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Study with the experts

Interactive Course on

Sleep Medicine

Antwerp, Belgium

November 10-12, 2005

ERS School Courses 2005

Thank you for viewing this document.We would like to remind you that this material is the

property of the author. It is provided to you by the

ERS for your personal use only, as submitted by the

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2005 by the author

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Cardiovascular morbidity in OSA

Dr Justin Pepperell

Centre for Respiratory Medicine

Churchill Hospital Site

Oxford Radcliffe HospitalOxford OX3 7LJ, United Kingdom

[email protected]

Aims of the presentationAt the end of the presentation you should be able to:

1. List some of the mechanisms of cardiovascular disease in OSA2. Appreciate the confounding factors in studies in this area3. Discuss the evidence for cardiovascular disease in OSA4. Discuss the evidence for CVD risk reduction in OSA

5. Decide in the clinic who and how to treat to reduce cardiovascular risk

Study design and confounding factorsBecause of the intimate relationship between cardiovascular risk factors such as obesity, hypertension

and sleep apnoea, it is difficult to adequately control for these in epidemiological studies.

Cardiovascular risk factors are themselves associated in general population samples and tend to cluster

in unhealthy individuals. Sleep apnoea subjects are typical of this, with high prevalences of obesity,

smoking, alcohol use, insulin resistance and reduced exercise. All of these should be controlled for, in

clinical studies.

An example of this for cardiovascular disease is the frequent prescription of antihypertensive and other

cardiac medications in this group of subjects. If we assume for example that sleep apnoea causes

hypertension, and that severe disease is more likely to do so, and then relatively more subjects with

severe disease will be receiving antihypertensives. As the antihypertensives lower blood pressure, thesubjects with more severe disease, and on antihypertensives, may have their raised BP masked. If we

then attempt to correlate sleep apnoea severity with blood pressure, the relationship will be weakened,

and this will affect both cross sectional and longitudinal studies. The same problem may arise with a

number of other cardiac active drugs and cardiovascular risk factors, e.g. lipid lowering agents.

Measurement errors

Regression to the mean and regression dilution biasRegression to the mean may be illustrated by a theoretical study investigating whether drug x lowers

blood pressure. The study design selects subjects for inclusion based on the criteria that their blood

pressure is higher than 140/90 on the day of assessment. We know that blood pressure is variable day

to day and this one off measurement does not reflect usual levels. As we have selected subjects above140/90 we will have included a number of subjects who happen to have been at the upper end of their

own individual normal range on the day of assessment. When we next measure these subjects blood

pressures it is statistically probable that their blood pressure will be lower and that this is independent

of any intervention given (such as drug x). Any trial with this design must therefore have an

appropriate control group with the same inclusion criteria to be able to correct or account for this

phenomenon.

Regression dilution bias may also be influenced by office blood pressure variability. Figure 1

illustrates the increased measurement variability at the extremes of blood pressure, the usual pattern

for variables prone to regression dilution bias. If we consider studies of office blood pressure

measurement and morbidity, there is a close linear relationship between blood pressure and morbidity

through the majority of the usual range of blood pressure. In the relatively few subjects with very high

blood pressure however, the relationship flattens. This suggests that very high blood pressure does notcause an increase in morbidity. What is actually happening in these studies however is that one office

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blood pressure measurement does not reflect the subjects usual blood pressure, it just happened to be

very high that day and the subjects usual blood pressure is much lower than this, as is their risk of

morbidity.

Blood pressure (mmHg)

60 80 100 120

Blood

pressurevariability

Figure1. An illustration of blood pressure variability across the normal range of blood pressure.A typical pattern for variables prone to regression dilution bias

Relevance of sleep studiesSleep studies are imprecise through high variance and this may reduce their ability to predict

cardiovascular morbidity, but do they ever actually reflect the important pathophysiological processes

through which obstructive sleep apnoea (OSA) might lead to the development of hypertension? In

epidemiological studies, AHIs as low as 10, appear to be associated with hypertension. However, it is

hard to believe that just these 10 events per hour really cause hypertension. What is perhaps more

likely is that the these subjects have associated more subtle pathophysiological changes, such as

increased inspiratory effort due to upper airway resistance, that may be present for a greater proportion

of the sleeping hours1

and which are more likely to be the trigger which raises blood pressure. AHIwould then be acting as an indirect marker of the real pathophysiological cause. It is also likely that

there are interactions between several parallel pathophysiological processes and a patients genotype,

which produce the end result of hypertension.

