Ral AnticDirector Thoracic Medicine

Head of Sleep ServicepRoyal Adelaide Hospital

Visiting Respiratory and Sleep PhysicianAlice Springs Hospitalp g p

Conflict of Interest

Past member of ResMed Medical BoardPast member of ResMed Medical BoardHonoraria from lectures for Novartis, Boehringer, GlaxoInvestigator in Insomnia Clinical TrialsInvestigator in Insomnia Clinical Trials

To discussSleep 

what is normal

Disordered breathing in sleep and its treatment

Sleep and the CVS The connection between sleep apnoea and chronic CV diseasesthe mechanisms by which abnormal sleep leads to cardiac injurythe management

4 key aspects of health4 key aspects of health

Nutrition

Health sleepE ercise Healthy sleepExercise

Mental health/Stress

Risk to health in sleepSl  i  ‘ i ’Sleep is ‘restorative’

In sleep there is a downturn in activity of all organs 

This is needed for ongoing health

This state can be destabilised by factors, conditions or pre‐existing diseases 

This impairs  homeostasis and creates a risk to the development of disease

Classification of Sleep DisordersClassification of Sleep Disorders CSD‐2 SYSTEMAmerican Academy of Sleep Medicine, 2005 

Insomniaconditions that are characterized by difficulty initiating or maintaining sleep, or by poor quality sleep

Sleep related breathing disorders

Parasomnias undesirable physical events (movements, behaviours) or experiences (emotions, perceptions, dreams) that occur during entry into Sleep related breathing disorders

abnormal respiration during sleep

Hypersomnias of central originprimary complaint is daytime 

dreams) that occur during entry into sleep, within sleep, or during arousals from sleep 

Sleep related movement disordersl hprimary complaint is daytime 

sleepiness that is not due to disturbed sleep or misaligned circadian rhythms 

simple, stereotypic movements that disturb sleep eg Restless Legs Syndrome

Isolated symptoms and normal Circadian rhythm sleep disorders chronic or recurrent sleep disturbance due to misalignment between the environment and an individual's sleep‐wake cycle 

Isolated symptoms and normal variants 

Other sleep disorders individual s sleep wake cycle 

A  i ifi   bli  h l h iA significant public health issue

E l i  i   b th k l d  & it  i id  Explosion in  both knowledge & its incidence in the last 10 years

Sleep creates a risky state

Physiological changes in Sleep

In non‐REM sleep (75‐85% sleep time)Parasympathetic tone increases and sympathetic Parasympathetic tone increases and sympathetic decreases

Decrease in HR, BP, systemic vascular resistance and cardiac outputoutputIncrease in cardiac stabilityDecrease in airway size

lin REM sleepDecrease in parasympathetic tone and increase in sympathetic toney p

Rise in BP, HR

Health is adversely affected by

Insufficient or excessive sleepInsufficient or excessive sleepAcutechronic

Fragmentation of sleepAcute Chronic

The Upper Airwaypp y

Sleep apnoearecurrent, sleep induced, partial or complete collapse of the pharyngeal airway

resulting in sleep fragmentation from arousals, daytime sleepiness, O2 desaturation, autonomic dysfunction and p , , yend‐organ damage

f d b d ( )Severity is quantified by Apnoea‐Hypopnoea Index (AHI)

Prevalence is highPrevalence is high

Pathophysiological influence ofPathophysiological influence of OSA in cardiovascular diseaseCycle of Sleep

ApnoeaHypoxaemiaPleural pressure and intramural pressure changeSympathetic activationy p

ArousalVentilation

Reoxygenation and restoration of mechanics 

OSA Heart rate BP and SaOOSA – Heart rate, BP and SaO2

TACHYCARDIA

APNEA APNEAACUTE HYPERTENSIONHYPERTENSION

S O2SaO2

Postulated mechanisms underlying the relationship between sleep apnoea and cardiacPostulated mechanisms underlying the relationship between sleep apnoea and cardiac disease.

Jaffe L M et al. Eur Heart J 2013;34:809-815

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: journals.permissions@oup.com

Obstructive sleep apnoea in epidemicObstructive sleep apnoea – in epidemic proportions nowPrevalence depends on definition

AHI > 5/hddl d d ddl d26 % middle‐aged men and 10 % middle‐aged women.

AHI ≥ 10/hr approximately 10 % of the middle‐aged population have OSA approximately 10 % of the middle aged population have OSA (1993)

AHI >20 in 25% of adult males in North West Adelaide ( )2011)

AHI >20 in 40‐70% with end organ damage – cardiac, renal, HTe a ,

I i i   d  hInvestigation and therapy

Signs and symptoms of sleep apnea

These are pointers to sleep apneasnoringh ki / i

ZZchoking/gasping

restless sleep waking unrefreshed

Z ZZ

Z Z

waking unrefresheddaytime sleepinessnocturianocturia

Cardiovascular Effects of SleepCardiovascular Effects of Sleep Apnea

Home study

Sleep Study Reportp y pNormal Sleep Apnoea

REMMOV AWK

1234

RW1234

SaO2

100

50

SpO2

100

50

Cn.AOb.AMx.AHypUns

+5+5+5+5+5

Cn.AOb.AMx.AHypUnsRERA

+5+5+5+5+5+5

Main indices Apnea Hypopnea Index (AHI)

+5+5

02 desaturation index (ODI)

Sleep apneas go on and on, and on…. 

