Chapter 3

Pathophysiology of OSA
E. Gaudette and R.J. Kimoff

Summary
The pathophysiology of obstructive sleep apnoea (OSA) is complex and the contributing factors may vary considerably between individuals. Reduced upper airway anatomic dimensions and altered tissue mechanics contribute to varying extents, but do not suffice to explain the upper airway collapse which occurs uniquely during sleep. Sleep-related changes in upper airway dilator muscle activation and reflex responsiveness play a key role. Varying degrees of impaired upper airway neuromuscular compensation during sleep are observed, and considerable work is still required to understand the basis of this impairment. Contributing factors may include upper airway neuropathy or impaired muscle function or mechanical coupling. Ventilatory control instability and alterations in the arousal threshold to respiratory stimuli appear to be important determinants of recurrent respiratory events in some patients. Innovative, broadly applicable approaches to phenotyping OSA are needed. More comprehensive characterisation of the specific contributing factors in individual subjects will facilitate both the study of genetic mechanisms in OSA and the development of therapies targeting specific pathophysiolgical factors in subsets of OSA patients. Keywords: Arousal, inflammation, neuromuscular function, obstructive sleep apnoea, respiratory control, upper airway
Respiratory Division and Sleep Laboratory, Dept of Medicine, McGill University Health Centre and Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada. Correspondence: R.J. Kimoff, McGill University Health Centre, Respiratory Division, Rm L4.08, 687 Pine Ave W, Montreal, QC, Canada, H3A 1A1, Email john.kimoff@mcgill.ca

Eur Respir Mon 2010. 50, 3150. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024009

bstructive sleep apnoea (OSA) is a common condition that affects at least 4% of males and 2% of females [1]. The OSA hallmark feature is the recurrent episodes of partial (hypopnoea) or complete (apnoea) upper airway collapse during sleep, which is associated with hypoxiareoxygenation and microarousal [2]. A diversity of factors have been identified that contribute to the pathophysiology of this condition, these include: alterations in upper airway anatomy; mechanical and tissue characteristics; neuromuscular function; and sleepwake and ventilatory control instability. It is now clear that different factors predominate in individual cases, producing different phenotypes of OSA. In this chapter, we will review current knowledge concerning the various pathophysiological factors contributing to upper airway narrowing and closure, and how these may interact to produce OSA.

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E. GAUDETTE AND R.J. KIMOFF

Anatomic factors
The upper airway is a complex structure which subserves a diversity of functions, including respiration, deglutition and speech. The latter requires considerable pharyngeal mobility, such that the hyoid bone in the human, which is a key anchoring site for pharyngeal muscles, is not firmly attached to the skeleton as it is in other mammals. Thus, while the upper airway has rigid support in its proximal (nasal) and distal (larynx) segments, for much of its length it is a collapsible tube, with the size of its lumen being subject to the influence of surrounding pressures and the activity of dilator muscles.

Upper airway configuration

The upper airway comprises four anatomic segments, which are the nasopharynx, velopharynx, oropharynx and hypopharynx. The nasopharynx extends from the nares to the hard palate. The velopharynx, also referred to as the retropalatal oropharynx, extends from the margin of the hard palate to that of the soft palate. The oropharynx represents the segment from the soft palate to the tip of the epiglottis and the hypopharynx is the segment between the epiglottis and the larynx. There is considerable evidence that the upper airway structure of OSA patients differs from that of normal subjects in a number of important respects.

Skeletal structures
Studies of cephalometric and computed tomography (CT) scans have highlighted differences in the craniofacial structure of OSA patients when compared with normal controls [35]. The main changes include an increased lower face height and retroposition of both the maxilla and the mandible. The mandibular rami also tend to be shorter and may be medially displaced. The changes correlate with decreased pharyngeal size. There is also a significantly longer distance from the hyoid bone to the mandibular plane [3], and this inferior displacement of the hyoid bone is associated with displacement of the tongue into the hypopharyngeal area. These changes correlate with OSA severity [6].

PATHOPHYSIOLOGY OF OSA

Soft tissues
Magnetic resonance imaging studies have shown that the airway in OSA subjects, when compared with controls, is smaller and narrowed laterally rather than in the antero-posterior dimension, with the most significant narrowing occurring at the retropalatal level region [7, 8]. Lateral narrowing is due to increased thickness of the muscular pharyngeal wall rather than enlargement of the parapharyngeal fat pad [7, 8], although some studies have reported increases in pharyngeal fat in OSA [9, 10]. Fat deposition in the upper airway appears to be more of a factor with respect to OSA in females than in males [11]. Tongue and total soft tissue volume are also increased, and soft tissue volume correlates with OSA severity [8].

Nasal obstruction
Nasal obstruction due to either mechanical (septal deviation, enlarged inferior turbinates and nasal polyps) or inflammatory/vasomotor (acute and chronic rhinitis) causes has been proposed to contribute to OSA [12]. Increased nasal airflow resistance requires increased inspiratory driving pressure to maintain ventilation, which would in turn decrease pressure in the collapsible segment of the upper airway, thus predisposing to OSA. However, the role of nasal obstruction in the pathogenesis of OSA remains controversial. Seasonal rhinitis can increase the frequency and severity of obstructive events [13], and nasal steroid treatment can improve OSA in this context [14]. However the role of mechanical obstruction is less clear. The use of nasal dilating stents has been shown not to improve OSA severity [15, 16] and surgical correction of mechanical nasal obstruction alone typically has minimal effects on OSA severity [17, 18].

