The Impact of OSA on Exercise:
A Window Into Chronic Disease
Risk
Trent A. Hargens, PhD
Department of Kinesiology
James Madison University
Outline
• Background on OSA-chronic disease
• Physiological mechanisms of disease link
• Exercise Testing as a diagnostic/prognostic
tool
• Variables of interest
• Exercise responses in OSA patients
• Summary
Hypoxemia
Reoxygenation
Hypercapnia
Sympathetic activation
Metabolic dysregulation
Left atrial enlargement
OSA
Disease
Mechanisms
Intrathoracic Pressure
Arousals
Sleep Deprivation
Endothelial dysfunction
Systemic inflammation
Hypercoagulability
Systemic
Pulmonary
Hypertension
Heart Failure
Arrhythmias
Associated CV
Disease
Sudden cardiac death
Somers et al., Circulation 2008;118:1080-1111.
Renal disease
Stroke
Myocardial infarction
OSA and Insulin Resistance
Homeostasis model
assessment index
Independent of age,
gender, ethnicity,
smoking status, BMI,
waist circumference,
and sleep duration
Punjabi et al., Am J Epidemiol 2004;160:521-530
OSA and Heart Failure
• Prevalence of OSA in CHF population
estimated to be as high as 40%
•
Javaheri, Circulation 1998;97:2154–2159
Significantly improved LV function
in CHF patients with OSA
following
CPAP treatment
Mansfield et al., Am J Respir Crit Care Med 2004;169:361-366
OSA and Heart Failure
*
*
*
*
*
LVEDD (mm)
LVESD (mm)
EF (%)
LVEDV (ml)
LVESV (ml)
Kourouklis SP, et al, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.09.101. Article in
press
OSA and Hypertension
P for trend = 0.005
ADJUSTED FOR BMI, NECK, WHR, ALCOHOL USE, SMOKING
Nieto et al., Jama 2000;283:1829-1836.
OSA and Hypertension
P for trend < 0.001
ADJUSTED FOR BASE-LINE HYPERTENSION STATUS, NON-MODIFIABLE RISK
FACTORS, HABITUS, AND WEEKLY ALCOHOL AND CIGARETTE USE
Peppard et al., N Engl J Med 2000;342:1378-1384
OSA and Cardiovascular Disease
Odds ratio for cardiovascular death
Diagnostic
Group
Adjusted OR
(95% CI)
P
Snoring
1.03 (0.31-1.84)
0.88
1.15 (0.34-2.69)
0.71
2.87 (1.17-7.51)
0.025*
1.05 (0.39-2.21)
0.74
Untreated mild
OSA
Untreated
severe OSA
CPAP
Marin et al., Lancet 2005;365:1046-1053.
OSA and Cardiovascular Disease
Odds ratio for non-fatal cardiovascular events
Diagnostic
Group
Adjusted OR
(95% CI)
P
Snoring
1.32 (0.64-3.01)
0.38*
1.57 (0.62-3.16)
0.22*
3.17 (1.12-7.52)
0.001*
1.42 (0.52-3.40)
0.29*
Untreated mild
OSA
Untreated
severe OSA
CPAP
Marin et al., Lancet 2005;365:1046-1053.
OSA and Cardiovascular Disease
Kaplan-Meier curves
A. Fatal
B. Non-Fatal
Authors conclude that OSA
independently increases risk for
CV events
Marin et al., Lancet 2005;365:10461053.
OSA and Cardiovascular Disease
Wisconsin Sleep Cohort
“Mortality follow-up of the Wisconsin Sleep Cohort,
comprising 20,963 person-years, indicates that
severe SDB is significantly associated with a 3-fold
increased all-cause mortality risk (P < 0.0008),
independently of age, sex, BMI, and other potential
confounders
OSA Disease Mechanisms
Hyperleptinemia
Baroreflex Sensitivity
Chemoreflex Activation
RAAS Activity
OSA
Sympathetic Activation
Insulin Resistance
Oxidative Stress
Endothelial Dysfunction
Systemic Inflammation
Adapted from Wolk et al., Clinics in chest medicine 2003;24:195-205.
HTN
Sympathetic Activation in OSA
Heightened SNA persists
during waking hours, not
just during sleep.
Improvements in SNA
during sleep were seen in
this group with CPAP
Somers VK et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest
1995;96:1897-1904.
Sympathetic Activation in OSA
SNA was:
1. Greater in Obese vs. lean
2. Greater in Obese + OSA vs Lean + OSA
3. Greater in OSA vs. without OSA (regardless of wt)
Therefore:
1. Sympathetic activation seen in obesity is independent of OSA
2. OSA’s impact on SNA is independent of body weight, but ADDITIVE
Grassi et al., Hypertension 2005;46:321-325.
Exercise Question
• If OSA impacts so many physiological systems,
how may those adaptations manifest during
acute exercise?
• Does it negatively impact their ability to exercise,
ability to improve health/fitness, etc?
• Could changes with exercise provide prognostic
or diagnostic clues as OSA risk?
