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Published ahead of print on May 13, 2003, doi:10.1164/rccm.200208-866OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 522-530, (2003)
© 2003 American Thoracic Society

Original Article

Identification of Upper Airway Anatomic Risk Factors for Obstructive Sleep Apnea with Volumetric Magnetic Resonance Imaging

Richard J. Schwab, Michael Pasirstein, Robert Pierson, Adonna Mackley, Robert Hachadoorian, Raanan Arens, Greg Maislin and Allan I. Pack

Center for Sleep and Respiratory Neurobiology, Pulmonary, Allergy, and Critical Care Division, and Division of Sleep Medicine, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Richard J. Schwab, M.D., Center for Sleep and Respiratory Neurobiology, 893 Maloney Building, University of Pennsylvania Medical Center, 3600 Spruce Street, Philadelphia, PA 19104-4283. E-mail: rschwab{at}mail.med.upenn.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We used sophisticated volumetric analysis techniques with magnetic resonance imaging in a case–control design to study the upper airway soft tissue structures in 48 control subjects (apnea–hypopnea index, 2.0 ± 1.6 events/hour) and 48 patients with sleep apnea (apnea–hypopnea index, 43.8 ± 25.4 events/hour). Our design used exact matching on sex and ethnicity, frequency matching on age, and statistical control for craniofacial size and visceral neck fat. The data support our a priori hypotheses that the volume of the soft tissue structures surrounding the upper airway is enlarged in patients with sleep apnea and that this enlargement is a significant risk factor for sleep apnea. After covariate adjustments the volume of the lateral pharyngeal walls (p < 0.0001), tongue (p < 0.0001), and total soft tissue (p < 0.0001) was significantly larger in subjects with sleep apnea than in normal subjects. These data also demonstrated, after covariate adjustments, significantly increased risk of sleep apnea the larger the volume of the tongue, lateral pharyngeal walls, and total soft tissue: (1) total lateral pharyngeal wall (odds ratio [OR], 6.01; 95% confidence interval [CI], 2.62–17.14); (2) total tongue (OR, 4.66; 95% CI, 2.31–10.95); and (3) total soft tissue (OR, 6.95; 95% CI, 3.08–19.11). In a multivariable logistic regression analysis the volume of the tongue and lateral walls was shown to independently increase the risk of sleep apnea.

Key Words: magnetic resonance imaging • lateral pharyngeal walls • obstructive sleep apnea • parapharyngeal fat pads • upper airway

Despite the high prevalence and major public health ramifications of obstructive sleep apnea, not enough is understood about its pathogenesis or the anatomic risk factors for this condition (1). Upper airway imaging techniques have provided insight into the biomechanical basis of obstructive sleep apnea (2, 3). Studies with nasal pharyngoscopy (4–6), cephalometry (7, 8), fluoroscopy (9), conventional and electron beam computed tomography (9–13), acoustic reflection (14), and magnetic resonance imaging (MRI) (15–25) have been used to examine the anatomy of the pharynx in patients with this disorder. Such studies have demonstrated that the size of upper airway structures—tongue, soft palate, parapharyngeal fat pads, lateral pharyngeal walls, and mandible—is an important determinant of upper airway caliber in sleep apnea (9, 12, 13, 15, 17–25). However, these studies have largely examined the upper airway in two dimensions, measuring distances (i.e., thickness or length) and cross-sectional areas of upper airway structures (9–11, 15–17, 23). We believe that a two-dimensional assessment of the upper airway soft tissue structures is an inadequate characterization of a three-dimensional structure.

To fully understand the anatomic risk factors for obstructive sleep apnea, we need to examine the volume of upper airway structures, that is, using a three-dimensional approach. Although other investigators have examined the volume of upper airway soft tissue structures (20, 21) these studies had small sample sizes and did not examine all the upper airway structures comprehensively. To pursue such an analysis, we used sophisticated computer reconstruction algorithms that allowed us to move beyond the measurement of dimensions to a three-dimensional volumetric approach. We have successfully tested this three-dimensional upper airway image analysis paradigm and performed validation studies of these newly developed volumetric MRI techniques (22). The primary goal of the present investigation was to determine the anatomic soft tissue risk factors for sleep-disordered breathing by using these state-of-the-art volumetric MRI methods.

