Sleep-Disordered Breathing and Stroke

Klar Yaggi, M.D., M.P.H.Assistant Professor

Yale University School of MedicineClinical Epidemiology Research Center (CERC)

Medical Director, VA CT Center for Sleep Medicine

Journal of the Canadian Medical Association; 2006

No relevant conflicts of interest

Outline

• Epidemiologic evidence linking sleep-disordered breathing to cerebrovascular outcomes

• Mechanisms of stroke in sleep-disordered breathing

• Impact of CPAP treatment on cerebrovascular risk

Outline

• Epidemiologic evidence linking sleep-disordered breathing to cerebrovascular outcomes

Sleep Apnea Cycle

VentilatioVentilationn

ApneaApnea

ArousalArousal

SleeSleepp

Hypoxia

Pleural pressure Δ

Sympathetic activation

Reoxygenation

Sleep Apnea and Diurnal Hypertension

Peppard; NEJM 2000

Apnea Hyponea Index0

> 0 - < 5≥ 5- <15

≥15

Adjusted* Odds Ratio Reference

1.422.032.89

*adjusted for baseline hypertension, age, gender, BMI, waist circumference, alcohol, and tobacco use

P for trend=0.002

Sleep Apnea among Patients with Stroke

Yaggi; Lancet Neurology 2003

Source

Study Design (N)

Confounding

adjustment

Prevalence of Sleep Apnea

Mohsenin

1995

Cross-sectional

(20)

Age, BMI, HTN, smoking

80%

Dyken

1997

Case-control

(43)

Age, sex 71%

Basetti

1999

Case-control

(153)

Age, BMI, diabetes, stroke severity

63%

Parra

2001

Cross-sectional

(161)

Age, race, sex, smoking, diabetes, HTN, BMI, Lipids

61%

Cerebrovascular Outcomes

Stroke leading to Sleep Apnea?

Askenasy; Stroke 1988

Sleep Apnea leading to Stroke?

• OSA strongly associated with Transient Ischemic Attacks (TIA)

• Persistent OSA post-stroke with resolution of neuromuscular weakness

• No consistent type/location of stroke in association with sleep apnea

• Stroke does not cause most sleep apnea

Neau; Sleep Med Rev 2002

Cerebrovascular Outcomes

Causal Direction?

Cerebrovascular Outcomes

Confounding?

Central Obesity-Hypertension-Diabetes-Lipids

Yale Study Design

Eligible Participants(without stroke)N=1022

(-)OSAN=325 (32%)

(+)OSAN=697(68%)

(+)TIA, Stroke,Death

(-) TIA, Stroke,Death

(+)TIA, Stroke,Death

(-) TIA, Stroke,Death

3-6 years of follow-up

Kaplan-Meier Estimates of the Probability of Event-free Survival among Patients with the Obstructive Sleep Apnea Syndrome and Controls

Yaggi, H. et al. N Engl J Med 2005;353:2034-2041

Event-free Survival (TIA, Stroke, Death)

Yaggi; NEJM 2005

Dose-Response (Trend) Analysis

Yaggi; NEJM 2005

P=0.005 (Chi-square test for linear trend)

Severity of Syndrome

Stroke or Death

No. of events No. of patients

Follow-up

yrs.

Hazard Ratio

(95% C.I.)

AHI ≤ 3 (ref) 13 271 3.08 1.00

AHI 4-12 21 258 3.06 1.75

(0.88-3.49)

AHI 13-36 20 243 3.09 1.74

(0.87-3.51)

AHI >36 34 250 2.78 3.30

(1.74-6.26)

Risk of Stroke or Death

Yaggi; NEJM 2005

Covariate

Unadjusted Hazard Ratio

(95% C.I.)

Adjusted Hazard Ratio

(95% C.I.)

