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Chapter 4
Epidemiology of OSAE. Lindberg
Summary
Approximately 37% of adult males and 25% of adult femalesinwestern countries and Asia suffer from symptomaticobstructive sleep apnoea syndrome (OSAS) and are thereforecandidates for treatment. In addition, a large percentage ofindividuals suffer from either snoring in combination with
sleepiness or OSA without overt daytime symptoms. Theclinical significance of this is still controversial.
Sex, obesity and age are all important risk factors for OSA.Moreover, smoking, alcohol consumption and physical inactivityappear to increase the occurrence of the disorder.
The relationship between OSA and daytime hypersomno-lence is not completely understood. Most subjects with verifiedOSA do not report daytime sleepiness and there is increasingevidence that snoring without apnoeas or hypopnoeas might
also relate to sleepiness.Cross-sectional studies indicate an independent link betweendiabetes and OSA but this has not yet been confirmed inlongitudinal surveys.
Keywords: Epidemiology, population-based, prevalence, sleepapnoea, snoring
Correspondence: E. Lindberg, Dept ofMedical Sciences, RespiratoryMedicine and Allergology, UppsalaUniversity, Akademiska sjukhuset,SE-751 85 Uppsala, Sweden, [email protected]
Eur Respir Mon 2010. 50, 5168.Printed in UK all rights reserved.Copyright ERS 2010.European Respiratory Monograph;ISSN: 1025-448x.DOI: 10.1183/1025448x.00025909
T
he clinical features of obstructive sleep apnoea syndrome (OSAS) were described in the
medical literature more than 30 yrs ago [1]. Despite being described, awareness of this newdiagnosis was slow to develop during the following years and it attracted very limited attention.Interest in OSAS outside the field of sleep medicine started to increase following reports fromepidemiological studies showing an association between snoring, the cardinal symptom of OSAS,and hypertension, as well as other cardiovascular diseases [26]. When, some years later,population-based studies reported an unexpected high prevalence of the disorder [710], thesituation changed dramatically and OSAS could no longer be ignored by healthcare systems.
The diagnosis of OSAS is based on the combination of laboratory findings taken from recording acomplete nights sleep and daytime symptoms. OSAS patients in sleep clinic cohorts have all beenreferred for the diagnostic sleep test because of symptoms suggestive of the diagnosis and they are,
most frequently, heavy snorers suffering from daytime sleepiness. As will be discussed later, mostpeople with sleep apnoea do not fulfil the diagnostic criteria for the full-blown syndrome and theimpact of sleep apnoea on future health, when daytime symptoms are not taken into account, canonly be analysed in population-based surveys. It is, therefore, important to bear in mind that theresults of clinical and epidemiological surveys within this field are not always comparable. As thereis still no general agreement on how to define OSAS and the parameters needed to define
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symptoms and determine negative health effects, both clinical and epidemiological studies arerequired to enable an improved understanding of the complete picture. The term sleep-disorderedbreathing is commonly used and includes a wide range of conditions linked with narrow upperairways and the loss of normal respiratory patterns during sleep. At one end of the spectrum thereare subjects with intermittent partial obstruction of the upper airways, giving rise to snoringwithout fragmentation of sleep i.e. simple snorers, and at other end patients who endure hypoxiaepisodes during sleep and extreme sleepiness during the day. Hence when not clearly specified,
sleep-disordered breathing can refer to anything from snoring or obstructive sleep apnoea (OSA)to OSAS with intermittent hypoxia, fragmentation of sleep and severe daytime sleepiness. It is,therefore, very important to consider which part of the syndrome is investigated in each study.Furthermore, as the prevalence of snoring, OSA and OSAS differ a great deal, it is extremelyimportant to identify the parts that have an impact on the outcome of a patients health.
The diagnosis of sleep apnoea in adults and in children will be discussed further in thisMonograph. When comparing epidemiological studies in which subjects do not fulfil the completediagnostic criteria for the syndrome, including daytime symptoms, the diagnostic criteria for sleepapnoea have an important effect on the outcome. The varying methodological approaches inepidemiological studies assessing the prevalence and health-related consequences of OSA
sometimes can limit accurate comparisons. For example, the chosen oxyhaemoglobin desaturationthreshold, i.e. 3 or 4%, used to define hypopnoea can lead to a differing total for the apnoea/hypopnoea index (AHI) and thereby varying the estimates for disease severity. Awareness of thesefactors is vital to improve the understanding of why studies with similar designs sometimesproduce wide discrepancies in their estimates for prevalence or measures of association.
In this chapter, the epidemiological literature on prevalence, risk factors and consequences of thedisorder has been reviewed. However, much of the current knowledge regarding epidemiologywithin this field is still based upon studies that analyse snoring and part of this literature has alsobeen included here. When not otherwise stated, cited data on the consequences of snoring refers to
studies where snoring has been used as a surrogate marker of OSA and not to snoring withoutsleep apnoea.
Prevalence
The most frequently used method for estimating the presence of snoring is a questionnaire and thesnoring prevalence is usually rated on a frequency scale; examples of the response options givenare: never, often or the number of nights that snoring occurred in a week. Although there were4,155 citations of snoring on Medline in March 2010, there is still no standard, uniformly acceptedtechnique for its objective measurement [11] and, as long as there is no gold standard for objective
measurements, the validation of self-reported snoring remains a problem. In a sleep clinic cohort,the validity of snoring as a marker of sleep apnoea was independent of age and sex [12].