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Other anatomic abnormalities

A variety of abnormalities compromising upper airway dimensions may predispose to OSA. These include marked craniofacial disproportion, in particular mandibular insufficiency such as occurs in Pierre Robin syndrome [3, 19], tonsillar hypertrophy, macroglossia [20] and acromegaly, which is associated with both bony and soft tissue changes [21]. PAYNE et al. [22] recently reported a high prevalence (76%) of OSA among patients scheduled for resection of oropharyngeal malignancies.

Lung volume dependence of upper airway calibre

Previous work in both animals and humans has demonstrated that lung volume affects upper airway patency [23, 24]. With increased lung volumes, there is an increase in the traction exerted on the trachea by mediastinal structures, resulting from negative intrathoracic pressures and diaphragm descent, and as a result, the upper airway resistance is reduced. In OSA patients compared to controls matched for body mass index (BMI), HOFFSTEIN et al. [25] demonstrated greater upper airway cross-sectional area dependence on lung volume across the range, from total lung capacity to residual volume. Lung inflation decreases the closing pressure of the passive velopharyngeal airway [23], reduces OSA severity [26] and reduces the continuous positive airway pressure (CPAP) level required to alleviate upper airway flow limitation in OSA [27]. In that changes in end-expiratory lung volume during recumbency may be quite pronounced in obese subjects, lung volume dependent effects on upper airway calibre is believed to be an important factor linking obesity and OSA.

Airway length
E. GAUDETTE AND R.J. KIMOFF

The longer a tube, the greater is its risk of collapse. Increased airway length has been linked to OSA severity in several studies. Cephalometric measures of airway length (i.e. distance between the hyoid bone and the mandibular plane) have been shown to predict upper airway collapsibility [28] and OSA severity [29]. In addition to gravitational effects, lengthening of the pharynx on assuming recumbency may in part explain supine worsening of OSA (see later section) [29]. The male predisposition to OSA may in part be explained by relatively increased pharyngeal length in males compared with pre-menopausal females [30]. Also of note, pharyngeal length was found to be greater among post-menopausal than pre-menopausal females, in keeping with the higher prevalence of OSA among post-menopausal females [31].

Gravity/body position
The frequency of OSA events may increase in the supine compared with the lateral recumbent posture. Positional OSA is typically defined as a supine apnoea/hypopnoea index (AHI) at least double that in the lateral position. Prevalence estimates vary considerably [32, 33], probably in part related to OSA severity. Positional OSA was recently identified in 49.5% of mild (AHI 515), 19.4% of moderate (AHI 1530) and 6.5% of severe (AHI o30) OSA patients [33]. The duration of obstructive events and extent of associated oxygen (O2) desaturation may also worsen in the supine position [34]. Snoring also tends to worsen supine [32]. Positional variability of OSA has been attributed to the effects of gravity on upper airway size and shape [32, 35]. Gravitational effects could be exerted directly on upper airway structures through displacement of soft tissues and/or mandibular retropulsion, or indirectly through displacement of abdominal contents and therefore reduced lung volume, compromising airway cross-sectional area or length as discussed previously. However, measurements of changes in pharyngeal size in the supine versus lateral position have produced inconsistent results [32, 35]. In a recent study using optical coherence tomography, WALSH et al. [35] demonstrated that in positional OSA, upper airway cross-sectional area did not change with body position, but the shape of the airway changed from a transversely oriented elliptical shape when supine to a more circular shape in the lateral position.

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It was hypothesised that increased circularity would decrease the propensity to airway collapse and thus may account for improvement in OSA in the lateral decubitus position.

Sites of airway collapse

Various techniques have been used to assess the site of upper airway collapse, including sequential pressure measurements, cinefluoroscopy, nasal pharyngoscopy, CT and magnetic resonance imaging. The primary site of collapse is in the retropalatal/oropharyngeal area in a majority of patients (up to 75%), with frequent caudal extension to the base of the tongue (2544%) and less often, to the hypopharynx (033%) [7, 3640]. The multi-level nature of upper airway closure has implications for surgical management. Indeed, the site of primary obstruction has been observed to migrate following uvulopalatopharyngoplasty [41]. The site of airway collapse is dictated in part by soft tissue and skeletal characteristics, as illustrated by one study in which obstruction occurred primarily at the velopharynx in obese OSA patients, but at both the velopharynx and oropharynx in non-obese OSA patients with reduced maxillo-mandibular dimensions [42]. However, neuromuscular factors also contribute in that the extent of the collapse varies with sleep stage, with more extensive caudal collapse occurring in rapid eye movement (REM) compared with nonrapid eye movement (NREM) sleep [43].