Age (yrs) 1.09 (1.06-1.11) 1.08 (1.06-1.11)

Male sex 0.99 (0.62-1.60) 0.78 (0.48-1.28)

Body Mass Index 0.99 (0.97-1.02) 0.99 (0.96-1.02)

Current Smoker 1.21 (0.90-1.64) 1.46 (0.78-2.98)

Diabetes Mellitus 1.56 (1.02-2.59) 1.31 (0.76-1.26)

Hyperlipidemia 1.04 (0.64-1.68) 1.01 (0.61-1.66)

Hypertension 1.48 (0.95-2.28) 1.20 (0.75-1.90)

Atrial Fibrillation 1.56 (0.79-3.12) 0.91 (0.45-1.86)

Obstructive Sleep Apnea 2.24 (1.30-3.86) 1.97 (1.12-3.28)

Risk of Coronary Artery Events or CV Death

Yaggi/Shah; Sleep and Breathing 2009

Covariate

Unadjusted Hazard Ratio

(95% CI)

Adjusted Hazard Ratio

(95% CI)

Age ( per yr) 1.07 (1.04-1.09) 1.08 (1.05-1.10)

Tobacco use 1.96 (1.12-3.42) 2.52 (1.43-4.44)

Male gender 1.45 (0.87-2.41) 1.30 (0.77-2.21)

Body Mass Index 1.02 (0.99-1.04) 1.02 (0.99-1.05)

Current Smoker 1.33 (0.86-2.07) 1.92 (1.22-3.02)

Diabetes 1.94 (1.18-3.17) 1.42 (0.85-2.39)

Hyperlipidemia 1.62 (1.05-2.52) 1.46 (0.93-2.30)

Hypertension 1.83 (1.16-2.88) 1.40 (0.87-2.25)

Obstructive Sleep Apnea 2.57 (1.39-4.72) 2.05 (1.10-3.84)

Patient Prognostic Factors for Stroke, Coronary Event, Death

Yaggi; J Clin Sleep Med 2009

Prognostic Factor Hazard Ratio 95% C.I Score

Age

<60

60-70

>70

1.00

2.60

5.03

--

1.78-3.80

3.45-7.33

1

2

4

Previous CVD 1.75 1.25-2.45 2

Hypertension or DM 1.52 1.02-2.18 2

Smoking 1.54 1.06-2.20 2

Obstructive Sleep Apnea 1.64 1.04-2.42 2

Prognostic Groups for Stroke, Coronary Event, or Death

Risk Group

Outcome

n/N (%)

Low Risk (1-5) 44/881 5.0

Intermediate Risk (6-7) 90/590 15.3

High Risk (8-12) 57/168 33.9

Yaggi; J Clin Sleep Med 2009

Prognostic Groups for Stroke, Coronary Event, or Death (cont.)

Yaggi; J Clin Sleep Med 2009

(VA) Validation Cohort(Yale) Development CohortKaplan-Meier Estimates for Event-Free Survival

(TIA, Stroke, M.I.,Death)

0 20 40 60 800 20 40 60 80

1.0

0.8

0.6

0.4

0.2

0.0 Pro

babi

lity

of

Eve

nt-F

ree

Sur

viva

l

1 2 3 4 5 6

Years

1 2 3 4 5 6

Years

Epidemiologic Studies Linking OSA to Cardiovascular Outcomes

• Cardiovascular Disease: Shahar, AJRCCM, 2001

• Stroke: Arzt, AJRCCM, 2005• Stroke: Munoz, Stroke, 2006• Stroke Mortality: Sahlin, Arch Int Med, 2008• Myocardial Infraction: Peker, Eur Respir J, 2006• Fatal/Non-fatal Cardiovascular Events: Marin, Lancet, 2005• Sudden Death: Gami, NEJM, 2005• All Cause Mortality: Young/Marshall, Sleep, 2008

Outline

• Epidemiologic evidence linking sleep-disordered Epidemiologic evidence linking sleep-disordered breathing to cardiovascular outcomesbreathing to cardiovascular outcomes

• Mechanisms of Stroke in sleep-disordered breathing

Mechanisms of Stroke in Sleep-Disordered Breathing

1. Intermittent hypoxia

2. Sympathetic activation

3. Mechanical load

4. Snoring and carotid atherosclerosis

5. Impaired sleep and metabolic dysregulation

1. Intermittent Hypoxia

• Repetitive episodes of hypoxia and reoxygenation

• Activation of vascular inflammatory pathways leading to atherosclerosis

• Severity of sleep apnea correlates with carotid intimal medial thickness

Ryan; Circulation 2005Saletu; J Neurobiol 2007Savransky; AJRCCM 2007Szaboova; Resp Physiol and Neurobiol 2007

