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Traditionally, the presence and severity of obstructive sleep apnea (OSA) have been defined by the apnea-hypopnea index (AHI). Continuous positive airway pressure is generally first-line therapy despite low adherence, because it reliably reduces the AHI when used, and the response to other therapies is variable. However, there is growing appreciation that the underlying etiology (i.e., endotype) and clinical manifestation (i.e., phenotype) of OSA in an individual are not well described by the AHI. We define and review the important progress made in understanding and measuring physiological mechanisms (or endotypes) that help define subtypes of OSA and identify the potential use of genetics to further refine disease classification. This more detailed understanding of OSA pathogenesis should influence clinical treatment decisions as well as help inform research priorities and clinical study design. In short, treatments could be individualized on the basis of the underlying cause of OSA; patients could better understand which symptoms and outcomes will respond to OSA treatment and by how much; and researchers could select populations most likely to benefit from specific treatment approaches for OSA.

There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato-oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately. The participants' median (interquartile range) age was 53 (46-58) years and body mass index was 34.8 (30.0-40.2) kg/m . ato-oxy lowered AHI by 63% (34-86%), from 28.5 (10.9-51.6) events/h to 7.5 (2.4-18.6) events/h (  < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62-88%) (  < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1-4.7)%/cm H O on placebo to 6.3 (3.0 to 18.3)%/cm H O on ato-oxy (  < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registered with www.clinicaltrials.gov (NCT02908529).

Abstract Study Objectives Precision medicine for obstructive sleep apnea (OSA) requires noninvasive estimates of each patient’s pathophysiological “traits.” Here, we provide the first automated technique to quantify the respiratory arousal threshold—defined as the level of ventilatory drive triggering arousal from sleep—using diagnostic polysomnographic signals in patients with OSA. Methods Ventilatory drive preceding clinically scored arousals was estimated from polysomnographic studies by fitting a respiratory control model (Terrill et al.) to the pattern of ventilation during spontaneous respiratory events. Conceptually, the magnitude of the airflow signal immediately after arousal onset reveals information on the underlying ventilatory drive that triggered the arousal. Polysomnographic arousal threshold measures were compared with gold standard values taken from esophageal pressure and intraoesophageal diaphragm electromyography recorded simultaneously (N = 29). Comparisons were also made to arousal threshold measures using continuous positive airway pressure (CPAP) dial-downs (N = 28). The validity of using (linearized) nasal pressure rather than pneumotachograph ventilation was also assessed (N = 11). Results Polysomnographic arousal threshold values were correlated with those measured using esophageal pressure and diaphragm EMG (R = 0.79, p < .0001; R = 0.73, p = .0001), as well as CPAP manipulation (R = 0.73, p < .0001). Arousal threshold estimates were similar using nasal pressure and pneumotachograph ventilation (R = 0.96, p < .0001). Conclusions The arousal threshold in patients with OSA can be estimated using polysomnographic signals and may enable more personalized therapeutic interventions for patients with a low arousal threshold.

Background Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea (‘silent hypoxemia’) in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). Methods Patients with COVID-19 ( N  = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation ( mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration ). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls ( N  = 23) provided a normative comparison. Results The adverse composite outcome (observed in N  = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p  = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p  = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p  = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. Conclusions Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

Excess adiposity is a reversible etiologic risk factor for obstructive sleep apnea. In this trial, tirzepatide reduced the apnea–hypopnea index of participants with obstructive sleep apnea and obesity.

Surgical interventions, like barbed reposition pharyngoplasty (BRP), are a valuable alternative for patients with obstructive sleep apnea (OSA) who are unable to tolerate continuous positive airway pressure (CPAP). However, predicting surgical success remains challenging, partly due to the contribution of non-anatomical factors. Therefore, combined medical treatment with acetazolamide, known to stabilize respiratory drive, may lead to superior surgical results. This double-blind, parallel-group randomized controlled trial evaluates the efficacy of acetazolamide as an add-on therapy to BRP in OSA. A total of 26 patients with moderate to severe OSA undergoing BRP were randomized to receive either acetazolamide or placebo post-surgery for 16 weeks. The group who was treated with BRP in combination with acetazolamide showed a reduction in AHI of 69.4%, significantly surpassing the 32.7% reduction of the BRP + placebo group (p < 0.01). The sleep apnea-specific hypoxic burden also decreased significantly in the group who was treated with BRP + acetazolamide (p < 0.01), but not in the group receiving BRP + placebo (p = 0.28). Based on these results, acetazolamide as an add-on therapy following BRP surgery shows promise in improving outcomes for OSA patients, addressing both anatomical and non-anatomical factors.

