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New Perspectives on the Pathogenesis of OSA - Anatomic Perspective

Richard J. Schwab, M.D. Professor of Medicine Interim Chief, Division of Sleep Medicine Medical Director, Penn Sleep Centers University of Pennsylvania Perelman School of Medicine

New Perspectives on the Pathogenesis of OSA: Anatomic Perspective - Disclosures

• NIH grants - PPG (phenotyping and OSA) • ResMed Grant/Registry to study OSA/CSA and CPAP in hospitalized patients • Jazz clinical trial (JZP-110) for daytime sleepiness in OSA • Inspire CT study to examine upper airway anatomy with hypoglossal nerve stimulation

1 New Insights into the Pathogenesis of Sleep Apnea: Anatomic Perspective

• Physical examination/anatomic risk factors for OSA • Anatomic pathogenesis of OSA – Increased size of upper airway soft tissues – Importance of fat – Dynamic upper airway imaging during respiration

Modified Mallampati Classification

Class 1 Class 2 Class 3 Class 4

• Tsai et al, AJRCCM 167,1427-1432, 2003 • Mallampati et al. (1985). A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaest Soc J, 32(4), 429-34, 1985

2 Modified Mallampati Classification

What is this patient’s Modified Mallampati score?

Anatomic Risk Factors for Sleep Apnea • Obesity and its effects on the upper airway tissues • Increased neck circumference • Nasal airway restriction: septal deviation, allergic rhinitis, nasal polyps • Macroglossia/tongue ridging • Adeno-tonsillar hypertrophy (palatine/lingual ) • Lateral peritonsillar narrowing • Enlargement/elongation of the soft • Recessed mandible (retrognathia)/maxilla • Narrowed - overbite/overjet • A combination of soft tissue and/or craniofacial risk factors is likely most important

3 Morphometric Measurements (Schellenberg AJRCCM 162;740-748, 2000)

• Macroglossia: tongue being above level of mandibular occlusal plane • Uvula enlargement: > 1.5 cm in length or > 1.0 cm in width • Enlargement of lateral walls: > 25% impingement pharyngeal space by peritonsillar tissues • Tonsillar enlargement: > 50% lateral impingement of posterior pharyngeal airspace

Normal Upper Airway (Schellenberg et al, AJRCCM 162;740-748, 2000)

4 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162;740-748, 2000)

Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162;740-748, 2000)

5 Normal Upper Airway (Schellenberg et al, AJRCCM 162;740-748, 2000)

Lateral Pharyngeal Grading System

• Class I = intersects at the edge of the tongue • Class II = palatopharyngeal arch intersects at 25% or more of the tongue diameter • Class III = palatopharyngeal arch intersects at 50% or more of the tongue diameter • Class IV = palatopharyngeal arch intersects at 75% or more of the tongue diameter

Tsai, et al. A Decision Rule for Diagnostic Testing in Obstructive Sleep Apnea. American Journal of Respiratory and Critical Care Medicine, Vol. 167, No. 10 (2003), pp. 1427-1432

6 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162;740-748, 2000)

Narrowed Hard Palate and Sleep Apnea

7 Physical Examination and Sleep Apnea (Schellenberg et al, AJRCCM 162;740-748, 2000)

Physical Examination and Sleep Apnea (Schellenberg AJRCCM 162;740-748, 2000) Adjusted Odds Ratio (OR) for Sleep Apnea Physical Finding OR 95% CI • Lateral Narrowing 2.6* 1.7 - 4.1 • Tonsillar hypertrophy 2.1* 1.1 - 4.2 • Macroglossia 2.0 1.1 - 3.6 • Enlarged 1.9 1.2 - 2.9 • Retrognathia 1.3 0.8 - 2.1 *Maintained significance after adjusting for BMI/neck size

8 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea)

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

Quantify Anatomic Risk Factors for OSA with Digital Morphometrics/Laser Ruler

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

9 Upper Airway Soft Tissue and Craniofacial Measurements

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

Intraoral Photographs with Indicated Measures

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

10 Craniofacial Photograph with Laser Ruler

The mandibular length is measured from the marked mandibular angle to the most prominent point on the chin Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

