INTRODUCTION

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Many patients with sleep apnea/hypopnea syndrome (SAHS) are obese (1). Obesity is believed to predispose to SAHS because of mass loading of the upper airway by adipose tissue in the neck (2). Obese patients with SAHS have been shown to have increased fat deposition adjacent to the upper airway when compared with obese control subjects (3). However, around 50% of patients with SAHS newly diagnosed in our sleep laboratory are not technically obese (BMI > 30 kg/m²). It is not clear why these nonobese patients develop SAHS. These nonobese patients have been shown to have increased frequency of cephalometric bony abnormalities (4), and this we have shown is familial (5). However, it is not known whether fat deposition in the neck may also contribute to the development of SAHS in this group.

We hypothesized that the amount of neck fat in nonobese patients with sleep apnea may be increased compared with control subjects matched for simple indices of obesity and age. We have therefore compared neck fat distribution using magnetic resonance imaging (MRI) and total body fat, measured using skinfold thickness, in control subjects and in nonobese patients with SAHS matched for age, BMI, and neck circumference and in obese patients with SAHS.

	METHODS

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Subjects

Nine nonobese, nonsnoring male control subjects, nine nonobese male patients with sleep apnea (BMI < 30), and nine obese patients with sleep apnea (BMI > 30) were studied. All groups were matched for age. The nonobese patients with sleep apnea were also matched to the normal control subjects for two simple indices of obesity, neck circumference and BMI. Daytime sleepiness was assessed using the Epworth score (6). The control subjects were recruited from university and hospital staff because they were nonsnorers who were not sleepy during the day.

Measurement of Total Body Fat

Percentage body fat and fat-free mass were calculated from the sum of four skinfold thickness measurements (7).

Neck Circumference

Neck circumference was measured at the level of the superior border of the cricothyroid membrane (8).

Sleep Studies

All patients with SAHS had laboratory polysomnography using our standard protocol (9). The control subjects had either laboratory polysomnography or home sleep studies (Eden Trace system, EdenTec 3711; Nellcor, Minneapolis, MN) and were not apneic.

Magnetic Resonance Imaging

Subjects were imaged in a Siemens 63SP 1.5T Magnetom Scanner (Siemens Medical, Erlangen, Germany) using a cervical spine coil. Subjects were supine with the head and neck in a neutral position supported by the cervical spine coil. Subjects were requested to breathe quietly through the nose.

Scout views were collected, followed by a set of T1-weighted spin-echo sagittal images (repetition time = 500 ms, echo time = 15 ms, field of view = 280 mm slice thickness, 0.3 mm slice gap, 256 matrix, two acquisitions). The field of view extended from the skull base to the top of the trachea, and sufficient slices were collected to cover the entire upper airway laterally.

Transverse T1-weighted spin-echo images (repetition time = 800 ms, echo time = 15 ms, field of view = 250 mm, thickness 4 mm with 1 mm slice gap) were then collected. Typically, 20 slices were sufficient to cover the upper airway from the hard palate to the vocal cords.

Image Analysis

Image data were transferred to an independent workstation (Sun Microsystems Inc., Mountain View, CA) and analyzed using the "analyze" package (Mayo Clinic, Rochester, MN).

The transverse spin-echo images were analyzed for total tissue and fatty tissue areas. Total and fatty tissue areas/volumes were determined by a "blind" observer using a "fat" threshold for each subject determined by inspection of the images. Tissue and fat volumes are reported as voxels (the conversion factor to mm³ is × 1.2).

Tissue areas/volumes were categorized in eight radial transverse segments centered on the airway (Figure 1). The anterior four segments were further subdivided by the line of the jaw where this was visualized, so that a comparison could be made between tissue within the jaw (mandible), which might have differing influences on airway characteristics compared with that outside.