The overlap syndrome (OVS), defined as coexisting chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), is linked to worse outcomes than either condition alone. Patients with COPD and OSA may have fewer obstructive events, but underlying mechanisms remain unclear. Using a large clinical cohort, we tested the hypothesis that OSA severity and pathophysiological traits differ in OVS versus OSA‐alone. Data from the SNOOzzzE cohort (3319 adults with in‐laboratory polysomnography 2017–2019) were used. OVS patients were identified through chart review and matched to OSA‐only patients (3:1) by age, sex, and body mass index. OSA severity was assessed using apnea hypopnea index (AHI), hypoxic burden (HB), and T90 (%time with SpO2 < 90%), while OSA traits were quantified from polysomnographic signals via validated algorithms. Mixed model analysis quantified group differences before and after adjustment for covariate differences (Black race, smoking) accounting for matching as a random effect. In our diverse cohort (103 OVS vs. 309 OSA‐only; 38% women, 44% non‐White, 17% Hispanic), OVS patients tended to have a lower AHI and HB (approximately −10%, p < 0.1), but significantly higher T90 (~50%, p = 0.003). OVS patients had less upper airway collapsibility, lower arousal threshold, lower ventilatory response to arousal (p < 0.05) and tended to have higher upper airway dilator muscle compensation (p = 0.09). In adjusted analyses, effect estimates were similar, but significance was attenuated. Hyperinflation and air trapping were inversely associated with AHI/HB. OSA severity and mechanisms differ in OVS versus OSA‐only. Future research should seek to evaluate these differences for their prognostic ability.

Key words: pathophysiology; endotypes; precision medicine

Therapies for obstructive sleep apnea (OSA) could be administered on the basis of a patient's own phenotypic causes (\"traits\") if a clinically applicable approach were available. Here we aimed to provide a means to quantify two key contributors to OSA-pharyngeal collapsibility and compensatory muscle responsiveness-that is applicable to diagnostic polysomnography. Based on physiological definitions, pharyngeal collapsibility determines the ventilation at normal (eupneic) ventilatory drive during sleep, and pharyngeal compensation determines the rise in ventilation accompanying a rising ventilatory drive. Thus, measuring ventilation and ventilatory drive (e.g., during spontaneous cyclic events) should reveal a patient's phenotypic traits without specialized intervention. We demonstrate this concept in patients with OSA (N = 29), using a novel automated noninvasive method to estimate ventilatory drive (polysomnographic method) and using \"gold standard\" ventilatory drive (intraesophageal diaphragm EMG) for comparison. Specialized physiological measurements using continuous positive airway pressure manipulation were employed for further comparison. The validity of nasal pressure as a ventilation surrogate was also tested (N = 11). Polysomnography-derived collapsibility and compensation estimates correlated favorably with those quantified using gold standard ventilatory drive (R = 0.83, P < 0.0001; and R = 0.76, P < 0.0001; respectively) and using continuous positive airway pressure manipulation (R = 0.67, P < 0.0001; and R = 0.64, P < 0.001; respectively). Polysomnographic estimates effectively stratified patients into high versus low subgroups (accuracy, 69-86% vs. ventilatory drive measures; P < 0.05). Traits were near-identical using nasal pressure versus pneumotach (N = 11, R ≥ 0.98, both traits; P < 0.001). Phenotypes of pharyngeal dysfunction in OSA are evident from spontaneous changes in ventilation and ventilatory drive during sleep, enabling noninvasive phenotyping in the clinic. Our approach may facilitate precision therapeutic interventions for OSA.

Obstructive sleep apnea is a risk factor for mortality, but its diagnostic metric-the apnea-hypopnea index-is a poor risk predictor. The apnea-hypopnea index does not capture the range of physiological variability within and between patients, such as degree of hypoxemia and sleep fragmentation, that reflect differences in pathophysiological contributions of airway collapsibility, chemoreceptive negative feedback loop gain, and arousal threshold. To test whether respiratory event duration, a heritable sleep apnea trait reflective of arousal threshold, predicts all-cause mortality. Mortality risk as a function of event duration was estimated by Cox proportional hazards in the Sleep Heart Health Study, a prospective community-based cohort. Gender-specific hazard ratios were also calculated. Among 5,712 participants, 1,290 deaths occurred over 11 years of follow-up. After adjusting for demographic factors (mean age, 63 yr; 52% female), apnea-hypopnea index (mean, 13.8; SD, 15.0), smoking, and prevalent cardiometabolic disease, individuals with the shortest-duration events had a significant hazard ratio for all-cause mortality of 1.31 (95% confidence interval, 1.11-1.54). This relationship was observed in both men and women and was strongest in those with moderate sleep apnea (hazard ratio, 1.59; 95% confidence interval, 1.11-2.28). Short respiratory event duration, a marker for low arousal threshold, predicts mortality in men and women. Individuals with shorter respiratory events may be predisposed to increased ventilatory instability and/or have augmented autonomic nervous system responses that increase the likelihood of adverse health outcomes, underscoring the importance of assessing physiological variation in obstructive sleep apnea.