Altered ventilatory responses to exercise testing in young adult men with obstructive sleep apnea
Obstructive sleep apnea (OSA) is a disorder characterized by repetitive obstructions of the upper airway. Individuals with OSA experience intermittent hypoxia, hypercapnia, and arousals during sleep, resulting in increased sympathetic activation. Chemoreflex activation, arising from the resultant oscillatory disturbances in blood gases from OSA, exerts control over ventilation, and may induce increases in sympathetic vasoconstriction, contributing to increased long-term risks for hypertension (HTN) and cardiovascular disease (CVD). To evaluate whether OSA elicits exaggerated ventilatory responses to exercise in young men, 14 overweight men with OSA and 16 overweight men without OSA performed maximal ramping cycle ergometer exercise tests. Oxygen consumption (VO(2)), ventilation, (V(E)), ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)), and V(E)/VCO(2) slope were measured. The VO(2) response to exercise did not differ between groups. The V(E), V(E)/VCO(2), V(E)/VO(2) were higher (p< 0.05, 0.002, and p<0.02, respectively) in the OSA group across all workloads. The V(E)/VCO(2) slope was greater in the OSA group (p<0.05). The V(E)/VCO(2) slope and AHI were significantly correlated (r=0.56, p<0.03). Thus, young, overweight men with OSA exhibit increased ventilatory responses to exercise when compared to overweight controls. This may reflect alterations in chemoreflex sensitivity, and contribute to increased sympathetic drive and HTN risk.
Altered ventilatory responses to exercise testing in
young adult men with obstructive sleep apne a
Trent A. Hargens
, Stephen G. Guill
, Adrian Aron
, Donald Zedalis
John M. Gregg
, Sharon M. Nickols-Richardson
, William G. Herbert
Laboratory for Health and Exercise Science, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic
Institute and State University, Blacksburg, VA, USA
Sleep Disorders Network of Southwest Virginia, Christiansburg, VA, USA
Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
Human Performance Laboratory, Clinical Exercise Physiology Program, Ball State University, Muncie, IN, USA
Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, USA
Health Research Group, LLC, Blacksburg, VA, USA
Received 3 June 2008; accepted 14 January 2009
Available online 13 February 2009
Background: Obstructive sleep apnea (OSA) is a disorder characterized by repetitive obstruc-
tions of the upper airway. Individuals with OSA experience intermittent hypoxia, hypercapnia,
and arousals during sleep, resulting in increased sympathetic activation. Chemoreﬂex activa-
tion, arising from the resultant oscillatory disturbances in blood gases from OSA, exerts control
over ventilation , and may induce increases in sympathetic vasocons triction, contributing to
increased long-term risks for hypertension (HTN) and cardiovascular disease (CVD).
Methods: To evaluate whether OSA el icits exaggerated ventilatory responses to exercise in
young men, 14 overweight men with OSA and 16 overweight men without OSA performed
maximal ramping cy cle ergometer ex ercise tes ts. Oxygen con sumption (VO
), ventilatory equivalents for oxygen (V
slope were measured.
Results: The VO
response to exercise did not differ between groups. The V
were higher (p < 0.05, 0.002 , and p < 0.02, respectively) in the OSA group across all work-
loads. The V
slopewasgreaterintheOSAgroup(p < 0.05). The V
slope a nd
AHI were signiﬁcantly correlated (r Z 0.56, p < 0.03). Thus, young, overweight men with
* Corresponding author. Department of Human Nutrition, Foods & Exercise, Virginia Polytechnic Institute and State University, 213 War
Memorial Hall (0531), Blacksburg, VA 24061, USA. Tel.: þ1 540 231 6565; fax: þ1 540 231 8476.
E-mail address: firstname.lastname@example.org (W.G. Herbert).
0954-6111/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Respiratory Medicine (2009) 103, 1063e1069
OSA exhibit increased ventilatory respons es to exercise when compared to overweight
controls. This may reﬂect alterations in chemoreﬂex sensitivity, and contribute to increased
sympathetic drive and HTN risk.
ª 2009 Elsevier Ltd. All rights reserved.
Obstructive sleep apnea (OSA) is a sleep disorder prevalent
in approximately 2e4% of the middle-aged adult pop-
Recent estimates, however suggest that over 85%
of those with signiﬁcant OSA, who would beneﬁt from
treatment, go undiagnosed.