Lavie; Sleep Med Review 2004

2. Sympathetic Activation

Wolk; Circulation 2003

Circadian Blood Pressure and “Nondipping”

Apnea No Apnea

Somers; J Clin Invest 1995 Ancoli-Israel; Chest 2002Hla; Sleep 2008

Normal Circadian Variation in Vascular Events

Marler; Stroke 1989

Day-Night Pattern of Sudden Death from Cardiac Causes in 78 Persons with and 34 Persons without Obstructive Sleep Apnea (OSA) and in the General Population

Gami, A. et al. N Engl J Med 2005;352:1206-1214

Day-night Pattern of Sudden Death in Obstructive Sleep Apnea

Gami; NEJM 2005

Association of Nocturnal Arrhythmias with Sleep-disordered Breathing

Mehra; AJRCCM 2006

Arrhythmia Type Odds ratio (95% CI)

Nonsustained ventricular tachycardia 3.40 (1.03-11.2)

Complex ventricular ectopy 1.74 (1.11-2.74)

Atrial fibrillation 4.02 (1.03-15.74)

3. Mechanical Load in Sleep Apnea

Bradley and Floras (eds); Marcel Decker 2000

END OF APNEABASELINE

Obstructive Apnea

• ↑ Transmural pressure (afterload)• ↓ Cardiac output

(Mueller maneuver)

Obstructive Apneas and Cerebral Blood flow

Balfors ; AJRCCM 1994

4. Snoring and Carotid Artery Atherosclerosis

• Vibratory stimuli causes pathologic damage to arterial wall endothelial cells1,2

• Snores originate in the upper airway during sleep and result in vibrations of the pharyngeal wall and associated structures

• The proximity of the carotid bifurcation to the lateral pharyngeal wall exposes it to these vibrations and may cause pathologic damage to the arterial wall endothelium3

1. Curry; Muscle and Nerve 20022. Puig; Sleep 20053. Hedner; Sleep and Beathing 1994

4. Snoring and Carotid Artery Atherosclerosis

• Cross-sectional study of 110 subjects who underwent PSG with quantification of snoring, carotid artery ultrasound

• Simultaneous quantification of femoral artery atherosclerosis as a distant (from the upper airway) control artery

• There was a significant increase in carotid artery atherosclerosis (in a dose-response fashion) with increased snoring, but not femoral atherosclerosis

Lee; Sleep 2008

Covariate Odds Ratio C.I.

Age, per decade 3.2 1.4-7.2

Male Sex 4.6 1.4-15.2

Smoking History 3.9 1.1-15.2

Hypertesnion 4.7 1.3-15.7

Snoring, % sleep time

0-25 -

25-50 1.7 0.4-6.9

>50 10.5 2.1-51.8

Lee; Sleep 2008

4. Snoring and Carotid Artery Atherosclerosis

5. Impaired Sleep and Metabolic Dysregulation

• ↓ Glucose tolerance and ↓ insulin release1

• ↑hunger and appetite and associated changes in leptin and ghrelin2

• Short sleep duration ↑ risk type 2 diabetes3

• Sleep apnea associated with insulin resistance and glucose intolerance4,5 1. Spiegel; Lancet 1999

2. Spiegel; Ann Intern Med 20043. Yaggi; Diabetes Care 20064. Punjabi; AJRCCM 20015. IP; AJRCCM 2001

Obstructive Sleep Apnea as a Risk Factor for Type 2 Diabetes Mellitus Covariate Unadjusted HR (95%CI) Adjusted HR (95% CI)

Age 0.99 (0.98-1.02) 1.00 (0.98-1.02)

Gender 1.41 (0.44-4.51) 1.09 (0.34-3.57)

Race (non-caucasian) 1.35 (0.64-2.85) 1.13 (0.56-2.30)

Fasting Glucose 1.04 (1.04-1.05) 1.05 (1.03-1.06)

BMI 1.06 (1.03-1.09) 1.04 (1.01-1.07)

Change in BMI 0.73 (0.69-0.78) 0.76 (0.70-0.83)

Sleep Apnea* 1.53 (1.21-94) 1.43(1.10-1.86)

Botros; Am J Med 2009

* Per Quartile of AHI

Sleep Apnea and Diabetes: The Impact of CPAP Treatment

Botros; Am J Med 2009

Sleep Apnea Syndrome(Syndrome “Zzzz”)