Community versus Clinic Based Studies

Large prospective epidemiological studies in the normal population are well suited to investigate the

relationship between exposures and outcomes in the long term and also to estimate the public health

burden of diseases in the general population. These studies may take many years to reach a conclusion,

as outcomes may only become apparent after prolonged exposure, or interval, between risk and

disease. Where there are established risk factors for a disease, it is useful to study not only the clinical

syndrome of interest but also any likely intermediaries, which link exposure to outcome, such as OSA

to hypertension.Associations between OSA and hypertension are likely to be apparent within shorter time spans than

for overall cardiovascular morbidity but perhaps more importantly, this allows the interactions

between the exposure, the intermediate and the outcome to be fully explored. This is useful as such

interactions can bias cross sectional studies. For instance, subjects with severe OSA and hypertension

may have a higher mortality rate than predicted for a given level of BP. However, because deceased

subjects cannot be accounted for in cross sectional studies, the prevalence of severe disease may be

underestimated, relationships between OSA and hypertension are weakened, and the prognostic value

of BP would therefore be underestimated. This prevalence / incidence bias (survival bias) is best

assessed by long term prospective epidemiological studies which include all the likely interacting

factors which may affect outcome.

Many of the early studies on BP and OSA used samples from clinic populations. Whilst these identify

more subjects with moderate or severe disease, and can explore relationships across the disease

spectrum, these samples are not usually representative (of all cases) with the condition in the general

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population, and cannot be used to estimate the public health impact of the disease. Clinic based studies

however can use more intricate measures of both BP and OSA severity, and are as such more likely to

uncover the more important intermediates between the syndrome and cardiovascular risk in the longer

term. Ultimately the clinic location is perhaps best placed to address the effects of different treatments

in modifying OSA severity, symptomatic benefits and changes in BP profile, but again caution is

needed in extrapolating these results back to the general population.

Cardiovascular Consequences of Obstructive Sleep Apnoea

MortalityThere are several reports of high mortality in snorers

2and obstructive sleep apnoea subjects

3Mortality

occurs more frequently at night than should occur by chance and is likely to be due to cardiovascular

disease.4-9

. More recent reports have demonstrated high mortality in untreated OSA patients.10-

12.These studies are not randomised and the control populations cannot be considered normal,

however they provide convincing evidence of improved mortality with CPAP, and surgery in OSA.

Stroke and transient ischaemic attacks

Some authors have suggested that sleep apnoea is important as a cause of stroke 13The nocturnalincrease in ischaemic stroke incidence is likely due to the combination or sympathetic activation and a

hypercoagulable state.

OSA can lead to stroke and vice versa14

.15-18

Transient ischaemic attacks may be more common in

OSA. Since TIA is a risk factor for stroke this implies that obstructive sleep apnoea is a risk factor for-

stroke per se19

.

In subjects with stroke, obstructive sleep apnoea is associated with worse functional outcome20

,

further stroke, and mortality14

. Although there are several studies of mortality and obstructive sleep

apnoea3-9

, few of these have looked specifically at stroke deaths.

Cardiac IschaemiaEpisodes of cardiac ischaemia are precipitated by disturbances in myocardial oxygen supply and

demand. Subjects with OSA therefore have a number of triggers for myocardial ischaemia which

occur repeatedly throughout the night, with apnoea associated tachycardia, blood pressure rise and

peripheral vasoconstriction increasing cardiac work at the time of minimal oxygen saturation.

Myocardial infarction and coronary artery diseaseFrom mortality studies in obstructive sleep apnoea subjects, 4 report associations between OSA and

ischaemic heart disease incidence6;21

%7;10;22

.

OSA is more common in patients with established ischaemic heart disease23;24

,25

.

The Sleep Heart Health Study examined cross sectional associations between sleep disordered

breathing measured from polysomnography and self-reported cardiovascular disease incidence in 6424

independent members of the normal population. The authors reported increased relative odds of

cardiovascular disease across the quartiles of sleep disordered breathing. The relative odds betweenthe upper and lower court files being 1.42 (1.13-1.78) for self-reported cardiovascular disease.

