Pathophysiology of Obstructive Sleep Apnea in Aging Women

AbstractThe following review is designed to explore the pathophysiology of sleep apnea in aging women. The review initially introduces four endotypes (i.e., a more collapsible airway, upper airway muscle responsiveness, arousal threshold, and loop gain) that may have a role in the initiation of obstructive sleep apnea. Thereafter, sex differences in the prevalence of sleep apnea are considered along with differences in the prevalence that exist between younger and older women. Following this discussion, we consider how each endotype might contribute to the increase in prevalence of sleep apnea in aging women. Lastly, we address how modifications in one form of respiratory plasticity, long-term facilitation, that might serve to mitigate apneic events in younger women may be modified in aging women with obstructive sleep apnea. Overall, the published literature indicates that the prevalence of sleep apnea is increased in aging women. This increase is linked primarily to a more collapsible airway and possibly to reduced responsiveness of upper airway muscle activity. In contrast, modifications in loop gain or the arousal threshold do not appear to have a role in the increased prevalence of sleep apnea in aging women. Moreover, we suggest that mitigation of long-term facilitation could contribute to the increased prevalence of sleep apnea in aging women.

O013 The pathogenesis of obstructive sleep apnea in individuals with comorbid insomnia and obstructive sleep apnoea (COMISA)

SLEEP Advances ◽

10.1093/sleepadvances/zpab014.012 ◽

2021 ◽

Vol 2 (Supplement_1) ◽

pp. A6-A7

Author(s):

E Brooker ◽

L Thomson ◽

S Landry ◽

B Edwards ◽

S Drummond

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Severity Index ◽

Loop Gain ◽

Comorbid Insomnia ◽

Arousal Threshold ◽

Obstructive Sleep ◽

High Loop ◽

Insomnia Severity

Abstract Obstructive sleep apnea (OSA) and Insomnia are prevalent sleep disorders which are highly comorbid. This frequent co-occurrence suggests a shared etiology may exist. OSA is caused by the interaction of four pathophysiological traits: a highly collapsible upper airway, elevated loop gain, a low arousal threshold, and poor muscle compensation. No study has ascertained whether these traits are influenced by insomnia. We aimed to quantify the four traits which contribute to OSA in individuals diagnosed with comorbid insomnia and OSA (COMISA). We non-invasively determined these traits in 52 COMISA patients (Age: 56±14 years) with mild-to-severe OSA (AHI=21.2±10.63 events/h) using polysomnography. Our results indicated that 83% of COMISA patients had a low arousal threshold and only 2% of patients exhibited a highly collapsible airway using previously defined thresholds. Multiple linear regression revealed the arousal threshold (b=0.24, 95%CI[0.11, 0.37], β=0.47, p<0.001) and loop gain (b=23.6, 95%CI[7.02, 40.18], β=0.33, p<0.01) were the strongest predictors of OSA severity in our sample. There was no significant relationship between the arousal threshold and insomnia severity measured by the insomnia severity index (ISI). Further work is being performed to compare these findings with a matched sample of OSA only participants. Our preliminary findings demonstrate OSA in COMISA is characterized by a mildly collapsible airway/low arousal threshold phenotype and is largely driven by non-anatomical factors including a low arousal threshold and high loop gain. OSA treatments which are effective in patients with mild anatomical compromise and raise the arousal threshold may provide therapeutic benefit in COMISA patients.

Targeting Endotypic Traits with Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the Current Literature

Journal of Clinical Medicine ◽

10.3390/jcm8111846 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1846 ◽

Cited By ~ 7

Author(s):

Taranto-Montemurro ◽

Messineo ◽

Wellman

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Muscle Activity ◽

Upper Airway ◽

Loop Gain ◽

Arousal Threshold ◽

The Past ◽

Obstructive Sleep ◽

Near Future ◽

Made In

Obstructive sleep apnea (OSA) is a highly prevalent condition with few therapeutic options. To date there is no approved pharmacotherapy for this disorder, but several attempts have been made in the past and are currently ongoing to find one. The recent identification of multiple endotypes underlying this disorder has oriented the pharmacological research towards tailored therapies targeting specific pathophysiological traits that contribute differently to cause OSA in each patient. In this review we retrospectively analyze the literature on OSA pharmacotherapy dividing the medications tested on the basis of the four main endotypes: anatomy, upper airway muscle activity, arousal threshold and ventilatory instability (loop gain). We show how recently introduced drugs for weight loss that modify upper airway anatomy may play an important role in the management of OSA in the near future, and promising results have been obtained with drugs that increase upper airway muscle activity during sleep and reduce loop gain. The lack of a medication that can effectively increase the arousal threshold makes this strategy less encouraging, although recent studies have shown that the use of certain sedatives do not worsen OSA severity and could actually improve patients’ sleep quality.

Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity

10.1152/japplphysiol.01074.2020 ◽

2021 ◽

Author(s):

Atqiya Aishah ◽

Richard Lim ◽

Scott A. Sands ◽

Luigi Taranto-Montemurro ◽

Andrew Wellman ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Loop Gain ◽

Double Blind ◽

Receptor Selectivity ◽

Arousal Threshold ◽

Solifenacin Succinate ◽

Obstructive Sleep ◽

Airway Physiology

The combination of the noradrenergic agent atomoxetine plus the anti-muscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different anti-muscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different anti-muscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology.10 people with predominantly severe OSA completed a double-blind, randomised, placebo-controlled, cross-over trial. Participants completed 3 overnight in-laboratory sleep studies after either 80mg atomoxetine+5mg solifenacin succinate (ato-sol) or 80mg atomoxetine+2mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next day subjective sleepiness (Karolinska Sleepiness Scale:KSS) and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnoea index versus placebo (p=0.63). Ato-sol caused a shift towards milder respiratory events with reduced frequency of obstructive apneas (13±14vs. 22±17events/h; mean±SD, p=0.04) and increased hypopneas during NREM (38±21vs. 24±18events/h, p=0.006) with improved nadir oxygenation versus placebo (83±4vs. 80±8%, p=0.03). Both combinations reduced loop gain by ~10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS=4.3±2.2vs. 5.6±1.6, p=0.03).Atomoxetine+biperiden hydrochloride reduces perceived sleepiness and atomoxetine+solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine+oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and anti-muscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.

The influence of episodic hypoxia on upper airway collapsibility in subjects with obstructive sleep apnea

10.1152/japplphysiol.01117.2006 ◽

2007 ◽

Vol 103 (3) ◽

pp. 911-916 ◽

Cited By ~ 18

Author(s):

James A. Rowley ◽

Ihab Deebajah ◽

Swapna Parikh ◽

Ali Najar ◽

Rajib Saha ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Obstructive Sleep ◽

Airway Collapsibility ◽

Episodic Hypoxia ◽

Before And After ◽

Upper Airway Collapsibility ◽

We have previously shown that in subjects with obstructive sleep apnea, repetitive hypoxia is associated with long-term facilitation as manifested by decreased upper airway resistance (Rua). Our objective was to study the influence of long-term facilitation on upper airway collapsibility as measured by the critical closing pressure (Pcrit) model and to determine whether changes in Rua correlated with changes in collapsibility. We studied 13 subjects (10 men, 3 women) with a mean apnea-hypopnea index of 43.9 ± 24.0 events/h. In the first protocol with 11 subjects, we measured collapsibility using a Pcrit protocol before and after episodic hypoxia. Brief (3 min) isocapnic hypoxia (inspired O2 fraction = 8%) followed by 5 min of room air was induced 10 times. A sham study without hypoxia was performed on eight subjects. Ventilatory parameters, Rua, and Pcrit before and after episodic hypoxia were measured. At 20 min of recovery, there was no change in minute ventilation but there was a significant decrease in Rua compared with the control period (control, 8.6 ± 4.8 cmH2O·l−1·s vs. recovery, 5.9 ± 3.8 cmH2O·l−1·s; P < 0.05). However, there was no change in Pcrit between the control (2.3 ± 1.9 cmH2O) and recovery (2.7 ± 3.2 cmH2O) periods. No changes in Rua or Pcrit were observed in the sham protocol. We conclude that long-term facilitation of upper airway dilators is not associated with changes in upper airway collapsibility in subjects with obstructive sleep apnea. These results corroborate previous evidence that changes in upper airway resistance and caliber can be dissociated from changes in upper airway collapsibility.