Studies, involving snoring prevalence, have reported large differences in their prevalence rates. On thebasis of epidemiological studies, 950% of males and 417% of females reported snoring [1320].However, very few multicentre studies have been performed. In one such study by JANSONet al. [21],which estimated the prevalence of snoring among age- and sex-matched populations in threecountries using the same questions answered on the same frequency scale, very similar results werefound. Thereby, indicating that the great differences in snoring prevalence between study populationsare probably due to methodological differences. Furthermore it was found, in a population-basedsample of males who reported their own snoring frequency and then had their snoring measured usinga microphone for one night, that the validity of self-reported snoring, as a marker of recorded snoringsounds foro10% of the night, did not significantly differ between the younger (age 4059 yrs) and theolder (age 6079 yrs) age groups [22].
Only 25 yrs ago OSAS was still regarded as an extremely rare disorder. Studies designed to estimatethe prevalence of undiagnosed OSA and OSAS commonly used the two-stage sampling procedures
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in which sleep studies were conducted on subsets of participants taken from large sample surveys.In the first prevalence surveys, sleep recordings were only performed in subsamples with a highrisk of OSAS in a first-stage screening procedure and the estimated prevalence in the wholepopulation was based on the assumption that there was no OSA at all among the remainingparticipants. The estimated prevalence of undiagnosed OSA in these studies ranged from 0.73.3%[7, 2326]. More recent studies that give prevalence estimates for OSA and OSAS in the generalpopulation are presented in table 1. As previously noted, comparisons between the results are
limited by methodological differences, including differences in sampling schedule, disparities intechniques used for monitoring sleep breathing, and the variability in definitions. However,although there is a fairly wide range regarding prevalence of sleep apnoea defined as an AHI .5events?h-1, the estimated prevalence of OSA and accompanying daytime sleepiness is relativelyconsistent across several population cohorts. With the exception of one study by NAKAYAMA-ASHIDAet al.[32], the prevalence of OSA syndrome is approximately 3 7% for adult males and 25% for adult females. NAKAYAMA-ASHIDAet al.[32] reported a much higher prevalence of OSAS inJapanese males. In their study, breathing was recorded with pressure sensors and a lower limit of3% desaturation was used to define hypopnoeas.
Risk factorsSex
Research studies have repeatedly and consistently confirmed that OSA is more common in malesthan females. The male-to-female ratio is estimated to be approximately 2:1 in the generalpopulation (table 1) and the prevalence of snoring shows similar sex differences [13, 33, 34]. Inclinical populations, the male predominance is usually even higher [35, 36]. The reason for thismale predominance is not exactly clear. Possible explanations include the effects of hormonalinfluences affecting muscles of the upper airway and its ability to collapse, sex differences in body
fat distribution, and differences in pharyngeal anatomy and function. It has been suggested thathormonal influences play an important role in the pathogenesis of OSA, as the prevalence is higherin post- versus pre-menopausal females [37]. However, the role of hormones in OSAspathophysiology is not clearly defined and a difference in its prevalence, with respect to sex isapparent in the elderly population [37].
Age
The available epidemiological data on the impact of age on sleep-disordered breathing highlightsthe differences between snoring, OSA and OSAS. Several population-based studies have reported
an increase in snoring with age, followed by a decrease after the ages of 5060 years in both males[13, 16, 24] and females [20]. In the case of sleep apnoea, there is also a clear increase in theprevalence with age that could not be explained by other risk factors such as obesity [26, 38, 39].Most prevalence studies of sleep apnoea have investigated only populations up to the age of60 years (table 1). However, when subjects above that age have also been included, there has beena continuous increase in the prevalence of OSA [26, 28]. However, this finding does not appear tomirror the true prevalence of clinically significant OSAS. In a study based on a two-stage generalrandom sample of 4,364 males, BIXLER et al. [26], found that the prevalence of OSA (AHI o5events?h-1) was present in 7.9% of males aged 2044 yrs, 18.8% of males aged 4564 yrs andincreased to 24.8% of males aged 65100 yrs. In the same cohort the prevalence of OSASdiagnosed according to Sleep Disorders Clinic criteria increased with age until the age of 5060 yrs, followed by a decline [26]. This finding suggests that while self-reported snoring anddoctor-diagnosed OSAS display similar age distributions showing a decline in the older age range,this is in contrast with the age distribution of OSA that seems to increase regardless of age.
There is no doubt that older adults with symptomatic OSAS benefit, similar to younger adults,from adequate treatment when it comes to symptom relief. Conversely, when it comes to the data
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Table1.Popu
lation-basedstudiesontheprevalenceofobstructivesleepapnoe
a(OSA)andobstructivesleepap
noeasyndrome
First
author
[Ref.]
