Cardiovascular Consequences of Obstructive Sleep Apnea.

Cardiovascular Consequencesof

Obstructive Sleep Apnea

Ronald J. Green, MD, FCCP, FAASM

Diplomate, American Board of Sleep MedicineSleep Medicine, Pulmonary Disease & Smoking

Cessation, The Everett Clinic

Associate Medical DirectorNorth Puget Sound Center for Sleep Disorders

Everett, WA425-339-5410; 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 ofcardiovascular disease

OUTLINE• Overview of obstructive sleep apnea syndrome (OSAS)• OSAS & the cardiovascular system: pathophysiology• OSAS and

– 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 compensationAwake: Small airway + neuromuscular compensationLoss of Loss of

neuromuscular neuromuscular compensationcompensation

SleepSleep OnsetOnset Hyperventilate: Hyperventilate: connect hypoxia connect hypoxia & hypercapnia& hypercapniaDecreased Decreased

pharyngeal muscle pharyngeal muscle activityactivity Airway opensAirway opens

Airway collapsesAirway collapsesPharyngeal Pharyngeal

muscle activity muscle activity restoredrestoredApneaApnea

Arousal from Arousal from sleepsleep

Hypoxia & Hypoxia & HypercapniaHypercapnia

Increased Increased ventilatory ventilatory

efforteffort

++

Clinical Consequences

Obstructive Sleep ApneaObstructive Sleep Apnea

excessive excessive daytime daytime

sleepinesssleepiness

Sleep fragmentation, Sleep fragmentation, Hypoxia / HypercapniaHypoxia / Hypercapnia

cardiovascular cardiovascular & metabolic & metabolic complicationscomplications

MorbidityMorbidityMortalityMortality

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.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.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 effectsSleep Apnea: Is Your Patient at Risk? NIH Publication No.95-3803.Sleep Apnea: Is Your Patient at Risk? NIH Publication No.95-3803.

Cardiovascular Consequencesof

Obstructive Sleep Apnea

Effects of normal sleep on the cardiovascular system (vs wake)

• 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


OSA triggers a cascade of events effecting the cardiovascular system


OSA Impact on Cardiovascular System

• Hypoxia– Increases metabolic demands on heart– Impairs cardiac contractility– Increases pulmonary artery pressures

Leung AJRCCM 2001Naughton Circulation 1995

NOCTURNAL ISCHEMIA

OSA Impact on Cardiovascular System

• Arousals from sleep– Surges in heart rate and blood pressure– Increases in sympathetic nervous activity

Leung AJRCCM 2001Naughton Circulation 1995

REPETITIVE STRAIN

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


Repetitive apnea-induced hypoxia and CO2 retention cause

• Pulmonary vasoconstrictionincreased RV afterload RV distention impaired LV diastolic filling decreased LV stroke volume

• Apnea cycles cause oscillations in sympathetically-mediated 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


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


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 & atherosclerosisBradley & 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


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

• 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:• Intermittent hypoxemia• Chemoreceptor stimulation• Sympathetic activation• Renin-angiotensin system

Chobanian JAMA 2003; Lesske J Hypertens 1997Fletcher Hypertension 1992; Brooks J Clin Invest 1997

Dose response effect of OSA severity and risk of HTN (adjusted for confounders)

Peppard NEJM 2000

0 0.1-4.9 5.0-14.9 >15.0 Baseline AHI

Adj

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Rat

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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.


OSAS and medication-resistant hypertension

• OSAS is VERY common in medication-resistant 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 2003Goncalves Chest 2007Logan J Hypertens 2001


• HTN in OSAS often associated with biochemical features of primary aldosteronism which in turn can lead to oxidative stressinflammation 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.


• 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

NONESDBCHFCHF + SDB

Years of Survival

Cum

ulat

ive

Surv

ival

2 4 6 8 10 12

Ancoli-Israel Chest 2003

OSAS and CHF prognosis

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

Wang JACC 2007

M-NSA: mild to no sleep apnea

Hazard ratio = 2.81

* 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


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

PVCsSomers, 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: 910-916Otto, 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


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.


• 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.


• 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 treatingOSAS in your patients with

• Hypertension, especially those on 3 or more anti-hypertensives

• Coronary artery disease• CHF• Atrial fibrillation• Stroke/TIA

The ultimate goal:

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Cardiovascular Consequences of Obstructive Sleep Apnea.

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