This disorder has been
associated with increased risk for the development of
several adverse health conditions,
and it has recently been
reported that OSA may also independently increase the risk
for cardiovascular morbidity and mortality.
gest relationship, however, appears to be that between OSA
and the occurrence of hypertension (HTN), which demon-
strates an independent, doseeresponse relationship
between OSA severity and HTN risk.
The mechanisms linking OSA to HTN are unclear, but
several proposed mechanisms suggest a complex interac-
tion of several factors. Heightened sympathetic nervous
system activation has been demonstrated in OSA, which
persists during waking hours, and is above that which is
seen in obesity alone.
Treatment of OSA with nasal
continuous positive airway pressure (CPAP) has been shown
to decrease sympathetic activity.
Chemoreﬂexes exert powerful control over ventilation
and contribute directly to sympathetic activation.
activation of the chemoreﬂexes, and a signiﬁcantly greater
ventilatory response to acute hypoxic breathing has been
documented in OSA patients at rest
above that which
has been previously noted in obesity alone.
another instance when chemoreﬂex sensitivity augments,
and recent studies examining individuals with central sleep
apnea (CSA) and congestive heart failure (CHF) demon-
strated an exaggerated ventilatory response to exercise in
CSA subjects, suggesting an enhanced chemosensitivity
above CHF alone.
Signiﬁcant correlations between CSA
severity and the V
slope, a marker of chemo-
sensitivity and predictor of poor prognosis with CHF, were
Limited data is available on the responses to graded
exercise testing in OSA, and no published studies have
examined the ventilatory responses at submaximal and
maximal exercise intensities. Therefore, the purpose of this
study is to evaluate the ventilatory responses to graded
exercise testing in young men with undiagnosed OSA, to
examine whether a possible alteration in chemoreﬂex sensi-
tivity may be an early clinical sign in the progression of OSA.
Sedentary overweight males with untreated OSA (n Z 14),
and control subjects matched for age, body mass index (BMI),
and central adiposity, but without OSA (n Z 16) were
recruited from the local university community through
campus notices as well as newspaper advertisements.
Subjects were between 18 and 26 years of age and were
classiﬁed as overweight according to BMI criteria.
subjects underwent pre-screening which included an initial
qualiﬁcation questionnaire to identify any potential exclusion
criteria, as well as a detailed health history questionnaire. All
subjects were non-smokers, who were free from acute
respiratory infection during the previous 6 weeks, including
tonsillitis and adenoiditis. Subjects were free from signiﬁcant
cardiovascular, pulmonary, metabolic, or musculoskeletal
disorders that would preclude maximal aerobic exercise
testing. Subjects were not taking any prescribed vasoactive
medications, hypnotics, sedatives, analgesics, psychotropics,
steroids, or sympathomimetics. Individuals who had partici-
pated in regular physical activity (>3 days per week, >30 min
per day) for the previous 6 months were considered physically
active and excluded.
All methods and procedures, approved
by the Institutional Review Board of Virginia Polytechnic
Institute and State University (Virginia Tech), Blacksburg, VA,
were explained to the subjects, who then read and gave
written informed consent.
Home sleep evaluation
Subjects underwent an unattended, limited home sleep
evaluation consisting of: (1) nasal ﬂow detection via nasal
cannula; (2) ﬁnger pulse oximetry; (3) respiratory effort
detection via belts positioned on the upper and lower torso;
and (4) body position detection, to screen for the presence
of OSA, utilizing the Embletta portable device (Embla,
Broomﬁeld, CO). The Embletta device and other portable
systems similar to the Embletta have previously been vali-
dated vs. nighttime polysomnography (PSG).
data were interpreted by a sleep technician and transposed
into an apnea hypopnea index (AHI), with the results veri-
ﬁed by the physician investigator who is a sleep specialist.
Apnea is deﬁned as a cessation of airﬂow for 10 s or greater.
Hypopnea is deﬁned a 50% or greater reduction in airﬂow
for at least 10 s coupled with a decrease in oxygen satu-
Subjects were then classiﬁed into either the
OSA group (OSA) (AHI > 5 events h
), or the no-OSA group
(No-OSA) (AHI < 5 events h
Body composition measurement
Subjects completed total body dual-energy X-ray absorpti-
ometry (DXA) scans (version 8.26a:3*, QDR4500A, Hologic
Inc., Bedford, MA) for measurement of fat mass (FM) and
body fat percentage (BF%). Central abdominal fat was
measured from total body DXA scans by examining the
region of interest deﬁned by the top edge of the second to
bottom edge of the fourth lumbar vertebra.
