Transcript Document

Cardiovascular Consequences
of
Obstructive Sleep Apnea
Ronald J. Green, MD, FCCP, FAASM
Diplomate, American Board of Sleep Medicine
Sleep Medicine, Pulmonary Disease & Smoking
Cessation, The Everett Clinic
Associate Medical Director
North Puget Sound Center for Sleep Disorders
Everett, WA
425-339-5410; www.ilikesleep.com
Cardiovascular disease is
• Common
• Dangerous
• Easily recognized
• Treatable
Obstructive Sleep Apnea Syndrome
(OSAS) is
• Common
• Dangerous
• Easily recognized
• Treatable
I hope to demonstrate to you today that
OSAS is associated with the
development of
cardiovascular disease
OUTLINE
• Overview of obstructive sleep apnea syndrome (OSAS)
• OSAS & the cardiovascular system: pathophysiology
• OSAS and
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–
–
–
–
Hypertension
Myocardial ischemia and infarction
Congestive heart failure
Stroke
Cardiac dysrhythmias, particularly Atrial fibrillation
• Effects of OSAS treatment on cardiovascular disease
• Conclusions
Overview of
The obstructive sleep
apnea syndrome
What is the “apnea” in sleep apnea?
• Apnea
– Cessation of airflow > 10 seconds
• Hypopnea
– Decreased airflow > 10 seconds
associated with:
• Arousal from sleep
• Oxyhemoglobin desaturation
Measures of Sleep Apnea Frequency
• Apnea Index
– # apneas per hour of sleep
• Apnea / Hypopnea Index (AHI)
– # apneas + hypopneas per hour of sleep
– > 5 considered abnormal in adults
Pathophysiology of an
obstructive apnea
Pathophysiology of
Obstructive Sleep Apnea
Awake: Small airway + neuromuscular compensation
Loss of
neuromuscular
compensation
Sleep Onset
+
Decreased
pharyngeal muscle
activity
Airway opens
Airway collapses
Pharyngeal
muscle activity
restored
Apnea
Hypoxia &
Hypercapnia
Hyperventilate:
connect hypoxia
& hypercapnia
Increased
ventilatory
effort
Arousal from
sleep
Clinical Consequences
Obstructive Sleep Apnea
Sleep fragmentation,
Hypoxia / Hypercapnia
excessive
daytime
sleepiness
cardiovascular
& metabolic
complications
Morbidity
Mortality
Obstructive Sleep Apnea:
Most common risk factors
• Obesity
• Increasing age
• Male gender
• Anatomic abnormalities of upper airway
• Family history of OSAS
• Alcohol or sedative use
Diagnosis: History
• Loud snoring (not all snore)
• Nocturnal gasping and choking
– Ask bed partner (witnessed apneas)
• Automobile or work related accidents
• Personality changes or cognitive problems
• Risk factors
• Excessive daytime sleepiness (often not recognized by
patient)
• Frequent nocturia
Sleep Apnea: Is Your Patient at Risk? NIH Publication, No 95-3803.
Diagnosis: Physical Examination
• Upper body obesity / thick neck
> 17” males
> 16” females
• Hypertension
• Obvious airway abnormality
Exam: Oropharynx
Physical Examination
Guilleminault C et al. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978.
Why Get a Sleep Study?
• Signs and symptoms poorly predict
disease severity
• Appropriate therapy dependent on severity
• Failure to treat leads to:
– Increased morbidity
– Motor vehicle crashes
– Mortality
• Help diagnose other causes of daytime sleepiness
Polysomnography
Treatment of
Obstructive Sleep Apnea
Syndrome
Treatment Objectives
• Reduce mortality and morbidity
– Decrease cardiovascular complications
– Reduce sleepiness
– Improve metabolic derangements, including
type 2 diabetes mellitus
• Improve quality of life
Therapeutic Approach
• Risk counseling
– Motor vehicle crashes
– Job-related hazards
– Judgment impairment
• Apnea treatment
– Weight loss; avoidance of alcohol & sedatives
– CPAP
– Oral appliance
– Surgery (UPPP)
Positive Airway Pressure
Positive Airway Pressure
Oral Appliance: Mechanics
Uvulopalatopharyngoplasty (UPPP)
Primary Care Management
• Risk counseling
• Behavior modification (weight loss, etc)
• Monitor symptoms and compliance
– Monitor weight and blood pressure
– Ask about recurrence of symptoms
– Evaluate CPAP use and side effects
Sleep Apnea: Is Your Patient at Risk? NIH Publication No.95-3803.
