Individuals with normal upper airway anatomy do not suffer from obstructive apneas or hypopneas even though they experience reductions in muscle tone and airway caliber during sleep. What anatomic factors predispose an individual to sleep apnea? Why are the upper airway structures enlarged in patients with OSA? This section will first highlight the differences between normal and apneic upper airways and then discuss the factors that confer/influence these differences.
The overwhelming majority of imaging studies have demonstrated that the upper airway of apneic subjects is smaller than that of the normal population (7,14, 23,29,37,41,43,52,66,67,82-84). The minimum caliber of the upper airway has been shown to be primarily located in the retropalatal oropharynx (23,39,43,49) and therefore this has become the main area of interest for studying airway collapse. In a minority of patients, the initial site of collapse is the retroglossal region (85). OSA patients in general demonstrate an excess of upper airway soft tissue for the space available bounded by the bony structures, which envelop the pharyngeal lumen. Studies have suggested that the reduction in aperture of the airway of OSA patients is a result of a relative or actual excess soft tissue and/or an altered bony cage (29,83). The craniofacial features (primarily determined with cephalometric techniques) of OSA patients include reduction in the length of the mandible, an inferi-orly-positioned hyoid bone, and a retroposition of the maxilla (58,67,86-90). Shorter, posteriorly displaced mandibles have been observed in up to two-thirds of OSA patients and correlate with decreased pharyngeal size (27,90). Several soft tissue abnormalities have also been shown to narrow the upper airway in patients with sleep apnea when compared to normals including an increase in the volume of the tongue, soft palate, parapharyngeal fat pads, and the lateral walls surrounding the pharynx (14,15,22,23,29,31,36,91). The larger the volume of the lateral pharyngeal walls, tongue, and total soft tissue (Fig. 5), the greater is the likelihood of developing OSA (29). Although the lateral parapharyngeal fat pads are enlarged in OSA patients when compared with controls, they do not necessarily affect the airway lumen (23).
The airway configuration also appears to be an important factor in apneic subjects. In contrast to normals, who have the major axis of the pharyngeal airway in the lateral dimension, OSA patients have an axis oriented anteroposteriorly. This type of narrowing is believed to be due to thickening of the lateral pharyngeal wall (29) and indeed, may compromise the pharyngeal dilator muscles' ability to maintain airway patency (92). Attention has also focused on airway length as another important anatomical variable influencing airway patency. Using finite element analysis modeling and MRI, it has been shown that normal men have significantly increased pharyngeal airway length (even after normalizing for body size), greater soft palate cross-sectional area, and increased pharyngeal volume compared to females (17). Based on this observed gender differences in airway anatomy, the investigators demonstrated that the male airway is more collapsible at any given negative airway pressure than the female airway. Cephalometry techniques have also demonstrated a lengthening of the pharynx in men with OSA compared to controls. This could increase the risk of upper airway collapse by lengthening the "at risk" portion of the airway lumen (55). In addition, cephalometric studies have shown inferior displacement of the hyoid bone in OSA patients compared with controls, and it is accompanied by an inferior displacement of the tongue into the hypopharynx (93). The distance between the hyoid bone and the mandibular plane has been shown to predict the critical collapsing pressure of an airway and the airway resistance in awake apnea patients (94,95). Furthermore, the extent of inferior hyoid displacement is correlated to the AHI (96).
It is thought that these soft tissue and craniofacial abnormalities predispose the patient with sleep apnea to have upper airway collapse during sleep. Several factors (obesity, edema, muscular dysfunction, gender, ethnicity, genetics) have been proposed to explain these abnormalities of upper airway soft tissue and craniofacial structures. These factors will be discussed below. It is important to note that these factors may be additive and interact conferring enhanced overall risk for the development of obstructive apneas. For example, a male who is obese is more likely to have OSA than a woman of similar body mass.