Study
population
Ageyrs
Samplesize,
sexandcriteria
AHI#
o5events?h
-1
AHI#
o15events?h
-1
OSA#
syndrome
Methodology
Hypopnoea
definition
M
F
M
F
M
F
YOUNG
[9]Randomsample
of3513state
employeesin
WI,USA
3060
350males,
250females
Habitualsnorers
(n5355)anda
randomsampleof
non-habitualsnorers
(n5247)
24
9
9
4
4
2
AttendedPSG
Discernible
reductionin
airflowand
o4%
oxygen
desaturation
BIXLER[26]
Random
sampleof
4364malesin
PA,USA
20100
741male
A
ge-stratifiedcohorts,
oversamplingof
high-riskindividuals
17
7
3.3
AttendedPSG
Discernible
reductionin
airflowand
o4%
oxygen
desaturation
IP[18,19]
3074"
office
workersin
HongKong,
China
3060
15
3males,106females
A
llparticipantsinvited
forPSG
18.8
3.7
5.3
1.2
4.1
2.1
AttendedPSG
Discernible
reductionin
airflowand
o4%
oxygen
desaturation
BIXLER[27]
Random
sampleof
1
2219females
inPA,USA,
20-100
1000males
Oversamplingof
high-riskindividuals
5
2
1.2
AttendedPSG
Discernible
reductionin
airflowplus
o4%
oxygen
desaturation
DURAN
[28]2148subjects
fromthe
general
populationin
V
itoria-Gasteiz,
Spain
3070
32
5males,235females
T
entativediagnosisof
O
SAH(n5390)anda
randomsample
(n5170)
26
28
14
7
3.4
3
AttendedPSG
50%
airflow
reductionand
eithero4%
oxygen
desaturationor
anEEGarousal
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Table1.Continued
First
author
[Ref.]
Study
population
Ageyrs
Samplesize,
sexandcriteria
AHI#
o5events?h
-1
AHI#
o15events?h
-1
OSA#
syndrome
Methodology
Hypopnoea
definition
M
F
M
F
M
F
UDWADIA
[29]
658healthy
m
alesattending
hospitalfor
routinehealth
checkin
B
ombay,India
3565
250males
Allsnorers
(n5171)and
25%
of
nonsnorers
19.5
8.4
7.5
HomePSG
Discernible
50%
reduction
inairflowand
o4%
oxygen
desaturation
KIM
[30]
Population
ba
sedsampleof
50
20residentsin
Seoul,Korea
4069
309males148
oversamplingof
habitual
snorers
27
16
10.1
4.7
4.5
3.2
Homeorin
laborato
ry
PSG
Discernible
reductionin
airflowand
o4%
oxygen
desaturation
SHARMA
[31]
2400citizensin
D
elhi,Indiawith
anexclusion
criterionof
se
veraldiseases
3060
88males,
63females
Habitualsnorers
n577and
nonsnorers
n574
19.7
7.4
4.9
2.1
Attended
in
laborato
ry
PSG
Discernible
50%
reduction
inairflow
ando4%
oxygen
desaturation
NAKAYAMA-
ASHIDA
[32]
466male
employeesofa
wholesale
companyin
Osaka,Japan
2359
322males
37.4
15.7
17.6
Hometyp
e3
portable
monitorsand
actigraphy
o50%
reductionin
nasal
pressureor
respiratory
effortand
o3%
oxygen
desaturation
AHI:apnoea/hy
popnoeaindex;M:male;F:fe
male;PSG:polysomnography;OSAH:obstructivesleepapnoe
a/hypopnoeasyndrome;EEG:electroencephalography.
#:estimatedpre
velance(givenasapercentage);
":M51,542,F51,532.
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on negative health effects attributable to OSA in the elderly population, there is moreinconsistency. Several studies have reported little or no association between sleep-disorderedbreathing and morbidity and/or mortality at an older age. It has been suggested that sleep apnoeain the elderly represents a specific entity compared with that seen in middle-aged adults [40]. Dueto the high prevalence of sleep apnoea in the older age range, there is an urgent need forprospective studies of population-based samples of elderly subjects analysing the long-term healtheffects of OSA and OSAS, with adequate control for confounding risk factors and comorbidity.
Obesity
Excess body weight is a major risk factor for snoring and sleep apnoea, 70% of patients with OSASare overweight [4143]. Although there is still a lack of randomised controlled studies evaluatingthe effect of weight loss the unvarying observation is that weight loss, either as a result of a calorierestricted diet or surgery, reduces the severity of the disease [4447]. PEPPARD et al. [39] twiceevaluated, at 4-yr intervals, a population-based sample of 690 males and females foranthropometric variables and sleep apnoea. Compared with subjects with stable weight overtime, a 10% weight gain predicted an approximate 32% (95% CI 2045%) increase in the AHI andpredicted a six-fold increase in the odds of developing moderate-to-severe sleep-disorderedbreathing defined as an AHI ofo15 events?h-1. For those who lost weight, it was observed that a10% weight loss predicted a 26% (95% CI 1834%) decrease in the AHI [39]. Regardless of thestarting weight, waist circumference, age or ethnicity, males are more likely than females toincrease their AHI at a given weight gain [48].
