Altered ventilatory responses to exercise testing in
young adult men with obstructive sleep apnea
Trent A. Hargensa,d, Stephen G. Guilla, Adrian Arona, Donald Zedalisb,e,
John M. Greggb,f, Sharon M. Nickols-Richardsonc, William G. Herberta,f,*
aLaboratory for Health and Exercise Science, Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic
Institute and State University, Blacksburg, VA, USA
bSleep Disorders Network of Southwest Virginia, Christiansburg, VA, USA
cDepartment of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
dHuman Performance Laboratory, Clinical Exercise Physiology Program, Ball State University, Muncie, IN, USA
eEdward Via Virginia College of Osteopathic Medicine, Blacksburg, VA, USA
fHealth 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 vasoconstriction, contributing to
increased long-term risks for hypertension (HTN) and cardiovascular disease (CVD).
Methods: 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 (VO2), ventilation,
(VE), ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2), and
VE/VCO2slope were measured.
Results: The VO2response to exercise did not differ between groups. The VE, VE/VCO2, VE/VO2
were higher (p < 0.05, 0.002, and p < 0.02, respectively) in the OSA group across all work-
loads. The VE/VCO2slope was greater in the OSA group (p < 0.05). The VE/VCO2slope and
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.
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Respiratory Medicine (2009) 103, 1063e1069
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.
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-
ulation.1Recent estimates, however suggest that over 85%
of those with significant OSA, who would benefit from
treatment, go undiagnosed.2,3This disorder has been
associated with increased risk for the development of
several adverse health conditions,4and it has recently been
reported that OSA may also independently increase the risk
for cardiovascular morbidity and mortality.5e7The stron-
gest relationship, however, appears to be that between OSA
and the occurrence of hypertension (HTN), which demon-
between OSA severity and HTN risk.8,9
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.10,11Treatment of OSA with nasal
continuous positive airway pressure (CPAP) has been shown
to decrease sympathetic activity.10,12
Chemoreflexes exert powerful control over ventilation
and contribute directly to sympathetic activation.13Tonic
activation of the chemoreflexes, and a significantly greater
ventilatory response to acute hypoxic breathing has been
documented in OSA patients at rest14,15above that which
has been previously noted in obesity alone.16Exercise is
another instance when chemoreflex sensitivity augments,17
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.18,19Significant correlations between CSA
severity and the VE/VCO2 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),
andcontrol subjectsmatchedfor age,bodymassindex(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.20All
subjects underwent pre-screening which included an initial
subjects were non-smokers, who were free from acute
respiratory infection during the previous 6 weeks, including
cardiovascular, pulmonary, metabolic, or musculoskeletal
disorders that would preclude maximal aerobic exercise
testing. Subjects were not taking any prescribed vasoactive
steroids, or sympathomimetics. Individuals who had partici-
patedinregularphysicalactivity(>3 daysperweek,>30 min
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).22e24Embletta
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-
ration (?4%).4Subjects were then classified into either the
OSA group (OSA) (AHI > 5 events h?1), or the no-OSA group
(No-OSA) (AHI < 5 events h?1).
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.25All DXA
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.26,27
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-
Medics?, Yorba Linda, CA) was utilized for each exercise
test. A standardized protocol for each subject was utilized,
which has been previously described.28Respiratory gas
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
consumption (VO2), minute ventilation (VE), carbon dioxide
production (VCO2), respiratory exchange ratio (RER) and
peak VO2(VO2pk). The two highest 10 s VO2values achieved
during the last minute of exercise were averaged to obtain
the VO2pk value. The VE/VO2 and VE/VCO2 ratios were
calculated at several submaximal workloads and at peak
exercise. The VE/VCO2slope was calculated from exercise
onset to peak as previously described.29,30
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.31The VO2responses
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,
VE/VCO2, and VE/VO2 responses were higher in the OSA
group at all workloads (p < 0.05, p < 0.002 and p Z 0.02,
respectively). The VE/VCO2slope was greater in the OSA
compared to the control group (p Z 0.045) (Fig. 2), and was
(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).
AHI(r Z 0.56,
p Z 0.001)
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 VE, VE/
VCO2, and VE/VO2measures across all submaximal exercise
intensities and peak exercise (Fig. 1). In subjects matched
for age, BMI, BF%, central abdominal fat, and VO2, those
withOSA demonstrated an
response relative to carbon dioxide output and oxygen
consumption. This finding is in contrast to that findings of
Lin et al.,32which reported no difference between the OSA
and control group in either peak VE/VO2or VE/VCO2.
Exaggerated VE/VCO2slope, a marker of chemoreflex
sensitivity, has previously been found to be a potent
predictor of poor prognosis in patients with CHF29,33e35,
a condition frequently seen in patients with central sleep
apnea (CSA) as well as OSA. Artz et al.19found, in middle-
age individuals with CHF and CSA, the VE/VCO2slope, with
exercise, was greater than those without CSA. They also
reported a significant correlation between the VE/VCO2
slope and AHI (r Z 0.613; p < 0.001).19More recently,
Meguro et al.18also reported a greater VE/VCO2slope in
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
OSA (n Z 14)No-OSA (n Z 16)
AHI (events h?1)
BMI (kg m?2)
% body fat
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 OSA1065
measure of chemoreflex sensitivity is increased in young
overweight men with OSA. We report a correlation between
the VE/VCO2slope and AHI similar to that of Artz et al.
(r Z 0.56 vs. 0.61).19Further 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.36Narkiewicz et al. previ-
ously demonstrated a tonic activation of the chemorecep-
tors inOSA patients,15
through breathing a hypoxic mixture that resulted in
a greater VEand muscle sympathetic nerve activation in the
OSA group vs. non-OSA controls at rest.14Results 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 functionare not
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.37,38
Studies utilizing animal and human models support an
increased peripheral chemoreceptor gain in response to
OSA patients in
slope of patients with OSA (n Z 14) vs. No-OSA (n Z 16).
The individual and mean values of the VE/VCO2
0 10 20 3040 50 6070
r = 0.56
p = 0.001
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.
Relation between VE/VCO2slope and the apneae
55 85115 145peak
during cycle ergometer exercise in young, sedentary men: (A)
VEwas greater across all workloads in the OSA (n Z 14) vs. No-
OSA (n Z 16) group (*p < 0.05); (B) VE/VCO2was greater across
all workloads in the OSA vs. No-OSA group (**p < 0.002); (C) VE/
VO2was greater across all workloads in the OSA vs. No-OSA
group (yp < 0.02).
Submaximal and maximal ventilatory responses
1066 T.A. Hargens et al.
chronic intermittent hypoxia.39e46Data 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.46Human studies
in OSA subjects have also reported increases in endothelin-1
or its precursors, and the potential for CPAP to improve
these factors.43e45. Our finding of an exaggerated ventila-
tory response to ramping exercise in young men with OSA
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.47,48Data from
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.47,48While we did not measure
lactate or catecholamine levels in the current study, we
observed no differences in the VO2or 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,22but 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 VO2 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, theresults
indicate that exercise testing results in exaggerated
ventilatory responses in young, overweight men with
untreatedOSA. These responses
alterations in chemoreflex sensitivity and breathing
efficiency in these individuals, beyond that seen with
obesity alone. These findings also suggest the 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 providedby SensorMedics,
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.
Cardiopulmonary and perceptual responses to
RER peak RPE peak
OSA (n Z 14)
Mean (SD) 27.1 (4.5)
27.4 (3.0) 1.14 (0.06) 17.5 (1.6)
No-OSA (n Z 16)
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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Ventilatory exercise responses in young men with OSA1069