Examples of the Four Classes of Modified Mallampati

• Class I indicates full visibility of the uvula and • Class II indicates visibility of upper portion of the uvula and partial visibility of the upper airway • Class III indicates visibility of the hard palate and base of the uvula • Class IV indicates visibility of the hard palate and no visibility of the soft palate Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

11 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Demographics

All Patients Controls (AHI<10) Apneics (AHI≥10) Measure p N Estimate N Estimate N Estimate

Age 844 47.4 ± 13.7 311 42.6 ± 13.9 533 50.2 ± 12.8 <0.0001

BMI 844 36.1 ± 9.9 311 32.1 ± 8.5 533 38.5 ± 9.9 <0.0001 Gender 0.027 Male 403 47.75% 133 42.77% 270 50.66% Female 441 52.25% 178 57.23% 263 49.34% Race 0.028 Caucasian 393 47.12% 155 50.49% 238 45.16% African 346 41.49% 110 35.83% 236 44.78% Other 95 11.39% 42 13.68% 53 10.06% AHI 844 26.3 ± 28.9 311 4.15 ± 2.83 533 39.2 ± 29.4 <0.0001

ln(AHI+1) 844 2.72 ± 1.18 311 1.45 ± 0.66 533 3.46 ± 0.67 <0.0001

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Results

All Patients Controls (AHI<10) Apneics (AHI≥10) Measure p N Estimate N Estimate N Estimate

Modified Mallampati 0.017

Class I 35 4.59% 20 7.30% 15 3.07% Class II 79 10.35% 34 12.41% 45 9.20% Class III 126 16.51% 46 16.79% 80 16.36% Class IV 523 68.55% 174 63.50% 349 71.37%

Airway Not Visible 649 85.06% 220 80.29% 431 87.73% 0.006

6.23 ± Mouth Width 792 6.17 ± 0.86 301 6.07 ± 0.86 491 0.012 0.85 5.16 ± Mouth Height 764 5.14 ± 1.04 291 5.09 ± 1.08 473 0.382 1.01 Mouth Area 771 24.0 ± 7.0 295 23.2 ± 7.4 476 24.4 ± 6.6 0.026 5.20 ± Tongue Width 726 5.12 ± 0.56 283 5.00 ± 0.52 443 <0.0001 0.57 Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

12 Digital Morphometrics: A New Paradigm to Assess Upper Airway Anatomical Risk Factors for Obstructive Sleep Apnea - Results All Patients Controls (AHI<10) Apneics (AHI≥10) Measure p N Estimate N Estimate N Estimate Mouth Width 709 6.01 ± 0.77 275 5.93 ± 0.81 434 6.07 ± 0.75 0.023 Tongue Width 782 5.23 ± 0.72 299 5.10 ± 0.71 483 5.30 ± 0.72 <0.001 Tongue Length 725 5.82 ± 1.23 270 5.85 ± 1.20 455 5.81 ± 1.26 0.680 Tongue Area 606 5.55 ± 1.94 236 5.39 ± 1.97 370 5.66 ± 1.91 0.099

Tongue Thickness 611 1.47 ± 0.30 239 1.41 ± 0.31 372 1.51 ± 0.28 <0.0001

Tongue Curvature 599 5.32 ± 1.24 235 5.35 ± 1.33 364 5.30 ± 1.17 0.642 Airway Width 146 2.18 ± 0.65 88 2.19 ± 0.61 58 2.15 ± 0.72 0.734 Uvula Length (Airway) 165 0.58 ± 0.27 91 0.56 ± 0.25 74 0.60 ± 0.30 0.302 Uvula Width (Airway) 351 0.89 ± 0.20 163 0.86 ± 0.18 188 0.91 ± 0.21 0.028 Uvula Area (Airway) 163 0.39 ± 0.22 89 0.35 ± 0.18 74 0.42 ± 0.24 0.046 Mandibular Length 731 7.38 ± 1.02 282 7.21 ± 0.94 449 7.48 ± 1.05 <0.001