Obesity is believed to predispose to OSA because of mass loading to the upper airway of the neck[49]. Controversy remains as to whether specific measurements of body habitus, such as neck orwaist circumference, are better predictors of sleep-disordered breathing as compared with bodymass index (BMI) alone. In a population-based sample of females subdivided by BMI groups,increasing neck circumference became more important as a risk factor for snoring than increasing
BMI alone [20].It has been estimated that 58% of the moderate-to-severe cases of OSA can be attributed to a BMIo25 kg?m-2 [48]. This highlights the need for effective strategies to implement long-term weight-loss programmes to prevent the ongoing epidemics of obesity and OSA. However, despite thestrong relationship with obesity, it is important to remember that not all subjects who are obese orhave a large neck circumference suffer from sleep apnoea [50] and that some one-third of OSASpatients are not obese.
Physical inactivity
In contrast to the large number of studies undertaken on obesity and sleep apnoea, there are fewreports on the role of physical activity on apnoea frequency. This might be a direct effect of thedifficulty associated with characterising the level of physical activity in large cohorts. The fewreports undertaken on the association between physical activity and snoring have producedsomewhat contradictory results. In a cross-sectional Finnish study by KOSKENVUOet al.[42], maleswith a reported low level of physical activity had a higher prevalence of snoring that could not beexplained by age or obesity. Similar findings were reported from a study by HU et al. [17] thatexamined the health of some 73,231 US nurses. The multivariate analysis from their study revealedthat there was an inverse dose-response relationship between the level of physical activity andsnoring. Compared with the physically inactive, the most active females were 34% (95% CI 27
39%) less likely to be regular snorers. In contrast to this LINDBERG et al. [51] showed that in aprospective population-based sample of 2,668 males, who were investigated over a 10-year periodfor the development of snoring, physical inactivity had no significant impact when otherconfounders were adjusted for. In addition a population-based Swedish female cohort study,stratified by BMI, showed an independent relationship between a low level of physical activity andsnoring only among the obese females with a BMI o30 kg?m-2 [20]. Collectively these data must
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be handled with caution due to the small number of studies undertaken within the field and thefact that the impact of physical activity on sleep-disordered breathing remains uncertain.
Smoking
Several cross-sectional epidemiological surveys have found significant associations betweencigarette smoking and snoring [13, 17, 33, 52, 53] or sleep apnoea [54, 55]. Possible underlying
mechanisms for this include airway inflammation and the fact that overnight withdrawal fromnicotine increases sleep instability, both of which have been linked to OSA [56]. According to aNordic multicentre study, never-smokers who have been exposed to passive smoking on a dailybasis display an increase in the odds of being an habitual snorer of 1.6 (95% CI 1.22.1) afteradjusting for age and BMI [53]. In a Swedish longitudinal study, smoking predicted thedevelopment of snoring in males below the age of 60 years but not in older males [16].
WETTER et al. [55] found a doseresponse relationship between smoking and the frequency ofapnoeas and hypopnoeas per hour of sleep. Heavy smokers ran the greatest risk, while formersmoking was unrelated to snoring and sleep-disordered breathing after the adjustment forconfounders. However, the role of smoking as an established risk factor for OSA is not without
controversy. In the analysis from the Sleep Heart Health Study, smokers actually displayed lesssleep apnoea than nonsmokers [57] and there are still no available data concerning the impact ofsmoking on the incidence or remission of sleep apnoea remission.
Alcohol
Experimental studies indicate that alcohol intake reduces motor output to the upper airways,resulting in hypotonia of the oropharyngeal muscles [58]. In studies performed in the laboratory,alcohol increases both the number of apnoeas and the duration of apnoea [59, 60]. When therelationship between chronic alcohol use and snoring or sleep apnoea has been analysed in
epidemiological studies, findings have been contradictory, an association has been found by some[61, 62] but not by others [16, 29, 41, 63]. This discrepancy might reflect the difficulty associatedwith finding reliable instruments for estimating alcohol use in epidemiological studies. However,when analysing the relationship between alcohol and snoring in different BMI categories,SVENSSON et al. [20] found that alcohol dependency was only significantly related to snoring infemales with a BMI ,20 kg?m-2. It is possible that the alcohol induced reduction in motor outputto the upper airways is more important in subjects who are either normal weight or underweight,as these subjects are less likely to have anatomical abnormalities in their upper airways, i.e. fatdeposits, as an explanation for their snoring compared with overweight females [58].
Consequences
Sleepiness
Excessive daytime sleepiness is the cardinal symptom of OSA. Numerous studies havedemonstrated an improvement in daytime sleepiness when clinically identified patients areeffectively treated with continuous positive airway pressure (CPAP) as compared with sham CPAPor oral placebo [6470]. In addition, in the general population there is evidence that both OSAand snoring are important causes of daytime sleepiness [9, 6971]. In the Wisconsin Sleep CohortStudy, approximately 23% of the females with an AHI o5 events?h-1 reported excessive daytime
sleepiness compared with only 10% of the nonsnoring females [9]. The corresponding prevalencein males was 16 and 3%, respectively. Similar findings were reported from the Sleep Heart HealthStudy using the Epworth sleepiness scale (ESS) score for measuring sleepiness [72]. There was asignificant progressive increase in sleepiness with an increasing AHI from a mean ESS score of 7.2,in subjects with an AHI ,5 events?h-1, to a score of 9.3 in those with an AHI o30 events?h-1. Theassociation between the AHI and the level of daytime sleepiness was similar in older and younger
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subjects and was independent of sex, age or BMI [69]. However, the relationship between OSA anddaytime hypersomnolence is not completely understood. It is generally believed that excessivedaytime sleepiness is caused by repeated arousals from apnoeas and hypopnoeas leading to sleepfragmentation. Attempts to find an association between the number of arousals and the severity ofsleepiness have failed [73, 74]. Furthermore, in patients with other chronic diseases the associationbetween OSA and sleepiness might be less evident. For example, patients with congestive heartfailure are known to report less daytime hypersomnolence regardless of whether they have OSA or
not [75]. Conversely, in other chronic diseases such as end-stage renal disease [76], or in elderlysubjects [77], sleepiness is a frequently reported symptom in the absence of OSA and is thereby nota useful clinical symptom to suggest the diagnosis of OSA in these patients.
