INVITED REVIEW SERIES:
OBESITY AND RESPIRATORY DISORDERS
SERIES EDITOR: AMANDA J PIPER
Obesity and obstructive sleep apnoea: Mechanisms for increased
collapsibility of the passive pharyngeal airway
SHIROH ISONO
Department of Anesthesiology, Graduate School of Medicine, Chiba University, Chiba, Japan
ABSTRACT
Epidemiological evidence suggests there are significant
links between obesity and obstructive sleep apnoea
(OSA), with a particular emphasis on the importance of
fat distribution in the development of OSA. In patients
with OSA, the structure of the pharyngeal airway col-
lapses. A collapsible tube within a rigid box collapses
either due to decreased intraluminal pressure or
increased external tissue pressure (i.e. reduction in
transmural pressure), or due to reduction in the longi-
tudinal tension of the tube. Accordingly, obesity should
structurally increase the collapsibility of the pharyn-
geal airway due to excessive fat deposition at two
distinct locations. In the pharyngeal airway region,
excessive soft tissue for a given maxillomandibular
enclosure size (upper airway anatomical imbalance)
can increase tissue pressure surrounding the pharyn-
geal airway, thereby narrowing the airway. Even mild
obesity may cause anatomical imbalance in individu-
als with a small maxilla and mandible. Lung volume
reduction due to excessive central fat deposition may
decrease longitudinal tracheal traction forces and pha-
ryngeal wall tension, changing the ‘tube law’ in the pha-
ryngeal airway (lung volume dependence of the upper
airway). The lung volume dependence of pharyngeal
airway patency appears to contribute more signi-
ficantly to the development of OSA in morbidly
obese, apnoeic patients. Neurostructural interactions
required for stable breathing may be influenced by
obesity-related hormones and cytokines. Accumulat-
ing evidence strongly supports these speculations, but
further intensive research is needed.
The Author: Dr. Isono is Associate Professor in the Department
of Anesthesiology, Graduate School of Medicine of Chiba Uni-
versity in Chiba, Japan. His areas of research interest include
respiratory physiology and sleep medicine, particularly the
pathophysiology of upper airway maintenance in unconscious
subjects.
Correspondence: Shiroh Isono, Department of Anesthesiology,
Graduate School of Medicine, Chiba University, 1-8-1 Inohana-
cho, Chuo-ku, Chiba 260-8670, Japan. Email: shirohisono@
yahoo.co.jp
Received 5 August 2011; invited to revise 25 August 2011;
revised 19 September 2011; accepted 25 September 2011.
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
resp_2093 32..42
Key words: closing pressure, collapsibility, fat distribu-
tion, obstruction, pharynx.
INTRODUCTION
Obstructive sleep apnoea (OSA) is characterized by
repetitive pharyngeal narrowing and closure during
sleep, with obesity being an important feature associ-
ated with the presence and development of this disor-
der. Longitudinal studies in the general population
consistently demonstrate that weight changes are
directly associated with increases or decreases in the
severity of OSA in both genders, although the associa-
tion is less robust in women than in men1,2 (Fig. 1).
Large cross-sectional studies in the general popula-
tion have also identified BMI as an independent pre-
dictor of OSA. However, other factors impact on the
association between obesity and OSA, with gender,
age and neck circumference also being significant
predictors of sleep disordered breathing.3 Notably,
there are similar associations between weight and
OSA across different races, despite a wide range of
BMI, suggesting an interaction between obesity
and craniofacial dimensions in the development of
OSA.4–7 In clinical populations, BMI is not a good pre-
dictor of OSA, with neck and waist circumferences
being more sensitive parameters for prediction of
OSA.8–10 Furthermore, the amounts of adipose tissue
adjacent to the pharyngeal airway and in the intra-
peritoneal space are directly associated with AHI
but not with BMI.11,12 Differences in fat distribution
between men and women, and the resulting mechani-
cal and functional influences, may partly explain
gender differences in the prevalence of OSA.13,14
Epidemiological and clinical evidence strongly sug-
gests that there is a complex interaction between
obesity and OSA. This review discusses the possible
contributions of obesity, and in particular, the role of
fat deposition in the neck, surrounding the pharyn-
geal airway, as well as intra-abdominal fat deposition,
in the pathogenesis of OSA, based on accumulating
knowledge of the pathophysiology of upper airway
(UA) obstruction in humans.
