Chapter 4

Epidemiology of OSA
E. Lindberg

Summary
Approximately 37% of adult males and 25% of adult females inwestern countries and Asia suffer from symptomatic obstructive sleep apnoea syndrome (OSAS) and are therefore candidates for treatment. In addition, a large percentage of individuals suffer from either snoring in combination with sleepiness or OSA without overt daytime symptoms. The clinical significance of this is still controversial. Sex, obesity and age are all important risk factors for OSA. Moreover, smoking, alcohol consumption and physical inactivity appear to increase the occurrence of the disorder. The relationship between OSA and daytime hypersomnolence is not completely understood. Most subjects with verified OSA do not report daytime sleepiness and there is increasing evidence that snoring without apnoeas or hypopnoeas might also relate to sleepiness. Cross-sectional studies indicate an independent link between diabetes and OSA but this has not yet been confirmed in longitudinal surveys. Keywords: Epidemiology, population-based, prevalence, sleep apnoea, snoring
Correspondence: E. Lindberg, Dept of Medical Sciences, Respiratory Medicine and Allergology, Uppsala University, Akademiska sjukhuset, SE-751 85 Uppsala, Sweden, Email eva.lindberg@akademiska.se

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

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 new diagnosis 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 from epidemiological 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], the situation 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 a complete nights sleep and daytime symptoms. OSAS patients in sleep clinic cohorts have all been referred 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, most people with sleep apnoea do not fulfil the diagnostic criteria for the full-blown syndrome and the impact of sleep apnoea on future health, when daytime symptoms are not taken into account, can only be analysed in population-based surveys. It is, therefore, important to bear in mind that the results of clinical and epidemiological surveys within this field are not always comparable. As there is 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 are required to enable an improved understanding of the complete picture. The term sleep-disordered breathing is commonly used and includes a wide range of conditions linked with narrow upper airways and the loss of normal respiratory patterns during sleep. At one end of the spectrum there are subjects with intermittent partial obstruction of the upper airways, giving rise to snoring without fragmentation of sleep i.e. simple snorers, and at other end patients who endure hypoxia episodes 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 extremely important 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 this Monograph. When comparing epidemiological studies in which subjects do not fulfil the complete diagnostic criteria for the syndrome, including daytime symptoms, the diagnostic criteria for sleep apnoea have an important effect on the outcome. The varying methodological approaches in epidemiological studies assessing the prevalence and health-related consequences of OSA sometimes can limit accurate comparisons. For example, the chosen oxyhaemoglobin desaturation threshold, 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 these factors is vital to improve the understanding of why studies with similar designs sometimes produce wide discrepancies in their estimates for prevalence or measures of association. In this chapter, the epidemiological literature on prevalence, risk factors and consequences of the disorder has been reviewed. However, much of the current knowledge regarding epidemiology within this field is still based upon studies that analyse snoring and part of this literature has also been 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 without sleep apnoea.

EPIDEMIOLOGY OF OSA

Prevalence
The most frequently used method for estimating the presence of snoring is a questionnaire and the snoring prevalence is usually rated on a frequency scale; examples of the response options given are: never, often or the number of nights that snoring occurred in a week. Although there were 4,155 citations of snoring on Medline in March 2010, there is still no standard, uniformly accepted technique 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 the basis 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 JANSON et al. [21], which estimated the prevalence of snoring among age- and sex-matched populations in three countries using the same questions answered on the same frequency scale, very similar results were found. Thereby, indicating that the great differences in snoring prevalence between study populations are probably due to methodological differences. Furthermore it was found, in a population-based sample of males who reported their own snoring frequency and then had their snoring measured using a microphone for one night, that the validity of self-reported snoring, as a marker of recorded snoring sounds for o10% of the night, did not significantly differ between the younger (age 4059 yrs) and the older (age 6079 yrs) age groups [22]. Only 25 yrs ago OSAS was still regarded as an extremely rare disorder. Studies designed to estimate the 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 high risk of OSAS in a first-stage screening procedure and the estimated prevalence in the whole population was based on the assumption that there was no OSA at all among the remaining participants. 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 general population are presented in table 1. As previously noted, comparisons between the results are limited by methodological differences, including differences in sampling schedule, disparities in techniques 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 .5 events?h-1, the estimated prevalence of OSA and accompanying daytime sleepiness is relatively consistent across several population cohorts. With the exception of one study by NAKAYAMAASHIDA et al. [32], the prevalence of OSA syndrome is approximately 3 7% for adult males and 2 5% for adult females. NAKAYAMA-ASHIDA et al. [32] reported a much higher prevalence of OSAS in Japanese males. In their study, breathing was recorded with pressure sensors and a lower limit of 3% desaturation was used to define hypopnoeas.

