Pathophysiology of adult obstructive sleep apnea
Pathophysiology of Adult Obstructive Sleep Apnea Danny J. Eckertl and Atul Malhotra1,2 1 Division of Sleep Medicine, Sleep Disorders Program, Brigham and Women’s Hospital, and Harvard Medical School; and 2Division of Pulmonary/Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Obstructive sleep apnea (OSA) is a common disorder characterized by repetitive narrowing or colapse of the pharyngeal airway during sleep.
The disorder is associated with major comorbidities including excessive daytime sleepiness and increased risk of orao pathophysiology is m ifa between individuals. ale sex, and aging. underlying these risk he underlying considerably clude obesity, cal mechanisms nderstood. This brief review summarizes the current understanding of OSA pathophysiology in adults and highlights the potential mechanisms underlying the principal risk factors. In addition, some ofthe pathophysiological characteristics associated with OSA that may modulate disease severity are illustrated.
Finally, the potential for novel treatment strategies, based on an improved understanding of the underlying pathophysiology, is also discussed with the ultimate aim of stimulating research deas in areas where knowledge is lacking. Keywords: arousal; genioglossus; lung volume; upper airway; ventilatory control stabillty Obstructive sleep apnea (OSA) is characterized by recurrent collapse of the pharyngeal airway during sleep, resulting in sub substantially reduced (hypopnea) or complete cessation (apnea) of airflow despite ongoing breathing efforts.
These disruptions to breathing lead to intermittent blood gas disturbances (hypercapnia and hypoxemia) and surges of sympathetic activation. Loud snoring is a typical feature of OSA and in most cases the culmination of a respiratory event is associated with brief awakening from sleep (arousal). These events result in a cyclical breathing pattern and fragmented sleep as the patient oscillates between wakefulness and sleep. In severe cases respiratory events can occur more than 100 times per hour and typically each event lasts 20-40 seconds (see Figure 1 for an example).
OSA is associated with major comorbidities includlng daytme somnolence, impaired cognition, poor qualiõy of life, and increased risk of motor vehicle accidents. There is emerging evidence to suggest that OSA is an independent risk factor for a variety of adverse cardiovascular outcomes (1, 2). The linical disorder, defined as more than five abnormal breathing disturbances (hypopneas or apneas) per hour of sleep combined with symptoms of daytime sleepiness, affects at least 2-4% ofthe adult population (3).
Although nonobese individuals may suffer fram OSA, obesity is the main epidemiologic risk factor. Indeed, increases in body mass index, central accumulation of adipose tissue, and neck circumference are strong predictors of disease (4). Further, the prevalence of OSA is two to three times greater in men than in women (3, 5, 6) and in older individuals (>65 yr) compared with middle-aged individuals (30-64yr) (7). The athophysiological causes of OSA likely vary considerably b PAGF middle-aged individuals (30-64 yr) (7). The pathophysiological causes of OSA likely vary considerably between individuals.
Important components likely include upper airway anatomy, the ability of the upper ain,uay dilator muscles to respond to respiratory challenge during sleep, the propensity to wake from increased respiratory drive during sleep (arousal threshold), the stability of the respiratory control system (loop gain), and the potential for state-related changes in lung volume to influence these factors. These various physiological traits and the potential or each to influence sleep apnea pathophysiology have been described in detail in review articles (8-10).
The focus of the current article is to (1) briefly review the key physiological factors, dlscuss how they may interact with one another, and highlight advances in our understanding of OSA pathogenesis; (2) discuss the potential physiological mechanisms underlying the key epidemiologic risk factors for OSA; (3) highlight some of the physiological factors associated with OSA that may modulate disease severity; and (4) briefly discuss potential treatment strategies according to the various underlying physiological auses of OSA.
Upper Airway Anatomy (Received in original form July 31, 2007; accepted in final form August 22, 2007) Supported by the Thoracic Society of Australia and by a New Zealand/AIlen and Hanburys respiratory research fellowship (D. J. E. ) and by NIH grants P50 HL060292-0g, AG024837-01, and ROI-HL73146 (A. M. ). correspondence and requests for reprints should be addressed to Danny Eckert, Ph. D. , Brigham and Women’s Hospital, DIViSlon of Sleep Medicine, Danny Eckert, Ph. D. , Brigham and Women’s Hosptal, Division of Sleep Medicine, Sleep Disorders Program, BIDMC, 75 Francis Street, Boston, MA 02115.
E-mail: deckert@rics. bwh. harvard. edu proc Am Thorac soc vol 5. pp 144-153, 2008 001: 200707-114MG Internet address: www. atsjournals. org The human upper airway is a unique multipurpose structure involved in performing functional tasks such as speech, swallowing of food/liquids, and the passage of air for breathing. The anatomy and neural control ofthe upper airway have evolved to enable these various functions. The airway, therefore, is composed of numerous muscles and soft tissue but lacks rigid or bony support. Most notably, it contains a collapsible portion that xtends from the hard palate to the larynx.