Respirology (2012) 17, 32–42
doi: 10.1111/j.1440-1843.2011.02093.x
Role of obesity in pharyngeal obstruction
COLLAPSIBILITY OF THE PHARYNGEAL
AIRWAY IN PATIENTS WITH OSA
A collapsible tube as a model for
understanding the behaviour of the
human pharyngeal airway
The pharynx, which is the site where OSA develops, is
inherently collapsible during sleep when the activity
of muscles dilating the UA decreases.15 The pharyn-
geal airway is structurally surrounded by soft tissues
Figure 1 Five year follow-up of changes in weight and
respiratory disturbance index (RDI) indicates a clear direct
relationship between the two, which was more marked
in males than in females. (From Newman et al.1 with
permission)
Figure 2 Most pharyngeal airway
behaviour can be modelled by a
collapsible tube in a rigid box. The
cross-sectional area of the tube is
determined by a ‘tube law’ repre-
senting the intrinsic mechanical
properties of the tube. Two distinct
mechanisms result in collapse of the
tube: reduction in transmural pres-
sure (Ptm) due either to a decrease in
intraluminal pressure (Plumen) or an
increase in surrounding tissue pres-
sure (Ptissue) (A to B), or a reduction
in longitudinal tension of the tube (A
to C), making the tube mechanically
more compliant and therefore the
slope of the ‘tube law’ more steep
(‘tube law’ 1 to ‘tube law’ 2).
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
33
such as the tongue, soft palate, tonsils and pharyngeal
fat pads, while it is also enclosed by bony structures,
such as the mandible, maxilla and cervical spine.16
This structure is mechanically analogous to an artifi-
cial collapsible tube in a rigid chamber (Fig. 2), and
the behaviour of an atonic or hypotonic pharyngeal
airway (passive pharynx) can be demonstrated by a
simple mechanical model.17
In this mechanical model, the cross-sectional area
of the tube is determined by a ‘tube law’, representing
the intrinsic mechanical properties of the tube and
transmural pressure (Ptm), the difference between
intraluminal and tissue pressures (Ptm = Plumen - Ptissue).
Plumen is defined as the lateral wall pressure acting on
the luminal surface of the tube, while Ptissue is defined
as the tissue pressure acting on the outside surface of
the tube. Two distinct mechanisms result in collapse
of the tube: reduction of Ptm due either to a decrease in
Plumen or an increase in Ptissue (A to B in Fig. 2), or reduc-
tion in the longitudinal tension of the tube (A to C in
Fig. 2), making the tube more compliant and there-
fore the slope of the ‘tube law’ more steep.18 In the
human pharyngeal airway, Ptissue may be increased by
anatomical imbalance of the UA due to the deposition
of fat surrounding the pharyngeal airway within
the maxillomandibular bony enclosure,16 while longi-
tudinal traction of the pharyngeal airway may be
decreased by lung volume reduction as discussed
below.
How can we assess pharyngeal airway
collapsibility in humans?
Because of the difficulty in measuring the Ptissue
surrounding the pharyngeal airway in humans, static
Plumen-area relationships have been determined by
measuring the pharyngeal cross-sectional area during
Respirology (2012) 17, 32–42
34
Table 1 Agreements among three different experimen-
tal approaches for exploring pharyngeal airway collaps-
ibility in responses to various mechanical interventions.
(summarized based on the references)
Conditions (references) Ptissue Pcrit Pclose
Neck flexion21,25,34 ↑ ↑
Mandibular advancement22,26,35 ↓ ↓
Tracheal traction or lung ↓ ↓
volume23,27,34
Mass loading28 ↑ N/A (↑)
UA muscle contraction24,29,36 ↓ ↓
step reductions of Plumen in cadavers of infants19 and in
anaesthetized humans20 as substitute models for the
‘tube law’. The static Plumen-area relationship is not
linear and is described by an exponential function,
irrespective of age, gender and the coexistence of
OSA, indicating that pharyngeal wall compliance,
defined as the slope of the curve, varies with changes
in Plumen.21 Over the steep portion in the lower range of
Plumen, significant pharyngeal narrowing occurs even
for a small reduction in Plumen, inducing inspiratory
flow limitation.22 In contrast, the pharyngeal airway is
stable along the flat portion in the higher range of
Plumen. The closing pressure of the pharyngeal airway
(Pclose), as determined by the intercept of the curve
on the Plumen axis, is an important mechanical param-
eter representing collapsibility of the pharyngeal
airway.