Risk factors
Sex
Research studies have repeatedly and consistently confirmed that OSA is more common in males than females. The male-to-female ratio is estimated to be approximately 2:1 in the general population (table 1) and the prevalence of snoring shows similar sex differences [13, 33, 34]. In clinical populations, the male predominance is usually even higher [35, 36]. The reason for this male predominance is not exactly clear. Possible explanations include the effects of hormonal influences 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 that hormonal influences play an important role in the pathogenesis of OSA, as the prevalence is higher in post- versus pre-menopausal females [37]. However, the role of hormones in OSAs pathophysiology is not clearly defined and a difference in its prevalence, with respect to sex is apparent in the elderly population [37].

Age
The available epidemiological data on the impact of age on sleep-disordered breathing highlights the 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 the prevalence 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 of 60 years (table 1). However, when subjects above that age have also been included, there has been a continuous increase in the prevalence of OSA [26, 28]. However, this finding does not appear to mirror the true prevalence of clinically significant OSAS. In a study based on a two-stage general random sample of 4,364 males, BIXLER et al. [26], found that the prevalence of OSA (AHI o5 events?h-1) was present in 7.9% of males aged 2044 yrs, 18.8% of males aged 4564 yrs and increased to 24.8% of males aged 65100 yrs. In the same cohort the prevalence of OSAS diagnosed according to Sleep Disorders Clinic criteria increased with age until the age of 50 60 yrs, followed by a decline [26]. This finding suggests that while self-reported snoring and doctor-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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54
EPIDEMIOLOGY OF OSA

Table 1. Population-based studies on the prevalence of obstructive sleep apnoea (OSA) and obstructive sleep apnoea syndrome Sample size, sex and criteria M 24 9 9 4 4 2 Attended PSG F M F M F Discernible reduction in airflow and o4% oxygen desaturation AHI# -1 o5 events?h Methodology AHI# -1 o15 events?h OSA# syndrome Hypopnoea definition

First author [Ref.]

Study population

Age yrs

Y OUNG [9] Random sample of 3513 state employees in WI, USA

3060

B IXLER [26] 17 7 3.3

Random sample of 4364 males in PA, USA 18.8 3.7 5.3 1.2 4.1

20100

350 males, 250 females Habitual snorers (n5355) and a random sample of non-habitual snorers (n5247) 741 male Age-stratified cohorts, oversampling of high-risk individuals 2.1

Attended PSG

I P [18, 19]

3074" office workers in Hong Kong, China 1000 males Oversampling of high-risk individuals 5

3060

153 males, 106 females All participants invited for PSG

B IXLER [27]

Random sample of 12219 females in PA, USA, 26 28

20-100

1.2

N [28] 2148 subjects D URA from the general population in Vitoria-Gasteiz, Spain

3070

325 males, 235 females Tentative diagnosis of OSAH (n5390) and a random sample (n5170)

14

3.4

Discernible reduction in airflow and o4% oxygen desaturation Attended PSG Discernible reduction in airflow and o4% oxygen desaturation Attended PSG Discernible reduction in airflow plus o4% oxygen desaturation Attended PSG 50% airflow reduction and either o4% oxygen desaturation or an EEG arousal

