Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

Neuroscience Research Australia, PO Box 1165, Randwick, New South Wales, Australia, 2031, +61 2 9399 1814, +61 2 9399 1027, Brigham and Women's Hospital and Harvard Medical School, Sleep Disorders Program, Division of Sleep Medicine, Boston, Massachusetts, United States
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2013; 188(8). DOI: 10.1164/rccm.201303-0448OC
Source: PubMed


Rationale: The pathophysiological causes of obstructive sleep apnea (OSA) likely vary between patients but have not been well characterized. Objectives: To define carefully the proportion of key anatomical and non-anatomical contributions in a relatively large cohort of OSA patients and controls to identify pathophysiological targets for future novel therapies for OSA. Methods: 75 men and women with and without OSA aged 20-65y were studied on 3 separate nights. Initially, the apnea/hypopnea index was determined via polysomnography followed by determination of anatomical (Pcrit), and non-anatomical (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA. Measurements and Main Results: Pathophysiological traits varied substantially between participants. 36% of OSA patients had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, 36% had high loop gain. 28% had multiple non-anatomical features. While overall the upper-airway was more collapsible in OSA patients (Pcrit; 0.3[-1.5,1.9] vs. -6.2[-12.4,-3.6]cmH2O, P<0.01), 19% had a relatively non-collapsible upper-airway similar to many of the controls (Pcrit; -2 to -5cmH2O). In these patients, loop gain was almost twice as high as patients with a Pcrit>-2cmH2O (-5.9[-8.8,-4.5] vs. -3.2[-4.8,-2.4]dimensionless, P=0.01). A 3-point scale for weighting the relative contribution of the traits is proposed. It suggests that non-anatomical features play an important role in 56% of OSA patients. Conclusions: This study confirms that OSA is a heterogeneous disorder. While Pcrit/anatomy is an important determinant, abnormalities in non-anatomical traits are also present in the majority of OSA patients.

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Available from: Atul Malhotra, Mar 02, 2015
    • "Prior studies aiming at phenotyping OSAS itself have extensively outlined its multi-aspect heterogeneity. More specifically, OSAS has been found to be heterogeneous regarding an anatomical or non-anatomical pathophysiological causality (Eckert et al., 2013), and stratified further by age (Edwards et al., 2014). Mild to moderate OSAS may be comprised of several phenotypes with regard to polysomnographic (PSG) features (Joosten et al., 2012), Finally, OSAS features such as excessive daytime somnolence combined with high diastolic blood pressure may be the hallmarks of a separate phenotype altogether (Wang et al., 2014). "
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    ABSTRACT: Phenotyping obstructive sleep apnea syndrome's comorbidity has been attempted for the first time only recently. The aim of our study was to determine phenotypes of comorbidity in obstructive sleep apnea syndrome patients employing a data-driven approach. Data from 1472 consecutive patient records were recovered from our hospital's database. Categorical principal component analysis and two-step clustering were employed to detect distinct clusters in the data. Univariate comparisons between clusters included one-way analysis of variance with Bonferroni correction and chi-square tests. Predictors of pairwise cluster membership were determined via a binary logistic regression model. The analyses revealed six distinct clusters: A, 'healthy, reporting sleeping related symptoms'; B, 'mild obstructive sleep apnea syndrome without significant comorbidities'; C1 : 'moderate obstructive sleep apnea syndrome, obesity, without significant comorbidities'; C2 : 'moderate obstructive sleep apnea syndrome with severe comorbidity, obesity and the exclusive inclusion of stroke'; D1 : 'severe obstructive sleep apnea syndrome and obesity without comorbidity and a 33.8% prevalence of hypertension'; and D2 : 'severe obstructive sleep apnea syndrome with severe comorbidities, along with the highest Epworth Sleepiness Scale score and highest body mass index'. Clusters differed significantly in apnea-hypopnea index, oxygen desaturation index; arousal index; age, body mass index, minimum oxygen saturation and daytime oxygen saturation (one-way analysis of variance P < 0.0001). Binary logistic regression indicated that older age, greater body mass index, lower daytime oxygen saturation and hypertension were associated independently with an increased risk of belonging in a comorbid cluster. Six distinct phenotypes of obstructive sleep apnea syndrome and its comorbidities were identified. Mapping the heterogeneity of the obstructive sleep apnea syndrome may help the early identification of at-risk groups. Finally, determining predictors of comorbidity for the moderate and severe strata of these phenotypes implies a need to take these factors into account when considering obstructive sleep apnea syndrome treatment options.
    Journal of Sleep Research 09/2015; DOI:10.1111/jsr.12344 · 3.35 Impact Factor
    • "However, there remains an ongoing debate regarding the contribution of induced controller gain abnormalities versus inherent LG traits in OSA [45] [72]. Further work in this area appears to be warranted given elevated LG in many OSA patients [9], CPAP reversal effects, non-CPAP treatment approaches to lower LG [10], and ongoing uncertainty regarding the contribution of inherent plant and controller gain versus induced controller gain abnormalities in OSA. "
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    ABSTRACT: Intermittent hypoxia and unstable breathing are key features of obstructive sleep apnoea (OSA), the most common pathological problem of breathing in sleep. Unstable ventilatory control is characterised by high loop gain (LG), and likely contributes to cyclical airway obstruction by promoting airway collapse during periods of low ventilatory drive. Potential new strategies to treat OSA include manipulations designed to lower LG. However, the contribution of inherent versus induced LG abnormalities in OSA remains unclear. Hence, a better understanding of the mechanisms causing high LG in OSA is needed to guide the design of LG based treatments. OSA patients exhibit abnormal chemoreflex control which contributes to increased LG. These abnormalities have been shown to normalise after continuous positive airway pressure treatment, suggesting induced rather than inherent trait abnormalities. Experimental intermittent hypoxia, mimicking OSA, increases hypoxic chemosensitivity and induces long term facilitation; a sustained increase in ventilatory neural output which outlasts the original stimulus. These neuroplastic changes induce the same abnormalities in chemoreflex control as seen in OSA patients. This review outlines the evidence to support that a key component of high LG in OSA is induced by intermittent hypoxia, and is reversed by simply preventing this inducing stimulus. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Sleep Medicine Reviews 10/2014; 22. DOI:10.1016/j.smrv.2014.10.003 · 8.51 Impact Factor
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    • "The negative pressure reflex is induced by pharyngeal negative pressure and mediated by pharyngeal mechanoreceptors, resulting in phasic muscle activation, that mitigates the tendency for pharyngeal collapse during inspiration (Horner et al., 1991). However, pharyngeal muscle responsiveness to negative pressure varies considerably (Eckert et al., 2013). Therefore, we hypothesized that robust pharyngeal muscle responsiveness to negative pressure could potentially explain why some OSA patients do not exhibit major NED (i.e. "
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    ABSTRACT: The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50 ± 10 years with a BMI of 35 ± 6 kg/m2 and severe OSA (apnea-hypopnea index = 52 ± 28 events/h) were studied. NED and phasic genioglossus muscle activity (EMGGG) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMGGG activity (p < 0.001), but NED worsened only by 3.6 ± 5.8% (p = 0.056). In conclusion, phasic EMGGG had little effect on NED. This finding suggests that individual differences in phasic EMGGG activation do not likely explain the variability in NED found among OSA patients.
    Respiratory Physiology & Neurobiology 09/2014; 201. DOI:10.1016/j.resp.2014.07.005 · 1.97 Impact Factor
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