Although not a direct measure of Ptissue, the critical
closing pressure (Pcrit), which is determined by assum-
ing the UA to be a Starling resistor that collapses
when Ptissue exceeds Plumen, is considered to reflect Ptissue
and is measurable in sleeping humans.23 However,
caution is required when interpreting Pcrit values
because Pcrit can be measured while the UA dilating
muscles are actively contracting (active Pcrit) or when
they are suppressed (passive Pcrit).24 Recently, Kairaitis
et al. developed a technique for measuring Ptissue sur-
rounding the pharyngeal airway in anaesthetized
rabbits and demonstrated changes in Ptissue and UA
resistance in response to various mechanical inter-
ventions, thereby providing support for the ‘tube
law’ concept and the increase in Ptissue as a mechanism
for increasing Pclose of the pharyngeal airway.25–29
Table 1 shows the agreement among Pclose,30–33 Pcrit34–36
and Ptissue25–29 in response to various mechanical
interventions.
Is the pharynx structurally more collapsible
in individuals with OSA than in those
without OSA?
Isono et al. assessed the collapsibility of the passive
pharynx under general anaesthesia and muscle
paralysis by eliminating neuromuscular control
mechanisms.20 They showed that Pclose of the passive
pharynx in OSA patients (0.6 ⫾ 1.5 cm H2O for mild
Respirology (2012) 17, 32–42
S Isono
↑
↓
↓
↓
Figure 3 Relationship between closing pressure (Pclose)
at the velopharynx (retropalatal airway) and Pclose at the
oropharynx (retroglossal airway), as determined in
anaesthetized and paralyzed age- and BMI-matched indi-
viduals without OSA (closed circles), or with mild OSA
(open squares), and in patients with severe OSA (closed
triangles). Note that the patients with OSA had higher
Pclose at both segments and that retropalatal Pclose values
were greater than retroglossal Pclose. (From Isono et al.20:
this is an original work of the author)
OSA, 2.2 ⫾ 3.0 cm H2O for severe OSA) was signifi-
cantly greater than that in age- and BMI-matched
subjects without OSA (-4.4 ⫾ 4.2 cm H2O), providing
evidence for abnormally collapsible pharyngeal
structures in OSA patients (Fig. 3). Interestingly, the
reported passive Pcrit values determined during sup-
pression of the UA dilating muscles agreed well with
the Pclose determined during anaesthesia and paraly-
sis, suggesting that the higher Pclose in OSA patients is
at least partly due to a higher Ptissue.37
Is Ptissue increased in obese patients with OSA?
In the collapsible tube model, an increase in Ptissue
narrows the cross-sectional area of the tube. The pha-
ryngeal airway shares space with soft tissues within
the maxillomandibular bony enclosure. The balance
between the size of the bony enclosure and the
amount of soft tissue may determine the airway space
and Ptissue.16,38 An increase in the amount of soft tissue
within the bony enclosure or a decrease in the size of
the bony enclosure would result in limitation of the
space available for the airway and consequently, a
narrowing of the airway and increase in Ptissue. Winter
et al. inflated a balloon inside the bony enclosure at
the level of the pharynx in anaesthetized pigs and
showed that UA resistance increased during balloon
inflation.39 Kairaitis et al. confirmed that an increase
in the mass of tissue surrounding the pharyngeal
airway resulted in increases in both Ptissue and UA
resistance in anaesthetized rabbits.28 Tsuiki et al.
found that OSA patients had significantly larger
tongues for any given maxillomandibular size com-
pared with BMI-matched subjects without OSA,
suggesting that increased Pclose and Ptissue were due
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
Role of obesity in pharyngeal obstruction
Figure 4 Relationship between passive Pcrit and BMI in
male and female patients with OSA. In both genders, there
was a significant correlation between passive Pcrit and BMI
(adjusted for age) for the entire sample. Note that the
distribution of subjects in the subset that was matched for
respiratory disturbance index, and BMI (closed symbols)
did not differ from the distribution of the entire subject
group (open and closed symbols). Dashed lines represent
95% CIs. (From Kirkness et al.37 with permission)
to an anatomical imbalance in OSA patients.40 The
dependence of the passive Pcrit on BMI in both men
and women is clear37 (Fig. 4). A 10 kg/m2 difference in
BMI has been estimated to produce 1.67 and 0.95 cm
H2O differences in passive Pcrit in men and women,
respectively.37 Interestingly, weight loss equivalent
to a 10 kg/m2 reduction in BMI resulted in a more
significant change in active Pcrit from 3.1 ⫾ 4.2 to
-2.4 ⫾ 4.4 cm H2O, suggesting improvement in neural
control mechanisms in addition to anatomical
balance.41,42
In which pharyngeal segments does obesity
increase collapsibility?