Table 1. Continued Sample size, sex and criteria M 250 males All snorers (n5171) and 25% of nonsnorers 19.5 8.4 7.5 309 males 148 oversampling of habitual snorers 27 16 10.1 4.7 4.5 88 males, 63 females Habitual snorers n577 and nonsnorers n574 19.7 7.4 322 males 37.4 15.7 4.9 3.2 Home PSG F M F M F Discernible 50% reduction in airflow and o4% oxygen desaturation Home or in laboratory PSG AHI# -1 o5 events?h Methodology AHI# -1 o15 events?h OSA# syndrome Hypopnoea definition

First author [Ref.]

Study population

Age yrs

U DWADIA [29]

K IM [30]

658 healthy 3565 males attending hospital for routine health check in Bombay, India Population 4069 based sample of 5020 residents in Seoul, Korea 2.1

S HARMA [31]

2400 citizens in Delhi, India with an exclusion criterion of several diseases

3060

Attended in laboratory PSG

466 male N AKAYAMAemployees of a A SHIDA [32] wholesale company in Osaka, Japan

2359

17.6

Home type 3 portable monitors and actigraphy

Discernible reduction in airflow and o4% oxygen desaturation Discernible 50% reduction in airflow and o4% oxygen desaturation o50% reduction in nasal pressure or respiratory effort and o3% oxygen desaturation

AHI: apnoea/hypopnoea index; M: male; F: female; PSG: polysomnography; OSAH: obstructive sleep apnoea/hypopnoea syndrome; EEG: electroencephalography. # : estimated prevelance (given as a percentage); ": M51,542, F51,532.

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on negative health effects attributable to OSA in the elderly population, there is more inconsistency. Several studies have reported little or no association between sleep-disordered breathing and morbidity and/or mortality at an older age. It has been suggested that sleep apnoea in the elderly represents a specific entity compared with that seen in middle-aged adults [40]. Due to the high prevalence of sleep apnoea in the older age range, there is an urgent need for prospective studies of population-based samples of elderly subjects analysing the long-term health effects 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 OSAS are overweight [4143]. Although there is still a lack of randomised controlled studies evaluating the effect of weight loss the unvarying observation is that weight loss, either as a result of a calorie restricted diet or surgery, reduces the severity of the disease [4447]. PEPPARD et al. [39] twice evaluated, at 4-yr intervals, a population-based sample of 690 males and females for anthropometric variables and sleep apnoea. Compared with subjects with stable weight over time, a 10% weight gain predicted an approximate 32% (95% CI 2045%) increase in the AHI and predicted a six-fold increase in the odds of developing moderate-to-severe sleep-disordered breathing defined as an AHI of o15 events?h-1. For those who lost weight, it was observed that a 10% weight loss predicted a 26% (95% CI 1834%) decrease in the AHI [39]. Regardless of the starting weight, waist circumference, age or ethnicity, males are more likely than females to increase 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 or waist circumference, are better predictors of sleep-disordered breathing as compared with body mass 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 BMI o25 kg?m-2 [48]. This highlights the need for effective strategies to implement long-term weightloss programmes to prevent the ongoing epidemics of obesity and OSA. However, despite the strong relationship with obesity, it is important to remember that not all subjects who are obese or have a large neck circumference suffer from sleep apnoea [50] and that some one-third of OSAS patients are not obese.