Factors Influencing Upper Airway Soft Tissue Structures Obesity
The best-studied factors that alter upper airway dimensions are obesity (97,98) and increased neck circumference. Obesity of the centripetal type (more common in men) where fat distribution predominates in the regions of the abdominal viscera, upper body, and neck is significantly more correlated with OSA than the peripheral pattern of obesity (more common in women) where fat locates to the hips and thighs (99,100). Neck circumference is a strong predictor of sleep apnea among anthropometric variables (98). Population studies have also demonstrated that neck circumference is an important predictor of sleep apnea (51,101). The enlarged neck size in apneics may be secondary to the increased centripetal fat deposition in the neck region of OSA patients. The strength of the association between obesity and sleep apnea should lead us to believe a causal relation. However, the mechanisms of obesity-induced apneas still are being unraveled. Nonobese individuals with sleep apnea have more total body fat and fat deposited in the upper airway than age-, BMI-, and neck circumference-matched controls (102).
Upper airway imaging studies have provided important data to enable investigators to try to better understand the relationship between sleep apnea and obesity. Imaging studies have shown increased adipose tissue surrounding the upper airway in obese patients with sleep apnea (23,24,27,41,102,103). MRI has allowed accurate quantification of fat tissue since fat has a short relaxation time and therefore has a higher intensity than other soft tissues in T1 weighted spin echo MRI. Fat has been proposed to alter upper airway structure through either loading of the pharynx or by luminal encroachment from fat deposits (53). Abdominal and chest wall fat reduces lung volume which, in turn, causes a decrease in upper airway caliber and an increase in compliance from loss of caudal traction on the trachea (53,104).
A majority of the imaging investigations pertaining to the role of obesity have reported increased fat deposition in the lateral pharyngeal fat pads. This finding has consequently been linked to the reduction of airway caliber of sleep apneics. This may not be the case. It has not been proven that increased fat deposition in the para-pharyngeal fat pads directly narrows the upper airway. Studies have shown that after controlling for BMI the volume of the parapharyngeal fat pads is not different in apneics and normals (29). Nonetheless, this does not mean that fat deposited around the upper airway is not important. Fat deposition in other sites such as the tongue, soft palate, and uvula or under the mandible may be important (21,27,105). Furthermore, the total amount of fat surrounding the upper airway has been proposed to be more pertinent than fat localized to a specific site. In fact, a correlation between the fat enclosed by the mandibular rami and AHI has been demonstrated (27). Finally, weight gain is known to increase muscle mass in addition to fat (106-108). Approximately 25% to 30% of the increased weight in obese patients is attributable to fat-free tissue (107,109). Therefore, weight gain may directly increase the size of the muscular soft tissue structures surrounding the airway in addition to the fat deposition in the fat pads.
Upper Airway Edema/Trauma
Chronic trauma or repetitive exposure to negative pressures during snoring or apnea also appears to be important factors leading to enlargement of upper airway soft tissue structures. The repetitive apneic events are thought to result in two consequences: edema and muscular dysfunction. The soft palate is especially at risk for the development of edema due to caudal tugging during apneic events. MRI has demonstrated this edema (39) and CPAP is thought to reduce it (43). Quantitative magnetic resonance mapping has demonstrated increased edema and/or fat in the genioglossus muscles of apneics compared to controls (110). Uvulas of OSA patients histologically have shown increased edema (70). Tobacco abuse may also play a role in provoking inflammatory edema and therefore compromise upper airway diameter (111,112). Thus, there is emerging evidence that edema may be important in the pathogenesis of upper airway soft tissue enlargement in apneics.
Muscular Dysfunction/Sensory Neuropathy
Experiments measuring two-point discrimination and vibratory sensation thresholds have shown that snorers and apneics have compromised upper airway mucosal sensory function compared to controls supporting the presence of a sensory neuropathy in the upper airway of such patients (113). Muscular dysfunction has also been shown in OSA patients (114). Histological investigations have demonstrated inflammatory cell infiltration in skeletal muscle of apneics, which leads to contractile dysfunction (114). An abnormally high ratio of type-IIa fatigable to type I fatigue-resistant muscle fibers has been observed in apneic subjects and this finding is used to support the notion that there is a myopathy of the pharyngeal dilators that compromises their ability to maintain patency of the airway. English bulldogs, an animal model for sleep apnea, also have increased type II fibers in the genioglossus muscle (115). The myopathy, however, has been shown to be a consequence of sleep apnea rather than a cause based on a study that showed reversal of the histological changes with the use of CPAP (115). Nonetheless, the myopathic changes in apneics may alter the structure/function of the muscles that surround the upper airway.
