Obstructive Sleep Apnea, Platelet Aggregation, and Cardiovascular Risk.

BACKGROUND: Although related, the precise mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease (CVD) are unclear. Platelets are mediators of CVD risk and thrombosis and prior studies suggested associations of OSA and platelet activity. The aim of this study is to assess the link between OSA, platelet activity, and CVD-related risk factors. METHODS AND RESULTS: We studied the association of OSA-measures and platelet aggregation in participants dually enrolled in the SHHS (Sleep Heart and Health Study) and FHS (Framingham Heart Study). We applied linear regression models with adjustment for demographic and clinical covariates and explored interactions with OSA and CVD-related factors, including age, sex, body mass index, hypertension, OSA diagnosis (apnea-hypopnea index 4%≥5), and aspirin use. Our final sample was of 482 participants (60 years [14.00], 50.4% female). No associations were observed between apnea-hypopnea index 4% and platelet aggregation in the main sample. Stratified analysis revealed an association in aspirin users (n=65) for our primary exposure (apnea-hypopnea index 4%, ß=0.523; P<0.001; n=65), and secondary exposures: hypoxic burden (ß=0.358; P<0.001), minimum saturation (ß=-0.519; P=0.026), and oxygen desaturation index 3% (ß=74.672; P=0.002). No associations were detected in nonaspirin users (n=417). CONCLUSIONS: No associations were detected between OSA and platelet aggregation in a community sample. Our finding that OSA associates with increased platelet aggregation in the aspirin group, most of whom use it for primary prevention of CVD, suggests that platelet aggregation may mediate the adverse impact of OSA on vascular health in individuals with existing CVD risk, supporting further investigation.

Nasal resistance and inflammation: mechanisms for obstructive sleep apnea from chronic rhinosinusitis.

STUDY OBJECTIVES: We have previously estimated that the prevalence of obstructive sleep apnea (OSA) among World Trade Center (WTC) rescue and recovery workers is 75% and identified that having symptoms of chronic rhinosinusitis (CRS) is an independent risk factor for OSA in this population. Nasal inflammation and/or elevated awake nasal resistance that carried over into sleep could explain this association. To understand the mechanism(s) for the elevated risk of OSA observed in WTC responders with chronic rhinosinusitis (CRS) symptoms we examined if elevated awake supine nasal resistance was associated with OSA, CRS and/or nasal inflammatory biomarkers. METHODS: 601 individuals (83% male, average age 53 years, BMI=29.9 ± 5.5 kg/m2) enrolled in the WTC Health Program and without significant pre-9/11 snoring, underwent two nights of home sleep apnea testing, measurements of anterior rhinomanometry in the supine position, and nasal lavage. RESULTS: Awake supine nasal resistance was not associated with OSA; 74.8% and 74.4% of the participants with low and high nasal resistance respectively, had OSA (P=NS). Patients with CRS had elevated nasal inflammatory markers (IL6, IL8, ECP and Neut) but did not have high nasal resistance. Nasal inflammatory markers were not correlated with nasal resistance. CONCLUSIONS: As awake nasal resistance did not explain the relationship of CRS to OSA in this large and well characterized dataset, our findings suggest that either "sleep" nasal resistance or other factors such as increased supraglottic inflammation, perhaps through impairing upper airway reflex mechanisms, or systemic inflammation are involved in the pathophysiology of OSA in the WTC population.

Lack of association of impaired upper airway sensation with the presence or absence of obstructive sleep apnoea or chronic rhinosinusitis in World Trade Center responders.

OBJECTIVE: Examine sensory function of the upper airway in four groups of subjects recruited from the World Trade Centre General Responder Cohort (WTCGRC), with/without obstructive sleep apnoea (OSA), and with/without chronic rhinosinusitis (CRS). METHODS: Upper airway sensory function was determined using 2-point discrimination (2-PD) and vibration threshold (VT) in 163 WTCGRC subjects with both OSA and CRS (cases), OSA or CRS alone and without OSA or CRS (controls). Presence of OSA was determined from clinical sleep studies or home sleep testing. Presence of CRS was determined by nasal symptom questionnaire. The relationship between the presence of OSA and CRS and upper airway sensory impairment was assessed using linear regression analysis with each of 2PD and VT sensory threshold values as the dependent variable; OSA, CRS and their interaction were the independent variables. Age, gender and body mass index were covariates in the statistical model. The primary analysis was comparison of OSA+CRS versus controls (no OSA and no CRS) evaluated by linear contrasts. RESULTS: There were no differences in 2-PD or VT in those with OSA+CRS, OSA and CRS alone or controls. However, both 2-PD and VT were significantly higher in the WTCGRC controls compared with values seen in historical controls using the same methodology (median 2-PD 13.0; CI (11.0 to 13.5) vs 10.5; CI (8 to 11); VT: mean±SEM (9.3±0.6 vs 2.2±0.1)). CONCLUSION: While no differences were found in upper airway sensation between cases of OSA and CRS versus controls in the WTGRC population, there was evidence of impaired upper airway sensation in the WTGRC overall.