Although the ability of the upper airway to change shape and momentarily close is essential for speech and swallowing during wakefulness, this feature also provides the opportunity for collapse at inopportune times such as during sleep. From a purely anatomic perspective, a narrow upper airway is generally more prone to collapse than a larger one. Accordingly, on the whole, the cross-sectional area of the upper airway as measured by computed tomography and magnetic resonance imaging during wakefulness is reduced in patients with OSA compared with subjects without OSA (11- 13).
Further, the arrangement of the surrounding soft tissues appears to be altered in patients with OSA which may place the upper airway at risk for collapse (1 1 Imaging studies during wakefulness, however, are complicated to interpret because ongoing upper airvuay dilator muscle activity may lead to potential differen to interpret because ongoing upper airway dilator muscle activity may lead to potential differences between groups, due to factors other than anatomy.
In addition to these imaging measures, a methodology to determine the pressure at which the upper airway collapses during sleep (Pcrit) as a gauge of passive upper irway anatomy is also in concordance with reduced upper airway caliber in patients with OSA (14, 15). Perhaps the most definitive data come from Isono and colleagues, who observed increased Eckert and Malhotra: Pathophysiology of Adult OSA 145 Figure 1.
Polysomnographic tracings of obstructive sleep apnea from a detailed experimental study of a patient with severe disease (apnea-hypopnea index 5 56 events/h). EMGgg 5 Electromyogram of the genioglossus muscle (intramuscular); EMGsub 5 EMG of the submental muscle (surface); EEG 5 electroencephalogram (C3- A2); Pepi 5 pressure at the level f the epiglottis; Flow 5 airflow measured via nasal mask and pneumotachograph; Sa02 5 arterial blood oxygen saturation measured via pulse oximetry at the finger. A) An 8-minute segment during stage 2 sleep, during which the patient is experiencing sleep-disordered breathing. Note the repeated oxygen desaturations as a result of severely impaired (hypopnea) or absent (apnea) airflow despite continual breathing efforts (Pepi) and the cyclical breathing pattern that ensues as the patient oscillates between sleep and arousal (downward pointing arrows). (B) An expanded segment during an obstructive event.
Note: Evidence of snoring on the flow tracing, quantification of the arousal threshold, and progressive increases in EMGgg activity throughout the obstructive PAGF s OF of the arousal threshold, and progressive increases in EMGgg activity throughout the obstructive event, although occurring, were not sufficient to restore flow without arousal in this instance. closing pressure (more collapsible) in OSA as compared with control subjects under conditions of general anesthesia and muscle paralysis (16).
Thus, in aggregate, multiple methodologies have shown that patients with OSA have anatomic compromise aking these individuals susceptible to pharyngeal collapse during sleep. Upper Airway Dilator Muscle Activity and Reflex Responsiveness During wakefulness, patients with OSA appear to compensate for an anatomically compromised upper airway through protective reflexes which increase upper airway dilator muscle activity to maintain airway patency (17).
Accordingly, the genioglossus, the largest and most extensively studied upper airway dilator muscle in humans, has higher activity in patients with OSA compared with control subjects. One mechanism believed to be important in the pathogenesis of OSA relates to he interaction between pharyngeal anatomy and a diminished ability of the upper airway dilator muscles to maintain a patent airway during sleep (17).
In support of this hypothesis, muscle tone measured via multiunit EMG intramuscular electrodes of the genioglossus is reduced at sleep onset in healthy individuals and patients with OSA (18, 19). Thus, whereas healthy individuals experience a loss of upper airway muscle tone at sleep onset and experience some degree of breathing instability (20), an individual reliant on muscle tone due to an anatomic vulnerability WIII be particularly susceptible to developing OSA. PAGF 6 muscle tone due to an anatomic vulnerability Will be particularly susceptible to developing OSA.
Accordingly, hypopneas and apneas commonly occur at the transition from wakefulness to sleep in OSA. As is discussed below, each event is typically associated with a cortical arousal such that the patient with OSA cycles between wakefulness and sleep, making it dificult to achieve deeper stages of sleep. Unlike the transition to sleep, slow wave sleep is associated with increased, not decreased, upper airway dilator muscle activity (21). Thus, when patients are able to achieve slow wave sleep, 146
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 5 2008 increased upper airway dilator muscle activity may be one important factor contributing to the improvement in apnea severity that is commonly observed in this sleep stage (21). Alternatively, patients with apnea may be able to enter slow wave sleep only when muscle activity is increased and breathing is already stabilized. Mechanistically, in addition to central respiratory drive, the genioglossus is importantly modulated by locally mediated (i. e. in the upper airway) mechanoreceptive reflex mechanisms that respond to negative pharyngeal pressure 22). One such mechanism is the genioglossus negative pressure reflex, whereby the muscle is activated in response to rapid changes in negative intrapharyngeal pressure (i. e. , pressures that are subatmospheric ar suction pressure) (23). Consistent with the nature of OSA being a state-related disease, the genioglossus negative pressure reflex has been shown to be diminished during nonREM sleep in healthy indlviduals (24, 25).