Cardiovascular Consequences
of
Obstructive Sleep Apnea
Effects of normal sleep on
the cardiovascular system (vs wake)
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•
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Decreased metabolic rate
Decreased sympathetic nervous activity
Decreased blood pressure
Decreased heart rate
Increased cardiac vagal tone
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Effects of obstructive sleep apnea on
the cardiovascular system (vs wake)
• Interruption of cardiovascular
quiescence:
– Increased sympathetic nervous activity
– Increased blood pressure
– Increased heart rate
– Decreased parasympathetic nervous activity
Bradley & Floras, The Lancet, 2009. 373: 82-93.
OSA triggers a cascade of events
effecting the cardiovascular system
Bradley & Floras, The Lancet, 2009. 373: 82-93.
OSA Impact on Cardiovascular System
• Hypoxia
– Increases metabolic demands on heart
– Impairs cardiac contractility
– Increases pulmonary artery pressures
NOCTURNAL
ISCHEMIA
Leung AJRCCM 2001
Naughton Circulation 1995
OSA Impact on Cardiovascular System
• Arousals from sleep
– Surges in heart rate and blood pressure
– Increases in sympathetic nervous activity
REPETITIVE
STRAIN
Leung AJRCCM 2001
Naughton Circulation 1995
Effects of OSAS on sympathetic nerve
activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, 1995. 96: 1897-1904.
Effects of OSAS on sympathetic nerve
activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, 1995. 96: 1897-1904.
Effects of OSAS on sympathetic nerve
activity and BP in OSA pt without HTN
Somers, et al, J Clin Invest, 1995. 96: 1897-1904.
Repetitive apnea-induced
hypoxia and CO2 retention cause
• Ineffective inspiratory effort increased
negative intra-thoracic pressure  increased LV
transmural pressure (increased afterload) which
causes LV hypertrophy
• Increased negative intra-thoracic pressure
increased RV preload (pulls blood into RV)
• Hypoxia causes pulmonary vasoconstriction
leading to pulmonary HTN
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Repetitive apnea-induced
hypoxia and CO2 retention cause
• Pulmonary vasoconstrictionincreased RV afterload
 RV distention impaired LV diastolic filling 
decreased LV stroke volume
• Apnea cycles cause oscillations in sympatheticallymediated peripheral vasoconstriction which raises
systemic BP
• Arousal from sleep which terminates the apnea results
in increased sympathetic tone and decreased vagal
tone  surge in heart rate and blood pressure
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Repetitive apnea-induced
hypoxia and CO2 retention
• Effects on blood pressure and heart rate
can be sustained into wakefulness resulting
in systemic HTN
• These changes are rapidly relieved with
treatment of OSAS by CPAP
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Vascular effects of OSAS
• Intermittent hypoxia  O2 free radicals 
activation of inflammatory pathways  impaired
vascular endothelial function & increased BP
independent of sympathetic activation.
• Hypercoagulability from increased expression of
adhesion molecules & vascular smooth muscle
proliferation
• This could predispose to HTN & atherosclerosis
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Vascular effects of OSAS
• Increased risk of thrombosis in OSAS
• increased platelet activation & aggregability
• Elevated morning fibrinogen levels
• Decreased plasminogen activator inhibitor
type-1 activity
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Given the pathophysiology just
discussed, if you think there is
an increased incidence of OSAS
in pts with cardiovascular
disease, you are right!
Higher prevalence of OSAS in
patients with cardiovascular disease
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Prevalence of OSAS in general population: 7-10%
Hypertension: 30-83%
Congestive heart failure: 12-53%
Ischemic heart disease: 30-58%
Stroke: 43-91%
Note that confounding variables including obesity need to be
taken into account so correlation does not prove causality
• You need to have HIGH index of suspicion for
OSAS in these patient populations
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Young, et al, N Engl J Med, 1993. 328: 1230-35.
