Obstructive Sleep Apnea and
Cardiovascular Disease: A Tale
of Two Unhappy Bedfellows
Najib Ayas MD MPH
Associate Professor of Medicine
Sleep Disorders Program
Critical Care and Respiratory Divisions
University of British Columbia
Multiple Lines of Evidence Suggest that OSA
causes Cardio Vascular Disease (CVD)
1.
Biologic Plausibility: Basic science/animal
studies demonstrating a potential
pathophysiologic link between OSA and CVD.
2.
Associations: OSA is strongly and independently
associated with CV Risk Factors and CVD in
epidemiologic studies across many populations.
3.
Experimental: Treatment of OSA leading to
improved outcomes.
Pathophysiology of Cardiovascular
Disease Caused by OSA
Recurrent upper airway obstruction
Arousal From
Sleep/Sleep
Fragmentation
Changes in
Pleural Pressure/
Hemodynamic stress
Activation of the Sympathetic Nervous System
Oxidative Stress
Activation of Systematic Inflammation
Hypercoagulability
Platelet Activation
Hormonal changes
Endothelial dysfunction
Hypertension
Acute strokes
Heart failure
Aortic Dissection
Coronary events
Glucose intolerance
Obesity
Hypoxemia/
Reoxygenation
Animal studies

Some have focused on simulating upper airway
closure
– Dogs with tracheostomies
– English bulldog
– Recent cat model different head positions

Most are focused on the effect of intermittent
hypoxia (IH) in rats/mice
– Easier to do
– Don’t reproduce all the aspects of human OSA
– Degree of hypoxia greater than that commonly seen in
patients with OSA
– IH associated with oxidative stress, hypertension
Intermittent Hypoxia and Atherosclerosis
40 mice exposed to 12 weeks of:

CIH (12 hrs/day, 5% FiO2) plus high cholesterol
diet

CIH plus normal diet

IA plus high cholesterol diet

IA plus normal diet
Savransy et al. AJRCCM 2007.
Aortic plaques found 9/10 mice in CIH
plus high cholesterol group


Associated with increased lipids,
increased markers of inflammation in
the liver
No plaques in other groups
Human Studies:
Presence of OSA Associated with a Variety of CV
Risk Markers:

Catecholamine levels

CRP

Endothelial dysfunction

Leptin, adhesion Molecules (serum ICAM-1,
sVCAM-1), Carotid intima media thickening

Markers of oxidative stress
2. Association studies:
Spanish study:

264 healthy men

377 snorers without sleep apnea

403 untreated mild/moderate disease

235 untreated severe disease

372 treated patients

patients followed for 10 years for incident CVD
(stroke,MI, PTCA, CABG)
Marin et al, Lancet 2005
Fatal Cardiovascular Events
Non-Fatal Cardiovascular Events

Untreated severe OSA compared to healthy
subjects:
– increased odds ratio of fatal CVD by 2.87 (1.17-7.51)
– nonfatal CVD by 3.17 (1.12-7.51)

Odds ratios were not increased in treated patients

Similar findings in older patients and women
(unpublished)
Epidemiologic Studies Linking OSA to Vascular
Outcomes

Aortic Dissection/Dilation: Kohler, Thorax 2009;
Sampol AJRCCM 2003

Stroke : Arzt, AJRCCM, 2005; Yaggi, NEJM 2005

Myocardial Infarction: Peker, Eur Respir J, 2006

Sudden Cardiac Death: Gami, NEJM 2005

Atrial Fibrillation: Gami, Circulation 2004

Hypertension: Peppard, NEJM 2000
Major problem with non-randomized
observational studies:

Confounding
– Confounding by indication/compliance
– Other factors associated with sleep apnea and
CVD
Confounding?
Cardiovascular
Outcomes
Central Obesity
-Hypertension
-Diabetes
-Lipids
Confounding by Indication/Compliance
Sleep Heart Health Study

Between 1995-1998, 6000 subjects enrolled in a variety of
epidemiologic cardiovascular cohorts had PSG

Followed for 9 years for incident CH disease (MI,
revascularization, death from CHD)
– Signal only in men <70 years (HR=1.10 for every 10 increase in
AHI; for AHI>30, 68% increased risk)
– Not in women, age>70
– Gottlieb et al. Circulation 2010

For stroke,
– AHI>19 (4th quartile) had a HR of 2.86 for stroke in men
– In women, association not as robust
– Redline et al. AJRCCM 2010.

?Difference in community (survival) based vs. clinic cohort
3. Experimental Studies (RCT) in OSA:
1.
short-term studies of surrogate endpoints
2.
Measurements of atherosclerosis in carotid
3.
long-term studies with clinically relevant
endpoints
•
Stroke, heart attacks
Surrogate Endpoints: BP
Blood Pressure:
 Reasonable surrogate as it is highly correlated with
future CV risks
 Effect consistent across most (but not all) drug
classes
CPAP (compared to the control group)

reduces BP but effect is overall effect fairly modest (2
mm Hg) though effect greater in patients with more
severe disease

Majority of studies were less than one month
AlAjmi et al, Lung 2007.; Haentjens, Arch Int Med, 2007
Two Recent Spanish RCT are consistent
with these results

Non-sleepy patients (ESS<11) with AHI>19/hr
– 359 hypertensive patients randomized to CPAP vs. control for 12
months
– Decreased systolic BP by 1.89 mm Hg, diastolic by 2.19 mm Hg
(signal greatest if used CPAP>5.6 hrs/night)
– Barbe et al. AJRCCM 2010.

Patients with systemic hypertension and AHI>15/hr
– Randomized 340 patients to CPAP vs. sham CPAP for 3 months
– 24 hr systolic BP decreased by 2.1 mm Hg, diastolic by 1.3 mm Hg
– Mean nocturnal BP decreased by 2.1 mm Hg
– Duran –Cantolla et al. BMJ 2010.
Other Surrogate Endpoints Positively
Impacted by CPAP:

Markers of inflammation (CRP), Metabolic derangements
(glucose/insulin, lipids), oxidative stress markers,
endothelial dysfunction

Most of these outcomes have less robust independent
associations with target outcomes than BP

Most of these studied small numbers of subjects, were one
month or less

Many were non-randomized studies (before and after)

Effects are inconsistent
Direct Measurements of Atherosclerosis
24 patients with severe OSA

Randomized to 4 months of CPAP vs. no CPAP

After 4 months of CPAP:
– Improved CRP, catecholamines
– Reduction of CIMT with CPAP
Drager et al. AJRCCM 2007.
Long-term studies with clinically relevant
outcomes:
Many are ongoing:

SAVE
– 5000 person RCT (McEvoy, Australia)

MOSAIC
– Cardiac risk factors in non-sleepy patients with OSA
(Stradling, UK)

ADVENT
– Sleep disordered breathing in patients with CHF
(Bradley, Toronto)
Other Unanswered Questions:

Impact of Non-CPAP treatments for OSA in
preventing CVD:
– Dental appliances
– Anti-oxidants
– Statins
– Weight loss
Take-Home Message

Accumulating data implicate OSA as a cause of
CVD

Larger RCT needed and in progress

Consider treatment in:
– Sleepy patients regardless of disease severity
– In non-sleepy patients, consider treatment if:
 Moderate to severe sleep apnea (especially in the setting of
hypoxemia)
 Underlying CVD/risk factors

Treat underlying risk factors