We used a case–control design to examine our a priori hypotheses that the volume of the soft tissue structures surrounding the upper airway was enlarged in patients with sleep apnea and that this enlargement was a significant risk factor for sleep apnea. We assessed the structural risk factors for sleep apnea, with a particular focus on volume of the lateral pharyngeal walls, tongue, soft palate, parapharyngeal fat pads and the total volume of upper airway soft tissues. Subjects with sleep apnea and control subjects were exactly matched for sex and ethnicity and frequency matched for age. Covariate adjustments were made for craniofacial size and parapharyngeal fat in the neck, both important determinants of apnea risk (19–22, 26, 27). Thus, in our analyses we report crude odds ratios for the effects of increased size of the soft tissue structures on risk of sleep apnea as well as adjusted odds ratios controlling for the exact matching factors (sex and ethnicity), age, with covariate adjustments for craniofacial size and parapharyngeal neck fat. Some of the results from our study have been previously reported in the form of an abstract (28).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Control (normal) subjects were recruited through local advertisements in the neighborhood (same school district) of the case subjects (patients with obstructive sleep apnea). Control subjects were of the same sex and ethnic background as the case subjects. To qualify as control subjects, individuals needed to be free of sleep apnea. This was detected in a sleep study and all control subjects were anticipated to have an apnea–hypopnea index (AHI) less than 5 episodes/hour.

Case subjects were recruited primarily from the Penn Center for Sleep Disorders (Philadelphia, PA) outpatient practice and were newly diagnosed as having sleep apnea. They had symptoms of sleep apnea. To qualify as a "case" such patients had to have an apnea–hypopnea index greater than 15 episodes/hour.

We report data on 48 case subjects and 48 control subjects. Potential control subjects presenting with symptoms of sleep apnea and an apnea–hypopnea index greater than 15 episodes/hour were recruited as case subjects. Control subjects with apnea–hypopnea indices greater than 5 but less than 15 episodes/hour were considered indeterminate and were not studied further (see online supplement for additional information).

Polysomnography
Standard polysomnography procedures and scoring were performed, as previously described from our laboratory (17, 18, 22, 29) (see online supplement for additional information).

MRI
Upper airway imaging was performed identically in normal subjects and subjects with sleep apnea, using a 1.5-T magnetic resonance imaging scanner (see online supplement for additional information).

Anatomic Definitions, Measurements, and Analysis
The analysis of MRI data was split into thee domains: airway measurements (Figures 1–3) , two-dimensional soft tissue measurements (see Figure E1 in online supplement) for comparison with previous studies, and three-dimensional volumetric measurements: lateral pharyngeal walls (retropalatal [RP] and retroglossal [RG]); soft palate; tongue (genioglossus muscle and then separately the entire tongue including genioglossus, geniohyoid, hyoglossus, myohyoid, digastric, and myohyoideus muscles); parapharyngeal fat pads; and, finally, total soft tissue, which includes all the measured soft tissues (see Figures 4 and 5 ; and see online supplement for additional information). A movie (Figure E3) highlighting the three-dimensional volumetric differences between normal subjects and subjects with sleep apnea is also available in the online supplement.



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  		Figure 1. Midsagittal magnetic resonance image (MRI) of a normal subject, demonstrating the upper airway regions: retropalatal (RP)—from the level of the hard palate to the caudal margin of the soft palate; and retroglossal (RG)—from the caudal margin of the soft palate to the base of the epiglottis. Soft palate, tongue, airway, mandible, and subcutaneous fat are denoted with arrows. Fat is bright (white) on an MRI.

 


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  		Figure 3. Three-dimensional volume rendering of the head, with an extracted upper airway (white) and a three-dimensional centerline (represented by the black dots within the white airway). Two oblique images locally perpendicular to the airway are depicted at the RP and RG regions.