Mandibular Width 652 9.99 ± 1.03 244 9.77 ± 0.98 408 10.11 ± 1.04 <0.0001

Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest, 152, 2017

Associations Between Photography Measurements and OSA and AHI - Conclusions • Apneics had higher scores on all measures of Mallampati, less airway visibility, larger mouth width and area, and larger tongue width and thickness • Also had more severe pharyngeal narrowing within the subpopulation where this measure was quantifiable • Measurements of intraoral crowdedness showed the strongest associations in OSA and AHI status • Apneics tended to have more crowded or less visible airways than controls Schwab, R. et al., (2017). Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in OSA. Chest., 152(2). doi:10.1016/j.chest.2017.05.005

13 Different Imaging Modalities to Phenotype the Upper Airway

• Morphometric examination/digital photography • Cephalometrics - craniofacial skeleton • Nasopharygnoscopy - awake and sleep induced (Propofol) • Acoustic Reflectance - airway • Optical Coherence Tomography - airway lumen • Computed Tomography • Magnetic Resonance Imaging

Normal Subject (Mid-Sagittal View) (Schwab, Am J Resp Crit Care Med 152:1673-1689, 1995)

Soft Palate Tongue Retropalatal Retroglossal Airway Subcutaneous Fat Mandible Subcutaneous Fat

14 Normal Subject (Axial View) (Schwab, Am J Resp Crit Care Med 152:1673-1689, 1995)

Airway Tongue Pharyngeal Wall

Mandible Mandible

Parapharyngeal Parotid Fat Pad Pharyngeal Wall

Subcutaneous Fat Spinal Cord

Sagittal Upper Airway MR Images (Schwab, Am J Resp Crit Care Med 152:1673-1689, 1995)

Normal Subject Apneic Patient

15 Axial Upper Airway MR Images (Schwab, Am J Resp Crit Care Med 152:1673-1689, 1995)

Normal Subject Apneic Patient

Schwab et al, AJRCCM 168; 522-530, 2003

Tongue Mandible Parapharyngeal Airway Fat Pads

Pharyngeal Soft Palate Normal Subject Walls

Tongue Mandible Parapharyngeal Airway Fat Pads

Pharyngeal Patient with Sleep Apnea Soft Palate Walls

16 Volumetric Anatomic Risk Factors for Sleep Apnea (Cases/Controls: N = 96) (Schwab et al, AJRCCM 168; 522-530, 2003) Adjusted§ Odds Ratio (OR) for Sleep Apnea: Soft Tissue Volume OR 95% CI • Fat pads 1.64 1.00 - 2.81 • Lateral Walls 6.01* 2.62 - 17.14 • Soft Palate 1.66 0.99 - 3.18 • Tongue 6.55* 2.81 - 19.42 • Total Soft Tissue 6.95* 3.08 - 19.11 §Adjusted for gender, ethnicity, age, craniofacial size and visceral neck fat * = Significant

Why are Upper Airway Soft Tissue Structures Enlarged in Apneics?

• Edema from negative pressure • Changes in blood flow/redistribution leg edema • Muscle disorder/function/exercise • Vibration/snoring/surface tension • Weight gain/obesity • Gender • Ethnicity • Genetic factors

17 Airway Airway

Normal Airway Airway

Apneic

We Still Do Not Understand the Effect of Obesity on Upper Airway Tissues

• Increased volume of adipose tissue (several studies have demonstrated this) – In parapharyngeal fat pads – increased tissue pressure? – ? Within tongue – does this size and function? – Fat under mandible and subcutaneous • Increased muscular tissue with weight gain – ? Increase in size of lateral walls, tongue, soft palate

18 Images from the Nashi autopsy study [Laryngoscope 117; 1467- 1473, 2007]. Left panel (A) shows a sagittal image of the tongue demonstrating a significant amount of fat in the posterior third of the tongue and in the sublingual region below the intrinsic tongue muscles; bottom (B) is a schematic demonstrating the percent of tongue fat in the anterior, posterior and sublingual regions in 121 tongue autopsy specimens. The right panel demonstrates another autopsy specimen with a significant amount of tongue fat.