EPIDEMIOLOGY OF OSA

Physical inactivity
In contrast to the large number of studies undertaken on obesity and sleep apnoea, there are few reports on the role of physical activity on apnoea frequency. This might be a direct effect of the difficulty associated with characterising the level of physical activity in large cohorts. The few reports undertaken on the association between physical activity and snoring have produced somewhat contradictory results. In a cross-sectional Finnish study by KOSKENVUO et al. [42], males with a reported low level of physical activity had a higher prevalence of snoring that could not be explained by age or obesity. Similar findings were reported from a study by HU et al. [17] that examined the health of some 73,231 US nurses. The multivariate analysis from their study revealed that there was an inverse dose-response relationship between the level of physical activity and snoring. 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 a prospective population-based sample of 2,668 males, who were investigated over a 10-year period for the development of snoring, physical inactivity had no significant impact when other confounders 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 and snoring 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 the fact that the impact of physical activity on sleep-disordered breathing remains uncertain.

Smoking
Several cross-sectional epidemiological surveys have found significant associations between cigarette 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 from nicotine increases sleep instability, both of which have been linked to OSA [56]. According to a Nordic multicentre study, never-smokers who have been exposed to passive smoking on a daily basis display an increase in the odds of being an habitual snorer of 1.6 (95% CI 1.22.1) after adjusting for age and BMI [53]. In a Swedish longitudinal study, smoking predicted the development 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 of apnoeas and hypopnoeas per hour of sleep. Heavy smokers ran the greatest risk, while former smoking was unrelated to snoring and sleep-disordered breathing after the adjustment for confounders. 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 less sleep apnoea than nonsmokers [57] and there are still no available data concerning the impact of smoking 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 the relationship 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 associated with 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 in females with a BMI ,20 kg?m-2. It is possible that the alcohol induced reduction in motor output to 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. fat deposits, as an explanation for their snoring compared with overweight females [58].

Consequences
Sleepiness
Excessive daytime sleepiness is the cardinal symptom of OSA. Numerous studies have demonstrated an improvement in daytime sleepiness when clinically identified patients are effectively treated with continuous positive airway pressure (CPAP) as compared with sham CPAP or oral placebo [6470]. In addition, in the general population there is evidence that both OSA and snoring are important causes of daytime sleepiness [9, 6971]. In the Wisconsin Sleep Cohort Study, 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 prevalence in males was 16 and 3%, respectively. Similar findings were reported from the Sleep Heart Health Study using the Epworth sleepiness scale (ESS) score for measuring sleepiness [72]. There was a significant 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. The association 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 and daytime hypersomnolence is not completely understood. It is generally believed that excessive daytime sleepiness is caused by repeated arousals from apnoeas and hypopnoeas leading to sleep fragmentation. Attempts to find an association between the number of arousals and the severity of sleepiness have failed [73, 74]. Furthermore, in patients with other chronic diseases the association between OSA and sleepiness might be less evident. For example, patients with congestive heart failure 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 elderly subjects [77], sleepiness is a frequently reported symptom in the absence of OSA and is thereby not a 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 snoring per se has been limited. When it was previously reported that sleepy snorers are significantly more frequently involved in occupational accidents, it was suggested that this was because of concomitant OSAS [78]. However, when it comes to the impact on daytime sleepiness there is increasing evidence that snoring is also related to sleepiness in the absence of apnoeas and hypopnoeas. YOUNG et al. [9] reported that habitual snorers with an AHI ,5 events?h-1 reported symptoms of hypersomnolence more frequently compared with nonsnoring control subjects. YOUNG et al. [79] also showed that habitual snorers with an AHI ,5 events ?h-1 run the risk of motor vehicle accidents to the same degree as subjects with an AHI .5 events?h-1. GOTTLIEB et al. [80] reported that snoring was related to an ESS score o11 across all categories of the respiratory disturbance 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 correlated significantly with self-reported snoring. Although sleep apnoea severity, as measured by the frequency dips in blood oxygen saturation of 4% during the night, was significantly related to the answers from three questions on sleepiness, it was never more important than snoring as a predictor of sleepiness and never reduced its significance. Moreover, when adjusting for sleep apnoea, 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 were reported by SVENSSON et al. [71], who studied a population-based sample of Swedish females aged 2070 years with questionnaires and polysomnography (PSG) to investigate whether symptoms of sleep apnoea are related to AHI, independent of snoring and vice versa. Habitual snoring was significantly 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 as readily 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 resistance syndrome that is characterised by episodes of increased respiratory effort followed by arousals and daytime sleepiness [82, 83]. Although there is no significant association between frequency of arousals and daytime hypersomnolence in the general population [73, 74], treatment with CPAP was also followed by symptom relief in symptomatic heavy snorers without OSA [84]. Another possible explanation for snore-related daytime sleepiness is that snoring induces vibrations within the pharynx, thereby inducing airway inflammation with the release of cytokines. Inflammatory cytokines, such as tmour necrosis factor (TNF)-a and interleukin-6, are elevated in sleep 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 antagonist significantly reduced both daytime sleepiness and AHI [86]. In conclusion, there is a growing body of evidence that snoring might also cause daytime sleepiness in the absence of OSA. However, the lack of a standardised accepted measurement of