Although self reported coronary heart disease prevalence alone was less strongly associated with

obstructive sleep apnoea, odds ratio between upper and lower AHI quartiles 1.27 (0.99 - 1.62)26

.

In summary OSA may precipitate cardiac ischaemia and nocturnal angina in subjects with CAD. In

addition there is some evidence that CPAP may reduce both OSA and nocturnal cardiac ischaemia in

these subjects although there is conflicting evidence as to whether OSA causes cardiac ischaemia in

the absence of coexisting CAD.

Arrhythmias

Obstructive sleep apnoea is accompanied by a characteristic cyclical Brady-tachyarrhythmia

associated closely with episodes of upper airway obstruction or increased upper airways resistance27.Bradycardia is very common following obstructive apnoeas with sinus pauses reported to occur in 5-

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10% of subjects, type II heart block in 4-8%, with prolonged sinus pauses up to 15.6 seconds

described28-31

. Some authors have suggested that cardiac arrhythmias occur more commonly below a

particular oxygen saturation threshold, and others showed that frequency of PVCs was correlated to

the duration of low oxyhaemoglobin saturation (5) demonstrated rhythm

disturbances in 16 (31%) Sinus arrhythmia was reported in 8 (14%) with marked bradycardia (heart

rate140mmHg, diastolic BP >90mmHg, or taking antihypertensive medications). Both mean systolic and

diastolic BP and the prevalence of hypertension increased significantly with increasing measures of

obstructive sleep apnoea.

The Wisconsin Sleep Cohort Study, a prospective population study of the association between

obstructive sleep apnoea and cardiovascular disease is ongoing but has reported some important data

on hypertension44

. After adjustment for confounders, the odds ratios for the presence of hypertension

at follow up for AHI 0.1-4.9 versus control (AHI 0- 0.1) was 1.42 (95% CI 1.13-1.78); AHI 5-14.9

versus control, 2.03 (95% CI 1.29-3.17); AHI > 15 versus control, 2.89 (95% CI 1.46-5.64). The

results were similar when a more conservative definition of hypertension was used (>160mmHg

systolic, >100mmHg diastolic), and for other cut points for hypertension between 130 / 85 and 180 /

110 mmHg.

Of note in all these studies is that even a mild degree of obstructive sleep apnoea, which is quiteprevalent within the general population, was associated with raised BP at baseline, and also at four

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years in the Wisconsin study. This suggestion is backed up by other population studies, which found

that self reported snoring, itself a soft marker of obstructive sleep apnoea, was associated with a higher

prevalence of hypertension at baseline and the incidence of hypertension in the longer term37;45

.

Clinic based epidemiology studies

Lavie et al, studied 2677 subjects over a 10-year period from their clinic. Excluding subjects on

antihypertensive medication, the data were explored using stepwise linear regression analysis to

identify the influence of obstructive sleep apnoea on morning BP. When corrected for age, sex and

neck circumference (the most influential marker of obesity on BP in this study), the AHI remained

significantly related to diastolic (r2

0.22) and systolic (r2

0.20) pressure, thus accounting for ~20% of

the variance in both systolic and diastolic BP. The model from this analysis predicted a rise of

0.1mmHg in systolic, and 0.04 mmHg in diastolic, pressure for each additional apnoea / hypopnoea

per hour of sleep. A subject with an AHI 60 should have a systolic pressure 6mmHg and a diastolic

pressure 4.7mmHg higher than a subject without OSA.

A further group has studied hypertension in a group of 741 men and 1000 women. The subjects were

divided into four groups on the basis of self reported snoring and apnoea / hypopnoea index. The

authors reported an independent association between both snoring and sleep apnoea, and hypertension

when corrected for age, sex, body mass index, race, alcohol and smoking. This relationship wasproportional to the severity of the sleep apnoea and decreased with advancing age.46

Case control studies

Lavie et al matched 674 subjects with AHI>10 to subjects with AHI

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Baroreflex sensitivity is reported to be depressed in non apnoeic snorers68

and subjects with

obstructive sleep apnoea69-72

. There is a loss of the normal nocturnal rise in baroreflex sensitivity in

subjects with obstructive sleep apnoea, with some groups also suggesting a reduced coupling between

respiration and cardiovascular variability73

. CPAP may improve nocturnal baroreflex sensitivity in

subjects with obstructive sleep apnoea as it does in subjects with heart failure and central apnoea74

.

