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1.  Sleep Apnea Is Associated with Subclinical Myocardial Injury in the Community. The ARIC-SHHS Study 
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.
doi:10.1164/rccm.201309-1572OC
PMCID: PMC3917380  PMID: 24156237
sleep disorders; troponin T; NT-proBNP; risk factors
2.  A Candidate Gene Study of Obstructive Sleep Apnea in European Americans and African Americans 
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.
doi:10.1164/rccm.201002-0192OC
PMCID: PMC2970865  PMID: 20538960
sleep apnea; body mass index; genetics; candidate gene study
3.  Associations of PM10 with Sleep and Sleep-disordered Breathing in Adults from Seven U.S. Urban Areas 
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.
doi:10.1164/rccm.200912-1797OC
PMCID: PMC2949406  PMID: 20508218
particulate matter; sleep-disordered breathing; sleep architecture
4.  Sleep-disordered Breathing and Prothrombotic Biomarkers 
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.
doi:10.1164/rccm.201001-0020OC
PMCID: PMC2949407  PMID: 20508215
sleep apnea; thrombosis; cardiovascular disease
5.  Obstructive Sleep Apnea–Hypopnea and Incident Stroke 
Rationale: Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population.
Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea.
Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea–hypopnea index (OAHI) and outcome was incident ischemic stroke.
Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1–7.4). In the mild to moderate range (OAHI, 5–25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2–10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25.
Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.
doi:10.1164/rccm.200911-1746OC
PMCID: PMC2913239  PMID: 20339144
sleep apnea; stroke; epidemiology
6.  Prospective Study of Sleep-disordered Breathing and Hypertension 
Rationale: Cross-sectional epidemiologic studies show an association between sleep-disordered breathing and hypertension, but only one cohort study has examined sleep-disordered breathing as a risk factor for incident hypertension.
Objectives: To examine whether sleep-disordered breathing increases the risk of incident hypertension among persons 40 years of age and older.
Methods: In a prospective cohort study, we analyzed data from 2,470 participants who at baseline did not have hypertension, defined as blood pressure of at least 140/90 mm Hg or taking antihypertensive medication. The apnea-hypopnea index (AHI), the number of apneas plus hypopneas per hour of sleep, was measured by overnight in-home polysomnography. We estimated odds ratios for developing hypertension during 5 years of follow-up according to baseline AHI.
Measurements and Main Results: The odds ratios for incident hypertension increased with increasing baseline AHI; however, this relationship was attenuated and not statistically significant after adjustment for baseline body-mass index. Although not statistically significant, the observed association between a baseline AHI greater than 30 and future hypertension (odds ratio, 1.51; 95% confidence interval, 0.93–2.47) does not exclude the possibility of a modest association.
Conclusions: Among middle-aged and older persons without hypertension, much of the relationship between AHI and risk of incident hypertension was accounted for by obesity. After adjustment for body mass index, the AHI was not a significant predictor of future hypertension, although a modest influence of an AHI greater than 30 on hypertension could not be excluded.
doi:10.1164/rccm.200712-1809OC
PMCID: PMC2695498  PMID: 19264976
sleep apnea; sleep-disordered breathing; hypertension; cohort study
7.  Association between Metabolic Syndrome and Sleep-disordered Breathing in Adolescents 
Rationale: Metabolic syndrome (MetS) affects 4 to 10% of adolescents. Risk factors include overweight, male sex, and Hispanic ethnicity. Although sleep-disordered breathing (SDB) has been implicated as a risk factor for MetS in adults, its association with SDB in adolescents is unknown.
Objectives: To define the association of SDB with MetS in adolescents.
Methods: Standardized measurements of SDB, anthropometry and bioassays, were made in 270 adolescents, aged 13.6 ± 0.7 years. MetS was identified if threshold levels were exceeded in three of five areas: waist circumference, blood pressure, triglyceride level, high-density lipoprotein cholesterol level, and glucose levels.
