mass index, then fully adjusted for conventional cardiovascular risk factors. During follow-up, 500 men experienced cCVD: 345 CHD, 117 CBD and 98 PAD events. In fully adjusted models, men with PLMAI≥5 compared to the referent PLMA<1 group had 1.26-fold increased relative hazard (RH) for cCVD. Similar findings were observed for PLMI and cCVD. For PAD, men with PLMI≥30 compared to the referent PLMI<5 group had a 2-fold increased RH (1.14–3.49, p=0.025). Compared to the referent group, men with PLMI ≥30 had an increased risk of CHD (RH=1.31, 1.01–1.70; p=0.045) after minimal adjustment, but this association attenuated after further adjustments. After stratification, risk of incident cCVD among high PLMI and PLMAI groups was significantly elevated only for men without prevalent hypertension (p interactions <0.10).

Conclusions

These findings provide evidence that PLMS frequency is associated with incident cardiovascular disease in community dwelling elderly men.

Introduction

Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin-6 (IL-6).

Methods

6 single nucleotide polymorphisms (SNPs) within IL-6 were genotyped in 259 African-Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n=124). OSA was dichotomized into apnea hypopnea index (AHI)>15 or on treatment vs. absent: AHI<5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI).

Results

SNP IL6-6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24; 95%CI [0.09–0.67]; p=0.006; q=0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p=0.23). The SNPs were studied in European-Americans, although the minor allele frequency in IL6-6021 was too low (4%) for meaningful comparisons.

Conclusion

A synonymous SNP within the IL-6 coding region was protective of OSA in African-Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL-6 may influence the risk of OSA in a pathway that is not explained by obesity.

Rationale: Obstructive sleep apnea (OSA) is hypothesized to be influenced by genes within pathways involved with obesity, craniofacial development, inflammation, and ventilatory control.

Objectives: We conducted the first candidate gene study of OSA using family data from European Americans and African Americans, selecting biologically plausible genes from within these pathways.

Methods: A total of 1,080 single nucleotide polymorphisms (SNPs) were genotyped in 729 African Americans and 505 SNPs were genotyped in 694 European Americans. Coding for SNPs additively, association testing on the apnea-hypopnea index (AHI) as a continuous trait, and OSA as a dichotomous trait (AHI ≥15) was conducted using methods that account for familial correlations in models adjusted for age, age-squared, and sex, with and without body mass index.

Measurements and Main Results: In European Americans, variants within C-reactive protein (CRP) and glial cell line–derived neurotrophic factor (GDNF) were associated with AHI (CRP: β = 4.6; SE = 1.1; P = 0.0000402) (GDNF: β = 4.3; SE = 1; P = 0.0000201) and with the dichotomous OSA trait (CRP: odds ratio = 2.4; 95% confidence interval, 1.5–3.9; P = 0.000170) (GDNF: odds ratio = 2; 95% confidence interval, 1.4–2.89; P = 0.0000433). In African Americans, rs9526240 within serotonin receptor 2a (HTR2A: odds ratio = 2.1; 95% confidence interval, 1.5–2.9; P = 0.00005233) was associated with OSA.

Conclusions: This candidate gene analysis identified the potential role of genes operating through intermediate disease pathways to influence sleep apnea phenotypes, providing a framework for focusing future replication studies.

Rationale: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.

Objectives: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM10) was associated with SDB among persons 39 years of age and older.

Methods: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O2 saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM10 and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).

Measurements and Main Results: In summer, increases in RDI or percentage of sleep time at less than 90% O2 saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM10. Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.

Conclusions: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.

Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis.

Objectives: We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB.

Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with SaO2 less than 90% (< 2%, ≥ 2%).

Measurements and Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5–20%; P < 0.001) and 11% (95% CI, 2–20%; P = 0.01), respectively per 5-unit AHI increase until an AHI of 15, when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3–17%; P < 0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12–13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels.

Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.

Background

Clinic-based observational studies in men have reported that obstructive sleep apnea (OSA) is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of OSA to incident coronary heart disease and heart failure in a general community sample of adult men and women.

Methods and Results

A prospective, longitudinal epidemiologic study of 1927 men and 2495 women aged ≥ 40 years and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed for a median of 8.7 years. After adjustment for multiple risk factors, OSA was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men age ≤70 years (adjusted hazard ratio 1.10 [95% CI 1.00, 1.21] per 10-unit increase in apnea-hypopnea index [AHI]), but not in older men or in women of any age. Among men age 40–70 years, those with AHI ≥30 were 68% more likely to develop coronary heart disease than those with AHI <5. OSA predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% CI 1.02, 1.26] per 10-unit increase in AHI). Men with AHI ≥30 were 58% more likely to develop heart failure than those with AHI <5.

Conclusion

OSA is associated with increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.