Obstructive Sleep Apnea and Cardiovascular Disease: A Tale of Two Unhappy Bedfellows

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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

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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.

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Pathophysiology of Cardiovascular Disease Caused
by OSA
Recurrent upper airway obstruction
Arousal From Sleep/Sleep Fragmentation
Changes in Pleural Pressure/ Hemodynamic stress
Hypoxemia/ Reoxygenation
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
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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
• Dont 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

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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.
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• 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

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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

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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
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Fatal Cardiovascular Events
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Non-Fatal Cardiovascular Events
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• 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)

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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

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• Major problem with non-randomized observational
  studies
• Confounding
• Confounding by indication/compliance
• Other factors associated with sleep apnea and CVD
  

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Confounding?
Cardiovascular Outcomes
?
Central Obesity
-Hypertension -Diabetes -Lipids
Confounding by Indication/Compliance
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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 lt70 years (HR1.10 for every
  10 increase in AHI for AHIgt30, 68 increased
  risk)
• Not in women, agegt70
• Gottlieb et al. Circulation 2010
• For stroke,
• AHIgt19 (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

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3. Experimental Studies (RCT) in OSA

• short-term studies of surrogate endpoints
• Measurements of atherosclerosis in carotid
• long-term studies with clinically relevant
  endpoints
• Stroke, heart attacks

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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
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Two Recent Spanish RCT are consistent with these
results

• Non-sleepy patients (ESSlt11) with AHIgt19/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 CPAPgt5.6
  hrs/night)
• Barbe et al. AJRCCM 2010.
• Patients with systemic hypertension and AHIgt15/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.

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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

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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.
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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)

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Other Unanswered Questions

• Impact of Non-CPAP treatments for OSA in
  preventing CVD
• Dental appliances
• Anti-oxidants
• Statins
• Weight loss

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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