Snoring is often regarded as a simple marker of sleep apnoea and the scientific interest in snoringper sehas been limited. When it was previously reported that sleepy snorers are significantly morefrequently involved in occupational accidents, it was suggested that this was because ofconcomitant OSAS [78]. However, when it comes to the impact on daytime sleepiness there isincreasing evidence that snoring is also related to sleepiness in the absence of apnoeas andhypopnoeas. YOUNGet al. [9] reported that habitual snorers with an AHI ,5 events?h-1 reportedsymptoms of hypersomnolence more frequently compared with nonsnoring control subjects.
YOUNGet al. [79] also showed that habitual snorers with an AHI ,5 events ?h-1 run the risk ofmotor vehicle accidents to the same degree as subjects with an AHI .5 events?h-1. GOTTLIEBet al.[80] reported that snoring was related to an ESS score o11 across all categories of the respiratorydisturbance index, independent of age, sex, race or BMI. In 850 randomly selected males,STRADLING et al. [81] found that positive answers to all questions regarding sleepiness correlatedsignificantly with self-reported snoring. Although sleep apnoea severity, as measured by thefrequency dips in blood oxygen saturation of 4% during the night, was significantly related to theanswers from three questions on sleepiness, it was never more important than snoring as apredictor of sleepiness and never reduced its significance. Moreover, when adjusting for sleepapnoea, reports of snoring were often associated with a five-fold increase in the chance of a subject
almost having an accident, while driving, due to sleepiness. More recently, similar results werereported by SVENSSONet al.[71], who studied a population-based sample of Swedish females aged2070 years with questionnaires and polysomnography (PSG) to investigate whether symptoms ofsleep apnoea are related to AHI, independent of snoring and vice versa. Habitual snoring wassignificantly related to several measures of excessive daytime sleepiness after adjustment for AHI,age, BMI, smoking, total sleep time, and percentage of slow-wave and rapid eye movement sleep.An AHI of 515 events?h-1 was not independently related to any daytime symptom, while an AHI.15 events?h-1 was only related to a dry mouth on awakening.
The mechanism underlying the relationship between snoring and sleepiness is unclear. Although
the validation of self-reported snoring remains a problem, a history of snoring is probably not asreadily affected by day-to-day variability as is AHI and is, thereby, a more stable parameter.Another possible explanation for snore-related daytime sleepiness is the upper airway resistancesyndrome that is characterised by episodes of increased respiratory effort followed by arousals anddaytime sleepiness [82, 83]. Although there is no significant association between frequency ofarousals and daytime hypersomnolence in the general population [73, 74], treatment with CPAPwas also followed by symptom relief in symptomatic heavy snorers without OSA [84].
Another possible explanation for snore-related daytime sleepiness is that snoring inducesvibrations within the pharynx, thereby inducing airway inflammation with the release of cytokines.Inflammatory cytokines, such as tmour necrosis factor (TNF)-aand interleukin-6, are elevated insleep apnoea independently of obesity and correlate to sleepiness and fatigue in patients with OSA[85]. In a placebo-controlled double-blinded study, treatment with a TNF-a antagonistsignificantly reduced both daytime sleepiness and AHI [86].
In conclusion, there is a growing body of evidence that snoring might also cause daytimesleepiness in the absence of OSA. However, the lack of a standardised accepted measurement of
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snoring remains a problem and all studies on snoring and sleepiness cited above are based on self-reported data. As long as the mechanism underlying the association of snoring with sleepiness isunclear, the available data must also be interpreted with caution. In addition, when it comes to theconsequences of sleep disordered breathing other than sleepiness, the negative health effects, suchas cardiovascular morbidity and mortality, have been proven for OSA but not for snoring withoutsleep apnoea.