Psoas muscle

Tongue

Histomicrographs of psoas muscle (A: top) and tongue (B: bottom) in an obese subject. Note there is greater fat in the tongue than the psoas muscle. Nashi Laryngoscope 117; 1467- 1473, 2007

19 Anterior and posterior percentage tongue fat correlates with increasing body mass index Nashi et al, Laryngoscope 2007; 117:1467-73

Study Objectives (Kim et al, Sleep 37;1639-1648, 2014)

• The primary goal of this study was to identify alterations in fat deposition within the tongue of obese apneics in comparison to obese subjects without sleep apnea using the three-point Dixon method (a method for fat/water discrimination) • Compared tongue fat to fat in the masseter muscles • Examined tongue fat topography • Compared men and women

20 Kim et al, (Sleep 37;1639-1648, 2014)

21 Demographics of Case and Control Subjects (Kim et al, Sleep 37;1639-1648, 2014)

Apneics (n=90) Controls (n=31) t test (p value) Factor Mean SD Mean SD Age, years 49.6 9.9 41.6 13.2 0.004 BMI, kg/m2 39.1 8.3 34.1 4.8 < 0.001

AHI, events/hour 43.2 27.3 4.1 2.7 < 0.001

Gender, M:F 42:48 10:21 0.162

Race, C:AA 39:51 18:13 0.281

Definition of abbreviations: AHI=apnea/hypopnea index; BMI=body mass index; C=Caucasian; AA=African American

22 Comparison of Muscle Volumes and Intramuscular Fat in Case and Control Subjects (Kim et al, Sleep 37;1639-1648, 2014)

Apneics (n=90) Controls (n=31) t Test (p value) 2p Soft Tissue Volume Mean SD Mean SD

Tongue, mm3 101,193 17,651 85,542 13,813 < 0.001 0.001

Tongue fat, mm3 32,791 9,175 23,390 5,511 < 0.001 0.002

Tongue fat, % 32.6 7.9 27.7 6.7 0.002 0.089

Left masseter, mm3 16,204 6,633 14,517 6,342 0.214 0.794

Left masseter fat, mm3 786 859 599 766 0.262 0.118

Left masseter fat, % 5.15 5.85 4.82 6.05 0.794 0.384 Significant differences (p < 0.05) are presented in bold. 2p indicates after adjustment for age, BMI, gender, and race

Comparison of Muscle Volumes and Intramuscular Fat in Apneics and Controls (Kim et al, Sleep 37;1639-1648, 2014)

Tongue volume and tongue fat increased in apneics compared to controls. No differences in masseter volumes or masseter fat volume

23 Kim et al, (Sleep 37;1639-1648, 2014)

Correlations between Muscle Volumes and Intramuscular Fat and AHI in Apneics (Kim et al, Sleep 37;1639-1648, 2014)

Increases in tongue volume and tongue fat increased the AHI

24 Main Findings (Kim et al, Sleep 37;1639-1648, 2014) • Obese apneics have enlarged tongue volumes and increased fat within the tongue in comparison to obese normal subjects after adjustment for differences in age, BMI, gender, and race • There is a heterogeneous distribution of fat within the tongue • Tongue fat distribution in apneics is increased in specific locations of the tongue (greater in the retroglossal region) • Tongue size and tongue fat are correlated with AHI • No difference in tongue fat between apneic men and women

Importance of Tongue Fat (Kim et al, Sleep 37;1639-1648, 2014) • Increased tongue fat increases AHI by increasing the size of the tongue (affects airway collapsibility and size) but may also adversely affect muscle function • Increased intramuscular fat may contribute to changes in contractile performance or tongue shape • What is the purpose of tongue fat? • Why do some individuals have greater tongue fat deposition - genetic/high fat diet? Is this visceral fat? • New therapeutic options (upper airway exercises, weight loss, hypoglossal nerve stimulation, dietary

25 Anatomical Imbalance The interaction between upper airway soft tissue structures and craniofacial structures

Watanabe, et al. AJCCM 165:260, 2002

Icelandic Sleep Apnea Cohort (ISAC) (Schwab et al, in preparation)

• All patients diagnosed with OSA in Iceland and referred for CPAP treatment at the Landspitali University Hospital in Reykjavik, Iceland, from September 2005 - August 2009 • 713 subjects had MRI (upper airway, neck and abdomen) and PSG (Embletta) • All apneics with wide range of severity - AHI/ODI • Three BMI categories < 30, 30-35, > 35 kg/m2 • Men and women but mostly men