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EPIDEMIOLOGY OF OSA

snoring remains a problem and all studies on snoring and sleepiness cited above are based on selfreported data. As long as the mechanism underlying the association of snoring with sleepiness is unclear, the available data must also be interpreted with caution. In addition, when it comes to the consequences of sleep disordered breathing other than sleepiness, the negative health effects, such as cardiovascular morbidity and mortality, have been proven for OSA but not for snoring without sleep apnoea.

Hypertension
Sleep-disordered breathing and hypertension are both prevalent in the community and many individuals suffer from both. Several large population-based cross-sectional studies have also reported an independent link between the two conditions when controlling for multiple potential confounding variables [33, 8790]. The impact of sleep-disordered breathing on hypertension has also been assessed in longitudinal studies. Self-reported snoring has been shown to be a predictor for the development of hypertension in both male and female populations [17, 51, 91]. PEPPARD et al. [92] analysed the odds ratio for the presence of hypertension at 4-yr follow-up among 709 middle-aged participants in the Wisconsin cohort, all of whom had been investigated with PSG at baseline. Compared with subjects with no OSA, the adjusted odds ratio for prevalent hypertension at 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 also provided data from a subgroup that were followed using 24-h blood pressure studies for a mean period of 7.2 years. Regardless of confounders, including baseline blood pressure and progress of sleep apnoea, there was a significant doseresponse relationship between the severity of sleepdisordered breathing at baseline and the risk of developing systolic nondipping blood pressure defined as a sleepwake blood pressure ratio .0.9 [93]. Results from population based samples indicate that the impact of snoring and OSA on hypertension 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 they consistently demonstrated an independent relationship among young and middle-aged participants, 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 o15 events?h-1 was independently associated with hypertension in subjects aged ,60 years, with an adjusted odds ratio of 2.38 (95% CI 1.304.38), while no significant relationship was found between 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 the onset of hypertension, it has been proposed that OSA is an independent risk factor for the development of essential hypertension [96]. Although observational studies indicate a causal relationship, the effectiveness of reducing blood pressure by treating OSA is less clear with intervention 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, if elevated blood pressure is caused by repetitive apnoeas and intermittent desaturations every night for years, the possibility that the vascular damage will become permanent and will not be cured by eliminating the apnoeas cannot be ruled out.
E. LINDBERG

Coronary artery disease

OSA frequently coexists undiagnosed in patients with cardiovascular disease and several crosssectional 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 cited studies sleep apnoea has been assessed after the CAD was established, thereby limiting the conclusion on an aetiological relationship. Cross-sectional epidemiological studies on self-reported CAD and snoring or objectively measured OSA have shown a positive association, although on 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, SHAHAR et al. [102] documented that subjects with the highest quartile of AHI (AHI .11 events?h-1) had an adjusted odds ratio of 1.27 for self-reported CAD after adjusting for several confounders including hypertension. The relative high age of the participants (mean age 64 years) could be a possible explanation for the rather modest association. In a prospective observational study with middle-aged patients, OSA had a significantly higher incidence 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 cardiovascular outcomes when it comes to both primary [103, 104] and secondary prevention [105]. Population-based prospective studies on objectively measured sleep apnoea and incidence of CAD are still lacking and in studies designed to assess the relationship between snoring and self-reported CAD the results are not conclusive. A significant association has been found in two [6, 106], while in a study of somewhat older participants (5474 yrs) no significant relationship was found [107].