Dynamics of upper airway closure

Upper airway closure can occur either at end expiration or the beginning of inspiration [44, 45]. Once airway closure occurs it may remain complete until termination of the apnoea, or there may be partial recovery of patency between obstructed inspiratory efforts [44]. Expiratory airflow may occur during apnoeas in some subjects, leading to a reduction in end-expiratory lung volume and thus of oxygen stores, worsening event-associated O2 desaturation [46]. Airway reopening at apnoea termination may be either abrupt or more gradual [44], with reopening extending from the caudal to cranial direction [47].

PATHOPHYSIOLOGY OF OSA

Mechanical factors
Pharyngeal collapsibility
As noted previously, due to a lack of rigid supporting structures, much of the human upper airway is a collapsible tube. The relationship between pressure and flow in the collapsible segment has been studied using the Starling-resistor model [4850]. The oropharynx represents the collapsible segment, whose critical closing pressure (Pcrit) is defined as the pressure inside the airway at which the airway collapses (fig. 1). Airflow through this segment depends on the pressure gradient, defined as PusPds, as well as on the resistance of the upstream and downstream segments. In this model, Pus is atmospheric pressure at the nares and Pds is tracheal pressure. When Pus and Pds exceed Pcrit, the airway is open; when Pcrit exceeds Pds but is less than Pus, flow limitation in the collapsible segment occurs, and when Pcrit exceeds Pus, complete airway collapse ensues. Classic Pcrit measurements have been made on the passive airway (passive Pcrit), during sleep or under general anaesthesia, and therefore reflect the mechanical properties of the airway and surrounding tissues. Experimentally, Pcrit can be determined by lowering the nasal pressure (Pus) until inspiratory flow ceases. Data from a series of studies [48, 49, 51, 52] indicate a continuum of upper airway collapsibility in subjects with normal breathing (Pcrit ,-10 cmH2O), non-apnoeic snoring (Pcrit range, -10 to -5 cmH2O), obstructive hypopnoea (Pcrit range, -5 to 0 cmH2O), and obstructive apnoea during sleep (Pcrit .0 cmH2O). Several epidemiological risk factors for OSA are also known to affect Pcrit. Obesity may adversely affect airway collapsibility either through fat deposition in the airway [9, 7, 10] or via reduction in lung volumes [53], which as noted previously leads to a reduced tethering effect on the upper airway. Weight loss is associated with reduction in Pcrit and the extent of Pcrit change was related

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to improvement in OSA [54]. With respect to the male preponderance of OSA, studies show a passive Pcrit elevation of 23 cmH2O in males versus pre-menopausal females matched for BMI and age [55, 56]. This difference may be accounted for by longer upper airway length and/or increased soft palate size in men, differences in fat distribution between males and females [30, 57] or other hormonal differences [58]. Ageing is associated with an increase in OSA prevalence of sleep-disordered breathing up to 65 yrs where it appears to plateau [59]. Older age is associated with increased pharyngeal collapsibility [60].

Surface tension
Upper airway collapsibility is affected by the surface tension of the liquid lining the airway. Animal studies have shown that both reopening and closing pressures increase as upper airway lining fluid surface tension increases [61]. Surface tension is reported to be elevated in OSA patients in comparison with normal subjects [62], which may be related to mucosal trauma during apnoeas, oral versus nasal breathing route, or other unidentified factors, although salivary flow is preserved in OSA [62]. Instillation of surfactant to reduce surface tension has been shown experimentally to improve airway collapsibility (reduced Pcrit) and reduce the AHI in subjects with OSA [6365].

Oedema
For patients in whom the upper airway lumen is relatively small, even a small amount of oedema could further compromise its patency. Recent studies have shown that cephalad displacement of fluid from the legs to the upper body increases neck circumference and pharyngeal resistance [66], as well as upper airway collapsibility [67] in healthy subjects, and that these effects correlate with the AHI in non-obese OSA subjects [68]. In another study of patients with severe OSA and decompensated diastolic heart failure, intensive diuresis was associated with an increase in oropharyngeal calibre by acoustic pharyngometry and a significant reduction in AHI [69]. Also, superior vena cava syndrome, which is characterised by venous engorgement and oedema of the head and neck, has been associated with OSA, and the relief of venous obstruction via intravascular stenting, chemotherapy or radiotherapy reduces or resolves OSA [7073]. Vascular tone may also play a role in pharyngeal collapsibility, as it has been shown in cats that vasodilatation increased and vasoconstriction tended to decrease upper airway closing and opening pressures [74].
Pcrit Nasal Pus Upstream segment Collapsible segment Zone 3 Nonflow-limited Pcrit Pus Pus>Pds>Pcrit Pds Pds Zone 2 Flow-limited Pcrit Pds Pus Pcrit>Pus,Pds Zone 1 Occluded Pcrit Pds Tracheal Pds Downstream segment

Upper airway tissue characteristics

While changes in upper airway tissue volume in OSA have been well characterised using imaging techniques, there is less known about the characteristics of the tissue within the upper airway walls.

Pus>Pcrit>Pds V' I,max=(PusPcrit)/Rus

Upper airway inflammation

There is, however, now substantial evidence that inflammation is increased in the upper airway in OSA [7580].

Figure 1. Starling-resistor model of the upper airway. Pcrit:

critical closing pressure; Pds: downstream pressure; Pus: upstream pressure; Rus: upstream resistance; V 9I,max: maximum inspiratory flow rate. Reproduced from [50] with permission from the publisher.

