Rationale: Symptom subtypes have been described in clinical and population samples of patients with obstructive sleep apnea (OSA). It is unclear whether these subtypes have different cardiovascular consequences. Objectives: To characterize OSA symptom subtypes and assess their association with prevalent and incident cardiovascular disease in the Sleep Heart Health Study. Methods: Data from 1,207 patients with OSA (apnea-hypopnea index > 15 events/h) were used to evaluate the existence of symptom subtypes using latent class analysis. Associations between subtypes and prevalence of overall cardiovascular disease and its components (coronary heart disease, heart failure, and stroke) were assessed using logistic regression. Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate whether subtypes were associated with incident events, including cardiovascular mortality. Measurements and Main Results: Four symptom subtypes were identified (disturbed sleep [12.2%], minimally symptomatic [32.6%], excessively sleepy [16.7%], and moderately sleepy [38.5%]), similar to prior studies. In adjusted models, although no significant associations with prevalent cardiovascular disease were found, the excessively sleepy subtype was associated with more than threefold increased risk of prevalent heart failure compared with each of the other subtypes. Symptom subtype was also associated with incident cardiovascular disease (P , 0.001), coronary heart disease (P = 0.015), and heart failure (P = 0.018), with the excessively sleepy again demonstrating increased risk (hazard ratios, 1.7-2.4) compared with other subtypes. When compared with individuals without OSA (apnea-hypopnea index , 5), significantly increased risk for prevalent and incident cardiovascular events was observed mostly for patients in the excessively sleepy subtype. Conclusions: OSA symptom subtypes are reproducible and associated with cardiovascular risk, providing important evidence of their clinical relevance.

SUMMARY Increasing data support a connection between obstructive sleep apnea (OSA) and cognitive impairment but a causal link has yet to be established. Although neuronal loss has been linked to cognitive impairment, emerging theories propose that changes in synaptic plasticity can cause cognitive impairment. Studies demonstrate that disruption to the blood–brain barrier (BBB), which is uniquely structured to tightly maintain homeostasis inside the brain, leads to changes in the brain’s microenvironment and affects synaptic plasticity. Cyclical intermittent hypoxia is a stressor that could disrupt the BBB via molecular responses already known to occur in either OSA patients or animal models of intermittent hypoxia. However, we do not yet know if or how intermittent hypoxia can cause cognitive impairment by mechanisms operating at the BBB. Therefore, we propose that initially, adaptive homeostatic responses at the BBB occur in response to increased oxygen and nutrient demand, specifically through regulation of influx and efflux BBB transporters that alter microvessel permeability. We further hypothesize that although these responses are initially adaptive, these changes in BBB transporters can have long-term consequences that disrupt the brain’s microenvironment and alter synaptic plasticity leading to cognitive impairment.

The impact of advances in sleep and circadian sciences over the last 20 years on medicine, health, and public safety has been limited in part by the lack of availability of objective tools capable of quantifying sleep and circadian function in point-of-care (p-o-c) settings. This whitepaper is a product of a workshop that was designed to bring together thoughtleaders in biomarker development, experts in sleep-circadian biology and sleep disorders to identify barriers and opportunities informing the future development of p-o-c diagnostic tools. The workshop entitled, "Developing Biomarker Arrays Predicting Sleep and Circadian-Coupled Risks to Health," was held in Bethesda April 27-28 2015, and was jointly sponsored by the National Heart Lung and Blood Institute, National Institute on Aging and the Sleep Research Society (hereafter referred to as the biomarker workshop, (http:// www.nhlbi.nih.gov/research/reports). The Sleep Research Society supported a number of early career investigators to attend the workshop. They contributed to the writing of this whitepaper. A biomarker is a "biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, condition or disease." 1,2 For the purpose of this whitepaper, "biomarkers" include quantifiable molecules and chemical properties of easily accessible biological samples (e.g., blood, urine, saliva). An ultimate goal is the development of robust and practical approaches for p-o-c or contact implementation in population-based research and most importantly, for clinical applications to enhance sleep and circadian health.Biomarkers to assess current alertness status, sleep health and circadian function are needed for: research to further understanding of sleep and circadian health science, p-o-c diagnosis of sleep and circadian disorders, for prognosis and to evaluate the risk of associated heart, lung, blood, and aging diseases and disorders, and to assess the adequacy of therapy. The ideal biomarker would show high sensitivity (correctly identify the state and degree of acute sleep loss, and possibly even duration that such a status has been ongoing), specificity (correctly identify the presence/absence of a chronic sleep deficiency, such as would be useful in an annual primary care medical visit). However, the field is currently without any viable biomarkers measurable in easily accessible bio-specimens. The availability of objective platforms capable of quantifying