1064 T.A. Hargens et al.
measures were conducted and analyzed by one investi-
gator. Weekly scans of an external soft tissue bar (Hologic
Inc.) were completed to ensure quality control for soft
tissue mass measurements. Testeretest reliability data for
this DXA have been reported elsewhere.
Ramp exercise testing
Subjects completed a maximal cycle ergometer exercise
test. Anthropometric measures of height, weight, neck
circumference (NC), waist circumference (WC), and hip
circumference (HC) were measured prior to the exercise
test. Resting heart rate (HR) and blood pressure were
obtained in the seated position, after a minimum of 5 min
of rest. An electronically braked cycle ergometer (Sensor-
, Yorba Linda, CA) was utilized for each exercise
test. A standardized protocol for each subject was utilized,
which has been previously described.
exchange measurements were obtained during the exercise
test using a computer controlled, breath-by-breath system
(SensorMedics Vmax 229
, Yorba Linda, CA). Values were
calculated to 10 s averages. Measurements included oxygen
), minute ventilation (V
), carbon dioxide
), respiratory exchange ratio (RER) and
). The two highest 10 s VO
during the last minute of exercise were averaged to obtain
value. The V
calculated at several submaximal workloads and at peak
exercise. The V
slope was calculated from exercise
onset to peak as previously described.
All statistical analyses were performed using SPSS version
15.0 (SPSS Inc., Chicago, IL). Independent t -tests were used
to evaluate differences in baseline descriptive character-
istics between groups. Effects of group, exercise intensity
(watts), and interactions on ventilatory measures were
evaluated using two-way repeated measures ANOVA.
Pearson r correlations were calculated to explore potential
relationships between select ventilatory measures and AHI.
A value of p < 0.05 was considered statistically signiﬁcant.
Demographic and descriptive characteristics for the study
participants are presented in Table 1. No differences were
noted between groups for age, BMI, NC, WC, HC, BF%, and
central abdominal fat. Central abdominal fat was positively
correlated with AHI (r Z 0.42, p Z 0.02) across all study
Exercise test measures
Heart rate and blood pressure responses did not differ
between the groups at rest or during exercise and these
ﬁndings are summarized elsewhere.
between groups did not differ at any submaximal exercise
intensity or at maximum effort (p Z 1.0), nor did peak work
rate (Watts) achieved (p Z 0.30). As shown in Fig. 1, VE,
, and V
responses were higher in the OSA
group at all workloads (p < 0.05, p < 0.002 and p Z 0.02,
respectively). The V
slope was greater in the OSA
compared to the control group (p Z 0.045) (Fig. 2), and was
positively correlated with AHI (r Z 0.56, p Z 0.001)
(Fig. 3). No difference in the RER between groups was
noted at any submaximal workload or at peak (p Z 0.30).
Peak exercise responses for all subjects are presented in
Table 2. Maximal test endpoints were achieved in both
groups (peak RER > 1.1; peak RPE > 16).
This study is the ﬁrst to evaluate ventilatory responses to
exercise in young, overweight men with untreated OSA. The
major ﬁnding is that OSA, and not obesity, results in
increased ventilatory responses to graded exercise testing
in young men, reﬂected by signiﬁcantly greater V
, and V
measures across all submaximal exercise
intensities and peak exercise (Fig. 1). In subjects matched
for age, BMI, BF%, central abdominal fat, and VO
with OSA demonstrated an exaggerated ventilatory
response relative to carbon dioxide output and oxygen
consumption. This ﬁnding is in contrast to that ﬁndings of
Lin et al.,
which reported no difference between the OSA
and control group in either peak V
slope, a marker of chemoreﬂex
sensitivity, has previously been found to be a potent
predictor of poor prognosis in patients with CHF
a condition frequently seen in patients with central sleep
apnea (CSA) as well as OSA. Artz et al.
found, in middle-
age individuals with CHF and CSA, the V
exercise, was greater than those without CSA. They also
reported a signiﬁcant correlation between the V
slope and AHI (r Z 0.613; p < 0.001).