 


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  		Figure 2. Representative three-dimensional upper airway volume in a patient with sleep apnea (left) and in a normal subject (right). Note that the upper airway volume is smaller in the RP region than in the RG region in both subjects and that the length of the total airway and the individual regions (RP/RG) is not equivalent between the apneic and normal subjects. Airway volume is smaller in the RP region in this apneic subject compared with the control subject; airway volume is similar in the RG region in this apneic subject compared with the control subject.

 


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  		Figure 4. Volumetric reconstructions from a series of 3-mm contiguous axial MR images of the mandible (gray), tongue (orange/rust), soft palate (purple), lateral parapharyngeal fat pads (yellow), and lateral/posterior pharyngeal walls (green) in a weight-matched normal subject (top) and patient with sleep apnea (bottom), both with an elevated body mass index (32.5 kg/m2). Note that the airway is larger in the normal subject than in the apneic subject. The tongue, soft palate, and lateral pharyngeal walls are larger in the patient with sleep apnea.

 


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  		Figure 5. T1-weighted axial MRI at the minimum airway level in the retropalatal region in a normal subject and a patient with sleep apnea. Note that the airway is smaller in the apneic subject than in the normal subject. The lateral pharyngeal walls are larger in the apneic subject than in the normal subject.

 
Statistical Analysis
Case subjects and control subjects were descriptively compared using {chi}2 tests for nominal characteristics and t tests for interval characteristics (or rank-based procedures, if specified). Our a priori hypothesis for this investigation was that the volume of the soft tissue structures surrounding the upper airway was enlarged in patients with sleep apnea and that this enlargement was a significant risk factor for sleep apnea. Therefore we selected the volume of the soft tissue structures as the primary analysis variables (volume of the soft palate, tongue, lateral pharyngeal walls, and total soft tissue). The airway measurements and two-dimensional measurements are considered exploratory and/or confirmatory analyses.

Our design used exact matching on sex and race, frequency matching on age, and statistical control for craniofacial structure and visceral, that is, parapharyngeal, fat in the neck. We adjusted on the basis of visceral fat in the neck (volume of parapharyngeal fat) because we believed this would be a much better measure of adiposity in the neck than body mass index, which can be affected by fat in the abdomen and in other locations. Analyses were performed with and without adjusting for visceral neck fat to determine the magnitude of case–control differences after removing the effect of adipose tissue in the neck. Multiple logistic regression models were used to obtain adjusted odds ratios and 95% confidence intervals (CIs) for the effects of a 1-SD change in the size of the various airway and soft tissue measurements. A reference set of SDs was constructed from the control sample (n = 48). Odds ratios with a 95% CI lower bound (LB) greater than one indicate that an increase in the size of that structure is associated with an increased risk of obstructive sleep apnea. In contrast, odds ratios with a 95% CI upper bound (UB) less than one indicate that reduction in the size of that structure is associated with an increased risk of obstructive sleep apnea. In addition, we performed a multivariable logistic regression analysis, which included all the a priori factors (upper airway soft tissue volumes) including the control variables (craniofacial size, parapharyngeal fat pad volume) plus age, sex, and ethnicity. This model takes into account any correlation between the volumes of the upper airway structures and independently examines the increased risk of sleep apnea for each of these factors. See the online supplement for additional information about statistical approaches.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics of Case Subjects and Control Subjects
Our case–control study consisted of 48 patients with apnea and 48 control subjects matched on sex (male, 43.8%) and race (39.6% white, 54.2% African American, 4.2% Asian, 2.1% Hispanic). Case subjects and control subjects differed significantly with respect to marital status, with more case subjects married (58.1%) compared with control subjects (27.9%). Differences in levels of education were not significant (for a more comprehensive description of the demographics of case subjects and control subjects, see Table E1 in the online supplement). Patients with apnea were required to have an AHI >= 15 (mean AHI, 43.8 ± 25.4 episodes/hour) and nonapneic control subjects were required to have an AHI < 5 (mean AHI, 2.0 ± 1.6 episodes/hour) (see Table 1) . Three control subjects had an AHI between 5 and 6 events/hour. They met all the other criteria for control subjects and were included in our analysis. Thirty-seven of 48 of the control subjects manifested quiet snoring but none of them had evidence of upper airway resistance syndrome (defined as snoring-related arousals). Case subjects tended to be older than control subjects (p = 0.054), but age ranges were comparable (27 to 64 versus 24 to 66 years) and we adjusted for residual age differences in the analysis. The body mass index of case subjects (36.2 ± 8.8 kg/m2) was significantly greater than that of control subjects (25.9 ± 4.8 kg/m2; p < 0.001), but many of the control subjects were overweight. In the multivariable analysis we adjusted for the effect of obesity on upper airway soft tissue structures on the basis of visceral fat in the neck (volume of parapharyngeal fat). We believed this would be a much better measure of adiposity in the neck than body mass index, which can be affected by fat in the abdomen and in other locations. Figure E2 (see the online supplement) provides comparisons of the distributions of the parapharyngeal fat pad volumes in all case subjects and control subjects. These data demonstrate that there was sufficient overlap in the distributions of parapharyngeal fat pad volumes to allow us to control for visceral neck fat as a covariate in the analysis. See the online supplement for additional information.