However, more recent data have demo PAGF 7 diminished during nonREM sleep in healthy individuals (24, 25). However, more recent data have demonstrated mantenance f genioglossus reflex activation in non-REM sleep, particularly in the supine posture when gravitational collapsing effects on the upper airway are maximal (26, 27). he identification of a secondary state-dependent suppression component to this reflex arc has raised the possibility that more pronounced reflex inhibition rather than a loss of excitation may mediate diminished pharyngeal reflex responses during sleep (26).
Indeed, advances in our understanding of the neuroanatomy of the genioglossus negative pressure reflex and hypoglossal motor nucleus inputs from rat studies have highlighted the extensive resence of inhibitory inputs to the genioglossus muscle (28- 30). Nonetheless, although genioglossus muscle responsiveness may be impaired during sleep compared with wakefulness, it is clear that the muscle does respond to sustained negative pressure (Figure 1) and potentially hypercapnia, particularly when combinations of stimuli are provided (31-33).
However, there appears to be substantial interindividual variability in the effectiveness ofthese compensatory responses to restore airflow during respiratory loading in sleep (32). To further advance our understanding of pharyngeal muscle control and its role in OSA athogenesis, single motor unit— recording techniques have been employed to assess genioglossus muscle activity in humans. This technique is based on highfrequency sampling and allows sorting of individual motor units to gain insight into their unique characteristics and regulation.
Although these studies are in their infan their unique characteristics and regulation. Although these studies are in their infancy, they have highlighted the heterogeneity of the genioglossus muscle and provide a powerful tool for studying the neural control of muscle activity (34, 35). It is hoped that, by combining neuroanatomic knowledge from nimal models with sensitive neurophysiological techniques in humans, novel therapeutic targets to increase muscle activity may ultimately be identified for some patients with OSA.
Although such approaches may lead to reduced severity of OSA for some patients, as is discussed below, given the heterogeneity of OSA pathogenesis such an approach Will Iikely not resolve sleep- disordered breathing for all patients. Nonetheless, there is evidence to suggest that novel training exercises of upper airway muscles may lead to some improvement in sleep-disordered breathing (36, 37).
However, on the basis of the state dependence of OSA, muscle training during wakefulness is unlikely to have major effects on airw’ay patency during sleep unless the increased muscle activity/efficiency is maintained during sleep. Arousal from Sleep Arousal from sleep at the cessation of a hypopnea or an apnea has long been believed to be an important protective mecha- nism for airway reopening (38, 39). In fact, most respiratory events are associated with cortical arousal and more severe events result in longer arousals (40).
However, work by Younes has provided insight into the functional role of arousal from leep in OSA and challenged the notion that it is essential for airway reopening (41). In studying the response to experimentally induced transient continuous positive airway reopenlng (41 In studying the response to experimentally induced transient continuous positive airway pressure (CPAP) reductions in patients with OSA, Younes noted that inspiratory flow increased in 22% of instances before arousal and was restored in 17% of trials in the absence of arousal (41).
More recently, Jordan and colleagues conducted a study to examine the mechanisms underlying these arousal-free restorations of airflow (32). Transient pressure reductions for up to 5 minutes resulted in increases in genioglossus muscle activity and changes in duty cycle. These compensatory responses were similar between patients with OSA and healthy individuals. However, patients with OSA were less able to restore ventilation without cortical arousal than were healthy indlviduals given stimuli of similar magnitude (32).
The findings that patients with OSA are able to restore ventilation in the face of respiratory loading without cortical arousal at least some of the time, albeit to a lesser extent than healthy individuals, raises the possibility that some patients may e able to maintain a patent ainnay during sleep if they are able to remain asleep for a sufficient duration to recruit compensatory mechanisms.
For example, because combinations of stimuli such as carbon dioxide and negative pressure can activate upper airway dilator muscles during sleep, delaying of arousals may be beneficial if it allows sufficient accumulation of respiratory stimuli to restore pharyngeal patency (31, 42). Should this be the case, strategies to prevent arousal from sleep (increase the arousal threshold) are likely to be most beneficial in patients who awaken easily (low arousal