• Given that SO MANY OSA sufferers go undiagnosed
•
93 and 82% of females and males, who would benefit from
treatment, remain undiagnosed (Young et al., 1997)
“Cardiopulmonary exercise testing (CPX) offers the
clinician the ability to obtain a wealth of information
beyond standard exercise electrocardiography
testing that when appropriately applied and
interpreted can assist in the management of
complex cardiovascular and pulmonary disease.”
Circulation. 2010;122:191-225
• “the addition of ventilatory gas exchange
measurements during exercise testing
provides a wide array of unique and
clinically useful incremental information
that heretofore has been poorly
understood and underutilized by the
practicing clinician. The reasons for this are
many...”
Gas Exchange Variables of Interest
• Peak rate of oxygen uptake (VO
2peak
)
• Reflects the capacity of the heart, lungs, and blood to deliver
O2 to the muscles. Criterion measure of Aerobic Fitness.
•
VO2max = (HR x SV) x [C(a-v)O2]
• Minute ventilation (V )
E
• Amount of air moved in and out of the lungs (Liters/min)
• Ventilatory Equivalent for oxygen consumption (V /VO )
E
• Volume of air you must move to consume 1 Liter of O .
• Marker of ventilatory efficiency
2
2
Gas Exchange Variables of Interest
• Ventilatory Equivalent for CO
2
(VE/VCO2)
• Volume of air that you must move to blow off
1 Liter of CO2.
• Marker of ventilatory efficiency for CO
2
clearance
• V /VCO
E
2
Slope
• Powerful marker of ventilatory efficiency
• Slope of relationship from onset of exercise to
peak
• MOST research done in area of heart failure
Peak VO2 responses in OSA
Reduced VO2peak
No Change in VO2peak
Lin et al., 2006
Kline et al., 2012
Grote et al., 2004
Maeder et al., 2008
Hargens et al., 2008
Tremel et al., 1999
Schonhofer et al., 1997
Vanuxem et al., 1997
Kaleth et al., 2007
Alonso-Fernandez et al.,
2006
Ozturk et al., 2005
Peak VO2 vs. VE/VCO2 Slope in CHF
Peak VO2 (ml.kg-1.min-1)
P1 < 13.0
P2 13-16.5
P3 16.6-21.6
P4 > 21.6
VE/VCO2 Slope
V1 < 27.7
V2 27.7-34.5
V3 34.6-42.1
V4 > 42.1 Francis et al.,
Eur Heart J 2000
Peak VO2 vs. VE/VCO2 Slope in CHF
slope > 30 now considered “abnormal”
Arena et al., Circulation. 2007;115:2410-2417
Pathophysiological mechanisms of an elevated
VE/VCO2 slope
Central
Decreased right sided cardiac output
Increased pressure in pulmonary vasculature
secondary to increased left sided pressure
Compromised pulmonary vessel dilation
secondary to decreased NO production
Increased ventilationperfusion mismatching
High
VE/VCO2 slope
Central
Abnormal chemoreceptor
reflex
Heightened
VE
response to
exercise
Peripheral
Abnormal
chemoreceptor
and ergoreceptor reflex
VE/VCO2 slope in CSA (with CHF)
VO2peak did not differ between groups
Artz et al., Circulation. 2003;107:1998-2003
Hargens et al., 2009
Altered ventilatory responses to exercise testing in young adult men with obstructive sleep apnea. Respir Med 2009;103:10639.
Hargens et al., 2009
VO2peak did not differ between
groups
Hargens et al., 2009
VE/VCO2 slope - AHI correlation: r = 0.56, P = 0.001
To date, no other studies have examined this explicitly in
OSA
Balady et al
“During dynamic exercise, heart rate increases linearly
with work rate and VO2, but the slope and magnitude of
heart rate acceleration are influenced by age,
deconditioning, body position, type of exercise, and
various states of health and therapy, including heart
transplant. Chronotropic incompetence, defined as either
failure to achieve 85% of the age-predicted maximal heart
rate or a low chronotropic index (heart rate adjusted to the
MET level), is associated with increased mortality risk in
patients with known cardiovascular disease.”
Group
Age
AHI
VO2peak
HRpeak
OSA
45.6
24.7*
21.9
152.3
Control
40.2
2.5
21.9
168.4
Sleep Med 2007;8:160-168.
Kaleth et al., 2007
“The repetitive blood pressure
surges during sleep and increased
sympathetic activity during
wakefulness may result in the
structural downregulation of cardiac
Beta-adrenergic receptors and/or
alter the baroreflex set point to a
higher level of pressure.”
Balady
Subjects were without a
history of heart failure or
coronary
revascularization and
without pacemakers.
6 year follow-up in
2428 subjects
N Engl J Med 1999;341:1351-1357.
Attenuated HR Recovery
•
Also a reflection of autonomic
dysfunction
•
Imbalance between sympathetic
and parasympathetic activation
Sleep 2008;31:104-110.
Hargens et al., 2008
Sleep 2008;31:104-110.