Long-term facilitation in obstructive sleep apnea patients during NREM sleep

10.1152/jappl.2001.91.6.2751 ◽

2001 ◽

Vol 91 (6) ◽

pp. 2751-2757 ◽

Cited By ~ 59

Author(s):

Salah E. Aboubakr ◽

Amy Taylor ◽

Reason Ford ◽

Sarosh Siddiqi ◽

M. Safwan Badr

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Recovery Period ◽

Upper Airway ◽

Flow Limitation ◽

Inspiratory Time ◽

Nasal Cpap ◽

Obstructive Sleep ◽

Repetitive hypoxia followed by persistently increased ventilatory motor output is referred to as long-term facilitation (LTF). LTF is activated during sleep after repetitive hypoxia in snorers. We hypothesized that LTF is activated in obstructive sleep apnea (OSA) patients. Eleven subjects with OSA (apnea/hypopnea index = 43.6 ± 18.7/h) were included. Every subject had a baseline polysomnographic study on the appropriate continuous positive airway pressure (CPAP). CPAP was retitrated to eliminate apnea/hypopnea but to maintain inspiratory flow limitation (sham night). Each subject was studied on 2 separate nights. These two studies are separated by 1 mo of optimal nasal CPAP treatment for a minimum of 4–6 h/night. The device was capable of covert pressure monitoring. During night 1 (N1), study subjects used nasal CPAP at suboptimal pressure to have significant air flow limitation (>60% breaths) without apneas/hypopneas. After stable sleep was reached, we induced brief isocapnic hypoxia [inspired O2 fraction (Fi O2 ) = 8%] (3 min) followed by 5 min of room air. This sequence was repeated 10 times. Measurements were obtained during control, hypoxia, and at 5, 20, and 40 min of recovery for ventilation, timing ( n = 11), and supraglottic pressure ( n = 6). Upper airway resistance (Rua) was calculated at peak inspiratory flow. During the recovery period, there was no change in minute ventilation (99 ± 8% of control), despite decreased Rua to 58 ± 24% of control ( P < 0.05). There was a reduction in the ratio of inspiratory time to total time for a breath (duty cycle) (0.5 to 0.45, P < 0.05) but no effect on inspiratory time. During night 2 (N2), the protocol of N1 was repeated. N2 revealed no changes compared with N1 during the recovery period. In conclusion, 1) reduced Rua in the recovery period indicates LTF of upper airway dilators; 2) lack of hyperpnea in the recovery period suggests that thoracic pump muscles do not demonstrate LTF; 3) we speculate that LTF may temporarily stabilize respiration in OSA patients after repeated apneas/hypopneas; and 4) nasal CPAP did not alter the ability of OSA patients to elicit LTF at the thoracic pump muscle.

Long-term Follow-up of the German Post-Market-Study for Upper Airway Stimulation for Obstructive Sleep Apnea

10.1055/s-0040-1711408 ◽

2020 ◽

Author(s):

S Jeschke ◽

J. Ulrich Sommer ◽

Joachim T. Maurer ◽

A Steffen ◽

B Hofauer ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Upper Airway Stimulation ◽

Obstructive Sleep ◽

Post Market ◽

Long Term Follow Up

0710 Hypoglossal Neurostimulation In Rem- Vs. Nrem-predominant Obstructive Sleep Apnea

SLEEP ◽

10.1093/sleep/zsaa056.706 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A270-A270

Author(s):

C I Cabrera ◽

B Szelestey ◽

K Strohl ◽

A Schell

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Univariate Analysis ◽

Disease Process ◽

Loop Gain ◽

Upper Airway Stimulation ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Baseline Characteristics ◽

Star Trial

Abstract Introduction Obstructive sleep apnea (OSA) is a chronic condition that requires appropriate treatment strategies to optimize outcomes while minimizing risk. In addition to anatomy, physiologic factors such as arousal threshold and loop gain (i.e. “endotypes”) play a known role in the disease process. Because loop gain tends to be higher and arousal threshold lower in NREM sleep, we hypothesize that patients with NREM-predominance may achieve less success with anatomical therapy such as upper airway stimulation (UAS). Our study aims to evaluate baseline characteristics and objective results related to NREM-predominance in patients treated with UAS. Methods Using data from the STAR trial, we identified patients (n=103) with at least 20 minutes of REM on baseline testing and complete demographic and disease data at baseline and month 18. Baseline NREM-predominant disease (percent NREM events > 50) was defined as a binary variable. We created two cohorts: 1) patients with REM-predominant disease and 2) those with NREM-predominant disease. ODI and AHI were evaluated at month 18. Results Overall 62% (n=64) of patients had NREM-predominant disease at baseline. Other baseline characteristics were similar between both groups. In univariate analysis, age was significantly associated with lower AHI in the NREM-predominant population (p<0.05) but not in the REM-predominant group (p>0.05). Results were similar for ODI. For both groups, increasing age was correlated negatively with increasing AHI; this correlation was stronger in the NREM-predominant group Conclusion A majority of patients in the STAR trial had NREM-predominant OSA at baseline. There appears to be an interaction between NREM-predominance and age as predictors of UAS outcomes. Support

