sleep-disordered breathing and stroke klar yaggi, m.d., m.p.h. assistant professor yale university...
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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