Hargens et al., 2008
Sleep 2008;31:104-
“Attenuation of the HR recovery
response in OSA may reflect
predominance and/or slower
withdrawal of sympathetic
influence; how this pattern may be
affected by parasympathetic
reactivation that normally slows HR
is uncertain.”
Maeder et al., 2008
Maeder MT, Munzer T, Rickli H, Schoch OD, Korte W, Hurny C, Ammann P. Association
between heart rate recovery and severity of obstructive sleep apnea syndrome. Sleep Med
2008;9:753-761.
Maeder et al., 2008
Kline et al., 2012
*
*
Kline et al., 2012. Int J Cardiol. In press
*
Maeder et al., 2009
• 40 subjects with
OSA (AHI = 37)
• ~ 8 months of
CPAP treatment
• Exercise test
responses
compared
pre/post
Maeder MT, et al. Continuous positive airway
pressure improves exercise capacity and heart rate
recovery in obstructive sleep apnea. Int J Cardiol
2009;132:75-83.
*
Maeder et al., 2009
Other ways to assess
autonomic function?
Heart Rate Variability
HRV is the variation of beat to beat intervals
among successive heart rate cycles.
Heart Rate Variability
•
Heart rate variability (HRV) serves as a reflection of the balance
between the sympathetic and parasympathetic nervous system
•
•
•
•
•
Frequency-domain analysis of HRV have been established as a simple and
non-invasive marker
LF = low frequency (0.04-0.15 Hz). Reflection of
sympathetic/parasympathetic balance
HF = high frequency (0.15-0.40 Hz). Reflection of parasympathetic activity
LF/HF = ratio. Reflection of sympathetic/parasympathetic balance
OSA patients have demonstrated autonomic dysfunction, reflected
in diminished vagal activity and heightened sympathetic activity,
measured through HRV. This is seen even during normal waking
hours. (At rest)
•
Aydin, Tex Heart Inst J 2004;31:132-6
Hargens et al., 2012
• 9 High risk OSA, 16 Controls
•
Max cycle exercise tests
Findings suggest that heightened
•
HRV assessed throughout exercise and recovery
sympathetic activation (LF) and reduced
parasympathetic activation (HF) may
At peak exercise
manifest during high intensity exercise.
Further examination is warranted.
*
*
Heart Rate Variability is Reduced at Peak Exercise in Individuals at Risk for Sleep Apnea. Medicine & Science in
Sports & Exercise 2012;44:S163.
So…GXT as a clinical
tool in OSA?
Methods of assessing HR recovery are
heterogeneous!
http://www.multibriefs.com/briefs/acsm/active11-2.htm, 2010
Hargens et al., 2013
• Purpose: To examine whether measures
obtained during exercise testing may aid in
clinical risk stratification for OSA
• 102 overweight subjects
• Cycle max exercise test
• Screened for possible OSA with Embletta
• Logistic regression analysis with AHI > 15
criteria for OSA
In press: Medicine & Science in Sports and
Exercise
Hargens et al., 2013
• Significant univariate correlations to AHI
• Age
• BMI
Epworth
• Total Cholesterol
BP were not
• Triglycerides
• Peak HR
• VO
• HR (minutes 1 - 5 of recovery)
2peak
diff
Hargens et al., 2013
• Logistic Regression revealed that HR
was
the ONLY significant independent predictor
of OSA
• Beta = -0.215, P = 0.009
• R for model = 0.57, P < 0.001
• HR : P = 0.053
2
diff3
• Univariate ROC analysis
• AUC for HR = 0.73, P = 0.002
• AUC for BMI = 0.77, P < 0.001
diff5
diff5
Hargens et al., 2013
HRdiff5
BMI
Hargens et al., 2013
Epworth
AUC = 0.41, P = 0.26
Current Study
• The impact of untreated OSA on Cardiac
Rehabilitation Participation
• Research question: Does untreated OSA negatively
impact the progress of patients undergoing cardiac
rehabilitation?
• Non-invasive impedance cardiography measures
•
Cardiac output, stroke volume, ejection fraction, systemic
vascular resistance
• Study in conjunction with Radford University,
Carillion Roanoke Community Hospital, Rockingham
Memorial Hospital
Current Study
• Currently have recruited and screened 48
subjects
• Screened for OSA with ApneaLink device and
read by sleep technician
• 38 subjects have AHI > 5
• Most did not know before screening. Small
number (< 5) may have known of OSA
presence/possibility
• 10 subjects have AHI < 5
Acknowledgements
•
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William Herbert, PhD
Stephen Guill, PhD
Adrian Aron, PhD
Shelly Nickols-Richardson, PhD,
RD
Donald Zedalis, MD
William Cale, MD
Katrina Butner, PhD, RD
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•
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Laura Newsome, PhD
Tom Rice, MS
Amanda Mallory, MS
Steve Vesbach, MS
Erin Ledden, MS
Cassandra Ledman, MS
Brooke Shafer, BS
Thank You!