View larger version (119K): [in this window] [in a new window]   View larger version (121K): [in this window] [in a new window]   Figure 1.   Equivalent cross-sectional T1-weighted magnetic resonance scans of a control subject (top panel ) and nonobese patient with SAHS (bottom panel ) showing distribution of neck fat. Radial segments were numbered 1 to 8 from 12 o'clock clockwise. Anterolateral segments are 2 + 7. The anterolateral fat deposits in the patient with SAHS are arrowed.

Airway cross-sectional area was determined by placing a "seed point" at the center of the airway on each transverse image and automatically "growing" a region outwards.

Reproducibility of MRI measurements was assessed by measuring total tissue and fat in two control subjects and in two nonobese and two obese patients with sleep apnea in a single-blind trial on four separate occasions.

Chest Wall Movement

Respiration was monitored during MRI scanning using an extensible rubber tube filled with air and strapped around the patient's chest. This was attached to a pressure sensor and displayed on screen in the MRI control room during scanning.

Data Analysis

Comparisons between the three subject groups were carried out using one-way analysis of variance with Student-Neuman-Keuls correction for multiple comparisons (SPSS package, Microsoft Corporation).

Reproducibility was quantified as the coefficient of variation (standard deviation/mean) × 100.

Percentage differences were calculated using the formula {(A  B)/[(A + B)/2]} × 100, which avoids group bias (10).

	RESULTS

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Reproducibility

The average coefficient of variation for the four trials was 11% for total fat and 2% for total tissue measurement.

Anthropometric Measurements

There were no significant differences in age between the groups (Table 1). There were no significant differences in BMI, neck circumference, or fat-free mass when comparing control subjects with nonobese patients with SAHS.

Nonobese Patients with SAHS Compared with Matched Control Subjects

There were significant differences in total body fat and neck fat between control subjects and nonobese patients with SAHS (Table 1). Total neck tissue volume was not significantly different statistically in control subjects and in nonobese patients with SAHS. There was no statistically significant difference in total neck fat volume when control subjects and nonobese patients with SAHS were compared, but there was significantly more neck fat in the anterolateral segments 2 + 7 (both within and outside the jaw line) in the nonobese patients with SAHS compared with the control subjects. Comparison of minimum airway cross-sectional area showed obese patients with SAHS to have a significantly smaller minimum than did nonobese patients with SAHS. The upper airway minimum was located retroglossally in two subjects in both the control and the nonobese SAHS groups and retropalatally in all other patients with SAHS and the control group.

Obese Patients with SAHS Compared with Control Subjects

Total body fat and neck fat were greater in obese patients with SAHS than in control subjects (Table 1). Total neck tissue volume was also significantly greater in obese patients with SAHS than in control subjects. There was a statistically significant difference in total neck fat volume when obese patients with SAHS were compared with control subjects. Comparison of neck fat in the anterolateral segments 2 + 7 (both within and outside the jaw line) showed substantially more fat in the obese patients with SAHS than in the control subjects. Comparison of minimum airway cross-sectional area showed obese patients with SAHS to have a significantly smaller minimum than control subjects. The upper airway minimum was located retropalatally in all of the obese patients with SAHS.

	DISCUSSION

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Reproducibility of total tissue measurement by MRI scanning was good, with a coefficient of variation of 2%. The reproducibility of fat measurement was not as good, but at 11% it was similar to that of many other physiological measurements. A relatively poor reproducibility would tend to increase data scatter and obscure differences between groups. We therefore feel that the conclusions drawn from our data are sound.

This study has demonstrated that nonobese patients with SAHS have increased fat deposition adjacent to the upper airway when compared with age- and BMI-matched control subjects, despite there being no statistically significant differences in neck circumference or neck tissue volume. However, comparison of fat in the anterolateral segments 2 + 7 showed a 42% difference in fat volume and a 52% difference if only the fat within the jaw line was analyzed, which were statistically highly significant differences. Analysis of fat in segments 1, 3, 6-8 as a whole demonstrated a difference of 26%, which reflects the increased total body fat in nonobese patients with SAHS (30%). Thus, it appears that even if BMI and neck circumference are similar, percentage body fat and neck fat are increased in nonobese patients with SAHS compared with that in control subjects, and there are striking and statistically significant increases in the deep deposits anterolateral to the airway (segments 2 + 7), which are most likely to be of pathologic significance.