20 min te recording20 minute recording

An Australian Invention

Prof. Colin SullivanUniversity of Sydney, 1981

The mechanisms of damageThe mechanisms of damage

Effects of obstructive sleep apnoea on pulmonary and nervous systems. p p p y y

Jaffe L M et al. Eur Heart J 2013;34:809-815

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: journals.permissions@oup.com

HypertensionCross sectional, longitudinal and prospective studies show strong rel between OSA & HT, independent of confoundersLoss of nocturnal BP dippingLoss of nocturnal BP dippingCycle of sleep disturbance causes sympathetic overdrive and HTResistant HT correlated with hyper‐aldosteronism which promotes accumulation of fluid in the neck when supine 

d   OSA  Bl ki  thi  i  OSA  d HTand worsens OSA. Blocking this improves OSA and HT

Hypertension and OSAThe Sleep Heart Health Study (Nieto et al., 2000) demonstrated:

  i i  b  h i   d OSA an association between hypertension and OSA independent of age, obesity and other known confounding factorsgprevalence of hypertension increased with increasing AHI values.

OSA Circadian Rhythm of BP in Controls & OSA

From: Davies: Thorax, Volume 55(9).September 1, 2000.736-740

Hypertension and OSAand can actually lead to nocturnal hypertension.

Hypertension and OSA

l ( ) f d h h k f d lVentura et al. (2004) found higher risk of cardiovascular complications associated with non‐dipping independent of daytime BP.y

Wisconsin Sleep Cohort Study

BP increases linearly with increasing AHI (p = .003)At AHI 15 (vs 0):

Systolic BP 3 6 mmHg higher      (95% CI 1 3 ‐ 6 0)Systolic BP 3.6 mmHg higher      (95% CI 1.3  6.0)Diastolic BP 1.2 mmHg higher    (95% CI 0.3 ‐ 3.3)

Risk of hypertension increases with increasing AHI:Risk of hypertension increases with increasing AHI:AHI 30 : OR 3.15 (95% CI 1.75 ‐ 5.67)AHI 15 :  OR 1.78 (95% CI 1.32 ‐ 2.38)

AHI 5:   OR 1.21 (95% CI 1.10 ‐ 1.34)

Coronary artery disease (CAD) & acuteCoronary artery disease (CAD) & acute coronary syndrome (ACS)

Correlation between CAD, ACS & OSA well established – 65% admitted for MI have OSA and carry poor prognosis

OSA when present with successful coronary intervention after ACS was associated with higher mortality (38% vs 9%), increased rate of stent restenosis (24%vs 5%)

Refractory nocturnal angina has higher rate of OSA, occurs at the same time and is reduced with nCPAP

Whilst treatment of OSA has not been shown to reverse progression of CAD, it might retard it and can decrease new events

OSA increases blood coagulability, viscosity and increased platelet aggregability, higher levels of clotting factors. This may contribute to CAD progression and in stent thrombus formation

ArrhythmiaOSA associated with hypoxaemia  autonomic derangements and OSA associated with hypoxaemia, autonomic derangements and cardiac structural changes all which predispose to arrhythmia

Cross sectional studies of SA show prevalence of 43 ‐ 73% in those Cross sectional studies of SA show prevalence of 43  73% in those with AF, and excess CAD and CSA +

In OSA > 25% greater risk of AF recurrence after ablation. Treatment In OSA   25% greater risk of AF recurrence after ablation. Treatment with nCPAP gives 8 fold improvement in lasting success of ablation

SA esp with heart failure linked with other dysrhythmias – nocturnal p y yasystole, brady‐arrhythmia, AV nodal block SVT and non‐sustained VT and malignant ventricular arrhythmias

nCPAP decreases rates of these arrhythmias

In patients with OSA and ArrhythmiasSinus arrhythmia is common, esp in REM sleepAbnormal rhythms are more common than with no OSA

AF – OR 4.02d ONon‐sustained VT – OR 3.40

Complex vent ectopics in severe OSA (bigeminy, trigeminy, quadrigeminy) even adjusting for other risk factors  – OR 1.74

There is a dose‐response relationship between increasing severity OSA and arrhythmia  and 

CVE has stronger rel to OSA and hypoxaemiaAF stronger rel with CSA, Cheyne Stokes breathing and underlying CVDIncrease in nocturnal sudden death in OSA  OR 2 57Increase in nocturnal sudden death in OSA  – OR 2.57

Sleep Apnea in Heart FailureContributory mechanisms

hypoxaemia,  hypercarbia, causing pulmonary vasoconstriction

increase in intra‐thoracic pressure changes from upper airway obstruction

Myocardial wall stress, atrial size increaseyoca d a a s ess, a a s e c easeImpairment in ventricular functionIncreased venous return causing  RV distension and compromise in LV fillingg