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  		TABLE 1. Demographics of case subjects and control subjects

 
Polysomnography
Sleep efficiency (p = 0.36), total sleep time (p = 0.10), and total test time, that is, time in bed (p = 0.12) were not significantly different between case subjects and control subjects (see Table E2 in the online supplement). Case subjects had significantly less rapid eye movement sleep than did control subjects (p = 0.04). In contrast, there was no significant difference between case subjects and control subjects for mean times spent in Stage 1 sleep (p = 0.08), Stage 2 sleep (p = 0.17), and delta sleep (p = 0.06). Presumably the reduction in rapid eye movement sleep time among the subjects with sleep apnea was related to their sleep-disordered breathing. There were also significantly more nocturnal arousals (45.6 ± 31.2 arousals/hour; p < 0.001) among the subjects with sleep apnea than among the control subjects (17.0 ± 7.3 arousals/hour).

Three-Dimensional Volumetric Measurements
The primary focus of this investigation was to identify soft tissue anatomic risk factors for obstructive sleep apnea, using volumetric MRI. Changes in the size of the upper airway structures are demonstrated in representative subjects in Figure 4. In Figure 4 the volumes of the soft palate and lateral pharyngeal walls are greater in the patient with sleep apnea than in the control subject. A three-dimensional movie (Figure E3) highlighting the enlargement of the upper airway soft tissue structures in subjects with sleep apnea compared with normal subjects is also available in the online supplement. These descriptive findings were confirmed when we examined the quantitative volumetric measurements between normal subjects and subjects with sleep apnea (Table 2) . The volumes of all upper airway structures (parapharyngeal fat pads, RP lateral pharyngeal walls, RG lateral pharyngeal walls, total lateral pharyngeal walls, soft palate, genioglossus, total tongue, and total soft tissue) were significantly greater in subjects with sleep apnea than in control subjects (see Table 2).


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  		TABLE 2. Crude comparisons of volumetric soft tissue measurements in case subjects and control subjects

 
When we adjusted for sex, ethnicity, age, and craniofacial size (Table 3) the volumes of all upper airway structures (RP lateral pharyngeal wall, RG lateral pharyngeal wall, total lateral pharyngeal wall, soft palate, genioglossus, total tongue, and total soft tissue) remained significantly greater in subjects with sleep apnea than in control subjects, except for the parapharyngeal fat pads (p = 0.06). When the differences in means were also adjusted for differences in visceral fat in the neck all the volumes of the soft tissue structures except the soft palate remained statistically significantly greater in subjects with sleep apnea than in control subjects. These data indicate that differences in the size of upper airway structures between case subjects and control subjects cannot simply be explained by fat. Factors other than obesity must be contributing to the increased volume of upper airway soft tissue structures.


