The Impact of OSA on Exercise: A Window Into

Chronic Disease RiskTrent A. Hargens, PhD

Department of KinesiologyJames 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

OSA

Disease Mechanisms

Associated CV Disease

HypoxemiaReoxygenationHypercapnia

Intrathoracic PressureArousals

Sleep Deprivation

Sympathetic activationMetabolic dysregulationLeft atrial enlargement

Endothelial dysfunctionSystemic inflammation

Hypercoagulability

HypertensionHeart FailureArrhythmias

Renal diseaseStroke

Myocardial infarction

Sudden cardiac death

Systemic

Pulmonary

Somers et al., Circulation 2008;118:1080-1111.

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

Mansfield et al., Am J Respir Crit Care Med 2004;169:361-366

Significantly improved LV function in CHF patients with OSA following CPAP treatment

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

ADJUSTED FOR BMI, NECK, WHR, ALCOHOL USE, SMOKING

P for trend = 0.005

Nieto et al., Jama 2000;283:1829-1836.

OSA and HypertensionP 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

Diagnostic Group

Adjusted OR (95% CI)

P

Snoring 1.03 (0.31-1.84) 0.88

Untreated mild OSA

1.15 (0.34-2.69) 0.71

Untreated severe OSA

2.87 (1.17-7.51)0.025

*

CPAP 1.05 (0.39-2.21) 0.74

Odds ratio for cardiovascular death

Marin et al., Lancet 2005;365:1046-1053.

OSA and Cardiovascular Disease

Diagnostic Group

Adjusted OR (95% CI)

P

Snoring 1.32 (0.64-3.01) 0.38*

Untreated mild OSA

1.57 (0.62-3.16) 0.22*

Untreated severe OSA

3.17 (1.12-7.52)0.001

*

CPAP 1.42 (0.52-3.40) 0.29*

Odds ratio for non-fatal cardiovascular events

Marin et al., Lancet 2005;365:1046-1053.

OSA and Cardiovascular DiseaseKaplan-Meier curvesA. FatalB. Non-Fatal

Authors conclude that OSA independently increases risk for CV events

Marin et al., Lancet 2005;365:1046-1053.

OSA and Cardiovascular DiseaseWisconsin 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

OSA HTNSympathetic Activation

Hyperleptinemia

Baroreflex Sensitivity

Chemoreflex Activation

Insulin Resistance

RAAS Activity

Oxidative StressEndothelial Dysfunction

Systemic Inflammation

Adapted from Wolk et al., Clinics in chest medicine 2003;24:195-205.

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. lean2. Greater in Obese + OSA vs Lean + OSA3. Greater in OSA vs. without OSA (regardless of wt)

Therefore:1. Sympathetic activation seen in obesity is independent of OSA2. 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)

Circulation. 2010;122:191-225

“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.”

• “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 (VO2peak)

• 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 (VE)

• Amount of air moved in and out of the lungs (Liters/min)

• Ventilatory Equivalent for oxygen consumption (VE/VO2)

• Volume of air you must move to consume 1 Liter of O2.

• Marker of ventilatory efficiency

Gas Exchange Variables of Interest

• Ventilatory Equivalent for CO2 (VE/VCO2)

• Volume of air that you must move to blow off 1 Liter of CO2.

• Marker of ventilatory efficiency for CO2 clearance

• VE/VCO2 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

Lin et al., 2006

Grote et al., 2004

Tremel et al., 1999

Schonhofer et al., 1997

Vanuxem et al., 1997

No Change in VO2peak

Kline et al., 2012

Maeder et al., 2008

Hargens et al., 2008

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 < 13.0P2 13-16.5P3 16.6-21.6P4 > 21.6

VE/VCO2 SlopeV1 < 27.7V2 27.7-34.5V3 34.6-42.1V4 > 42.1 Francis et al., Eur Heart J 2000

Peak VO2 vs. VE/VCO2 Slope in CHF

Arena et al., Circulation. 2007;115:2410-2417

slope > 30 now considered “abnormal”

Pathophysiological mechanisms of an elevated VE/VCO2 slope

CentralDecreased right sided cardiac output

Increased pressure in pulmonary vasculaturesecondary to increased left sided pressure

Compromised pulmonary vessel dilationsecondary to decreased NO production

HighVE/VCO2 slope

Central

Abnormal chemoreceptorreflex

Peripheral

Abnormal chemoreceptor

and ergoreceptor reflex

Increased ventilation-perfusion mismatching

HeightenedVE

response toexercise

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;103:1063-9.

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

“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.”

Balady et al

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.”

N Engl J Med 1999;341:1351-1357.

Subjects were without a history of heart failure or coronary revascularization and without pacemakers.

6 year follow-up in 2428 subjects

Balady

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;31:104-110.

“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

• HRV assessed throughout exercise and recovery

* *

At peak exercise

Findings suggest that heightened sympathetic activation (LF) and reduced parasympathetic activation (HF) may 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

• Total Cholesterol

• Triglycerides

• Peak HR

• VO2peak

• HRdiff (minutes 1 - 5 of recovery)

EpworthBP were not

Hargens et al., 2013• Logistic Regression revealed that HRdiff5 was

the ONLY significant independent predictor of OSA

• Beta = -0.215, P = 0.009

• R2 for model = 0.57, P < 0.001

• HRdiff3: P = 0.053

• Univariate ROC analysis

• AUC for HRdiff5 = 0.73, P = 0.002

• AUC for BMI = 0.77, P < 0.001

Hargens et al., 2013

HRdiff5 BMI

Hargens et al., 2013

EpworthAUC = 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• William Herbert, PhD

• Stephen Guill, PhD

• Adrian Aron, PhD

• Shelly Nickols-Richardson, PhD, RD

• Donald Zedalis, MD

• William Cale, MD

• Katrina Butner, PhD, RD

• Laura Newsome, PhD

• Tom Rice, MS

• Amanda Mallory, MS

• Steve Vesbach, MS

• Erin Ledden, MS

• Cassandra Ledman, MS

• Brooke Shafer, BS

Thank You!