26 Intra-Mandibular Volume (IMV): the Amount of Tissue within “the Box” (Schwab et al, in preparation)

Severity of AHI: Based on Craniofacial and Soft Tissue Interactions in Men in ISAC (Schwab et al, in preparation)

AHI 15 - 30 AHI 30 - 50 AHI ≥ 50 Unadjusted p *Adjusted p n = 137 n = 211 n = 201 Total Soft Tissue 210,241 ± 213,874 ± 220,314 ± 0.003 0.45 (mm3) 24,905 26,316 26,799 259,539 ± 259,533 ± 258,042 ± IMV (mm3) 0.89 0.16 32,518 32,669 27,334 1.17 ± TST/IMV Ratio 1.12 ± 0.14 1.12 ± 0.12 0.007 0.02 0.13 *Adjusted for BMI and age The ratio of the total soft tissue (TST) to intra- mandibular volume (IMV) was significantly greater in the patients with the most severe apnea

27 Relationship of Tongue Size, Mandibular Length and AHI in ISAC

Schwab et al, in preparation

Log AHI was greatest when tongue volume was largest and mandibular length was smallest

Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) • Methods: • Subjects included 157 obese apneics and 46 obese controls • Dynamic magnetic resonance imaging was performed during wakefulness in the mid- sagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal) • Differences in measurements were examined using linear regression

28 Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) • A) Mid‐sagittal image showing the location of the axial images (RP, RG and Epi) • B) Mid‐sagittal image showing the upper boundary set through the top of hard palate and lower boundary through the bottom of C4; the airway between these two boundaries represents the mid‐sagittal airway area and the perpendicular distance between two boundaries is the length of airway.

Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted)

• C‐E are examples of images in the three axial regions: retopalatal (C),retroglossal (D) and epiglottal (E). F shows an example of the method used to measure airway lateral and anterposterior dimensions. The lateral and anterposterior dimensions are measured in the three axial regions. RP = retropalatal, RG = retroglossal, EPI = epiglottal, AA = airway area, AL = airway length, UB = upper boundary, LB = lower boundary, AP = anterposterior, LAT = lateral

29 Mid-Sagittal Dynamic MRI

Mid-Retropalatal Dynamic MRI

30 Mid-Retroglossal Dynamic MRI

Demographic Characteristics of the Study Sample

Measure Overall AHI ≤ 5 AHI ≥ 15 p† N 203 46 157 – Age, years 48.9 ± 11.6 42.7 ± 13.1 50.7 ± 10.5 <0.0001 Male, % 44.8% 37.0% 47.1% 0.222 Race, % 0.927 Caucasian 43.4% 43.5% 43.3% African American 53.2% 52.2% 53.5% Other 3.5% 4.4% 3.2% BMI, kg/m2 37.8 ± 7.5 34.6 ± 4.9 38.7 ± 7.8 <0.0001 AHI, events/hour 33.4 ± 29.2 2.7 ± 1.4 42.4 ± 27.3 <0.0001 Significant (p<0.05) differences shown in bold; †p-value from T-test or chi-squared test comparing OSA vs. controls for continuous or categorical variables, respectively.

Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted)