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  		TABLE 3. Soft tissue volumes: adjusted mean differences

 
Table 4 summarizes the relative risk analyses for the volumetric soft tissue measurements. The unadjusted odds ratios for all the volumetric structures were significantly greater than one, reflecting increased risk of sleep apnea among subjects with larger volumes. The odds ratios for all the volumetric soft tissue measurements increased or stayed the same (odds ratio for parapharyngeal fat pad volume decreased slightly) after adjusting for sex, ethnicity, age, and craniofacial size. After also adjusting for visceral fat in the neck, the odds ratios for most of the volumetric soft tissue measurements remained significant (with little change in magnitude) except for soft palate: (1) RP lateral pharyngeal wall (OR, 1.77; 95% CI, 1.10–3.03), (2) RG lateral pharyngeal wall (OR, 3.17; 95% CI, 1.68–6.87), (3) total lateral pharyngeal wall (OR, 6.01; 95% CI, 2.62–17.14), (4) genioglossus (OR, 6.55; 95% CI, 2.81–19.42), (5) total tongue (OR, 4.66; 95% CI, 2.31–10.95), and (6) total soft tissue (OR, 6.95; 95% CI, 3.08–19.11). These data indicate that enlargement of the upper airway soft tissue structures (particularly the volume of the tongue, lateral walls, and total soft tissue) is an important risk factor for sleep apnea independent of obesity, specifically visceral fat in the neck, craniofacial size, age, sex, and ethnicity.


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  		TABLE 4. Odds ratios with 95% confidence intervals for sleep apnea for 1-SD increase in soft tissue volume

 
Although these data indicate that enlargement of several of the upper airway soft tissue structures increases the risk for sleep apnea, the size of these structures may be correlated with each other. To address this issue we performed a multivariable logistic regression analysis, which encompassed all the a priori factors (upper airway soft tissue volumes) including the control variables (cranial size/fat pad volume) plus age, sex, and ethnicity. This model takes into account any correlation between the volumes of the upper airway structures and independently examines the increase risk of sleep apnea for each of these factors. These data are presented in Table 5 and demonstrate that total tongue volume (OR = 4.36, 95% CI = 1.72–13.19) and total lateral wall volume (OR = 5.21, 95% CI = 1.99–18.18) significantly increase the risk of sleep apnea. These data demonstrate that volumetric enlargement of the tongue and lateral pharyngeal walls are independent risk factors for sleep apnea after controlling for age, sex, ethnicity, head size, and upper airway visceral fat.


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  		TABLE 5. Multivariable logistic regression model for odds ratio with 95% confidence intervals for sleep apnea for 1 standard deviation increases in soft tissue volumes

 
Airway Measurements
The results from the airway measurements are considered exploratory. The size of the upper airway is smaller in subjects with sleep apnea than in control subjects (see Figures 2 and 5). This is also well demonstrated in the movie (see Figure E3 in online supplement). Descriptive comparisons of mean values for the airway measurements between case subjects and control subjects are displayed in Table E3 in the online supplement. These data demonstrated that in the retropalatal region the average airway area per slice, minimum airway area, and lateral and anterior–posterior dimensions were significantly smaller in subjects with sleep apnea than in control subjects. There were no significant differences in the RG measurements.

Differences in mean values for the airway measurements adjusted for covariates are displayed in Table E4 in the online supplement. In the retropalatal region airway volume, the average airway area per slice, minimum airway area, and lateral and anterior–posterior dimensions were significantly smaller in subjects with sleep apnea than in control subjects after controlling for sex, ethnicity, age, craniofacial size, and parapharyngeal fat.

We next expressed these differences in terms of unadjusted and adjusted relative risks by estimating odds ratios for the effects of 1-SD differences in the measurements of airway size (see Table E5 in online supplement). A reference SD value was derived from the control sample for each measurement and the specific values used are provided in the online supplement tables. Even after covariate adjustments, there was a significantly increased risk of developing sleep apnea the smaller the retropalatal airway volume, airway area, anterior–posterior dimension, and lateral dimension. In contrast, changes in caliber of the retroglossal airway were not associated with an increased risk of developing obstructive sleep apnea. See the online supplement for additional information.