These results are consistent with those of Shelton and colleagues (2) who demonstrated a correlation between the fat enclosed by the mandibular ramus and apnea/hypopnea index. The differences in deep fat could also explain why BMI and neck circumference, although good predictors of apnea/hypopnea index compared with other indices, are relatively poor in absolute terms, accounting for no more than 30% of the variance (8, 11). The localized areas of deep fat are small in relation to overall neck volume and therefore may have a greater influence on airway caliber but a lesser influence on neck circumference compared with the circumferential subcutaneous fat. Comparison of obese patients with SAHS and control subjects supports this premise. Obese patients with SAHS had 44% more total body fat and 67% more total neck fat than did control subjects but 77% more fat in segments 2 + 7 (88% for segments 2 + 7 within the jaw line) despite only a 14% difference in neck circumference. These large differences in deep fat distribution may contribute to the highly significant differences observed in the upper airway minimum cross-sectional area between the groups (Table 1) and the observation of lateral compression of the upper airway in patients with SAHS compared with anteroposterior compression in control subjects (15). The increased upper airway compression by fat in both obese and nonobese patients with SAHS is consistent with the results of upper airway mass loading (16) and with the increased dilator muscle activity reported during spontaneous breathing in patients with SAHS compared with control subjects both awake (17) and asleep (18). The large differences in anterolateral fat in nonobese patients with SAHS compared with control subjects and the corresponding differences in upper airway minimum cross-sectional area, but with no difference in neck circumference between the two groups, could help to explain the findings of Katz and colleagues (8) who were able to explain a greater degree of the variance in apnea/hypopnea index by using upper airway (internal) circumference rather than by neck (external) circumference.

The level of minimum cross-sectional area (assessed from hard palate to cords) was either retropalatal or retroglossal with no marked positional trend between the three groups. These levels also correspond to the position of the anterolateral fat deposits. We have reported minimal upper airway cross-sectional area because this is most likely to be relevant pathophysiologically, being associated with the highest inspiratory negative (collapsing) pressure. We believe measurements were made in awake subjects because during the studies we monitored chest wall movement with a pressure sensor and did not note any apneas or hypopneas. In addition the scan times were relatively short in this study (6 min), and scanning is noisy; therefore, it is unlikely that any of the subjects fell asleep during upper airway measurements, and our values, therefore, represent measurements made during quiet nasal breathing in awake supine subjects.

Abnormal craniofacial structure has been shown to be important in the pathogenesis of SAHS in thin patients (4), and it may be related to a familial tendency to SAHS (5). The present study suggests that anterolateral fat deposition in nonobese patients may also be important and could, therefore, also be associated with a familial tendency to SAHS. A potential problem with the present study is that although we matched control subjects and nonobese patients with SAHS on group basis for age, neck circumference, and BMI, the patients with SAHS had a nonsignificant trend toward a 4% greater neck circumference (p = 0.1) and BMI (p = 0.2). However, not only were these differences nonsignificant, but they were also extremely small compared with the 52% difference observed in the fat anterolateral to the upper airway within the jaw line and 30% difference in total body fat.

We conclude that nonobese patients with SAHS have more total body fat than do age-, BMI-, and neck-circumference-matched control subjects and that they have substantially greater deposits of fat anterolateral to the upper airway. This might predispose to the observed upper airway narrowing we have demonstrated in the patients with SAHS when awake and may also, therefore, contribute to upper airway narrowing and collapse during sleep. These findings may also explain the poor predictive power of conventional indices of obesity with respect to apnea/hypopnea index.