Various techniques, including multi-sensor catheter,
pharyngeal endoscopy, fluoroscopy, dynamic MRI
and fast CT scanning have been used to determine
the sites of pharyngeal obstruction during sleep in
patients with OSA. Although obstruction may occur at
any segment along the pharyngeal airway, it is most
frequently observed in either the retropalatal and/or
retroglossal regions of the airway. The pattern and
severity of pharyngeal occlusion are significantly
influenced by a number of factors, including dynamic
changes in respiratory effort, varying activity of the
UA dilator muscles and the level of consciousness
during natural OSA.43–45 Therefore, in order to deter-
mine the airway segment(s) primarily responsible for
OSA, Plumen should ideally be controlled and the activ-
ity of UA muscles suppressed.
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
35
Only two techniques can successfully achieve
both these conditions. Remmers and colleagues sup-
pressed UA muscle activity in patients with OSA by
applying optimal CPAP and manipulating Plumen to
induce pharyngeal obstruction during either natural
or diazepam-induced sleep. They then determined
segmental Pclose by endoscopic observation during
measurements of airflow and pharyngeal pres-
sures.21,46,47 As described previously, Isono et al. elimi-
nated UA muscle activity under general anaesthesia
and total paralysis and measured segmental Pclose
during step Plumen reduction in OSA patients and age-
and BMI-matched control subjects.20 Both techniques
identified two distinct patterns of primary site(s)
of pharyngeal closure. Approximately half the OSA
patients showed a Pclose greater than atmospheric
pressure exclusively in the retropalatal segment,
while the other half showed a positive Pclose in both the
retropalatal and retroglossal segments. Furthermore,
obesity appeared to be more frequently associated
with the former type of airway closure, whereas cran-
iofacial abnormalities were more common in the
latter type.16 Structurally, the tongue is located ante-
rior to the soft palate and the retropalatal airway is
narrower than the retroglossal airway. In anaesthe-
tized and paralyzed humans, Pclose at the retropalatal
airway has been shown to be greater than Pclose at
the retroglossal airway20 (Fig. 3). It is likely that as a
consequence of these structural arrangements, the
retropalatal airway narrows earlier than the retroglo-
ssal airway when there is accumulation of fat in both
the lateral pharyngeal wall and the tongue.
MECHANICAL CONSEQUENCES OF
FAT DEPOSITION WITHIN THE
MAXILLOMANDIBULAR ENCLOSURE
ON PHARYNGEAL COLLAPSIBILITY
Is fat deposited excessively within the
maxillomandibular enclosure in patients
with OSA?
Shelton et al. demonstrated a correlation between
the amount of fat enclosed by the mandibular ramus
and AHI, but not BMI.11 Horner et al. showed that
there was significantly more fat deposition at the level
of the soft palate in OSA patients compared with
weight-matched control subjects without OSA.48 Even
relatively non-obese OSA patients show excess fat
deposition, especially anterolateral to the UA, as com-
pared with individuals without OSA with similar BMI
and neck circumferences.49
In order to better understand the anatomical
risk factors for OSA, Schwab et al. performed detailed
three dimensional volumetric soft tissue measure-
ments at various UA regions in a group of subjects
with OSA (44 ⫾ 25 events/h) and compared this
with data from a group of control subjects who
were matched for gender, age and ethnicity.50 While
enlargement of the soft tissues at all UA regions in
OSA patients was observed, multivariate analysis
identified tongue volume and lateral pharyngeal wall
Respirology (2012) 17, 32–42
36
Figure 5 (A) Standardized digital image of sagittal
section of the tongue, demonstrating extramyocellular
fat within the posterior third of the tongue and in the
sublingual region just below the intrinsic tongue muscu-
lature. (B) Average percentage fat content in the anterior,
posterior,and sublingual regions (95% CI of mean). (From
Nashi et al.51 with permission)
volume as independent risk factors for sleep apnoea.
Although fat deposits are easily identifiable in the
lateral pharyngeal wall, it is difficult to accurately
assess fat deposition within the tongue musculature.
However, using consecutive autopsy specimens from
the general population, Nashi et al. showed that fat
content in the posterior tongue (30%) was signifi-
cantly higher than that in the anterior tongue (11%) or
other somatic muscles (3%), and was correlated with
BMI51 (Fig. 5).