Longitudinal Association between Growth Hormone Therapy and Obstructive Sleep Apnea in a Child with Prader-Willi Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-1445 ◽

2011 ◽

Vol 96 (1) ◽

pp. 29-33 ◽

Cited By ~ 18

Author(s):

Gillian M. Nixon ◽

Christine P. Rodda ◽

Margot J. Davey

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Prader Willi Syndrome ◽

Upper Respiratory Tract ◽

Gh Treatment ◽

Obstructive Sleep ◽

Longitudinal Association ◽

Tract Infections

Context: Descriptions of the development of symptoms of upper airway obstruction and sudden death of children with Prader-Willi Syndrome (PWS) while on GH therapy have led to concern about GH contributing to obstructive sleep apnea (OSA), especially early in treatment. However, two studies using monitoring with polysomnography (PSG) have not shown deterioration in OSA after 6 wk on GH, except as related to upper respiratory tract infections. Objective: The aim was to describe the evolution of OSA in a girl with PWS on GH treatment in order to highlight important aspects of long-term clinical monitoring for patients with PWS on GH treatment. Patient and Research Design: GH was commenced when the patient was 2.9 yr of age. PSG was performed at baseline and 7 wk after commencing GH, plus at intervals throughout treatment based on symptoms of OSA. Intervention: GH was given at doses ranging from 4.2 to 4.7 mg/m2 · wk over a period of 3 yr. Main Outcome Measure: OSA was quantified by PSG. Results: OSA was not present at baseline or after 7 wk on GH but developed after 6 months, following a small increase in GH dose. Cessation of GH was accompanied by resolution of OSA. GH was restarted 2 yr later, again associated with the development of OSA that resolved after cessation of GH. Conclusion: This case highlights that OSA may develop late in GH treatment. Children should be monitored for the symptoms of OSA throughout GH treatment, and PSG should be repeated if symptoms develop.

Chronic Intermittent Hypoxia Induces the Long-Term Facilitation of Genioglossus Corticomotor Activity

Canadian Respiratory Journal ◽

10.1155/2018/5941429 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Ying Zou ◽

Wei Wang ◽

Xinshi Nie ◽

Jian Kang

Keyword(s):

Obstructive Sleep Apnea ◽

Intermittent Hypoxia ◽

Magnetic Stimulation ◽

Upper Airway ◽

Emg Activity ◽

Chronic Intermittent Hypoxia ◽

Experimental Conditions ◽

Obstructive Sleep ◽

Obstructive sleep apnea (OSA) is characterized by the repetitive collapse of the upper airway and chronic intermittent hypoxia (CIH) during sleep. It has been reported that CIH can increase the EMG activity of genioglossus in rats, which may be related to the neuromuscular compensation of OSA patients. This study aimed to explore whether CIH could induce the long-term facilitation (LTF) of genioglossus corticomotor activity. 16 rats were divided into the air group (n=8) and the CIH group (n=8). The CIH group was exposed to hypoxia for 4 weeks; the air group was subjected to air under identical experimental conditions in parallel. Transcranial magnetic stimulation (TMS) was applied every ten minutes and lasted for 1 h/day on the 1st, 3rd, 7th, 14th, 21st, and 28th days of air/CIH exposure. Genioglossus EMG was also recorded at the same time. Compared with the air group, the CIH group showed decreased TMS latency from 10 to 60 minutes on the 7th, 14th, 21st, and 28th days. The increased TMS amplitude lasting for 60 minutes was only observed on the 21st day. Genioglossus EMG activity increased only on the 28th day of CIH. We concluded that CIH could induce LTF of genioglossus corticomotor activity in rats.

Variations in loop gain and arousal threshold during NREM sleep are affected by time of day over a 24-hour period in participants with obstructive sleep apnea

10.1152/japplphysiol.00376.2020 ◽

2020 ◽

Vol 129 (4) ◽

pp. 800-809

Author(s):

Shipra Puri ◽

Mohamad El-Chami ◽

David Shaheen ◽

Blake Ivers ◽

Gino S. Panza ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Nrem Sleep ◽

Time Of Day ◽

Loop Gain ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Critical Closing Pressure ◽

Chemoreflex Sensitivity ◽

Closing Pressure

Loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep are greater in the morning compared with the afternoon and evening. Loop gain measures are correlated to chemoreflex sensitivity and the critical closing pressure measured during NREM sleep in the evening, morning, and afternoon. Breathing (in)stability and efficaciousness of treatments for obstructive sleep apnea may be modulated by a circadian rhythmicity in loop gain and the arousal threshold.