Meguro et al.
also reported a greater V
middle-aged CHF patients with CSA compared to CHF
subjects without CSA (p < 0.01). To our knowledge, no
studies have examined the response to exercise in OSA
subjects. Results from the current study indicate that this
Table 1 Subject characteristics.
OSA (n Z 14) No-OSA (n Z 16)
Age (years) 22.4 (2.8) 21.4 (2.6)
AHI (events h
1) 22.7 (18.5)
Height (cm) 171.6 (18.6) 178.2 (6.1)
Weight (kg) 99.6 (13.4) 99.4 (12.4)
BMI (kg m
2) 32.0 (3.7) 31.4 (3.7)
NC (cm) 40.8 (2.1) 40.6 (2.6)
WC (cm) 100.5 (8.1) 95.4 (9.7)
HC (cm) 115.4 (8.1) 110.1 (8.4)
FM (kg) 29.1 (7.6) 26.0 (7.2)
% body fat 28.5 (4.7) 25.9 (4.5)
CAF (kg) 8.7 (2.4) 7.0 (1.9)
Values are means with SD in parentheses. AHI, apnea/hypopnea
index; BMI, body mass index; NC, neck circumference; WC,
waist circumference; CAF, central abdominal fat.
* p < 0.0001.
Ventilatory exercise responses in young men with OSA 1065
measure of chemoreﬂex sensitivity is increased in young
overweight men with OSA. We report a correlation between
slope and AHI similar to that of Artz et al.
(r Z 0.56 vs. 0.61).
Further examination of this relation-
ship with OSA is required.
The possible mechanisms underlying the exaggerated
ventilatory responses may be multifaceted. The repetitive
nocturnal bouts of hypoxia and hypercapnia operant in OSA
have been implicated to induce alterations in the central
and peripheral chemoreceptors.
Narkiewicz et al. previ-
ously demonstrated a tonic activation of the chemorecep-
tors in OSA patients,
and further demonstrated
exaggerated chemoreﬂex sensitivity in OSA patients
through breathing a hypoxic mixture that resulted in
a greater V
and muscle sympathetic nerve activation in the
OSA group vs. non-OSA controls at rest.
Results of the
current study agree with, and extend those of Narkiewicz
suggesting that the intermittent nighttime
hypoxia of OSA potentiates increased peripheral chemore-
ceptor sensitivity that persists during waking hours, and
manifests during graded exercise testing. The underlying
mechanisms that contribute to the alterations in chemo-
receptor function are not well understood. Recent
evidence suggests that multiple adaptive mechanisms may
play a role, including alterations in vascular endothelial
function, increased angiotensin II activity, as well increased
generation of reactive oxygen species.
Studies utilizing animal and human models support an
increased peripheral chemoreceptor gain in response to
Figure 2 The individual and mean values of the V
slope of patients with OSA (n Z 14) vs. No-OSA (n Z 16).
r = 0.56
p = 0.001
Figure 3 Relation between V
slope and the apneae
hypopnea index (AHI) in 30 overweight young men. The AHI is
a measure of obstructive sleep apnea and its severity, as
assessed by overnight somnography.
55 85 115
55 85 115 145 peak
Figure 1 Submaximal and maximal ventilatory responses
during cycle ergometer exercise in young, sedentary men: (A)
was greater across all workloads in the OSA (n Z 14) vs. No-
OSA (n Z 16) group (*p < 0.05); (B) V
was greater across
all workloads in the OSA vs. No-OSA group (**p < 0.002); (C) V
was greater across all workloads in the OSA vs. No-OSA
group (yp < 0.02).
1066 T.A. Hargens et al.
chronic intermittent hypoxia.
Data from these studies
suggest that increased endothelin-1, a potent modulator of
the peripheral chemoreceptors that is produced in the
vascular endothelium, increases chemoreﬂex sensitivity.
Rey et al. further showed an increased ventilatory response
in animals exposed to hypoxic breathing.
in OSA subjects have also reported increases in endothelin-1
or its precursors, and the potential for CPAP to improve
. Our ﬁnding of an exaggerated ventila-
tory response to ramping exercise in young men with OSA
is consistent with this hypothesized mechanism of
increased chemoreceptor gain due to chronic intermittent
hypoxia, possibly involving related alterations in vascular
endothelial function. Further study is needed to clarify
these adaptive mechanisms, particularly with respect to
effects in exercise.