Two-Dimensional Soft Tissue Measurements
The results from the two-dimensional soft tissue measurements are also considered exploratory. Figure 5 demonstrates changes in the two-dimensional soft tissue measurements at the level of the minimum airway in the retropalatal region between a normal subject and an apneic subject. In Figure 5, airway caliber is smaller in the subject with sleep apnea. In addition, the lateral pharyngeal walls are larger in the subject with sleep apnea compared with the normal subject. When we examined the descriptive data (see Table E6 in online supplement) from all subjects, we found that the thickness of the retropalatal lateral pharyngeal wall was significantly larger in subjects with sleep apnea compared with control subjects. After controlling for sex, ethnicity, age, craniofacial size, and visceral fat in the neck, only the thickness of the lateral pharyngeal wall in the retropalatal region remained significantly greater in subjects with sleep apnea compared with control subjects (see Table E7 in online supplement). This relationship is expressed in terms of sleep apnea relative risk in Table E8 (see online supplement). A 1-SD increase in the thickness of the lateral pharyngeal wall was associated with a 2.30 (95% CI, 1.34–4.23)-fold increased risk of sleep apnea. However, the odds ratios for the volumetric soft tissue structures were substantially greater than those for the two-dimensional measurements.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Volumetric MRI is a powerful tool to identify and quantify anatomic risk factors for obstructive sleep apnea. We have demonstrated that (1) the volume of upper airway soft tissue structures is enlarged in patients with sleep apnea, even after controlling for key covariates including volume of the parapharyngeal fat pads; (2) enlargement of these structures is a significant risk factor for sleep apnea; these volumetric risk factors have much higher odds ratios for sleep apnea than measures derived from the two-dimensional analysis, which is the analysis that has been performed in most upper airway imaging studies to date (10, 11, 15–17); (3) tongue and lateral wall volumes are particularly important independent risk factors for sleep apnea; and (4) the identification of these risk factors provides a quantifiable data set to examine heritability of upper airway structures in future studies. These data highlight the importance of upper airway anatomy in predisposing patients to sleep-disordered breathing.

Study Design and Methodology
For study design and methodology limitations, see the online supplement.

Upper Airway Risk Factors for Sleep Apnea
Imaging studies during wakefulness have demonstrated that the upper airway in patients with sleep apnea is smaller than in control subjects (10, 15, 17). However, most of these imaging studies have not specifically examined the region (retropalatal or retroglossal) in which the airway is smallest. Studies have suggested that upper airway narrowing can be present in both the retropalatal and retroglossal regions (4, 5, 30). In a previous investigation using two-dimensional image analysis techniques (17), we demonstrated that the minimum airway was significantly smaller in subjects with sleep apnea compared with normal subjects and that the minimum airway occurred exclusively in the retropalatal region. Our data from the present investigation replicated these findings, demonstrating that airway caliber in the retropalatal region is significantly smaller in subjects with sleep apnea compared with control subjects. However, our data also demonstrated that airway caliber in the retroglossal region is similar in size in subjects with sleep apnea compared with normal subjects. These data may have important implications for the pathogenesis of sleep apnea. Airway closure during an apneic event may be more likely to occur in the retropalatal region than in the retroglossal region because of anatomic narrowing in this region. We have previously shown by state-dependent imaging that upper airway size decreases in the retropalatal region during sleep in normal subjects but does not decrease in the retroglossal region (18). That investigation suggested that the upper airway may not narrow during sleep like a homogeneous tube but may narrow in a regional manner. Other investigators using nasopharyngoscopy have demonstrated that upper airway collapse is more likely to occur in the retropalatal region in patients with sleep apnea (4).