Measurements and Main Results: Although 70% of children with SDB (apnea–hypopnea index ⩾ 5) were overweight and 59% had MetS, 16% of children without SDB had MetS. Twenty-five percent of those with MetS had SDB. After adjusting for age, race, sex, and preterm status, children with SDB had a 6.49 (95% confidence interval, 2.52, 16.70) increased odds of MetS compared with children without SDB. Indices of SDB stress associated with MetS included respiratory event frequency, degree of oxygen desaturation, and sleep efficiency. Analyses of individual metabolic parameters showed that, after adjustment for body mass index, SDB was associated with systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and fasting insulin levels.
Conclusions: A majority of adolescents with SDB are overweight and meet criteria for MetS. The close association between MetS and SDB and their putative interacting pathophysiologies suggests a need to develop screening, prevention, and treatment strategies for both disorders in high-risk, overweight adolescents.
doi:10.1164/rccm.200703-375OC
PMCID: PMC1994215  PMID: 17541017
sleep apnea; metabolic syndrome; obesity
8.  Pediatric Sleep Apnea 
Over the last 30 years, the prevalence of overweight across all pediatric age groups and ethnicities has increased substantially, with the current prevalence of overweight among adolescents estimated to be approximately 30%. Current evidence suggests that overweight is modestly associated with obstructive sleep apnea syndrome (OSAS) among young children, but strongly associated with OSAS in older children and adolescents. The rising incidence of pediatric overweight likely will impact the prevalence, presentation, and treatment of childhood OSAS. The subgroup of children who may be especially susceptible include ethnic minorities and those from households with caregivers from low socioeconomic groups. OSAS, by exposing children to recurrent intermittent hypoxemia or oxidative stress, may amplify the adverse effects of adiposity on systemic inflammation and metabolic perturbations associated with vascular disease and diabetes. When these conditions manifest early in life, they have the potential to alter physiology at critical developmental stages, or, if persistent, provide cumulative exposures that may powerfully alter long-term health profiles. An increased prevalence of overweight also may impact the response to adenotonsillectomy as a primary treatment for childhood OSAS. The high and anticipated increased prevalence of pediatric OSAS mandates assessment of optimal approaches for preventing and treating both OSAS and overweight across the pediatric age range. In this Pulmonary Perspective, the interrelationships between pediatric OSAS and overweight are reviewed, and the implications of the overweight epidemic on childhood OSAS are discussed.
doi:10.1164/rccm.200606-790PP
PMCID: PMC2176093  PMID: 17158283
sleep apnea; childhood obesity; childhood overweight
9.  Association of Nocturnal Arrhythmias with Sleep-disordered Breathing 
Rationale: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development.
Objective: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing.
Methods: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index ⩾ 30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index < 5).
Results: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p = 0.003) for atrial fibrillation; 5.3 versus 1.2% (p = 0.004) for nonsustained ventricular tachycardia; 25.0 versus 14.5% (p = 0.002) for complex ventricular ectopy. Compared with those without sleep-disordered breathing and adjusting for age, sex, body mass index, and prevalent coronary heart disease, individuals with sleep-disordered breathing had four times the odds of atrial fibrillation (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.03–15.74), three times the odds of nonsustained ventricular tachycardia (OR, 3.40; 95% CI, 1.03–11.20), and almost twice the odds of complex ventricular ectopy (OR, 1.74; 95% CI, 1.11–2.74). A significant relation was also observed between sleep-disordered breathing and ventricular ectopic beats/h (p < 0.0003) considered as a continuous outcome.
Conclusions: Individuals with severe sleep-disordered breathing have two- to fourfold higher odds of complex arrhythmias than those without sleep-disordered breathing even after adjustment for potential confounders.
doi:10.1164/rccm.200509-1442OC
PMCID: PMC2662909  PMID: 16424443
arrhythmia; cohort studies; epidemiology; sleep apnea syndromes

Results 1-9 (9)