Another potential mechanism has been suggested by
recent investigations that have reported alterations in the
skeletal muscle function as a result of OSA.
these studies indicated that OSA patients have a reduced
peak blood lactate response during maximal exercise, as
well as a diminished rate of blood lactate clearance. Taken
together, these ﬁndings suggest a defect in muscle oxidative
metabolism in OSA subjects.
While we did not measure
lactate or catecholamine levels in the current study, we
observed no differences in the VO
or RER responses in the
two study groups. This suggests similar oxygen cost at
the same power output, as well as a similar metabolic fuel
mix. Taken together, it is unlikely that possible OSA-related
differences in muscle oxidative metabolism would be
an explanation for exaggerated ventilatory responses
One potential limitation is that nighttime PSG testing
was not utilized for OSA diagnosis. Nighttime PSG is the
standard and accepted tool for OSA diagnosis. The Embletta
has been validated relative to PSG results,
but is depen-
dent upon the subject’s ability to properly set up the device
independently. Subjects were provided verbal and visual
instruction by study personnel, written instructions for
device setup, and contact information for study personnel
in case further instruction was needed. Another limitation
was that cycle ergometry was utilized for the ramp exercise
test rather than treadmill walking. Cycle ergometry can
result in lower peak VO
values. In the current study,
however, peak RER values for each group were greater than
maximal criteria (RER > 1.1), suggesting maximal efforts in
In conclusion, the results of the current study
indicate that exercise testing results in exaggerated
ventilatory responses in young, overweight m en wi th
untreated OSA. These responses are suggestive of
alterations in chemoreﬂex sensitivity and breathing
efﬁciency in these individuals, beyond that seen with
obesity alone. These ﬁndings also suggest t he potential
for clinical exercise testing in improving risk stratiﬁca-
tion and clinical decision making leading to patient
selection for OSA diagnostic testing with PSG.
Respiratory gas exchange equipment for this research
was provided by SensorMedics, Yorba Linda, CA,
a Division of VIASYS Healthcare, Inc. Parts of this
research were supported by a grant from the ResMed
Foundation, La Jolla, CA, and ResMed Corporation, San
Diego, CA. Research conducted in the Laboratory for
Health and Exercise Science, Department of Human
Nutrition, Foods and Exercise, on the campus of Virginia
Polytechnic Institute and State University, Blacksburg,
VA , and the Sleep Disorders Network of Southwest
Virginia, Christiansburg, VA.
Conﬂict of interest statement
Trent A. Hargens, Stephen G. Guill, Adrian Aron, Donald
Zedalis, John M. Gregg, Sharon M. Nickols-Richardson, and
William G. Herbert have no conﬂicts to disclose.
Table 2 Cardiopulmonary and perceptual responses to
RER peak RPE peak
OSA (n Z 14)
1 29.6 24.2 1.22 N/A
2 23.5 25.7 1.10 17
3 35.3 25.5 1.10 15
4 26.8 25.9 1.04 19
5 31.3 32.7 1.18 17
6 35.3 22.6 1.04 18
7 21.2 30.5 1.13 17
8 23.6 28.8 1.15 20
9 26.1 26.8 1.11 17
10 27.0 29.6 1.15 16
11 22.1 26.5 1.09 19
12 24.5 31.7 1.22 19
13 29.3 24.7 1.23 19
14 24.0 28.9 1.15 20
Mean (SD) 27.1 (4.5) 27.4 (3.0) 1.14 (0.06) 17.5 (1.6)
No-OSA (n Z 16)
1 24.5 23.4 1.16 16
2 28.9 25.4 1.09 17
3 25.9 27.7 1.16 18
4 25.8 26.0 1.1 18
5 22.7 28.5 1.11 17
6 26.3 23.4 1.11 18
7 19.6 23.9 1.12 17
8 24.9 25.3 1.12 15
9 26.0 23.8 1.15 17
10 25.2 26.5 1.13 20
11 26.5 25.6 1.07 19
12 34.3 27.5 1.19 18
13 31.4 23.2 1.21 16
14 35.1 23.5 1.04 16
15 26.7 28.4 1.14 19
16 44.2 25.6 1.12 18
Mean (SD) 28.0 (5.8) 25.5 (1.8) 1.13 (0.04) 17.4 (1.3)
RER, respiratory exchange ratio; RPE, rating of perceived
Ventilatory exercise responses in young men with OSA 1067
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