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E. GAUDETTE AND R.J. KIMOFF

Noninvasive measurements have shown increased inflammatory markers in nasal lavage, induced sputum and exhaled breath condensate from OSA subjects compared with controls [75, 8185]. There is also evidence from direct studies on upper airway mucosal tissue for increased inflammatory cell infiltration [7679] and expression of pro-inflammatory cytokines and chemokines [80, 86] Inflammation is also increased within the muscular compartment in moderate-severe OSA [76, 80]. Factors contributing to increased inflammation are believed to include: mechanical trauma associated with snoring vibration, suction collapse and traction during apnoeas and intense activation of muscles at airway reopening; and increased oxidative stress related to hypoxia-reoxygenation [75, 76, 87, 88]. Other potential pro-inflammatory factors in OSA include acid-pepsin reflux [89, 90], alchohol, smoking [91], allergic inflammation [92] and effects of systemic inflammation [75, 93] (fig. 2).

Consequences of inflammation
Repeated or sustained upper airway inflammation could have important consequences for airway structure and function (fig. 2). As noted previously for oedema due to fluid shift, inflammatoryrelated oedema could reduce upper airway calibre and increase airway collapsibility. Inflammatory responses to mechanical trauma or oxidative stress could have beneficial effects in promoting tissue repair, but in the context of repeated intense inflammation, could also contribute to tissue injury and/or fibrosis. Indeed, there are reports of increased connective tissue content in OSA both in the upper airway mucosa [80, 94, 95] and in some [80, 9698], although not all [99, 100] upper airway muscles. Also, disorganisation of the elastic tissue fibrillar network in uvular mucosal tissue from severe OSA patients has been described [79]. Changes in connective tissue content and/or organisation would be expected to alter airway dimensions and compliance and could also impair mechanical coupling between the contractile and noncontractile elements of the upper airway [101].

PATHOPHYSIOLOGY OF OSA

Pro-inflammatory stimuli

Mechanical trauma (snoring, suction collapse/traction muscle loading) Smoking

Acid-pepsin Alcohol

Allergic inflammation Systemic inflammation

Hypoxia-rexoygenation oxidative stress

Adverse sequelae Muscle inflammation/ dysfunction

Upper airway

Injury

Inflammation

Adaptation/repair

Neural injury Afferent Efferent Muscle denervation

Lining fluid/ surface tension

Oedema

Tissue alterations Increased collapsibility

Impaired neuromuscular responses

Reduced airway calibre

Figure 2. Proposed schema depicting factors contributing to upper airway inflammation in obstructive sleep
apnoea and potential adverse consequences. Pro-inflammatory stimuli are believed to include oxidative stress, mechanical loading/trauma and other factors. The resulting inflammatory response is probably important for tissue adaptation and repair, but if excessive and repeated could have a diversity of adverse effects on upper airway structure and function.

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Neuromuscular function
Motor function
The human pharynx contains more than 20 muscles which influence airway calibre and fall into three functional groups: muscles controlling the position of the hyoid bone (geniohyoid and sternohyoid), muscles of the tongue (genioglossus, the major upper airway dilator) and palatal muscles (palatopharyngeus, tensor palatine and levator palatini). Some of these demonstrate only tonic activity, while others, notably genioglossus, demonstrate inspiratory phasic and tonic expiratory activity. A fundamental observation is that despite compromised upper airway anatomic dimensions, OSA patients demonstrate upper airway obstruction only during sleep. Thus, the upper airway musculature can maintain patency during wakefulness, but has a reduced ability to do so during sleep. This is believed to be in large part related to reduction in upper airway dilator muscle activity, which occurs in the transition from wakefulness to sleep [102105] and then becomes progressively more marked during established NREM and REM sleep [104]. During wakefulness, electromyogram (EMG) activity of both genioglossus and tensor palatini is increased in OSA patients compared with controls [106]. Furthermore, at sleep onset, the relative decrease in genioglossus EMG is greater in OSA patients than controls [107]. These findings appear to indicate that drive to the upper airway muscles is increased during wakefulness in OSA to compensate for anatomic compromise, and that when sleep-associated decrements in muscle activity occur, the latter is no longer adequate to maintain airway patency and closure ensues.

Negative pressure reflex

One of the major determinants of upper airway dilator muscle activity is mechanoreceptor stimuli related to negative intraluminal pressure. One of the best studied responses is the genioglossus negative pressure reflex, characterised by a short-latency increase in genioglossus activity in response to a pulse of negative pressure applied to the upper airway. This protective reflex which is readily demonstrable during wakefulness, has been reported to be reduced or absent during NREM sleep in normal subjects, potentially contributing to impaired defence of airway patency during sleep. However, more recently it has been shown that this reflex may be maintained during sleep when airway loading is increased, e.g. in the supine position [108, 109]. In addition, recent data indicate there are both initial excitatory and subsequent inhibitory components to the genioglossus response to negative pressure stimuli which are differentially affected by state. The morphology and amplitude of the excitatory peak appears preserved during NREM sleep, but the inhibitory component becomes more pronounced during NREM and further during REM sleep compared to wakefulness [109]. Thus in normal subjects, negative pressure responsiveness is attenuated during sleep, which may in part be due to augmentation of the inhibitory component. These reflexes have been much less well studied in OSA patients.
E. GAUDETTE AND R.J. KIMOFF

