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Rationale: Randomized trials have shown inconsistent cardiovascular benefits from obstructive sleep apnea (OSA) therapy. Intermittent hypoxemia can increase both sympathetic nerve activity and loop gain ("ventilatory instability"), which may thus herald cardiovascular treatment benefit. Objectives: Test the hypothesis that loop gain predicts changes in 24h-mean blood pressure (Δ24h-MBP) in response to OSA therapy and compare its predictive value against other novel biomarkers. Methods: The HeartBEAT trial assessed the effect of 12 weeks of continuous positive airway pressure (CPAP) vs oxygen vs control on 24h-MBP...

RATIONALE: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. OBJECTIVE: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. METHODS: In 40 patients with suspected or diagnosed OSA (1-98 events/hour), airflow was recorded via pneumotach attached to an oronasal mask, ventilatory drive using calibrated intraesophageal diaphragm electromyography, and snore loudness using a calibrated microphone attached over the trachea...

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies...

RATIONALE: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). Following withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, however, the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whilst negative pressures increase, providing means to assess their individual contributions to the time-course of genioglossus activity...

STUDY OBJECTIVES: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥3%) but not arousal (AHI≥3%Only ) versus events with arousals but no desaturation (AHIArOnly ) with obstructive sleep apnea (OSA)-related comorbidities and incident cardiovascular disease (CVD) across multiple cohorts. METHODS: In the Sleep Heart Health Study (SHHS, N=5473), the Multi-Ethnic Study of Atherosclerosis (MESA, N=1904), and the Osteoporotic Fractures in Men Study (MrOS, N=2685), we examined the independent associations of AHI≥3%Only and AHIArOnly with hypertension, diabetes, and daytime sleepiness, and incident CVD...

RATIONALE: Sleep apnea is the manifestation of key "endotypic traits" including greater pharyngeal collapsibility, reduced dilator muscle compensation and elevated chemoreflex loop gain. OBJECTIVES: We investigate how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index, AHI). METHODS: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N=1971, age: 54-93yr)...

RATIONALE: A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO2-mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing arousal threshold in OSA and subsequently reducing OSA severity. OBJECTIVES: We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes)...

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h). METHODS: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs...

RATIONAL: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Here, in this post-hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pre-treatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes...

BACKGROUND: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements. METHODS: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight...

RATIONALE: Rapid eye movement sleep (REM) is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity versus non-REM (nREM) for reasons not fully elucidated. Here we use direct physiological measurements to determine whether the pharyngeal compromise in REM OSA is most consistent with 1) withdrawal of neural ventilatory drive or 2) deficits in pharyngeal pathophysiology per se (i.e. increased collapsibility, decreased muscle responsiveness). METHODS: 63 OSA participants completed sleep studies with gold-standard measurements of ventilatory "drive" (calibrated intra-esophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG (EMGgg)...

BACKGROUND AND OBJECTIVE: Animal studies indicate that alpha-1 adrenergic receptor agonists and antimuscarinic agents improve genioglossus muscle activity during sleep and may be candidates for the pharmacological treatment of OSA. On the other hand, noradrenergic stimulants may be wake-promoting or cause insomnia symptoms if taken before bedtime, and the addition of a medication with sedative properties, such as an antihistaminic, may reduce these side effects. In this study, we aimed to determine the effects of the combination of an alpha-1 adrenergic agonist (pseudoephedrine) and an antihistaminic-antimuscarinic (diphenhydramine) on OSA severity (AHI), genioglossus responsiveness and other endotypic traits (Vpassive , muscle compensation, LG and arousal threshold)...

Rationale: Randomized controlled trials have been unable to detect a cardiovascular benefit of continuous positive airway pressure in unselected patients with obstructive sleep apnea (OSA). We hypothesize that deleterious cardiovascular outcomes are concentrated in a subgroup of patients with a heightened pulse-rate response to apneas and hypopneas (ΔHR). Methods: We measured the ΔHR in the MESA (Multi-Ethnic Study of Atherosclerosis) ( N  = 1,395) and the SHHS (Sleep Heart Health Study) ( N  = 4,575)...

BACKGROUND: Conventional metrics to evaluate sleep disordered breathing (SDB) have many limitations including their inability to identify subclinical markers of cardiovascular (CV) dysfunction. RESEARCH QUESTION: Does sleep study-derived circulation time (Ct) predict mortality, independent of CV risks and SDB severity? STUDY DESIGN AND METHODS: We derived average lung to finger Ct (LFCT) from sleep studies in older men enrolled in the multi-center Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study...

BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality and although it is linked to sleep apnea, which physiological stressors most strongly associate with incident disease is unclear. We tested whether sleep apnea-specific hypoxic burden (SASHB) predicts incident HF in two independent cohort studies. RESEARCH QUESTION: In comparison with apnea-hypopnea index (AHI), how does sleep apnea-specific hypoxic burden predict incident HF? STUDY DESIGN AND METHODS: The samples were derived from two cohort studies: The Sleep Heart Health Study (SHHS), which included 4,881 middle-aged and older adults (54...

STUDY OBJECTIVES: Oral appliance therapy is an increasingly common option for treating obstructive sleep apnea (OSA) in patients who are intolerant to continuous positive airway pressure (CPAP). Clinically applicable tools to identify patients who could respond to oral appliance therapy are limited. METHODS: Data from three studies (N = 81) were compiled, which included two sleep study nights, on and off oral appliance treatment. Along with clinical variables, airflow features were computed that included the average drop in airflow during respiratory events (event depth) and flow shape features, which, from previous work, indicates the mechanism of pharyngeal collapse...

OBJECTIVES: The bases for sex disparities in obstructive sleep apnea (OSA), is poorly understood. We quantified the influences of event definitions, sleep-state, and body position on apnea-hypopnea indices (AHI) in men and women, and evaluated sex differences in pathophysiological endotypes. METHODS: Polysomnography data were analyzed from 2,057 participants from the Multi-Ethnic Study of Atherosclerosis. Alternative AHIs were compared using various desaturation and arousal criteria...

KEY POINTS: Some patients with obstructive sleep apnoea (OSA) respond well to oral appliance therapy but others do not for reasons that are unclear. In this study we used gold-standard measurements to demonstrate that patients with a posteriorly-located tongue (natural sleep endoscopy) exhibit a preferential improvement in collapsibility (lowered critical closing pressure, Pcrit) with oral appliances. We also show that patients with both posteriorly-located tongue and less severe collapsibility (predicted responder phenotype) exhibit greater improvements in OSA severity (reduction in event frequency by 83%, in contrast to 48% in predicted non-responders)...

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