Saito et al. recently demonstrated that in rats that
became obese after being fed a high-fat diet, the per-
centages of oil droplet areas increased in the genio-
glossus and geniohyoid muscles but not in the
masseter muscle. This resulted in an increase in
muscle fibre diameter, particularly in the slow-type
myofibres, but there was no change in the composi-
tion of the fibre types in these muscles.52 However,
intermittent hypoxaemia, which frequently occurs as
a consequence of upper airway obstruction, appears
to induce a transition from endurance type IIa fibres
to more fatigable type IIb fibres.53 In patients with
OSA, this transition has been shown to be reversible
with CPAP treatment.54
Tongue volume, however, is not always greater55–59
and does not necessarily decrease after moderate
weight reduction in OSA patients.60 It should be
noted that measurements of soft tissue volume alone,
without controlling for craniofacial dimensions, do
not reflect the anatomical balance of the UA and Ptissue.
In fact, in two studies in which tongue volumes were
not greater in patients with OSA,58,59 the anatomical
Respirology (2012) 17, 32–42
S Isono
balance of the UA, as assessed by the ratio of relative
soft tissue volume to maxillomandibular dimensions,
differed between OSA patients and control subjects
without OSA. Furthermore, patients with position
dependent OSA, defined as a ratio of AHI in the lateral
position to AHI in the supine position of 0.5 or less,
had a smaller lateral pharyngeal wall volume than
patients with non-positional OSA, indicating the
importance of regional anatomical balance.59
In summary, fat may be deposited in any part of the
soft tissue surrounding the UA, thereby increasing the
total volume of soft tissue within the maxilloman-
dibular enclosure. However, fat accumulation in the
lateral pharyngeal wall and posterior tongue appears
to play an important role in the development of OSA.
How much of an increase in UA soft tissue
volume is necessary for the development
of OSA?
As discussed previously, during weight gain fat may
accumulate within the UA soft tissues, leading to an
anatomical imbalance. However, it remains unclear
how much of an increase in soft tissue volume is
necessary before OSA develops. Schwab et al. reported
that total UA soft tissue volumes were approximately
30 cm3 greater in obese patients with OSA than in non-
obese control subjects, although BMI and craniofacial
dimensions were not controlled.50 Interestingly, the
difference in soft tissue volumes within the maxillo-
mandibular enclosure were unexpectedly small, con-
sidering the significant differences in BMI between the
groups (36 vs 26 kg/m2). It should be noted that the
participants in that study were primarily Caucasians
and African-Americans, and that according to the UA
anatomical balance concept, the amount of excess soft
tissue underlying the development of OSA may differ
between races and in those with craniofacial abnor-
malities.40 In fact, three dimensional soft tissue mea-
surements performed on Japanese males showed that
the difference in UA soft tissue volumes between OSA
patients and subjects without OSA, who were matched
for craniofacial size, was approximately 20 cm3, which
is smaller than the difference reported by Schwab
et al..59 Sutherland et al. showed that a decrease in
total UA fat volume of approximately 17 cm3 after
moderate weight reduction (7.8 ⫾ 4.2 kg) resulted in a
31% reduction in AHI in Caucasian patients with
OSA.61 To my knowledge, no other study has measured
changes in UA soft tissue volume before and after
successful weight loss and resolution of OSA. Upper
airway imaging studies in adults suggest that OSA
would presumably develop following a 20–30 cm3
increase in UA soft tissue volume, depending on the
size of the maxillomandibular enclosure.
Why do patients with OSA have excessive UA
soft tissue in the submandibular region?