Altered upper airway neuromechanical function

PATIL et al. [52] assessed upper airway critical pressure during sleep under hypotonic or transient (passive Pcrit) and active or sustained (active Pcrit) conditions in OSA subjects and normal controls (fig. 3). OSA patients were found to have a significantly higher mechanical load (passive Pcrit), but also reduced neuromuscular responses in comparison to normal subjects, as indicated by a failure to lower their critical pressures under active conditions. In contrast, while some normal controls had an elevated mechanical load, they were able to significantly reduce Pcrit under active conditions, thus reducing the propensity to airway collapse. These data indicate that on average, upper airway neuromuscular compensatory mechanisms during sleep are attenuated in OSA patients compared with controls. Differences in EMG activation appear to account in part for this

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impairment [110]. However even when EMG activation equivalent to that in control subjects occurs in response to transient reductions in CPAP pressure, OSA subjects often fail to restore airway patency in the absence of arousal [111]. These findings further point to impaired neuromechanical function as a factor in OSA.

Upper airway neuropathy

One potential contributing factor could be impaired upper airway afferent neural function, which would attenuate transmission of information related to intraluminal pressure. Upper airway sensory impairment in OSA was initially characterised as impaired thermal sensitivity [112], but subsequent work has demonstrated impaired mechanosensitivity at the level of the oropharynx [113115], which in several studies has shown a relationship to OSA severity [114, 115]. This sensory impairment is partially reversible with CPAP treatment [113]. NGYUEN et al. [116] also demonstrated sensory impairment in the velopharynx and larynx in OSA using an endoscopic technique. For subjects with abnormal laryngeal sensation, there was a close correlation between the severity of laryngeal afferent impairment and AHI [116]. These findings point to the presence of an upper airway neuropathy in OSA, which has been proposed to be due to mechanical trauma associated with snoring and apnoeas, oxidative stress related to hypoxia-reoxygenation, and inflammation resulting from both of these insults [75, 76, 89, 113, 116119]. Indeed, there is pathological evidence for neural injury in upper airway tissue, characterised by alterations in nerve endings suggestive of injury, proliferation and repair, consistent with an ongoing neuropathic process [117, 119]. Also of note, both laryngeal sensory dysfunction and OSA severity were found to positively correlate with endoscopic morphological inflammation scores [89].
PATHOPHYSIOLOGY OF OSA

a) 0
***

b)

Muscle denervation
There is also evidence for an efferent component to OSA upper airway neuropathy, in the form of muscle denervation. Classic immunohistochemical findings of muscle denervation including fibre type grouping, grouped atrophy, and increased fibre size variability have been reported by several groups in OSA upper airway muscle specimens [97, 120122]. Furthermore, neural cell adhesion molecule, a subsarcolemmal protein which is transiently expressed in denervated muscle cells, was found to be significantly increased in OSA upper airway muscle tissue compared with controls, providing further evidence for ongoing, active denervation in OSA palatal muscle [76]. Recent single motor unit electromyographic studies in OSA patients have also revealed characteristic findings of muscle denervation [120, 123]. In addition to local upper airway neural changes, upper airway muscle denervation could

Pcrit cmH2O

-4

*** ***

* *

-8

-12 Passive Active Passive Active

Figure 3. Data illustrating differences in upper airway mechanical

characteristics and neuromechanical compensation during sleep between obstructive sleep apnoea (OSA) subjects ($) and age-, sex- and body mass index-matched controls (#). a) Data for all subjects. OSA patients on average demonstrate a higher mechanical load (passive critical closing pressure, Pcrit) than controls, and under dynamic conditions (active Pcrit) demonstrate considerably less lowering of Pcrit by neuromechanical compensatory mechanisms. b) Data for a subset of OSA subjects and controls matched for mechanical load (passive Pcrit). Significantly less active neuromechanical compensation is evident in OSA subjects than controls. *: p,0.05; ***: p,0.001. Reproduced from [52] with permission from the publisher.

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also result from damage to brainstem motoneurons, as has recently been reported to occur in a murine intermittent hypoxia model [124].