The stability of slow-wave sleep and EEG oscillations across two consecutive nights of laboratory polysomnography in cognitively normal older adults.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3 hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.

Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

Rationale: The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. Objectives: We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Methods: Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to 1) derive the normative range of VB, 2) assess the relationship between degree of upper airway obstruction and VB, and 3) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm. Measurements and Main Results: The 95th percentiles of VB in asymptomatic healthy subjects across the EPISONO and the DAYFUN cohorts were 25.2% and 26.7%, respectively (median [interquartile range], VBEPISONO, 5.5 [3.5-9.7]%; VBDAYFUN, 9.8 [6.4-15.6]%). VB was associated with the degree of upper airway obstruction in a dose-response manner (VBuntreated, 31.6 [27.1]%; VBtreated, 7.2 [4.7]%; VBsuboptimally treated, 17.6 [18.7]%; VBoff-treatment, 41.6 [18.1]%) and exhibited low night-to-night variability (intraclass correlation coefficient [2,1], 0.89). VB was predictive of all-cause and CVD mortality in the SHHS cohort before and after adjusting for covariates including hypoxic burden. Although AHI was predictive of all-cause mortality, it was not associated with CVD mortality in the SHHS cohort. Conclusions: Automated VB can effectively assess obstructive sleep apnea severity, is predictive of all-cause and CVD mortality, and may be a viable alternative to the AHI.

Night-to-night reliability and agreement of obstructive sleep apnea pathophysiologic mechanisms estimated with phenotyping using polysomnography in cognitively normal elderly participants.

STUDY OBJECTIVES: Phenotyping using polysomnography (PUP) is an algorithmic method to quantify physiologic mechanisms underlying obstructive sleep apnea (OSA): loop gain (LG1), arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp). The consecutive-night test-retest reliability and agreement of PUP-derived estimates are unknown. From a cohort of elderly (age ≥55 years), largely non-sleepy, community-dwelling volunteers who underwent in-lab polysomnography (PSG) on 2 consecutive nights, we determined the test-retest reliability and agreement of PUP-estimated physiologic factors. METHODS: Participants who had an apnea-hypopnea index (AHI3A) of at least 15 events per hour on the first night were included. PUP analyses were performed on each of the two PSGs from each participant. Physiologic factor estimates were derived from NREM sleep and compared across nights using intraclass correlation coefficients for reliability and smallest real differences (SRD) for agreement. RESULTS: Two PSGs from each of 43 participants (86 total) were analyzed. A first-night effect was evident with increased sleep time and stability and decreased OSA severity on the second night. LG1, ArTH, and Vpassive demonstrated good reliability (ICC > 0.80). Vcomp had modest reliability (ICC = 0.67). For all physiologic factors, SRD values were approximately 20% or more of the observed ranges, suggesting limited agreement of longitudinal measurements for a given individual. CONCLUSIONS: For NREM sleep in cognitively normal elderly individuals with OSA, PUP-estimated LG1, ArTH, and Vpassive demonstrated consistent relative ranking of individuals (good reliability) on short-term repeat measurement. For all physiologic factors, longitudinal measurements demonstrated substantial intraindividual variability across nights (limited agreement).

International Consensus Statement on Obstructive Sleep Apnea.

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy.

The Link between Obstructive Sleep Apnea and Neurocognitive Impairment: An Official American Thoracic Society Workshop Report.

There is emerging evidence that obstructive sleep apnea (OSA) is a risk factor for preclinical Alzheimer's disease (AD). An American Thoracic Society workshop was convened that included clinicians, basic scientists, and epidemiologists with expertise in OSA, cognition, and dementia, with the overall objectives of summarizing the state of knowledge in the field, identifying important research gaps, and identifying potential directions for future research. Although currently available cognitive screening tests may allow for identification of cognitive impairment in patients with OSA, they should be interpreted with caution. Neuroimaging in OSA can provide surrogate measures of disease chronicity, but it has methodological limitations. Most data on the impact of OSA treatment on cognition are for continuous positive airway pressure (CPAP), with limited data for other treatments. The cognitive domains improving with CPAP show considerable heterogeneity across studies. OSA can negatively influence risk, manifestations, and possibly progression of AD and other forms of dementia. Sleep-dependent memory tasks need greater incorporation into OSA testing, with better delineation of sleep fragmentation versus intermittent hypoxia effects. Plasma biomarkers may prove to be sensitive, feasible, and scalable biomarkers for use in clinical trials. There is strong biological plausibility, but insufficient data, to prove bidirectional causality of the associations between OSA and aging pathology. Engaging, recruiting, and retaining diverse populations in health care and research may help to decrease racial and ethnic disparities in OSA and AD. Key recommendations from the workshop include research aimed at underlying mechanisms; longer-term longitudinal studies with objective assessment of OSA, sensitive cognitive markers, and sleep-dependent cognitive tasks; and pragmatic study designs for interventional studies that control for other factors that may impact cognitive outcomes and use novel biomarkers.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

BACKGROUND: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER: NCT03053908.