HypertensionSleep-disordered breathing and hypertension are both prevalent in the community and manyindividuals suffer from both. Several large population-based cross-sectional studies have alsoreported an independent link between the two conditions when controlling for multiple potentialconfounding variables [33, 8790]. The impact of sleep-disordered breathing on hypertension hasalso been assessed in longitudinal studies. Self-reported snoring has been shown to be a predictorfor the development of hypertension in both male and female populations [17, 51, 91]. PEPPARDetal. [92] analysed the odds ratio for the presence of hypertension at 4-yr follow-up among 709middle-aged participants in the Wisconsin cohort, all of whom had been investigated with PSG atbaseline. Compared with subjects with no OSA, the adjusted odds ratio for prevalent hypertensionat the follow-up was 2.03 (95% CI 1.293.17) for mild OSA (AHI 514.9 events?h-1) and 2.89(95% CI 1.465.64) for moderate-to-severe OSA (AHI o15 events?h-1). The same group alsoprovided data from a subgroup that were followed using 24-h blood pressure studies for a meanperiod of 7.2 years. Regardless of confounders, including baseline blood pressure and progress ofsleep apnoea, there was a significant doseresponse relationship between the severity of sleep-disordered breathing at baseline and the risk of developing systolic nondipping blood pressuredefined as a sleepwake blood pressure ratio .0.9 [93].
Results from population based samples indicate that the impact of snoring and OSA onhypertension is less pronounced in overweight and obese subjects than compared with subjects
with normal weights [17, 87, 89]. Furthermore, when the data were analysed by age theyconsistently demonstrated an independent relationship among young and middle-agedparticipants, while the impact of snoring or OSA on hypertension is insignificant in the elderly[50, 89, 90, 94, 95]. Among 6,120 participants in the Sleep Heart Health Study, an AHI o15events?h-1 was independently associated with hypertension in subjects aged ,60 years, with anadjusted odds ratio of 2.38 (95% CI 1.304.38), while no significant relationship was foundbetween sleep apnoea and hypertension among subjects above that age [90].
As a consequence of the uniformity of these positive results that OSA can precede and predict theonset of hypertension, it has been proposed that OSA is an independent risk factor for thedevelopment of essential hypertension [96]. Although observational studies indicate a causal
relationship, the effectiveness of reducing blood pressure by treating OSA is less clear withintervention studies using CPAP producing mixed results [97]. This could be due, at least in part,to the different study designs undertaken and the short follow-up periods observed. However, ifelevated blood pressure is caused by repetitive apnoeas and intermittent desaturations every nightfor years, the possibility that the vascular damage will become permanent and will not be cured byeliminating the apnoeas cannot be ruled out.
Coronary artery disease
OSA frequently coexists undiagnosed in patients with cardiovascular disease and several cross-
sectional studies support a strong association between OSA and prevalent coronary artery disease(CAD), defined as myocardial infarction and/or angina pectoris [98100]. However, in the citedstudies sleep apnoea has been assessed after the CAD was established, thereby limiting theconclusion on an aetiological relationship. Cross-sectional epidemiological studies on self-reportedCAD and snoring or objectively measured OSA have shown a positive association, althoughon a considerably smaller magnitude than that observed in case controlled studies [13, 101].
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Among 6,424 participants who underwent PSG at home in the Sleep Heart Health Study, SHAHARetal.[102] documented that subjects with the highest quartile of AHI (AHI .11 events?h-1) had anadjusted odds ratio of 1.27 for self-reported CAD after adjusting for several confounders includinghypertension. The relative high age of the participants (mean age 64 years) could be a possibleexplanation for the rather modest association.
In a prospective observational study with middle-aged patients, OSA had a significantly higherincidence of CAD (16.2%) compared with snorers without OSA (5.4%) during a follow-up period of
7 years [103]. Efficient treatment with CPAP significantly reduces the risk of adverse cardiovascularoutcomes when it comes to both primary [103, 104] and secondary prevention [105].
Population-based prospective studies on objectively measured sleep apnoea and incidenceof CAD are still lacking and in studies designed to assess the relationship between snoring andself-reported CAD the results are not conclusive. A significant association has been found intwo [6, 106], while in a study of somewhat older participants (5474 yrs) no significantrelationship was found [107].
Arrhythmias
Recurrent intermittent hypoxia and sympathetic nervous system activity surges, together with themechanical effects of intrathoracic pressure swings, can all be caused by OSA and may provide amilieu for cardiac arrhythmia development. In patients with OSAS, a minimum arterial oxygensaturation was related to both nocturnal sinus bradycardia and supraventricular tachycardia [108].GARRIGUEet al. [109] investigated consecutive patients who had a pacemaker, but without knownsleep apnoea, using a PSG and found that no fewer than 21.4% of these subjects had severe sleepapnoea with an AHI .30 events?h-1. It has also been postulated that arrhythmias might explainthe reported relationship between severe sleep apnoea and fatal cardiovascular events during thenight [110]. More recently, a Japanese group reported that, in OSA patients, treatment with CPAPtherapy significantly reduced the occurrences of atrial fibrillation, premature ventricularcontraction, sinus bradycardia and sinus pause [111].
Clinical studies have indicated that OSA is strongly associated with atrial fibrillation and patientswith untreated OSA run a higher risk of atrial fibrillation recurrence at 1 year after electricalcardioversion (82 versus 42% in untreated patients and treated patients respectively; p50.013)[112]. In a cohort study of 3,542 patients referred for the evaluation of sleep apnoea, both obesityand the magnitude of nocturnal oxygen desaturation (and, to a lesser extent, also AHI) wereindependent risk factors for incident atrial fibrillation during a mean follow-up of 4.7 years insubjects aged ,65 years. In participants older than 65 yrs of age, heart failure, but neither obesitynor OSA, predicted incident atrial fibrillation [113].
