sleep apnea & cardiovascular disease: what have we learned over the last 25 years
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Sleep Apnea & Cardiovascular Disease: What Have We Learned Over The Last 25 Years. Stuart F. Quan, M.D. Division of Sleep Medicine Harvard Medical School. Overview. Obstructive sleep apnea-- a bit of history OSA and CVD: Biological plausibility/physiology - PowerPoint PPT PresentationTRANSCRIPT
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Sleep Medicine
Sleep Apnea & Cardiovascular Disease: What Have We Learned
Over The Last 25 Years
Stuart F. Quan, M.D.Division of Sleep Medicine
Harvard Medical School
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Sleep Medicine
OverviewOverview• Obstructive sleep apnea-- a bit of
history• OSA and CVD: Biological
plausibility/physiology• Time machine to ~1970s-80s: What we
knew then• Present time: What we know now• Current knowledge gaps• Clinical Trials: Opportunities to Address
Knowledge Gaps
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Sleep Apnea in AntiquitySleep Apnea in Antiquity• Dionysius………..Dionysius……….. So his physicians prescribed he shouldSo his physicians prescribed he should get some fine needles, exceedinglyget some fine needles, exceedingly long, which they thrust through his ribslong, which they thrust through his ribs and belly whenever he happened to falland belly whenever he happened to fall into a deep sleep…then he would beinto a deep sleep…then he would be thoroughly aroused.thoroughly aroused.
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Historical Medical AccountsHistorical Medical Accountsof Sleep Apneaof Sleep Apnea
When a person, especially advanced in years, is lying on his back in When a person, especially advanced in years, is lying on his back in heavy sleep and snoring loudly, it very commonly happens that every heavy sleep and snoring loudly, it very commonly happens that every now and then the inspiration fails to overcome the resistance in the now and then the inspiration fails to overcome the resistance in the pharynx, of which stridor or snoring is the audible sign, and there will pharynx, of which stridor or snoring is the audible sign, and there will be perfect silence through two, three, or four respiratory periods, in be perfect silence through two, three, or four respiratory periods, in which there are ineffectual chest movements; finally air enters with a which there are ineffectual chest movements; finally air enters with a loud snort, after which there are several compensatory deep loud snort, after which there are several compensatory deep inspirations…..inspirations…..
Broadbent, WHBroadbent, WH
Lancet, 1877Lancet, 1877
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Sleep MedicineBurwell et al, Am J Med 1956
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Sleep Medicine
Why Might OSA be a Risk Factor for CVD?
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Sleep Medicine
Physiological ConsequencesPhysiological Consequences• Intrathoracic Pressure Changes
– Preload, afterload and transmural pressure– Trigger baroreceptors
• Hypoxemia, hypercapnia, and arousal – SNS overdrive– Systemic and Pulmonary Vasoconstriction– Abnormal HRV and increased HR
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Sleep Medicine
Tracheal Pressure(mmHg))
LV Pressure(mmHg)
LV Transmural Pressure (mmHg)
LV End Systolic Volume (mL))
Parker Am J Respir Crit Care Med 1999; 160: 1888-96.
•Increased preload
•Increased LV afterload (increased transmural pressure)
•Impaired diastolic function
•Atrial and aortic enlargement
Negative Intrathoracic Pressure Swings
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Sleep Medicine
State of Affairs 1970’s-1980’s
or otherwise “What I knew when I was an intern?”
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Sleep Medicine
1970s and 1980s
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Sleep MedicineAnn Intern Med. 1985 Aug;103(2):190-5.
Circa ~1980s
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Snoring and Hypertension in San Marino
N=5713
Lugaresi et al, Sleep 1980; 3:221-4
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Snoring and Hypertension:Finnish Twin Study
N=3847 N=3664KOSKENVUO et al, Lancet, 1985
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Koskenvuo M, BMJ, 1987 N=4388 men
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Sleep MedicineBoudoulas H, et al. J Med 1983:14:223-38
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Effect of AI on MortalityHe et al, Chest 94:9-14, 1988
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Sleep MedicinePartinen et al Chest 1988
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No Increase in Mortality in OSA Patients
Circa 1988• 91 patients with treated and untreated
OSA• 35 patients with symptoms of OSA, but
negative PSG• Retrospective f/u for 7-98 months• Mortality
– 4/35 (11.4%) Controls and 9/91 (9.8%) OSA patients
Gonzalez-Rothi et al, Chest, 1988
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Sleep Medicine
Acute Hemodynamic Changes with OSA
Cyclical increases in ABP
Cyclical increases in PAP
Apnea
Schroeder et al, in Sleep Apnea Syndromes, 1978
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Cardiovascular Pathogenesis of OSA--1976
Tilkian et al, Ann Intern Med 1976
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Sleep Medicine
State of Affairs 2011
or otherwise “What do wise men and women know now?”
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SDB and Incident HypertensionSDB and Incident HypertensionAdjusted Odds Ratios for Hypertension at Follow-upAdjusted Odds Ratios for Hypertension at Follow-up
00.5
11.5
22.5
33.5
44.5
5
Adj BL Htn Adj Age/Sex Full Adj
0 /hr0.1-4.9 /hr5-14.9 /hr>15 /hr
Peppard et al, N Engl J Med 2000; 342:1378
Odds Ratio
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Gottlieb et al, Circulation 2010
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Incident CHD and OSAAlthough there was an increased risk of incident CHD in clinic-derived samples, those who were treated with CPAP had the same risk as controls
Marin, Lancet 2005
Treated with CPAP
No CPAP
12 year follow-up12 year follow-upAll MenAll MenN=1651N=1651
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Mooe T AJRCCM 2001:164
Major Adverse Cardiovascular Major Adverse Cardiovascular Events (MACE) In Patients with Events (MACE) In Patients with
CAD and OSACAD and OSA• 407 consecutive patients with CAD• 38% with ODI >5• Increased 5-year MACE
– ♂ AHI ≥10: 28% vs. 16%– ♀ AHI ≥ 10: 20% vs. 14%
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Yumino, D. AJC 2007:99
OSA Increases Risk of MACE and Re-stenosis After Percutaneous Coronary
Intervention• 89 consecutive pts with ACS followed
for mean 227 days, – 57% OSA (AHI>10)– Higher CRP but otherwise comparable
• MACE in OSA vs non-OSA:– 23.5% vs. 5.3% – HR: 11.6 (2.2,62.2)
• Quantitative Coronary Arteriography – Late Loss: 1.28 vs 0.69 mm MLD– Binary restenosis: 37% vs 15%
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Gottlieb et al, Circulation 2010
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All Cause Mortality: Busselton Health Study*
RDI ≥15/hr, 6 deaths,HR = 6.24, 95% CL 2.01, 19.39
*N=380
Marshall et al, Sleep. 2008 August 1; 31(8): 1079–1085
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All Cause Mortality: Wisconsin Sleep Cohort*
Young et al, Sleep. 2008 August 1; 31(8): 1071–1078*N=1496,CPAP Treated Excluded
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0.7
0.8
0.9
1.0S
urvi
val P
roba
bilit
y
0 1 2 3 4 5 6 7 8 9 10Years
< 5.05.0 – 14.9
15.0 – 29.9> 30.0
Numbers at risk: 6294 6205 6110 6001 5868 5732 5566 5411 4756 2357 300Total Deaths: 0 59 143 241 359 478 616 757 875 989 1046
Apnea-hypopnea index (events/hr)
Sleep Apnea and All-Cause Mortality in SHHS
Punjabi et al, PLOS Med 2009
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Nocturnal Predilection for Nocturnal Predilection for Sudden Cardiac Death in OSASudden Cardiac Death in OSA
Gami AS NEJM 2005:352N=112
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Adjusted Odds Ratio of Nocturnal Arrhythmia By Sleep Apnea (AHI>30) In SHHS
Adjusted OR 95% CI Atrial Fibrillation 4.5 1.2, 17CVE or NSVT 1.8 1.2, 2.8AF or NSVT 3.7 1.7, 8.0
Odds > 7.0 for those 50 to 60 years oldMehra R AJRCCM 2006
Case-Cross-Over Study: Relative Risk of a Paroxysmal Arrhythmia
Occurring After an Apnea/Hyponea: 17 Monahan JAAC 2008
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1 excess episode of PAF or NSVT for every 1000 hours of sleep or 40000 respiratory disturbances
For a person with moderate Sleep Apnea (AHI = 25 events/hour) sleeping 8 hours/night 1 excess arrhythmia in 7 months
Absolute Risk of Nocturnal Arrhythmias In Association with
Apneas in SHHS
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Sleep Medicine
Obstructive Sleep Apnea and Recurrence of AFib
CP1073966-6Kanagala and Somers
Sleep apnea – CPAP Sleep apnea – CPAP (n=12)(n=12)Sleep apnea – no Sleep apnea – no CPAP (n=27)CPAP (n=27)Controls – no sleep Controls – no sleep studystudy
118 pt – successful cardioversion
Untreated pt – mean Untreated pt – mean nocturnal fall in O2 satnocturnal fall in O2 sat
P=0.034P=0.034• Recurrence – 18%Recurrence – 18%• No recurrence – 8%No recurrence – 8%
0
20
40
60
80
100Recurrence of AFib (12 mo)
Pt Pt (%)(%)
P=0.013 P=0.009
4253
82
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Sleep Medicine
OSA and CVD
Mechanistic Observations
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OSA and Cardiac Morphology• SHHS (n=2058), AHI < 5 vs AHI > 30
• Adjusted LVMI 7% higher: 41. 3 vs 44.1 g/m 2.7
• LVH: Odds Ratio: 1.78 (1.14, 2.79, 95% CI)• Increased LVIDd• Eccentric Hypertrophy
– Stronger associations with hypoxemia indices vs AHI
Chami et al. Circulation. 2008. 117:2599
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Impaired LV Diastolic Function• Cross-sectional Findings
– 15 controls; 27 OSA (Avg AHI 44)– No co-morbidities
• OSA: 56% abnormal LV– Longer IVRT and DT and lower E/A
41% Impaired Relaxation
• 12 week intervention– CPAP vs sham – Improved E/A, IVRT, mitral DT – No change in BP,
catecholamines
Arias MA Circulation 2005:112:375
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Prevalence of Metabolic Syndrome in OSA vs non OSA Patients
01020
304050
607080
Met Syn Htn Dyslipid DM BMI
OSANo OSA
Parish et al, J Clin Sleep Med 2007;3: 467–472
*
**
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Sleep Apnea and Oxidative Stress
• Recurrent hypoxia and reoxygenation– Increase flux of free radicals– Induce endothelin expression– Suppress NO generation – Induce local vasoconstriction and changes in vascular permeability
• Results in oxidative stress causing generation of ROS (superoxide)
Prabhakar NR, JAP, 2001
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Pro-Inflammatory and Atherogenic Effects
• Upregulation of inflammatory mediators• IL6, sIL6R, IL-8, TNFα, CRP, (NF-Kappa B)
• Enhanced thrombotic potential– PAI-1, P-selectin, fibrinogen, – VEGF
• Oxidation of serum proteins and lipids
• Endothelial dysfunction
• Insulin Resistance and DyslipidemiaHansson NEJM 352: 2005
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Loresnzi-Filho AJRCCM 2007:175
IntermittentHypoxia
↑hepatic HIF-1 Hypoxic inducible factor 1
AtherosclerosisAtherosclerosis DyslipidemiaTNFα gene
SCD-1
SREBP-1
IA, Nl diet CIH, Nl diet
IA, H Fat CIH, H Fat
Savransky AJRCCM 2007: 177Savransky Circ Res 2008:103
Mice: CIH + fat diet> ↑ 70% SCD-1 mRNA, Mice: CIH + fat diet> ↑ 70% SCD-1 mRNA, VLDL, atherosclerosisVLDL, atherosclerosis(reversed by blocking SCD-1)(reversed by blocking SCD-1)
Est 12 wks CIH in M~1 yr HC Diet in FEst 12 wks CIH in M~1 yr HC Diet in F
Humans: hepatic SCD-1 Humans: hepatic SCD-1 αα overnight overnight hypoxemia (r=.68)hypoxemia (r=.68)
+ high fat diet
stearoyl-Coenzyme A desaturase 1
sterol regulatory element–binding protein-1
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SLEEP-Apnea
Chronic Intermittent Hypoxia
Ventilatory Overshoot Hyperoxia
Increased Sympathetic Nervous System Activity
Intrathoracic Pressure Swings
Hypercapnia
Increased Arousals
Reduced Sleep Duration
Increased Inflammation
Increased Oxidative Stress
Metabolic Dysfunction/
Insulin Resistance
Hyper-coaguability
Endothelial Dysfunction
Autonomic Dysfunction
Systemic Hypertension
Atherosclerosis
Diastolic Dysfunction
Congestive Heart Failure
Stroke
Increased Mortality and Sudden Death
Cardiac Arrhythmias
PHYSIOLOGIC PERTURBATIONS
INTERMEDIATE MECHANISMS
CLINICAL OUTCOMES
Mehra R Curr Resp Med Rev 2007
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Sleep Medicine
OSA and CVD:Knowledge Gaps
• Hypertension– Does treatment of OSA reduce incident hypertension?– In whom does treatment of OSA significantly lower
BP?• Coronary Heart Disease/CHF/Stroke
– Does adverse impact of OSA affect only men?– Does treatment of OSA decrease risk of
CHD/CHF/Stroke?– What treatments will be effective?
• Mortality– Does treatment of OSA decrease mortality risk?
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Sleep Medicine
Lack of Interventional RCTs (1)Lack of Interventional RCTs (1)• No published large scale interventional RCTs on
benefit of OSA treatment on CVD/Mortality• RICCADSA: Randomized Intervention with CPAP in
Coronary Artery Disease and Sleep Apnoea– 400 CAD ppts: 100 each to 1) non-sleepy OSA/CPAP, 2) non-sleepy
OSA/no CPAP, 3) sleepy OSA/CPAP, 4) CAD but no OSA– Follow-up for 3 years for CVD morbidity and mortality– Scand Cardiovasc J. 2009 Feb;43(1):24-31.
• HEARTBEAT: Randomize ~270 ppts with stable CAD or high risk for CAD to CPAP, O2 or healthy lifestyle
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Sleep Medicine
Lack of Interventional RCTs (2)Lack of Interventional RCTs (2)
• Sleep Apnea Cardiovascular Endpoints Study (SAVE)– Multinational randomised, controlled trial to
determine the effects of nasal continuous positive airway pressure (CPAP) in preventing cardiovascular (CV) disease in high risk patients with moderate-severe obstructive sleep apnea (OSA)
– Plan to randomize >5000 ppts to CPAP or CMT and follow for 3-5 years
– Sites in Australia, New Zealand, China, India and South America
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Sleep Medicine
• BestAIR: Best Apnea Interventions In Research– Prepares for Phase 3 study
• Sham vs CMT as control arms• CBT-guided CPAP adherence vs RT-guided adherence• Control vs Active PAP – 24 BP, cardiac function, biomarkers
• ABC: Apnea, Bariatric Surgery, and CPAP Trial– Bariatric surgery as a first line treatment
(vs CPAP)
• COMET: Comparative Effectiveness CPAP Management– Oral Appliances vs CPAP in women with OSA
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Final Thoughts• Substantial progress has been made in the
past 25-30 years in our understanding of the OSA/CVD relationship
• Accumulating evidence implicates SDB as an independent risk factor for hypertension, CHD and Stroke
• Risk may not be the same for all segments of the population
• Treatment appears to mitigate the risk in some clinical populations
• Unclear whether treatment is beneficial in patients without symptoms
SLEEP MEDICINE
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GOT SLEEP?
http://understandingsleep.org“Healthy Sleep” web site launched January 2008
“Apnea” coming April 2011
GOT SLEEP? Get it at http://understandingsleep.org
Presented by: Harvard Medical School
Division of Sleep Medicine
& WGBH Educational Foundation