Compared to a control population matched for sex and body mass index, obstructive sleep apnoea

subjects have faster heart rates with reduced overall heart rate variability and an increased component

of low frequency variation (thought to represent sympathetic modulation of heart rate)75

.Other groups

have also reported reduced heart rate variability in association with sleep apnoea76-78

with one group

reporting an increase in the very low frequency component of heart rate variability79

and another

suggesting that very low frequency power may reduce after CPAP80

.

Endothelial function

In keeping with abnormal sympathetic activation, forearm blood flow responses to infused vasoactive

agents are abnormal in subjects with sleep apnoea compared to controls81-83

, which may improve

following CPAP treatment84

. In addition they appear to have abnormal in vivo vasoconstriction

responses to hypoxic eucapnic challenge85

.

As well as high Atrial Natriuretic Peptide levels, OSA subjects also have high Renin, Angiotensin andAldosterone levels, again there is some suggestion that these may improve following CPAP86

CPAP is reported to improve cardiac function in OSA subjects87

and may reduce the incidence of

cardiovascular disease following long term use88

. Apart from its effect on BP, little is known about

other mechanisms of benefit. Although studies of CPAP in subjects with cardiac failure suggest that it

may work in part by reducing LV wall tension.

Cardiovascular risk overall

Although there is a great deal of interest in sleep disordered breathing and cardiovascular disease there

are few studies of overall cardiovascular risk in obstructive sleep apnoea. Maekawa et al mention

cardiovascular risk in their short report on ischaemic heart disease89

but the only full report is from

Keilly et al. In this study the authors allocated subjects with obstructive sleep apnoea a 10 year

cardiovascular risk based on the Framingham dataset models90-92

. They found that subjects withobstructive sleep apnoea had a high risk of future cardiovascular events from their baseline

cardiovascular risk profile independent of sleep apnoea severity. For example men had a 10 year risk

of stroke of 12.3% (95% CI 9.4 15.1) or coronary heart disease 13.9 (12.1 16.0).

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Cardiovascular Morbidity inSleep Apnea

Just in Pepperel l

Taunton and Somerset NHSTrust, UK

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ERS School Course on Sleep Medicine

TD Bradley Ed, Marcel Dekker 2000

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Mechanisms

Renin angiotensin activation

Vascular dysfunction Sympathetic activation

Endothelial dysfunction

Oxidative stress

Inflammation Platelet activation

Gene activation apoptosis

Obesity / leptin

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Sympathetic activation

Muscle sympatheticnerve activityincreased in OSA

Plasma and urinarycatecholaminesincreased in OSA

Night-time and overall

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Flow mediated vasodilation

normals and OSA

Ip et al AJRCCM Vol

169. pp. 348-353,(2004)

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Daytime sleepiness, Obesity andinflammatory cytokines

Vgontzas AN, The Journal of Clinical Endocrinology& Metabolism Vol. 82, No. 5 1313-1316

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Platelet activation in sleep apnea

G Bokinsky, 1995;108;625-630Chest

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Study Design and Confounders

Measurement errors

Regression to the mean

Regression dilution bias

Relevance of sleep studies

Hypoxia, intrathoracic pressure and arousalCommunity versus clinic based studies

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Measurement

variability

BP

BP value high

high

low

low

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BP value highlow

number

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Regression dilution bias

CVD

risk

Blood pressure

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Evidence for CVD disease in OSA

Risk Factors for CVD

Overall CVD risk

Prevalence of CVD

Incidence of CVD

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Intermediaries of CVD in OSA;

Diabetes

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Intermediaries of CVD;

Hyperlipidaemia

High total cholesterol 46%

High triglycerides 47%

Either high 63%

n=114 mean age 52 AHI ~45

Kiely, JL,et al Eur Respir J2000;16,128-133

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Overall cardiovascular risk in OSA patients

Kiely, JL,et al Eur Respir J2000;16,128-133

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CVD in OSA BP

Prevalence hypertension higher clinic and community, IncidenceHypertension higher, BP higher than matched controls