Metabolic Syndrome(Syndrome X)

•Central Obesity•Hypertension •Insulin Resistance

•High Triglycerides•Low HDL

•Cyclic Hypoxia•Nocturnal Sympathetic Activation•Sleep Loss

Cyclic HypoxiaOxidative stressInflammationEndothelial dsfxn. Atherosclerosis

Nocturnal Sympathetic ActivationBlood pressure surgesCardiac arrhythmia∆s Cerebral blood flow

MechanicalLoadVibration injury↑ afterload↓ cardiac output

Metabolic DysregulationGlucose IntoleranceInsulin ResistanceObesityDiabetes

Cardiovascular disease and Stroke

Outline

• Epidemiologic evidence linking sleep-disordered Epidemiologic evidence linking sleep-disordered breathing to cardiovascular outcomesbreathing to cardiovascular outcomes

• Mechanisms of stroke in sleep-disordered breathingMechanisms of stroke in sleep-disordered breathing

• Impact of CPAP treatment on cerebrovascular risk

Cardiovascular outcomes in Obstructive Sleep Apnea With and Without Treatment

Marin; Lancet 2005

Stroke Mortality in Sleep Apnea With and Without Treatment

Martinez-Garcia; AJRCCM 2009

Impact of CPAP on Blood Pressure

Haentjens; Arch Int Med 2007

Severity of Sleep Apnea Effective CPAP Use

Inferring Coronary Heart Disease and Stroke Risk Reduction from Antihypertensive effect of

CPAP

Collins; Lancet 1990

CPAP Treatment and Cerebrovascular Risk

• ↓ Blood pressure1

• ↓ Sympathetic activity and catecholamines2,5

• ↓ Recurrent atrial fibrillation3

• ↑ Left ventricular function4

• ↓ Early Signs of Atherosclerosis5

1. Haentjens,;Arch Int Med 20072. Faccenda; AJRCCM 20013. Kanagol; Circulation 20034. Kaneko;NEJM 20035. Drager; AJRCCM 2007

Study Design: CPAP Treatment Decreases Early Signs of Atherosclerosis

Randomized(without comorbidity)

N=24

No treatmentN=12

CPAP treatmentN=12

Vascular Parameters

Intima-media thicknessArterial stiffnessCarotid diameter24 hour BPLipid profileCatecholaminesC-reactive protein

4 months of follow-up

Assessed for Eligibility

(severe OSA)N=400

Exclusion N=376HypertensionDiabetes Heart FailureCoronary Artery DiseaseStrokeSmoking

Drager; AJRCCM 2007

Primary Outcome:Intima-Media Thickness

Drager; AJRCCM 2007

Secondary Outcome: Carotid-Femoral Pulse-Wave Velocity

Drager; AJRCCM 2007

Serum and Blood Pressure Measures in Control and CPAP groups

Control Group CPAP group

Measures Baseline 4 mo Baseline 4 mo p valueBMI 29.7 29.4 29.9 29.8 NS

Systolic BP 122 121 123 119 NS

Diastolic BP 66 67 73 69 NS

Total Cholesterol 226 224 242 235 NS

LDL 147 145 158 152 NS

HDL 48 47 51 49 NS

C-reactive Protein 3.1 3.3 3.7 2.0 <0.001

Catecholamines 362 357 365 205 <0.001

Drager; AJRCCM 2007

Rationale:Treatment of Sleep Apnea in TIA• Patients with acute TIA are ideal candidates for

prevention of recurrent vascular events– 300,000 TIAs occur annually in U.S.1

– No neurologic deficit (< 24 hours)– High risk of poor outcomes despite prevention strategies:

• 25% will have stroke, cardiovascular event, or death 90 days post-TIA (half of events occur within first 72 hrs)2

• New approach to reduce recurrent vascular event rate is needed (particularly in acute post-TIA period)

1. Johnston, NEJM, 20022. Johnston, JAMA, 2000

Methods: OverviewDesign: Randomized controlled trial, (90days)

Sample: TIA patients (focal neurologic deficit < 24 hoursconfirmed by study neurologist)