In a large, community-dwelling group of males aged 65 years and older (n52,911), MEHRA et al.[114]recently demonstrated that an increasing severity of sleep-disordered breathing was associated with aprogressive increase in the odds of nocturnal atrial fibrillation or flutter and complex ventricularectopy (CVE). In this age group, only CVE was associated with obstructive sleep apnoea and hypoxia,whereas nocturnal atrial fibrillation or flutter was most strongly associated with central sleep apnoea.The authors suggested that different sleep-related stresses may contribute to atrial and ventriculararrhythmogenesis in older males.
An association between sleep-disordered breathing and nocturnal cardiac arrhythmias has alsobeen analysed in a cross-section community-based sample in the Sleep Heart Health Study [115],
in which individuals with a respiratory distress index (RDI) o30 were compared with controlswith an RDI ,5 for the prevalence of arrhythmias. Subjects with severe sleep-disordered breathinghad a two- to four-fold higher ratio of complex arrhythmias than those without sleep-disorderedbreathing, even after adjustment for age, sex, BMI and prevalent coronary heart disease. The highestodds were found for atrial fibrillation (OR 4.02, 95% CI 1.0315.74), followed by nonsustainedventricular tachycardia (OR 3.40, 95% CI 1.0311.20) and CVE (OR 1.74, 95% CI 1.112.74).
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There was also a significant interaction with age, as sleep apnoea was much more strongly associatedwith CVE at the younger ages.
Stroke
Independent associations between self-reported snoring and the incidence of stroke have beenreported from two large epidemiological prospective surveys [6, 106]. Data from clinical cohorts
also suggest an important link between sleep-disordered breathing and suffering a stroke. SPRIGGSet al. [116] followed patients with recent stroke until death or for 6 months and found thatprevious stroke and regular snoring were the only two risk factors that adversely affected mortality.In patients with coronary artery disease who were investigated by sleep apnoea recordings,VALHAM et al. [117] found a dose-response relationship between the AHI at baseline and theincidence of stroke during a 10-yr follow-up after adjusting for potential confounders. Moreover,in stroke survivors the occurrence of OSA, but not central sleep apnoea, was a significant predictorof early death [118].
It seems reasonable to assume that one of the possible factors, explaining an increased risk ofsuffering a stroke among patients with sleep apnoea is apnoea-induced hypertension. But
nocturnal cerebral ischaemia and an increased risk of arteriosclerosis may also play an importantrole. However, in contrast to hypertension, there are also data indicating a relationship betweenOSA and strokes in elderly subjects. From a 6-yr longitudinal study of a population-based cohortof non-institutionalised, initially event-free subjects aged 70100 yrs, MUNOZet al.[119] reportedthat severe sleep apnoea (AHI o30 events?h-1) at baseline was associated with a significantlyincreased risk of developing an ischaemic stroke (adjusted hazard ratio 2.52, 95% CI 1.046.01).ARZTet al.[120] investigated a younger population-based cohort of 1,189 subjects with a mean ageof 47 yrs, using PSG. During the following 4 yrs, 14 subjects suffered a first-ever stroke and thiswas related to sleep apnoea defined as an AHI o20 events?h-1 at baseline, although the associationdid not reach statistical significance after adjusting for age, sex and BMI (adjusted OR 3.08, 95%
CI 0.7412.81).
Diabetes
Sleep-disordered breathing and diabetes share several risk factors. Cross-sectional studies revealthat, in the general population, there is an association between snoring [121, 122] or sleep apnoea[123128] and insulin resistance and/or type 2 diabetes, independent of obesity and otherconfounders. Furthermore, an independent association between self-reported snoring and incidentdiabetes has been reported in both males [129] and females [130]. However, longitudinal studiesshowing an independent link between OSA at baseline and the development of diabetes are
lacking. Among 1,387 participants in the Wisconsin Sleep Cohort, subjects with an AHI o15events?h-1 did not differ significantly from those with an AHI ,5 events?h-1 when it came to therisk of developing diabetes over a 4-yr period (OR 1.62 , 95% CI 0.73.6) when adjusting for age,sex, and body habitus [126]. Similar findings were reported from the Busselton health study [131],no significant association was found between sleep apnoea at baseline and diabetes at follow-upwithin 4 years, after adjusting for confounders.
Mortality
The results of some clinic-based studies suggest that patients with OSAS have a higher mortality
risk [132] and that treatment with tracheostomy or CPAP attenuates this risk [133135]. Inpatients with CAD, concomitant sleep apnoea also increases the risk of adverse outcome, includingmortality [136, 137]. The lack of randomised controlled interventional trials clearly limits theevidence level, as untreated patients have either not been compliant with prescribed therapy orhave, for some reason, not been selected for effective treatment. In addition, clinical mortalitystudies might be biased, as patients under treatment for some other serious morbidity might also
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be more likely to be referred for anevaluation of sleep apnoea, leadingto an overestimation of mortalityin this group.