Combined  long term sympathetic overactivity from OSA and HFMyocyte apoptosis, B adrenoceptor down regulation, decreased y y p p , p g ,HR variability, arrhythmias and increased mortality rate

Heart FailureOSA in 47‐76%

Complex mechanisms – increase in sympathetic tone and heart rate in already failing heart can lead to myocyte injury, cardiac B adrenergic desensitisation and functional and structural abnormalities

H  f il       d  b  OSA  d CSAHeart failure can cause and exacerbate OSA and CSA

CSR carries poor prognosis in HF

Diastolic dysfunction is highly correlated with sleep disordered breathing – 70% SA in HF with preserved ejection fraction, mainly OSA ? whyOSA ? why

Sleep Apnoea – Central ( Cheyne Stokes Respiration )

Decreased ventilatory drive

Heart failure, stroke, drugs

Enhanced chemoreceptor sensitivity +/‐ prolonged circulation time

Cheyne-Stokes respiration

32n=32

n=56

Javaheri 2007

„In summary, although CSA has been associated withincreased mortality in heart failure patients, a causal role for

CSA in the morbidity and mortality of heart failure awaitsmore definitive evidence. A number of treatment strategiesfor CSA have been tested, but presently none is ideal with

t t b th ffi d t l h il blrespect to both efficacy and tolerance, nor has any availabletherapy been demonstrated to improve survival.“

Teschler H et. al; AJRCCM 2001

b / fOSA better 3/12 after CVA

Parra AMJRCC 2000

Cardiovascular Effects of Sleep ApnoeaMild-Mod OSA CPAP treated OSASevere OSA

Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005 Mar 19-25;365(9464):1046-53.

Linked epidemicsObesity, Metabolic  Syndrome and Sleep Apnoea

Incidence and prevalence of Sleep Apnoea is rising as we speak

The Weight of the MatterThe Weight of the Matter

10% increase in weight predicted 6-fold increase in odds of developing moderate to severe OSA (AHI≥15)

Peppard 2003

moderate to severe OSA (AHI≥15)

Therapy with nCPAP is very cost effective

Condition/Treatment Cost per QALY

CPAP for moderate-severe OSA $3000-5000 /QALY gained

Condition/Treatment Cost per QALY

Treatment for Erectile Dysfunction $6,400/QALY

*Physician Counseling for Smoking $7,200/QALY

Total Hip Replacement $9 900/QALYTotal Hip Replacement $9,900/QALY*Outreach for Flu and Pneumonia $13,000/QALY

Treatment of Major Depression $20,000/QALY

Gastric Bypass Surgery $20 000/QALYGastric Bypass Surgery $20,000/QALY

Treatment for Osteoporosis $38,000/QALY

*Screening For Colon Cancer $40,000/QALYImplantable Cardioverter Defibrillator $75 000/QALYImplantable Cardioverter Defibrillator $75,000/QALY

Lung-Volume Reduction Surgery $98,000/QALY

Tight Control of Diabetes $154,000/QALY

*Treating Elevated Cholesterol ( + 1 risk factor) $200 000/QALYTreating Elevated Cholesterol ( + 1 risk factor) $200,000/QALY

Resuscitation After Cardiac Arrest $270,000/QALY

Left Ventricular Assist Device $900,000/QALY

Evidence for a causal link between OSA and cardio‐vascular disease remains circumstantial

Studies of intermediate markers small subject numbers, short follow‐up (months)j , p ( )

Population and clinic studies positive associations between OSA and CV diseasepositive associations between OSA and CV disease

NO large, long‐term RCTs exploring link between OSA and “hard” cardiovascular endpointshard  cardiovascular endpoints

The SAVE trialThe SAVE trial

l ( ) lMulticentre RCT (n=5000) CPAP versus usual care (2008‐2013)

P ti t   ith d t d CV di  PLUS  d tPatients with documented CV disease PLUS moderate‐severe OSA 

“Hard” CV outcomes –myocardial infarction  stroke  Hard  CV outcomes  myocardial infarction, stroke, sudden death, hospital admission for TIA or unstable angina

SITES

1 site

5 sites, 3 initiated2 ti t

1 site

46 sites, 1164 patients

8 sites, 67 patients

1 site initiated 2 patients

p12 sites,

184 patients 15 sites

5 sites, 87 patients

SummarySl   lit   d  tit  i  f d t l t  h lthSleep quality and quantity is fundamental to health

Sleep disordered breathing  is common  It causes Sleep disordered breathing  is common. It causes substantial morbidity and mortality

OSA is one of the important risk factors to the cardiovascular system 

That risk is reduced by its control with nCPAP

Definitive RCT awaited in a number of areas

Recent reviewsImportance and management of chronic sleep apnoea in p g p pCardiology, Jaffe et al, European Heart Journal 2013, 34,809‐815

Obstructive Sleep Apnoea in adults, Usmani et al Post Grad Medicine 2013, 89: 148‐156