31 Dynamic Airway Measurements in Apneics and Controls

AHI≤5 AHI≥15 Measurement p† N Mean ± SD N Mean ± SD Mid-Sagittal Average airway area, mm2 42 733.3 ± 275.8 149 895.4 ± 299.9 0.0019 CV of airway area, % 42 6.8 ± 4.0 149 7.9 ± 4.7 0.2037 Airway length in slice with maximum area, mm 42 74.6 ± 11.1 149 80.1 ± 11.7 0.0066 Airway length in slice with minimum area, mm 42 74.4 ± 10.8 149 79.8 ± 11.9 0.0088 Maximum airway area corrected for length, mm 42 11.2 ± 2.8 149 12.9 ± 3.4 0.0032 Minimum airway area corrected for length, mm 42 8.3 ± 2.5 149 9.1 ± 2.6 0.0907 Middle Soft Palate (Retropalatal) Average airway area, mm2 45 227.0 ± 118.4 149 168.8 ± 112.1 0.0030 CV of airway area, % 45 11.0 ± 12.3 149 16.5 ± 13.2 0.0138 Maximum airway area, mm2 45 275.9 ± 143.9 149 221.1 ± 132.7 0.0183 Minimum airway area, mm2 45 188.0 ± 107.4 149 125.0 ± 101.8 0.0004 Lateral distance at maximum area, mm 45 14.9 ± 5.1 149 14.0 ± 5.1 0.2844 Lateral distance at minimum area, mm 45 12.3 ± 5.2 149 10.2 ± 5.3 0.0205 AP distance at maximum area, mm 45 19.8 ± 6.8 149 17.6 ± 5.9 0.0371 AP distance at minimum area, mm 45 17.6 ± 7.2 149 14.0 ± 6.2 0.0010 Significant or suggestive (p<0.05) differences shown in bold. †p-value from T-test comparing dynamic measure between apneics and controls. CV = coefficient of variation.

Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted)

Dynamic Airway Measurements in Apneics and Controls

AHI≤5 AHI≥15 Measurement p† N Mean ± SD N Mean ± SD Middle Tongue (Retroglossal) Average airway area, mm2 45 173.4 ± 89.8 153 190.6 ± 101.7 0.3086 CV of airway area, % 45 11.2 ± 7.1 153 16.5 ± 12.5 0.0005 Maximum airway area, mm2 45 225.9 ± 122.8 153 262.9 ± 160.7 0.1023 Minimum airway area, mm2 45 135.4 ± 73.4 153 130.9 ± 83.9 0.7441 Lateral distance at maximum area, mm 45 18.7 ± 7.6 153 18.6 ± 8.6 0.9459 Lateral distance at minimum area, mm 45 14.7 ± 5.7 153 12.5 ± 6.2 0.0377 AP distance at maximum area, mm 45 14.9 ± 4.2 153 17.3 ± 4.6 0.0019 AP distance at minimum area, mm 45 12.6 ± 3.5 153 13.3 ± 4.6 0.2335 Middle Epiglottis (Epiglottal) Average airway area, mm2 45 321.0 ± 143.0 154 361.0 ± 151.3 0.1155 CV of airway area, % 45 7.7 ± 4.9 154 11.3 ± 6.8 0.0002 Maximum airway area, mm2 45 385.2 ± 187.5 154 461.2 ± 206.1 0.0277 Minimum airway area, mm2 45 264.6 ± 115.4 154 277.5 ± 129.4 0.5477 Lateral distance at maximum area, mm 45 24.7 ± 6.8 154 26.1 ± 7.0 0.2349 Lateral distance at minimum area, mm 45 21.2 ± 5.2 154 21.1 ± 6.0 0.9010 AP distance at maximum area, mm 45 19.1 ± 4.9 154 22.3 ± 5.2 0.0004 AP distance at minimum area, mm 45 16.7 ± 4.2 154 18.7 ± 4.7 0.0101 Significant or suggestive (p<0.05) differences shown in bold. †p-value from T-test comparing dynamic measure between apneics and controls. CV = coefficient of variation. Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted)

32 Dynamic Upper Airway Imaging During Wakefulness in Obese Subjects with and without Sleep Apnea (Feng et al, AJRCCM conditionally accepted) • Conclusions: • Upper airway caliber during respiration was significantly narrower in obese apneics than obese controls in the retropalatal region • There were strong correlations between AHI and dynamic airway caliber in the retropalatal and retroglossal regions • These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of OSA in obese subjects

New Perspectives on the Pathogenesis of OSA: Anatomic Perspective - "Take Home Messages" • Increased volume of upper airway soft tissue structures is an important risk factor for sleep apnea • Reduction in mandibular size is also an important risk factor for OSA • The combination of increased upper airway soft tissue structures and reduced craniofacial skeleton increases OSA risk • Tongue fat may explain the relationship between obesity and sleep apnea • During respiration upper airway caliber is significantly narrower in obese apneics than obese controls in the retropalatal region

33 New Perspectives on the Pathogenesis of OSA - Anatomic Perspective Thank you for your attention! Any Questions? [email protected]

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