Upper airway muscle function

Another potential mechanism contributing to altered neuromechanical responses in OSA could be impaired contractile function of upper airway dilator muscles. There is currently controversy surrounding this issue (for a more complete discussion see [125, 126]). In OSA the upper airway muscles are subjected to considerable loading under hypoxic conditions and potentially to eccentric contraction and injury [96, 127]. A typical response to loading is for skeletal muscle fibre phenotype to undergo modification, shifting from oxidative slow-twitch, fatigue resistant type I, to glycolytic fast-twitch type II fibres, which generate increased force but are more prone to fatigue. Several groups have evaluated upper airway muscle histological, biochemical and in vitro contractile properties in OSA. SERIES and co-workers [99, 101, 128] found an increased proportion of fast-twitch type IIa fibres in the uvula and the genioglossus muscles, along with augmented levels of enzymes associated with anaerobic metabolism in the uvula OSA patients versus snorers. Thus, OSA probably leads to shifts and in vitro muscle contractility is preserved or even slightly increased, but at the cost of increased fatigability. In keeping with this shift to a fast-twitch but more fatigue-prone fibre type, CARRERA and co-workers [100, 129] have demonstrated increased genioglossus fatigability in untreated non-obese OSA subjects, while CPAP-treated OSA subjects showed normal genioglossus endurance. While muscle may undergo adaptive responses to increased loading, high levels of loading/ activation under adverse (e.g. hypoxic) conditions, such as occurs at the termination of obstructive apnoeas, can lead to muscle injury and inflammation which would compromise contractile function [76, 80, 96, 127]. Local increases in pro-inflammatory cytokines and oxidative stress can induce muscle dysfunction [130, 131]. Muscle denervation could also reduce force generation [76, 120]. Moreover, even if muscle contractility per se were preserved, tissue changes in OSA may alter mechanical coupling of upper airway muscles such that tissue displacement for a given contractile force generated is less [101]. It is likely that the balance of adaptation versus injury differs considerably between patients with muscle dysfunction playing an important role in some, but no meaningful role in others.

Implications for EMG findings

As noted previously, during wakefulness, multi-unit EMG activity expressed as per cent of maximum voluntary activity, is increased during wakefulness for both genioglossus and tensor palatini in patients with OSA compared with controls [106]. Some of the foregoing considerations concerning upper airway muscle function challenge the classic notion that this necessarily represents increased drive to intact muscles to compensate for anatomic compromise. For example, EMG activity is expressed in units relative to maximum voluntary EMG amplitude, but if contractile dysfunction is present, the maximum voluntary EMG could in fact be considerably reduced compared with normal. Thus an increased relative activation could in fact represent normal or even reduced muscle mechanical activity and force generation. Furthermore, in a recent study of genioglossus single motor unit firing patterns in OSA subjects and controls during wakefulness, there was no consistent evidence of increased motor unit firing frequency in OSA subjects, which is an electrophysiological hallmark of increased central drive [123]. In addition, OSA subjects demonstrated classic findings of denervation, characterised by increased duration and area of the motor unit action potentials. Conceivably, classic multi-unit EMG recordings comprised of many denervated motor units could have an increased compound amplitude, providing an alternate explanation for increased relative dilator EMG activity in OSA. Innovative approaches will need to be developed to evaluate the relationship between upper airway dilator muscle EMG activity, force generation and tissue displacement.

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E. GAUDETTE AND R.J. KIMOFF

Hydrostat hypothesis
It has been hypothesised that the muscles of the pharynx function as a muscular hydrostat [132]. Muscular hydrostats, examples of which include octopus tentacles and elephant trunks, are organs composed almost entirely of muscle, with a complex muscular arrangement within the organ. During muscle contraction the organ will maintain a constant volume as muscle tissue is mostly water and hence incompressible. Muscle contraction redistributes tissue pressure within the organ, changing organ shape. Muscle fibre orientation, and therefore contractile effect varies with shape, so that the mechanical effect of individual muscle contraction within the muscular hydrostat is dependent on the integrated activity of all other muscles. The mammalian tongue is considered to represent a hydrostat, with its respiratory and other functions depending upon a complex, interdependent and reciprocal action of the intrinsic and extrinsic tongue musculature [133, 134]. The pharynx as a whole also fulfills many of the characteristics of a hydrostat [132]. The importance of this concept may lie in the emphasis on the combined, integrated role of the pharyngeal musculature in determining airway patency. While evaluation of pharyngeal calibre in OSA has typically focused on EMG activation in a small number of muscles (e.g. genioglossus and palatal muscles), the hydrostat concept mandates a more global assessment of integrated muscular function. Thus airway calibre depends not only upon the level of neural drive to the musculature, but on the instantaneous shape, orientation, distribution of tissue pressures and cross muscle relationships within the pharynx, which will determine the integrated effects of neural activation [132]. This approach underscores the potential effects of the structural changes within the airway wall discussed previously (e.g. increased fat deposition, inflammation, increased connective tissue deposition, neuropathic or myopathic changes), which have the potential to alter the complex orientation and interaction of the pharyngeal musculature, distribution of tissue pressures, and thereby airway shape and size. A more detailed understanding of integrated pharyngeal muscle function and how this is altered in OSA could also ultimately yield innovative therapeutic strategies targeted at preferentially modifying the activity of specific upper airway muscle groups, rather than attempting to globally increase muscle activity during sleep.

PATHOPHYSIOLOGY OF OSA

Ventilatory control instability

There has been a growing understanding of the role of ventilatory control instability in the pathogenesis of OSA (see [135, 136] for detailed reviews).