Characterizing sleep-wake patterns in mothers and children in an agrarian community: results from the Ghana Randomized Air Pollution and Health Study.

STUDY OBJECTIVES: Several studies have examined sleep patterns in rural/indigenous communities, however little is known about sleep characteristics in women of reproductive age, and children within these populations. We investigate sleep-wake patterns in mothers and children (ages 3-5 years) leveraging data from the Ghana Randomized Air Pollution and Health Study (GRAPHS). METHODS: The GRAPHS cohort comprises of rural/agrarian communities in Ghana and collected multiday actigraphy in a subset of women and children to assess objective sleep-wake patterns. Data were scored using the Cole-Kripke and Sadeh algorithms for mothers/children. We report descriptive, baseline characteristics and objective sleep measures, compared by access to electricity/poverty status. RESULTS: We analyzed data for 58 mothers (mean age 33 ± 6.6) and 64 children (mean age 4 ± 0.4). For mothers, mean bedtime was 9:40 pm ± 56 min, risetime 5:46 am ± 40 min, and total sleep time (TST) was 6.3 h ± 46 min. For children, median bedtime was 8:07 pm (interquartile range [IQR]: 7:50,8:43), risetime 6:09 am (IQR: 5:50,6:37), and mean 24-h TST 10.44 h ± 78 min. Children with access to electricity had a reduced TST compared to those without electricity (p = 0.02). Mean bedtime was later for both mothers (p = 0.05) and children (p = 0.08) classified as poor. CONCLUSIONS: Mothers in our cohort demonstrated a shorter TST, and earlier bed/risetimes compared to adults in postindustrialized nations. In contrast, children had a higher TST compared to children in postindustrialized nations, also with earlier sleep-onset and offset times. Investigating objective sleep-wake patterns in rural/indigenous communities can highlight important differences in sleep health related to sex, race/ethnicity, and socioeconomic status, and help estimate the impact of industrialization on sleep in developed countries.

Immediate Physiological Responses to Inspiratory Flow Limited Events in Mild Obstructive Sleep Apnea.

Rationale: Inspiratory flow limitation (IFL), characterized by flattening of individual breaths on the airflow/time tracing, is a noninvasive indicator of elevated upper airway resistance. An IFL "event" in isolation has not been defined, nor has the ability to reproducibly identify event occurrence been tested. IFL events and their association with immediate physiological responses-as well as the impact of characteristics such as age, sex, sleep stage, sleepiness, and event duration on their association with such outcomes-have not been studied. Symptomatic patients with a normal to mildly abnormal apnea-hypopnea index who have predominant IFL on their polysomnography may benefit from treatment. Objectives: To test the reproducibility of identifying IFL events and their termination and to determine the frequency of the immediate physiological response to their occurrence, including desaturation, electroencephalography (EEG) arousal, and increased heart rate (HR). Methods: Fifty-eight patients with obstructive sleep apnea (OSA) underwent full diagnostic polysomnography. IFL events and their termination were identified manually using predefined rules from the unscored nasal cannula flow channel alone and were evaluated for responses such as EEG arousal, oxygen desaturation of ⩾3%, and HR increase. Results: Interscorer reliability was acceptable, with an average percent agreement for occurrence of 82% ± 3%. Of all IFL events, 24% (regardless of the definition) were not associated with an EEG arousal, an increase in HR, or O2 desaturation. Of all IFL events scored, 25% caused O2 desaturation, 40% were associated with an EEG arousal, and 55% were associated with an increase in HR; 67% caused either an EEG arousal and/or an increase in HR. Responses were observed to occur either in isolation or in combination. IFL events that terminated with at least two non-IFL breaths, one of which had a 200% increase in amplitude, were significantly associated with O2 desaturation, EEG arousal, and increase in HR compared with events that ended in one non-IFL breath. IFL events that had a >50% reduction in flow amplitude compared with baseline were significantly associated with O2 desaturation compared with events that had a 30% reduction or less. Conclusions: Most IFL events resulted in immediate physiological responses, and no single consequence reliably occurred after every event. We propose a framework that can incorporate the scoring of IFL events into assessing the diagnosis and severity of OSA and suggest that no single consequence be used to define IFL as a respiratory event. The relationship of IFL events to OSA outcomes remains to be tested.