OSAS and hypertension
– OSA is one known cause of HTN
• Patients with OSA more likely to develop HTN
• OSA listed by Joint National Committee on the Detection
& Management of HTN as important identifiable cause of
HTN
– Possible mechanisms:
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•
•
•
Intermittent hypoxemia
Chemoreceptor stimulation
Sympathetic activation
Renin-angiotensin system
Chobanian JAMA 2003; Lesske J Hypertens 1997
Fletcher Hypertension 1992; Brooks J Clin Invest 1997
Adjusted Odds
Ratio of
developing HTN
Dose response effect of OSA severity and risk
of HTN (adjusted for confounders)
0
Peppard NEJM 2000
0.1-4.9
5.0-14.9
Baseline AHI
>15.0
Experimental evidence:
OSAS can raise blood pressure
• Dogs exposed to OSA developed HTN during
sleep and wake which resolved on reversal of
the OSA
• Rats exposed to intermittent hypoxia (mimicking
OSA) developed HTN. This was prevented by
sympathectomy or peripheral chemoreceptor
denervation.
Bradley & Floras, The Lancet, 2009. 373: 82-93.
OSAS and
medication-resistant hypertension
• OSAS is VERY common in medicationresistant HTN
• 3 observational studies:
– >70% of patients with difficult-to-treat or resistant
HTN have sleep disordered breathing (versus its
presence in <40% of patients with controlled HTN)
Logan Eur Respir J 2003
Goncalves Chest 2007
Logan J Hypertens 2001
OSAS and
medication-resistant hypertension
• HTN in OSAS often associated with
biochemical features of primary
aldosteronism which in turn can lead to
oxidative stressinflammation LV
fibrosis and hypertrophy
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Logan, J Hypertension, 2001. 19: 2271-77.
Marney & Brown, Clin Sci (Lond), 2007. 113:267-78.
OSAS and
medication-resistant hypertension
• If your patient is on 3 or
more anti-hypertensive
medications, think OSAS
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Logan, J Hypertension, 2001. 19: 2271-77.
Marney & Brown, Clin Sci (Lond), 2007. 113:267-78.
Risk of myocardial ischemia and
infarction in OSAS
• Marin, et al: prospective study showed more fatal and
non-fatal MI in severe, untreated OSAS vs control. No
difference in rates in OSAS treated w/ CPAP vs control.
• In CAD patients, OSAS associated with higher
mortality, more major cardiac events and higher
restenosis rate after PTCA vs controls without OSAS.
• Case-control study: graded increase in odds of acute MI
with increased sleep apnea severity.
• People with OSA more likely than those without to have
family hx of premature death from CAD
Somers, et al, Circ, 2008. 118: 1080-1111.
Marin, et al, The Lancet, 2005. 365: 1046-53.
Yumino, et al, Am J Cardiol, 2007. 99: 26-30.
OSAS and CHF
CHF patients with sleep apnea
have worse prognosis than
CHF patients without sleep
apnea
Ancoli-Israel Chest 2003
OSAS and CHF prognosis
Cumulative Survival
NONE
SDB
CHF
CHF + SDB
2
4
Ancoli-Israel Chest 2003
6
8
Years of Survival
10
12
OSAS and CHF mortality
• 164 patients with LVEF < 45%
• OSA = AHI > 15
• At 3 year follow-up:
– Patients with OSA had higher cardiac mortality than
patients without OSA
– 8.7 vs 4.2 deaths/100 patient-years
Wang JACC 2007
OSAS and CHF mortality
Hazard ratio = 2.81
M-NSA: mild
to no sleep
apnea
Wang JACC 2007
* Adjusted for LVEF, NYHA class, age
Cerebrovascular effects of OSAS
• Decrease in cerebral blood flow due to
decreased cardiac output
• If flow-limiting carotid atherosclerosis present,
could predispose to ischemic events
• OSAS patients vs controls: greater carotid
intima-media thickness, decreased arterial
compliance and higher incidence of silent brain
infarcts
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Stroke and OSAS
• Mod-severe OSA (AHI > 20) vs no OSA: 4.33
greater odds of stroke
• Sleep Heart Health Study, in OSAS: 1.58 times
higher stroke risk in highest vs lowest AHI
quartiles
• Study of pts > age 70, severe OSA (AHI > 30) vs
OSA with AHI < 30, 2.52-times increased risk of
stroke at 5 year follow up.