Apnoeic threshold
During NREM sleep, reductions in CO2 below eupnoeic levels will produce apnoea, while this phenomenon does not occur during wakefulness [137141]. The CO2 level at which this occurs (apnoeic threshold) is typically 12 mmHg below waking eupnoeic levels. Thus, a sudden increase in ventilation occurring in association with arousal, such as typically occurs at the termination of apnoeas or hypopnoeas, will lead to hypocapnia so that when the patient returns to sleep the CO2 is below the apnoeic threshold (ventilatory overshoot) and another apnoea ensues [142146]. This mechanism is important in the pathogenesis of central apnoeas, and accounts in part for the respiratory instability associated with sleepwake state instability. While in the context of central apnoea it is the respiratory pump muscles and chest mechanics which dictate the response to blood gas changes, in OSA it is the response of the upper airway muscles and mechanics which play a determining role. Thus post-ventilatory overshoot loss of drive to the upper airway may lead to airway collapse and initiation of a subsequent obstructive event. Other factors may also contribute to reduced drive following post-apnoeic hyperpnoea, including vagal stimuli generated during large inspired volumes [147] and baroreceptor-mediated

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ventilatory inhibition due to post-apnoeic blood pressure surges [148]. Thus, depending upon upper airway characteristics, these factors may also contribute to the genesis of subsequent central or obstructive apnoeas.

Loop gain
Loop gain is an engineering term which describes the sensitivity of a negative-feedback loop. In the context of the respiratory control system, a disturbance which increases alveolar ventilation from some steady-state level and lowers arterial carbon dioxide tension (Pa,CO2), evokes a negative corrective action from the controller to suppress the disturbance. Loop gain is the ratio of the magnitude of the corrective action to the initial disturbance [149, 150]. The two principal components of loop gain are controller gain and plant gain. Controller gain largely represents chemoreceptor responsiveness to hypoxia and hypercapnia; in general, high controller gain is due to increased hypercapnic responsiveness [149, 150]. Plant gain reflects the effectiveness of a given level of ventilation to eliminate CO2. Thus, in the context of high plant gain, a small change in ventilation would produce a large change in Pa,CO2. High values of loop gain are associated with ventilatory instability, i.e. a propensity to perpetuate cyclical variations in ventilation. This may be important in the pathophysiology of OSA in that loop gain will affect the output of the central controller, which affects drive to the upper airway. Also, loop gain will influence the ventilatory response to arousal and thus the propensity to ventilatory overshoot and crossing the apnoeic threshold; thus high loop gain could contribute to cyclical apnoea events. Loop gain measurements have been made in human subjects using proportional assist ventilation. On average, patients with OSA have increased loop gain compared with controls, although a wide range of values is observed [151153]. Several recent observations support the concept that increased loop gain may contribute to OSA pathogenesis in some patients. WELLMAN et al. [151] reported that loop gain values correlated directly with AHI in OSA patients with Pcrit values near atmospheric pressure, while no correlation was observed among subjects with higher or much lower upper airway closing pressures. This group also demonstrated that administration of nocturnal oxygen to OSA patients with high versus low loop gain significantly lowered loop gain and reduced AHI in the high loop gain subjects, but had no significant effect on either measure among low loop gain subjects [154]. Arousal During a majority of, although not all, obstructive apnoeas and hypopnoeas, arousal from sleep occurs in association with termination of the event, reopening of the airway and post-apnoeic hyperpnoea. A substantial body of evidence supports the concept that arousal from sleep is an important and potentially life-saving response to asphyxic stimuli, in the context where reflex responses to these stimuli leading to increased ventilatory drive and effort fail to restore blood gas homeostasis [155, 156] (fig. 4). However, as noted previously, sleepwake instability or a low arousal threshold may also have a destabilising effect on ventilation and precipitate repeated apnoeas or hypopnoeas [143]. In a series of publications, YOUNES [135, 146, 157] has emphasised the potentially disadvantageous effects of early or unnecessary arousal, which may occur before the activation of compensatory reflex mechanisms have sufficient time to compensate for upper airway obstruction and apnoea/hypopnoea. Thus, rather than restoration of stable breathing, precipitous arousal leads to ventilatory overshoot and intitiation of another apnoea. Arousal responses, which are mediated through effort-related stimuli [156, 158], are on average impaired in OSA subjects [156, 159, 160] and improve following treatment of OSA [161, 162]. An increase in arousal threshold during the course of untreated OSA would often be expected to be disadvantageous by leading to prolongation of respiratory events and worsened hypoxaemia. However delayed arousal might be adaptive in the context of an inherently low arousal threshold, permitting sufficient time for recruitment of compensatory reflexes and stabilisation of breathing.
E. GAUDETTE AND R.J. KIMOFF

41

Wakefulness Upper airway open Stable breathing Sleep onset Loss of wakefulness drive Attenuation of protective reflexes Anatomic compromise Increased collapsibility Airway patent Stable breathing Ventilatory overshoot hypocapnia Airway collapse Apnoea-hypopnoea hypoventilation Increasing chemical/ mechanical stimuli

These considerations suggest that there should be a subset of OSA patients with relatively intact chanisms but low arousal threshold, in whom for example, pharmacological intervention to delay arousal (without suppression of neuromuscular function) could improve OSA. However, practical clinical applicability of this concept has yet to be demonstrated.

Adequate activation; occurs before arousal

Post-apnoeic hyperpnoea Arousal

Neuromodulation of upper airway muscle activity during sleep

There is growing knowledge concerning the neural pathways and neurotransmitter systems responsible for the wakefulness drive to breathe and sleep-associated changes in ventilatory control. Of particular relevance to OSA is the neuromodulation of output from the hypoglossal motor nucleus which drives the major upper airway dilator muscle, i.e. genioglossus. Identification of neuromodulators responsible for sleep-associated decrements in upper airway dilator muscle activity during sleep could represent potent therapeutic targets for OSA.