However, in studies designed toinvestigate mortality in patients withOSAS, results have diverged, as no
increase in mortality was reported insome of the works. When investigat-ing elderly populations, no associa-tion was found between apnoea/hypopnoea scores in two prospectivestudies [138, 139], while in anotherstudy a significant association wasseen only in females [140]. Further-more, in a prospective study, LAVIEet al. [132] found that the apnoea
index was a predictor of excessmortality in the fourth and fifthdecade but not in elderly males.This is in accordance with theresults from of a population-basedstudy from Uppsala in Swedenwhere males aged 3069 yrs wereinvestigated by postal questionnaireand followed up for mortality over10 yrs [141]. Snoring males, who
also reported excess daytime sleepi-ness, had a significant increase inmortality but the age-adjusted rela-tive risk decreased with increasingage and was no longer significantafter the age of 50 yrs. Snoring alonehad no impact on mortality in anyof the age groups (table 2).
The impact of OSA on mortality in
population-based cohorts has recentlybeen analysed in the Wisconsin Study[143], as well as in the Sleep HeartHealth Study [144], and both re-ported a decrease in survival withincreasing OSA severity (table 2).After adjusting for potential con-founders including anthropometricvariables and comorbidity, partici-pants with an AHI o30 events?h-1
had an adjusted hazard ratio forall-cause mortality of 3.0 (95% CI1.46.3) [143] and 1.46 (1.141.86)[141], respectively, compared withthose with an AHI ,5 events?h-1.Similar results were obtained for
Table2.Popu
lation-basedstudiesdesignedto
investigatetherelationshipbetweensleep-disorderedbreathing(S
DB)andmortality
First
author
[Ref.]
Population
Follow-u
p
periodyrs
Sample
sizen
Ageyrs
Co
nfounders
MarkerofS
DB
AdjustedHR
(95%
CI)
All-causemortality
LINDBERG
[141]
Sampleof3100
malesinUppsala,
Sweden
10
3100
3069
Age,BMI,
hy
pertension,
he
artdisease,
diabetes
Nosnoringor
EDS#
SnoringnoEDS
EDSnosno
ring
Snoringand
EDS
1.1(0.81.5)
1.1(0.61.9)
1.8(1.22.5)
Instratifiedanalyses:
Significantonlyin
males,60years
"
YOUNG
[142]
WisconsinSleep
cohort
18
1522
3060
Ag
e,BMI,sex
AHI0,5
#
AHI5,1
5
AHI15,30
AHIo30
1.6(0.92.8)
1.4(0.63.3)
3.0(1.46.3)
Nosignificant
interactionwithage,
sexorEDS
PUNJAB
[143]
SleepHeartHealth
Study
8.2
6441
Meanage
62.911.0
Ag
e,BMI,sex,
race,smoking,
diabetes,
bloodpressure,
cardiovascular
disease
AHI0,5
#
AHI5,1
5
AHI15,30
AHIo30
0.93(0.801.08)
1.17(0.971.42)
1.46(1.141.86)
Instratifiedanalyses
theadjustedHR
wasonlysignificant
inmales,70yrs
+
BMI:bodymass
index;EDS:excessivedaytimesleepiness;AHI:apnoea/hypopnoe
aindex.
#:reference:
":adjustedHR2.7(1.64.5);+:adjustedHR2.09(95%CI1.313.33).
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cardiovascular mortality in both studies and the exclusion of subjects treated for sleep apnoea didnot change the results. However, when the 6,441 participants in the Sleep Heart Health Study werestratified by age and sex, the adjusted hazard ratios for severe sleep apnoea only remained significantin males aged ,70 yrs, while no excess mortality was found for participants aged .70 yrs. Amongfemales aged ,70 yrs, the number of subjects with severe sleep apnoea was lower and the adjustedhazard ratio for mortality did not reach statistical significance (1.76, 95% CI 0.773.95) [143]. Inaddition to AHI, sleep-related hypoxaemia, but not arousal index, was significantly related to excess
mortality.
Total health burden of OSA
Most subjects with OSAS are still undiagnosed and epidemiological data indicates that the totalhealth burden of this might be enormous.
As OSA is associated with conditions that account for the leading causes of mortality in adults, it is achallenge to the scientific society to determine what cut-off limit for AHI that can be deemedreasonable for treatment of non-symptomatic individuals, thereby reducing morbidity and mortality.
There is no doubt that the 37% of males and 25% of females who meet minimal diagnosticcriteria for the sleep apnoea syndrome [144] should be offered treatment to improve quality of lifeand avoid consequences such as traffic and job accidents. However, there are about four times thatnumber who are asymptomatic but have an AHI .5 events?h-1. Available epidemiological datasuggests, regardless of daytime symptoms, that an AHI .30 events?h-1 is followed by an increase inmortality while the cut-off limit for the risk of developing hypertension is much lower. Amongmiddle-aged adults who do not report daytime sleepiness the prevalence of an AHI .15 events?h-1
is prevalent in 3% of females and 4% of males who are nonsnorers while the correspondingprevalence in non-sleepy habitual snorers are 9 and 38%, respectively [9]. If it will turn out in thefuture that treatment of an AHI .15 events?h-1 is followed by a significant reduction in morbidity
and mortality, regardless of daytime symptoms, another 4% of females and 16% of males will thenfulfil the treatment criteria.
Statement of Interest
None declared.
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