Although airway differences were notably more significant for many of the measures taken in the retropalatal region compared with the retroglossal region, enlargement of the soft tissues that form the airway was noted in both the retropalatal and retroglossal regions. Narrowing of the airway in the retropalatal region is likely related to enlargement of the lateral walls and the tongue, but why is the retroglossal airway also not reduced in caliber if the soft tissue structures are enlarged in this region? These data reflect the complexity of the upper airway. There are a number of potential reasons for this: (1) airway caliber in the retroglossal region is greater than in the retropalatal region (17) (mostly secondary to the disappearance of the soft palate in this region), so that although the soft tissues are enlarged in this region they might not have as meaningful an effect on airway caliber; (2) increases in the volume of the soft tissue structures surrounding the retroglossal region may be a global risk factor for sleep apnea because of their effect in the retropalatal region, not because of their effect in the retroglossal region (i.e., tissue enlargement throughout the entire airway); (3) the correlation between minimal airway area and volume of the lateral walls and tongue (which form the airway) is likely not linear; and (4) the volumetric enlargement of the tongue which affects airway caliber in both the RP and RG regions may not be uniform (i.e., more effect in the RP region than the RG region). However, further research is needed to definitively answer this question.

Upper Airway Soft Tissue Risk Factors for Sleep Apnea
Previous studies using older upper airway imaging paradigms demonstrated two-dimensional enlargement of the tongue, soft palate, lateral pharyngeal walls, and parapharyngeal fat pads in patients with sleep-disordered breathing (9–11, 15–17, 23). However, we moved beyond a two-dimensional analysis approach to demonstrate that the volume of the upper airway soft tissue structures was significantly greater in subjects with sleep apnea than in normal subjects. We have shown that a three-dimensional volumetric approach better characterizes the enlargement of the soft tissue structures of the upper airway than does the conventional two-dimensional approach. The identification of upper airway soft tissue risk factors (odds ratios) for sleep apnea was substantially greater with the volumetric measurements than with the two-dimensional measurements. Therefore, we believe that volumetric MRI should become the standard for quantifying enlargement of the upper airway soft tissue structures in patients with sleep-disordered breathing.

An important goal of this investigation was to determine which of the upper airway soft tissue structures (tongue, soft palate, lateral pharyngeal walls, and parapharyngeal fat pads) was the most important anatomic risk factor for sleep-disordered breathing. The volume of each of these soft tissue structures was significantly greater in subjects with sleep apnea compared with control subjects. After adjusting for sex, ethnicity, age, craniofacial size, and visceral fat in the neck the greatest odds ratios for the development of sleep apnea were associated with increased volume of the lateral pharyngeal walls, tongue, and total soft tissue. In our multivariable analysis tongue volume and lateral pharyngeal wall volume were independent risk factors for sleep apnea. We, therefore, believe that the size of the lateral pharyngeal walls and tongue is particularly important in the development of obstructive sleep apnea. Other studies have also demonstrated the importance of the lateral pharyngeal walls in mediating changes in airway caliber during respiration (10), the Mueller maneuver (6), sleep (18), weight loss (22), and with continuous positive airway pressure (31).

Pathogenesis of the Enlargement of Upper Airway Soft Tissue Structures
Why are the upper airway soft tissue structures enlarged in patients with sleep apnea? Although the underlying pathogenesis of the increase in volume of these structures is not known, the most likely reasons are genetic factors, obesity, consequences of the disease itself (over time the soft tissues enlarge secondary to snoring and repeated apneic events), and neuromechanical factors. Obesity has been shown to be an important risk factor for obstructive sleep apnea in adults (26, 32). It has been hypothesized that increased upper airway adipose tissue, specifically deposited in the lateral parapharyngeal fat pads, plays a major role in the pathogenesis of sleep apnea (19, 20, 22). Upper airway imaging studies (15, 17, 19, 20) have confirmed that the total volume of fat in the lateral parapharyngeal fat pads is greater in subjects with sleep apnea than in normal subjects. Fat has been demonstrated on histologic sections of the uvula of patients with sleep apnea (33, 34). Fat has also been demonstrated in the tongue on MRI scans (2, 3). What is not known is whether obesity increases the size of upper airway soft tissue structures independent of the direct deposition of adipose tissue. Our data indicate that the amount of visceral fat in the neck may not be the most important factor in the enlargement of the upper airway soft tissue structures, because when we adjusted for volume of the parapharyngeal fat pads (Table 3) the volumetric differences between case subjects and control subjects for the soft tissue structures were not reduced significantly. Therefore other factors besides obesity (in addition to age, sex, craniofacial size, and ethnicity, which were controlled for in the analysis) must be important in mediating the increase in the size of the tongue and lateral pharyngeal walls.