Setting: Emergency departments/inpatients at 3 CT hospitals

Exclusions: Established OSA, mechanical ventilation, COPDrequiring O2, pregnancy, symptom onset >72hrs, lifeExpectancy <6 months, residence outside CT

Intervention: Early/immediate Auto-CPAP (ideally within 1st

or 2nd night of TIA) for 90 days (stopped if no evidenceof sleep apnea/response to flow limitation)

Control: Usual care

Outcomes

• Primary outcomes– Sleep apnea prevalence (baseline portable study)

– CPAP adherence rates• No use

• Some use (< 4hr/night or < 70% of nights)

• Good use (≥ 4hr/night and ≥ 70% of nights)

• Secondary Outcome (preliminary data)– 90-day post-TIA recurrent vascular event rate

• TIA, stroke, myocardial infarction, hospitalization for CHF, or death

• Intention-to-treat, CPAP use category (pre-specified)

Prevalence of Obstructive Sleep Apnea

Characteristic Baseline Sleep Study 90-day Sleep Study

OSA prevalence n/N (%) 12/21 (57) 27/45 (59)

AHI: Mean (+/-SD) 11.1 (12) 11.0 (13)

AHI: median, range 6.5, 0-63 6.7, 0-62

Yaggi; Stroke 2010 (In Press)

Time to CPAP or Portable Sleep Study

Time

Intervention

CPAP

(n=45)

Control

Sleep study

(N=25)

From TIA symptom onset, Hours: mean (+/-SD) 39.4 (23) 45.0 (37)

<24 hours: n (%) 8 (18) 4 (16)

≥ 24 < 48 hours: n (%) 27 (60) 15 (60)

≥ 48 hours 10 (22) 6 (24)

Yaggi; Stroke 2010 (In Press)

Auto-Titrating CPAP Use

CPAP Use Category

Intervention Patients on CPAP

N=29

Number hrs/night used: mean (+/-SD)

Range

5.6 (1.9)

1.5-8.5

CPAP Use: N (%) -

None: 0 hrs/night or 0 nights 0 (0)

Some: <4 hrs/night or <70% nights 14 (48)

Good: ≥4 hrs/night and ≥ 70% nights 15 (52)

Yaggi; Stroke 2010 (In Press)

Recurrent Vascular Events:Overall

(Intention-To-Treat)

(+) Outcome (-) Outcome

Intervention 1

(2%)

44 45

Control 3

(12%)

22 25

P=0.13; 2-sided

Yaggi; Stroke 2010 (In Press)

Recurrent Vascular Events: Evidence of Sleep Apnea

(CPAP Use Category)(+) Outcome (-) Outcome

Good 0

(0%)

15 15

Some 1

(7%)

13 14

None 3

(16%)

16 19

P=0.09; 2-sidedYaggi; Stroke 2010 (In Press)

Summary• Sleep apnea is a valid syndrome of stroke risk.

• Epidemiologic studies demonstrate that sleep apnea is independently associated with hypertension, stroke, myocardial infarction, fatal and non-nonfatal cardiovascular events, and sudden death, all cause mortality

• Physiological studies suggest mechanisms (intermittent hypoxia, sympathetic activation, changes in cerebral blood flow, mechanical load, metabolic dyregulation) whereby sleep apnea provides a substrate for the development of stroke.

Implications

• The high prevalence of sleep apnea confers a high population attributable risk for cerebrovascular outcomes

• CPAP treatment is likely result in decreased cerebrovascular risk.

• Longer-term randomized controlled trials examining the impact of treatment on cerebrovascular outcome events are needed.

Acknowledgements

John Concato, M.D.

Vahid Mohsenin, M.D.

Judy Lichtman, Ph.D.

Rachel Lampert, M.D.

Dawn Bravata, M.D. (Indianapolis)

Kingman Strohl, M.D. (Cleveland)

Mark Gorman, M.D. (Vermont)

Zhu Wang, Ph.D.

Nader Botros, M.D., M.P.H.

Neomi Shah, M.D., M.P.H.

Bernardo Selim, M.D.

Frederick Struve, Ph.D

Vincent McClain, M.D.

Yale Center for Sleep Medicine VA CT Center for Sleep MedicineVA Clinical Epidemiology Research CenterVA HSR&D Research CDA/Merit ProgramVA CSR&D Merit Program