Bradley & Floras, The Lancet, 2009. 373: 82-93.
Artz, et al, Am J Respir Crit Care Med, 2005. 172: 1447-51.
Shahar, et al. Am J Respir Crit Care Med, 2001. 163: 19-25.
Munoz, et al. Stroke, 2006. 37: 2317-21.
Stroke and OSAS
• Several studies suggest post-stroke pts with
OSAS (vs those without OSAS) have decreased
motivation and cognitive capacity;
• Post-stroke pts with OSAS may have increased
risk of recurrent stroke and death.
• In rehab unit, post-stroke pts with OSAS had
worse functional impairment and spent longer
time in hospital and rehab.
Somers, et al, Circ, 2008. 118: 1080-1111.
Hsu, et al, J Neurol Neurosurg Pshychiatry, 2006. 77: 1143-1149.
Palombini, et al, Eur J Neurol, 2006. 13: 198-200.
Kaneko, et al, Sleep, 2003. 26: 293-297.
Cardiac dysrhythmias and OSAS
• More frequent in people with OSAS
• Increase with number of apneic episodes
• Increase with severity of oxygen
desaturations
• Occur in up to 50% of OSAS patients
• Most common: NSVT, sinus arrest,
frequent PVCs
Somers, et al, Circ, 2008. 118: 1080-1111.
Atrial fibrillation and OSAS
• Increased likelihood of Afib vs controls (odd ratio
4.02)
• Potential mechanisms:
• Hypoxemia, sympathetic activation, pressor
surges, transmural pressure changes,
systemic inflammation in OSAS Afib
• OSAS is associated with left atrial enlargement
Somers, et al, Circ, 2008. 118: 1080-1111.
Mehra, et al, Am J Respir Crit Care Med, 2006. 173: 910-916
Otto, et al, Am J Cariol, 2007. 99: 1298-1302.
Romero-Corral, et al, Chest., 2007. 132: 1863-1870.
Atrial fibrillation and OSAS
• In OSAS, persistent atrial tachyarrhythmias more
likely to occur at night.
• 50% of OSAS pts with Afib are likely to have Afib
recurrence after cardioversion vs 30% likelihood
in general cardiology clinic population without
OSAS.
Somers, et al, Circ, 2008. 118: 1080-1111.
Mitchell, et al, Am Heart J, 2003. 146: 902-907.
Gami, et al, Circulation, 2004. 110: 364-367.
OSAS treatment with CPAP
decreases
cardiovascular consequences
Physiologic effects of CPAP
• Immediate reversal of nocturnal hypoxemia and
hypercapnia
• Resolution of nocturnal apnea-induced arousals
• Rapid reversal of intrathoracic pressure abnormalities
and cardiac distention
• Decreased inflammatory marker levels (TNF alpha,
interleukin 8, C-reactive protein, interleukin 6)
• Drop in morning fibrinogen levels
Bradley & Floras, The Lancet, 2009. 373: 82-93.
CPAP therapy: Effects on HTN
• Acute and significant decrease in BP and
sympathetic activity.
• 3 studies showed drop in BP with
therapeutic vs sham (control) CPAP use.
• In patients intolerant of CPAP, oral
appliance therapy may also lower BP.
Somers, et al, J Clin Invest, 1995. 96: 1897-1904.
Pepperell, et al, Lancet, 2002. 359: 204-210.
Dimsdale, et al, Hypertension, 2000. 35: 144-147.
Becker, et al, Circulation, 2003. 107: 68-73.