Unlike the cranial space, the maxillomandibular bony
enclosure is not a closed space. Excessive soft tissue
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
Role of obesity in pharyngeal obstruction 37

surrounding the pharynx may be displaced outside the
bony enclosure through the submandibular space,
possibly offsetting its impact on Ptissue and pharyngeal
airway patency. This excess submandibular soft tissue
may be detected in patients with OSA as an increased
neck circumference, a ‘double chin’, or reduced crico-
mental space, which have high negative predictive
values for exclusion of OSA.62 Although caudal dis-
placement of the hyoid bone is a common finding in
lateral cephalograms of patients with OSA, this may
arise as a result of UA anatomical imbalance rather
than being a cause of OSA.63 A significantly greater
distance between the hyoid and mandibular planes
(MP-H) (26 mm vs 16 mm) has been measured in
patients with OSA compared to control subjects
without OSA, who were matched for BMI and cranio-
facial dimensions.40 Mandibular advancement, with
either an oral appliance or by surgery, which improves
the anatomical imbalance, was reported to decrease
the MP-H.64,65 The caudal displacement of excessive
soft tissue not only compensates for the UA anatomi-
cal imbalance but, at the same time, elongates the
pharyngeal airway. Some researchers consider that
lengthening of the pharyngeal airway by 15–30% may
contribute to the development of OSA. As the airway is
longer in males than in females, even after normaliza-
tion for body height, this may partly explain the gender
difference in the prevalence of OSA, despite the
relatively small impact of airway length on airway
resistance, as compared with that of cross-sectional
area.61,66,67 Alternatively, a longer UA in patients with
OSA and in males could be considered beneficial in
increasing the longitudinal tension of the pharyngeal
airway. Shortening of the long UA in patients with
OSA, without changes in other structural dimensions,
would further increase UA collapsibility. In the
mechanical collapsible tube model, shortening of the
tube will increase its collapsibility by decreasing lon-
gitudinal tension, and therefore increasing the slope of
the ‘tube law’. Caudal displacement of the trachea
has been demonstrated to decrease Ptissue, Pcrit and UA
resistance in experimental animal models.27,34 Further
studies are required, but a thick neck, double chin and
lower hyoid bone are clinical markers of UA anatomi-
cal imbalance and caudal displacement of excessive
UA soft tissue. These changes may serve to compen-
sate for UA anatomical imbalance by decreasing Ptissue
and increasing longitudinal pharyngeal wall tension,
although further investigations are necessary to
confirm this.
volume, but not subcutaneous fat volume, is directly
associated with AHI in patients with OSA.12 Despite
having a similar BMI and total fat weight, patients
with OSA accumulate more visceral adipose tissue
than individuals without OSA.68,69 Short-term nasal
CPAP reduces visceral fat and serum leptin levels even
without changes in BMI.70 Interestingly, in women,
both the prevalence of OSA and increases in visceral
fat are accelerated by menopause.71,72 Furthermore,
the prevalence of sleep disordered breathing is
lower in postmenopausal women receiving hormone
replacement therapy72,73 and higher in women with
polycystic ovarian syndrome.74,75 Despite the potential
importance of visceral fat in the pathogenesis of OSA,
we still have little understanding of the link between
OSA and visceral fat volume. As discussed below, both
mechanical and functional influences of increased
visceral fat on OSA need to be considered, although
these associations have yet to be proven.
Does obesity-related reduction in lung volume
influence UA patency?
A reduction in FRC due to reduced expiratory reserve
volume without changes in residual volume is the
most significant and consistent effect of obesity on
pulmonary function76–79 (Fig. 6). Clinically significant
impairment of dynamic pulmonary function param-
eters such as FVC and FEV1 only occurs in extremely
obese subjects. Contrary to general belief, Babb et al.
failed to demonstrate that abdominal fat distribution
was a predominant factor accounting for the reduc-
tion in end expiratory lung volume (EELV) either in

POSSIBLE INFLUENCES OF VISCERAL

FAT ON OSA
Do patients with OSA have excessive
visceral fat?

Although the ratio of visceral fat volume to subcuta-

neous fat volume is small, metabolic consequences
such as metabolic syndrome and type II diabetes are
predominantly caused by intra-abdominal adipose
tissue. This may also hold true for the pathogenesis
of OSA and associated consequences. Visceral fat
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
Figure 6 Relationship between BMI and FRC with an
exponential regression line, in 373 individuals of both
genders with normal FEV1/FVC. (From Jones and
Nzekwu78 with permission)
Respirology (2012) 17, 32–42
38
obese men or obese women. They concluded that the
reduction in EELV most likely arose from the cumula-
tive effect of increased chest wall fat rather than any
specific regional distribution of chest wall fat.80 In
morbidly obese patients, weight loss significantly
improved expiratory reserve volume as well as resting
blood gas parameters.81
While a reduction in FRC underlies the develop-
ment of severe hypoxaemia during OSA, decreased
lung volume per se, is thought to contribute to pha-
ryngeal airway obstruction; this is based on the land-
mark work of Hoffstein et al., who demonstrated the
dependence of pharyngeal airway patency on aug-
mented lung volume in obese, awake patients with
OSA.82 Using acoustic reflection, this group showed
that pharyngeal cross-sectional area decreased sig-
nificantly more during slow exhalation from total lung
capacity to residual volume in obese patients with
OSA than in weight-matched control subjects without
OSA. Notably, the FRC of obese, apnoeic subjects was
significantly lower than that of obese non-apnoeic
subjects, suggesting the possible importance of the
type of obesity. Interestingly, the same investigators
also reported significant differences in lung volume
dependence between females with or without
OSA, despite similar reductions in FRC, suggesting
an interaction between reduced lung volume and
increased pharyngeal collapsibility.83
How do tonic and phasic tracheal traction
forces influence pharyngeal airway
collapsibility?