Gender (See Also Chapter 14)
Gender-related differences have been reported in relation to upper airway structures (17,52,68,98,116-125). The prevalence and severity of sleep-disordered breathing is markedly increased in men (98,116). Explanations of these gender-related differences are multi-factorial and include differences in body fat distribution, hormones, control of breathing, upper airway dimensions, and abnormalities in the upper airway mechanics. Investigators have compared normal males and females using acoustic reflection, cephalometry, CT, and MRI and have found many anatomical differences. Women have been shown to have a smaller upper airway (52,117), smaller neck size (118,119), more fat distributed to the lower body and extremities (peripheral fat distribution) (120-122), smaller airway soft tissue structures/volume (17,122,123), and shorter upper airway length (17). The differences listed above are not widely established findings except for body fat distribution. Men with OSA have demonstrated a more collapsible upper airway during non-rapid eye movement (NREM) sleep when compared to BMI-matched women with OSA (125). Inconsistent data exist with regard to differences in pharyngeal mechanics between men and women; however, it appears that women "defend" their airway better in the supine position than men (68). Some investigators argue that the gender difference in collapsibility can be attributed to differences in neck circumference since the increased airway compliance observed in males is not observed when corrected for neck circumference (124). Gender differences in upper airway structure and function may also be explained by sex hormones, that is, postmenopausal women have a higher prevalence of OSA compared to premenopausal and postmenopausal women receiving hormone replacement therapy (116). In addition, new onset of OSA has been reported in a woman who received exogenous testosterone (126). Thus, it is likely that multiple factors explain the gender differences that exist between men and women in OSA.
Emerging evidence suggests that sleep apnea can be explained on the basis of genetics (127-132). Sleep apnea has been shown to cluster in families: relatives of an afflicted patient exhibit increased relative risk of OSA (127,128) even after adjusting for BMI. A single major gene inherited in an autosomal recessive fashion has been shown to account for approximately 20% of the variance among Caucasians and African-Americans in the Cleveland Family Study (129). Preliminary linkage studies have shown specific areas of the genome that are linked to sleep apnea as a quantitative trait (130,131). A more recent investigation used volumetric MRI to address the question of familial aggregation with regard to size of upper airway structures (132). These data demonstrated heritability for the size of tongue, lateral walls, and total soft tissue independent of obesity, age, gender, craniofacial size, and ethnicity. Further, it was demonstrated that the increased volume of the soft palate, lateral pharyngeal walls, and total soft tissue volume was associated with increased likelihood of having a sibling with apnea after adjusting for gender, age, ethnicity, cranio-facial size, and visceral neck fat (132). These data suggest that genetic factors have an important role in the pathogenesis of the enlargement of the upper airway soft tissue structures in apneics.
Several studies have also demonstrated family aggregation of craniofacial morphology in patients with OSA (119,133). A study on first-degree relatives of probands with sleep apnea showed that family members had retroposed mandibles and inferiorly displaced hyoid bones (119). Cephalometric data also support craniofacial differences (retroposed maxillae and mandibles, shorter mandibles, longer soft palates, and wider uvulas) in first-degree relatives of nonobese OSA patients compared to age-, sex-, height-, and weight-matched controls (133). Craniofacial morphology is also influenced by gender and race similar to upper airway soft tissue structures. Bimaxillary prognathism is more frequent in African-Americans than Hispanics and Caucasians (134). Asians have shorter maxillae and mandibles, smaller anterior-posterior facial dimensions, and lower BMIs than Caucasians (135-137). Therefore, many of the factors that modify the size of the upper airway soft tissue structures also modify the size of the craniofacial structures.
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