CPAP therapy: Effects on HTN
• Most robust BP response to CPAP most
likely in patients with:
• More severe OSA
• Difficult-to-control HTN
• Better CPAP compliance
Somers, et al, J Clin Invest, 1995. 96: 1897-1904.
Pepperell, et al, Lancet, 2002. 359: 204-210.
Dimsdale, et al, Hypertension, 2000. 35: 144-147.
Becker, et al, Circulation, 2003. 107: 68-73.
CPAP therapy: Effects on HTN
• Chronic effects on blood pressure
are less clear due to lack of
longitudinal, controlled studies.
Somers, et al, Circ, 2008. 118: 1080-1111.
CPAP therapy:
Effects on myocardial ischemia and infarction
• Treated OSAS pts had fewer cardiac
events than untreated OSAS pts.
• Treated OSAS pts had decreased cardiac
mortality than untreated OSAS pts.
• Nocturnal angina and ST depressions are
improved with CPAP therapy.
Somers, et al, Circ, 2008. 118: 1080-1111.
Milleron, et al, Eur Heart J, 2004. 25: 728-34.
Doherty, et al, Chest, 2005. 127: 2317-22.
CPAP therapy: Effects on CHF
• CPAP can eliminate recurring nocturnal
hypoxia and reduce nocturnal BP & heart
rate.
• After one month on CPAP, LVEF increased
from 37% to 49% and returned to baseline
one week after CPAP stopped.
Tkacova, et al, Circulation, 1998. 98: 2269-2275.
Malone, et al, Lancet, 1991. 338: 1480-1484.
Somers, et al, Circ, 2008. 118: 1080-1111.
CPAP therapy: Effects on CHF
• CPAP vs no CPAP: after one month in pts on optimum
CHF med therapy, LVEF increased from 25% to 34%
AND morning SBP dropped from 126 to 116 mm Hg.
• CPAP induced a lowering of sympathetic
vasoconstrictor nerve discharge in CHF.
• CPAP treated pts had increase of LVEF from 38 to 43%
and decrease in nocturnal urinary norepinephrine.
Kaneko, et al , N Engl J Med, 2003. 348:1233-41.
Usui, et al, J Am Coll Cardiol , 2005. 45: 2008-11.
Mansfield, et al. Am J Respir Crit Care Med, 2004. 169: 361-66.
Bradley & Floras, The Lancet, 2009. 373: 82-93.
CPAP therapy: Effects on stroke
• CPAP compliance and tolerance
are poor in stroke pts and
beneficial effects have not been
confirmed.
• These pts should still be treated.
Somers, et al, Circ, 2008. 118: 1080-1111.
CPAP therapy:
Effects on cardiac dysrhythmias
• 82% risk of Afib recurrence after cardioversion in
untreated OSAS pts (which is double the risk of
pts treated for OSAS).
• Randomized, controlled trial: 58% reduction in
frequency of PVCs after one month on CPAP in
pts with OSAS and systolic dysfunction and
reduction in urinary norepinephrine
concentrations.
Somers, et al, Circ, 2008. 118: 1080-1111.
Kanagala, et al, Circulation, 2003. 107: 2589-2594.
Ryan, et al, Thorax, 2005. 60: 781-785.
Unanswered questions
• Does OSAS contribute or independently lead to the development
of CAD, CHF, Afib and stroke?
• Is HTN an intermediate step between OSAS and development of
cardiovascular disease?
• Does treatment of OSAS actually decrease risk of developing
HTN and cardiovascular disease?
• In established cardiovascular disease, does treatment of OSAS
decrease CV morbidity and mortality?
• Is there a long term mortality benefit of treating CHF patients with
CPAP?
Somers, et al, Circ, 2008. 118: 1080-1111.
Bradley & Floras, The Lancet, 2009. 373: 82-93.
IN CONCLUSION
Cardiovascular disease and OSAS are
•
•
•
•
Dangerous
Common
Easily recognized
Treatable
• Inter-related
Think about diagnosing and treating
OSAS in your patients with
• Hypertension, especially those
on 3 or more anti-hypertensives
• Coronary artery disease
• CHF
• Atrial fibrillation
• Stroke/TIA
The ultimate goal: