Sleep Apnea & Cardiovascular Disease: What Have We Learned Over The Last 25 Years

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

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

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.

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

Sleep MedicineBurwell et al, Am J Med 1956

Sleep Medicine

Why Might OSA be a Risk Factor for CVD?

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

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

Sleep Medicine

State of Affairs 1970’s-1980’s

or otherwise “What I knew when I was an intern?”

Sleep Medicine

1970s and 1980s

Sleep MedicineAnn Intern Med. 1985 Aug;103(2):190-5.

Circa ~1980s

Snoring and Hypertension in San Marino

N=5713

Lugaresi et al, Sleep 1980; 3:221-4

Snoring and Hypertension:Finnish Twin Study

N=3847 N=3664KOSKENVUO et al, Lancet, 1985

Koskenvuo M, BMJ, 1987 N=4388 men

Sleep MedicineBoudoulas H, et al. J Med 1983:14:223-38

Effect of AI on MortalityHe et al, Chest 94:9-14, 1988

Sleep MedicinePartinen et al Chest 1988

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

Sleep Medicine

Acute Hemodynamic Changes with OSA

Cyclical increases in ABP

Cyclical increases in PAP

Apnea

Schroeder et al, in Sleep Apnea Syndromes, 1978

Cardiovascular Pathogenesis of OSA--1976

Tilkian et al, Ann Intern Med 1976

Sleep Medicine

State of Affairs 2011

or otherwise “What do wise men and women know now?”

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

Gottlieb et al, Circulation 2010

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

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%

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%

Gottlieb et al, Circulation 2010

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

All Cause Mortality: Wisconsin Sleep Cohort*

Young et al, Sleep. 2008 August 1; 31(8): 1071–1078*N=1496,CPAP Treated Excluded

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

Nocturnal Predilection for Nocturnal Predilection for Sudden Cardiac Death in OSASudden Cardiac Death in OSA

Gami AS NEJM 2005:352N=112

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

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

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

Sleep Medicine

OSA and CVD

Mechanistic Observations

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

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

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

*

**

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

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

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

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

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?

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

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

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

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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http://understandingsleep.org“Healthy Sleep” web site launched January 2008

“Apnea” coming April 2011

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Presented by: Harvard Medical School

Division of Sleep Medicine

& WGBH Educational Foundation