IHD OSA common in IHD patients, IHD prevalence and incidence

higher in OSA subjects

Heart Failure More common in OSA, OSA gives worse prognosis

Stroke Snoring risk for stroke, OSA risk for TIA, OSA after stroke means

worse recovery, recurrent stroke and mortality

Mortality High in OSA and snoring, Occurs at night more commonly than

expected

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Hypertension in OSA

p for trend = 0.002

2.89 (1.46-5.64)67> 15

2.03 (1.29-3.17)1325 14.9

1.42 (1.13-1.78)5070.1 4.9

1.001870

Odds ratio of developing

hypertension (95%

CI)**

Wisconsin Sleep Cohort

Study n=

Apnoea Hypopnoea index

Events per hour

p for trend = 0.005

1.37 (1.03-1.83)373>30

1.25 (1.00-1.56)71915 29.9

1.20 (1.01-1.42)17515.0 14.9

1.07 (0.91-1.26)15981.5 4.9

1.001691< 1.5

Odds ratio of having

hypertension (95% CI)*Sleep Heart Health Study n=

Apnoea Hypopnoea index

Events per hour

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Sleep Heart Health Study Log odds ratios

of CVD for AHI

ShaharE et al , Am. J. Respir. Crit. Care Med.,Volume 163, Number 1, January 2001, 19-25

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OSA and mortality

He et al 385 male OSA (Chest 1988) 8 year cumulative mortality 37% OSA vs 4% for AHI >20

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Hypertension increasesmortality

Days of Survival

0 500 1000 1500 2000 2500 3000 3500 4000

Cumulativesurvival(%)

0

10

20

30

40

50

60

70

80

90

100

without hypertension

with hypertension

Noda et al, J Clin Neuroscience, 1998, 52,79

N=148

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Evidence for reducing CVD risk in

OSA with treatment

CPAP

Intermediaries, BP, CVD, CHD, death

Obesity management

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Evidence for reducing CVD risk in

OSA with treatment

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Flow mediated vasodilation afterCPAP

Ip et al AJRCCM Vol169. pp. 348-353,(2004)

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Improved insulin sensitivity after

CPAP

AHarsch AJRCCM 2004169. pp. 156-162, (2004)

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Treatment CPAP

after treatment

Time from wake and sleep onset (hours)

Meanbloodpressure(mmHg)

85

90

95

100

105

110

115

120

wake 4 8 12 16 sleep 4 8

before treatment

Meanbloodpressure(mmHg)

85

90

95

100

105

110

115

120

Becker et al Circulation 2003 Pepperell et al, Lancet

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Change in mean BP split by median

SaO2 diprate

sleepiness

Groups split by median baseline oxygen saturation dip rate( 4% dips / hour)

33Changein24hourmeanbloodpress

ure(mmHg)

-6

-4

-2

0

2

4 p=0.4 p=0.001

Groups split by median Osler test above below 20 minutes

>20

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BMI and mortality

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Treatment Behavioural

Weight reduction

5kg~5/3mmHg

Orlistat/ sibutramine

Diet

Reduce salt 40

BMI > 35 + complications

Bariatric surgery JAMA. 2004 Oct

13;292(14):1724-37 Buchwald

22,094 patients 16-64 yrs

BMI 46.9 lost 60% ofexccess weight

Mortality .1%-1.1%

Improved Diabetes 77%

BP 62%, Lipids 70%, OSA86%

Sjostrom et al Hypertension 1998

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How to use this information in clinic

Standard CVD risks Assess and treat Obesity, Smoking, Diabetes, BP, Cholesterol

Standard OSA Treat

Asymptomatic OSA Assess CVD risk

Assess OSA severity

Investigate resistant hypertension for OSAConsider secondary causes / hyperaldosterone if compliant on CPAP

and resistant BP

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Asymptomatic

OSA Signs of secondary

causes OSA CVD

Investigations

Secondary causes

Target organ damage

Cardiovascular risk

Vascular tone

Confirm blood pressure

Sleep apnoea severity

Symptoms and AHI

riskcalculator.exe

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sleepiness

Sleepapnea

severity

Tendencyfor CPAP

trial

10 yr CVDrisk >20%

ESS 5

AHI /SaO2

diprate 10

10 yr CVD

risk

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Summary

Modify normal cardiovascular risks

Obesity, Smoking, Diabetes, BP, Cholesterol

Treat OSA to releive symptoms

Try CPAP in severe OSA if CVD risk high

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Aims

mechanisms of CVD in OSA

confounding factors in studies in thisarea

evidence for CVD in OSA

evidence for CVD risk reduction in OSA

who and how to treat in clinic to reducecardiovascular risk

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