Inadequate activation Neuromechanical activation

Increased neural drive

Figure 4. Schematic diagram depicting the roles of arousal and neuromechanical mechanisms during repeated episodes of upper airway collapse during sleep. With sleep onset, reductions in upper airway muscle activity lead to closure of the susceptible airway. A series of compensatory reflexes are activated, which in some instances may lead to neuromechanical compensation sufficient to reopen the airway and stabilise ventilation without sleep disruption. If, however, precipitous arousal occurs before neuromechanical compensation can occur, a cycle of hyperpnoea, ventilatory overshoot below the apnoeic threshold, and recurrence of apnoea will be perpetuated. Alternatively, if neuromechanical compensatory mechanisms are impaired, the arousal response becomes critical for relief of upper airway obstruction and restoration of ventilation. Blunting of the arousal response in this context would be associated with worsening of apnoea-associated hypoxaemia.

PATHOPHYSIOLOGY OF OSA

Facilitatory influences

There was considerable initial interest in serotonin in this regard in that serotonergic neurons play an important role in promoting wakefulness [163, 164]. Also, based on studies in anesthetised, reduced animal preparations, withdrawal of serotonergic excitation reduces hypoglossal motor output [165]. However, human studies using selective serotonin reuptake inhibitors showed only modest effects on OSA severity [166168]. Subsequent animal studies have indicated that serotonin effects are most prominent in vagotomised preparations, and that its role in intact, freely behaving animals is much less pronounced [169]. This probably accounts for the relative lack of clinical efficacy of serotonin agonists in human OSA. Subsequent work has shown however, that other elements of the aminergic arousal system provide tonic drive to the respiratory system [170, 164]. Noradrenergic inputs to the hypoglossal motor pool contribute to both the tonic and phasic components of genioglossus muscle activity in wakefulness, and withdrawal of noradrenergic input accounts for some of the reduction in hypoglossal motor activity during NREM sleep, although the effect during REM appears to be

42

minimal [170]. Glutamatergic inputs have also been found to play a similar role at both the hypoglossal and trigeminal motor nuclei [164, 171].

Inhibitory influences
The two main inhibitory neurotransmitters in the central nervous system are glycine and the c-amino butyric acid (GABA). Both neurotransmitters appear to exert tonic inhibitory effects on upper airway muscle activity during wakefulness and NREM sleep, but considerably less during REM sleep [172174]. Thus in vivo stimulation of GABA or glycine receptors at the hypoglossal nucleus suppresses respiratory-related genioglossus muscle activity, while antagonism of those receptors increases genioglossus activity in wakefulness and NREM sleep and, to a lesser degree, in REM sleep. Of interest, strychnine, a glycine antagonist, was shown to increase tensor veli palatini and genioglossus activity and reduce respiratory events in a human OSA case [175].

Neuroanatomic pathways
While many of the key neuroanatomic pathways responsible for upper airway motor control have been known for decades, specific projections for some of the neurotransmitter systems influencing the hypoglossal nucleus just cited are still being sought. Of note, the specific pathway mediating the negative pressure reflex has recently been described by CHAMBERLIN et al. [176] using a retrograde labelling technique. This approach not only has elucidated an important pathway relevant to OSA, but also suggests a possible strategy for targeted delivery of therapeutic agents aimed at altering brainstem neuromodulation of upper airway motor activity during sleep.

Genetic factors
There is ample evidence for a heritable component to OSA, even when accounting for familial predisposition to obesity [177179]. Anatomic traits such as the volume of upper airway soft tissues [180], and ventilatory control and respiratory responses to resistive loads during sleep [181, 182], all appear to share a genetic basis. Genetic influences are also evident in studies pointing to differences in OSA pathogenesis of OSA among racial groups [183185]. For example, Asians have shorter maxillae and mandibles as well as smaller anterior-posterior facial dimensions and lower BMI than Caucasians for a given degree of OSA severity [186188], while AfricanAmericans compared to Caucasians show a greater role of soft tissue factors in susceptibility to OSA [189, 190]. The search for candidate genes in OSA has been hampered by the variability of OSA phenotypes, i.e. the diversity of factors contributing to OSA, and the varying extent to which each may contribute in individual subjects. Efforts to date have been more successful in identifying genes related to OSA consequences, rather than OSA pathogenesis [191, 192]. Overlap with obesity, which also has both environmental and genetic determinants, has been particularly challenging. Whole genome scan studies aimed at identifying susceptible loci for OSA and for obesity suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity [184, 185, 191]. It has been suggested that further advances in genotyping of OSA will depend in large part on improved and more comprehensive approaches to phenotyping of OSA [191, 193].

Statement of Interest
None declared.

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Acknowledgements
Work from the authors laboratory cited in this chapter was supported by: Canadian Institutes of du Que bec (Montre al, QC, Health Research (Ottawa, ON, Canada), Fonds de Recherche en Sante al), Lloyd Carr Harris Foundation Canada), Richard & Edith Strauss Foundation (Montre al) and the McGill University Health Centre Research Institute (Montre al). (Montre

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