We believe genetic factors may be important in mediating the enlargement of these soft tissue structures. There is growing evidence that obstructive sleep apnea has a genetic basis: (1) there is an increased prevalence of sleep apnea among patients with genetic mutations or chromosomal defects, for example, Treacher–Collins syndrome (35) and Down syndrome (macroglossia has been demonstrated in this syndrome) (36); (2) obstructive sleep apnea has been reported in multiply affected members of families (37–39); (3) increased prevalence of sleep apnea has been demonstrated among relatives of affected probands (39–41); (4) studies have demonstrated family aggregation of sleep apnea by comparing the prevalence of sleep apnea among relatives of affected probands with relatives of control subjects (39, 40); and (5) in the ongoing Cleveland Family Study, inheritance patterns of sleep apnea among white subjects and African Americans have demonstrated a recessive mode of inheritance, with a single major gene in both of these populations (42). This study has now demonstrated with genome-wide linkage analysis several candidate genes that showed significant linkage to the apnea–hypopnea index (43). Because there is compelling evidence that sleep apnea has a genetic component it would be reasonable to hypothesize that the size of the upper airway soft tissue structures is partially determined by genetic factors. At present this remains speculative because no study, to date, has addressed the issue of heritability of size of upper airway soft tissue structures.

Another factor that could affect the size of the upper airway structures is sleep apnea itself and disease duration (44, 45). Trauma from recurrent apneas with reported high negative intralumenal pressure and repeated bouts of snoring with vibration may increase the size of the upper airway structures. Finally, state-dependent and neuromechanical factors may affect the size of the upper airway and surrounding soft tissue structures (5, 18).

Phenotyping the Pharynx
Our data led us to the opinion that MRI is the ideal modality to phenotype the upper airway in patients with sleep apnea. Volumetric MRI provides the capability of determining intermediate traits for sleep apnea by quantifying in three dimensions craniofacial structure (this is currently being addressed by us) and upper airway soft tissue morphology, including fat deposition in the neck. Our present investigation has identified increased tongue, total soft tissue, and lateral pharyngeal wall volumes as anatomic risk factors for sleep apnea. Each of these risk factors can be considered an intermediate trait for sleep apnea. If, in future studies, we can demonstrate family aggregation and heritability of these soft tissue anatomic risk factors, we will be able to take another step toward elucidating the genetics of obstructive sleep apnea.

Conclusions
We have used volumetric MRI to identify structural risk factors for obstructive sleep apnea. Our MR imaging and computer-based analysis techniques allowed us to objectively quantify the volume of the tongue, soft palate, parapharyngeal fat pads, and lateral pharyngeal walls. Increased tongue, total soft tissue, and lateral pharyngeal wall volumes are all important risk factors for sleep apnea. After adjusting for ethnicity, sex, age, craniofacial size and visceral fat in the neck there was a significantly increased risk of developing sleep apnea the larger the volume of the tongue, lateral pharyngeal walls, and total soft tissue. We believe these quantifiable structural risk factors can be used to optimally phenotype the upper airway in future studies to determine whether heritability of these intermediate traits exists.


   Acknowledgments
 
R.J.S. has no declared conflict of interest; M.P. has no declared conflict of interest; R.P. has no declared conflict of interest; A.M. has no declared conflict of interest; R.H. has no declared conflict of interest; R.A. has no declared conflict of interest; G.M. has no declared conflict of interest; A.I.P. has a grant from ResMed to study the relative role of ambulatory recording of sleep-disordered breathing as it compares to full sleep study.


   FOOTNOTES
 
Supported by National Institutes of Health grants HL-60287, HL-57843, HL-67948, RR-00040.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form August 14, 2002; accepted in final form May 9, 2003


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