Although the lung is located at a distance from the
pharyngeal airway, the trachea connects the two
mechanically. Static and dynamic inflation of the lung
produces tonic and phasic tracheal traction forces,
respectively. The tonic force may be reduced in obese
patients with lower FRC through alterations in the
intrinsic mechanical properties of the pharyngeal
airway, that is, ‘tube law’ or static Plumen-area curve.
The phasic tracheal traction force varies during the
respiratory cycle and may serve to stabilize the pha-
ryngeal airway and airflow during inspiration, as pre-
dicted by the behaviour of an artificial collapsible
tube.
Does reduction in lung volume increase
pharyngeal airway collapsibility?
In both animal and human studies, UA resistance
and collapsibility decreases in response to either
direct changes in tonic tracheal traction force or lung
inflation.27,32,34,84–88 In sleeping individuals without
OSA, genioglossus activity decreases in response
to lung inflation, despite a reduction in UA resis-
tance,85,86 indicating that the lung volume depen-
dence of pharyngeal airway patency is primarily due
to structural mechanisms, such as increased tonic
tracheal traction forces. In anaesthetized cats, the
impact of direct tracheal traction on UA patency
Respirology (2012) 17, 32–42
S Isono
was greater during tongue displacement84 and neck
extension,34 suggesting an interaction between UA
anatomical balance and lung volume dependence.
Kairaitis and colleagues showed that there were small
but significant reductions in Ptissue in response to tra-
cheal traction in anaesthetized rabbits.27
Tagaito et al. showed that following an increase
in lung volume of 0.7 litre, there was a small but sig-
nificant reduction in retropalatal Pclose of 1.2 cm H2O,
in anaesthetized, paralyzed patients with OSA (BMI
23.1–30.8 kg/m2).32 Although this study included
few obese patients with OSA, the direct association
between changes in retropalatal Pclose and BMI sug-
gests there are differences in the lung volume depen-
dence of pharyngeal collapsibility between obese and
non-obese patients with OSA.32 A greater reduction
in Pcrit (2.2 cm H2O to -1.0 cm H2O) was observed in
response to a 0.6 litre lung inflation during non-rapid
eye movement sleep in more obese patients with OSA
(BMI 25.5–45.5 kg/m2).87 Squier et al. elegantly dem-
onstrated an indirect relationship between Pcrit and
EELV in non-obese men and women88 (Fig. 7). These
authors estimated that there was approximately a
2 cm H2O reduction in Pcrit in response to an increase
in lung volume of one litre in these subjects. Interest-
ingly, the Pcrit value for a given lung volume was more
negative in women than in men, suggesting that
protective factors other than lung volume may be
operating in women.
If a reduction in lung volume is involved in the
development of OSA, lung inflation during sleep
should decrease the frequency of OSA. Such a finding
has been documented in a case report89 and in a
Figure 7 Relationships between absolute end expiratory
lung volume (EELV) and upper airway critical closing
pressure (Pcrit), as determined by the isovolumetric tech-
nique in men (n = 11) and women (n = 7) without OSA.
There was an inverse relationship between EELV and Pcrit
in both genders with the upper airway being more col-
lapsible in men than in women for the same EELV. (From
Squier et al.88 with permission)
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
Role of obesity in pharyngeal obstruction
clinical trial of obese patients with OSA90 but could
not be confirmed in another trial involving less obese
patients with OSA.91 However, these conflicting results
based on just 22 individuals with OSA do not provide
conclusive evidence for the lung volume hypothesis.
Nevertheless, the difference in the severity of obesity
between these studies is worthy of note, and the find-
ings are likely to be explained by differences in study
protocols and populations.
What is the role of tracheal tug during OSA?
In humans, the trachea is reported to move caudally,
even during tidal breathing.92 Van de Graaff demon-
strated that a phasic inspiratory increase in tracheal
traction forces was evident in anaesthetized dogs
breathing through a tracheostomy, but this disap-
peared after mechanical disconnection of the trachea
from the UA.93 Furthermore, as illustrated in Figure 8,
he showed that augmentation of oesophageal pres-
sure and a decrease in caudal movement of the carina
during inspiratory occlusion increased tracheal trac-
tion, but maintenance of the carina in position during
expiratory obstruction failed to maintain the tracheal
traction forces.94 This suggests that lung inflation may
not be essential for producing and maintaining
phasic tracheal traction forces. A ‘tracheal tug’ is often
evident in patients with OSA during progressively
increasing respiratory drive in OSA. This has two con-
tradictory influences on pharyngeal obstruction; it
serves to terminate obstruction by a progressive
increase in tracheal traction forces and also maintains
obstruction by increasing the negative Plumen. The
phasic tracheal traction force is believed to operate
more efficiently during OSA in obese patients with
Figure 8 Respiratory changes in tracheal traction force
(Ttx) in a spontaneously breathing, anaesthetized and
tracheotomized dog. Note that inspiratory occlusion (4th
breath) resulted in augmentation of oesophageal pres-
sure (Pes) and Ttx but decreased caudal movement of the
carina (Dcar). Maintenance of the carina in position during
expiratory obstruction (9th breath) failed to maintain Ttx.
(From Van de Graaff 94 with permission)
© 2011 The Author
Respirology © 2011 Asian Pacific Society of Respirology
39
reduced lung volumes because of the increased dia-
phragmatic curvature at lower lung volumes.95
Visceral fat and stability of UA neural
control mechanisms
While the main focus of this paper has been the
mechanisms promoting increased pharyngeal airway
collapsibility, recent evidence suggests possible con-
tribution of increased visceral fat, and particularly cir-
culating leptin, to breathing instability during sleep in
some patients with OSA. In short, obesity is associ-
ated with increased levels of circulating leptin, which
is possibly a respiratory stimulant.96 In obese patients
with OSA, any increase in the loop gain of negative
feedback to the respiratory system will promote res-
piratory instability and consequently produce more
frequent OSA oscillations. While this is speculative,
patients with OSA have been shown to have a higher
respiratory loop gain during sleep,97 and this loop gain
was significantly associated with AHI in OSA patients
with a Pclose near atmospheric pressure.98 Increased
gas exchange efficacy because of a low lung volume,
low dead space, low metabolic rate, low cardiac
output and high arterial carbon dioxide, all of which
are common in obese patients with OSA, may also
contribute to the increased respiratory loop gain.99
Patients with OSA who are eucapnic but not those
with hypercapnia, have higher serum leptin levels
and hypercapnic ventilatory responses than BMI-
matched individuals without OSA.100 Interestingly,
higher leptin levels in obese patients with OSA were
independent of obesity and were reversed by short
term use of CPAP.70,101. Evidence that serum leptin
levels are higher in obese individuals and those with
OSA suggests the potential for leptin resistance
to contribute to the development of obesity and
resistance to weight loss. Excess visceral adipose
tissue secretes a number of other hormones and
pro-inflammatory cytokines that may also influence
breathing in obese patients with OSA.102 While this
line of investigation may be fruitful, further intensive
research is still required to better understand the
pathogenesis of OSA.
SUMMARY
Obese individuals may develop OSA due to excessive
deposition of fat at two distinct locations, as summa-
rized in Figure 9. In the pharyngeal airway region,
excessive soft tissue within the maxillomandibular
enclosure may increase tissue pressure, leading to
pharyngeal airway narrowing. Even mild obesity may
cause an anatomical imbalance in patients with a
small maxilla and mandible. Excessive submandibu-
lar soft tissue indicates and serves to compensate
for this anatomical imbalance. Excessive central fat
deposition may decrease lung volumes and longitu-
dinal pharyngeal wall tension. The lung volume
dependence of pharyngeal airway patency may be
more significant in obese patients with OSA. Obesity-
Respirology (2012) 17, 32–42
40
Figure 9 Hypothetical neuroanatomical relationships
between obesity and OSA. See text for detailed
explanation.
related hormones and cytokines such as leptin may
impair the neuro-anatomical interactions necessary
for stable breathing, thereby increasing the frequency
of OSA. Although current evidence strongly supports
these speculations, further intensive research is
required.
ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid no.
21592000 from the Ministry of Education, Culture,
Sports, Science and Technology, Tokyo, Japan.
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