Arrhythmias
Recurrent intermittent hypoxia and sympathetic nervous system activity surges, together with the mechanical effects of intrathoracic pressure swings, can all be caused by OSA and may provide a milieu for cardiac arrhythmia development. In patients with OSAS, a minimum arterial oxygen saturation was related to both nocturnal sinus bradycardia and supraventricular tachycardia [108]. GARRIGUE et al. [109] investigated consecutive patients who had a pacemaker, but without known sleep apnoea, using a PSG and found that no fewer than 21.4% of these subjects had severe sleep apnoea with an AHI .30 events?h-1. It has also been postulated that arrhythmias might explain the reported relationship between severe sleep apnoea and fatal cardiovascular events during the night [110]. More recently, a Japanese group reported that, in OSA patients, treatment with CPAP therapy significantly reduced the occurrences of atrial fibrillation, premature ventricular contraction, sinus bradycardia and sinus pause [111]. Clinical studies have indicated that OSA is strongly associated with atrial fibrillation and patients with untreated OSA run a higher risk of atrial fibrillation recurrence at 1 year after electrical cardioversion (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 obesity and the magnitude of nocturnal oxygen desaturation (and, to a lesser extent, also AHI) were independent risk factors for incident atrial fibrillation during a mean follow-up of 4.7 years in subjects aged ,65 years. In participants older than 65 yrs of age, heart failure, but neither obesity nor 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 a progressive increase in the odds of nocturnal atrial fibrillation or flutter and complex ventricular ectopy (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 ventricular arrhythmogenesis in older males. An association between sleep-disordered breathing and nocturnal cardiac arrhythmias has also been 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 controls with an RDI ,5 for the prevalence of arrhythmias. Subjects with severe sleep-disordered breathing had a two- to four-fold higher ratio of complex arrhythmias than those without sleep-disordered breathing, even after adjustment for age, sex, BMI and prevalent coronary heart disease. The highest odds were found for atrial fibrillation (OR 4.02, 95% CI 1.0315.74), followed by nonsustained ventricular tachycardia (OR 3.40, 95% CI 1.0311.20) and CVE (OR 1.74, 95% CI 1.112.74).

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EPIDEMIOLOGY OF OSA

There was also a significant interaction with age, as sleep apnoea was much more strongly associated with CVE at the younger ages.

Stroke
Independent associations between self-reported snoring and the incidence of stroke have been reported 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. SPRIGGS et al. [116] followed patients with recent stroke until death or for 6 months and found that previous 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 the incidence 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 predictor of early death [118]. It seems reasonable to assume that one of the possible factors, explaining an increased risk of suffering 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 important role. However, in contrast to hypertension, there are also data indicating a relationship between OSA and strokes in elderly subjects. From a 6-yr longitudinal study of a population-based cohort of non-institutionalised, initially event-free subjects aged 70100 yrs, MUNOZ et al. [119] reported that severe sleep apnoea (AHI o30 events?h-1) at baseline was associated with a significantly increased risk of developing an ischaemic stroke (adjusted hazard ratio 2.52, 95% CI 1.046.01). ARZT et al. [120] investigated a younger population-based cohort of 1,189 subjects with a mean age of 47 yrs, using PSG. During the following 4 yrs, 14 subjects suffered a first-ever stroke and this was related to sleep apnoea defined as an AHI o20 events?h-1 at baseline, although the association did 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 reveal that, 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 other confounders. Furthermore, an independent association between self-reported snoring and incident diabetes has been reported in both males [129] and females [130]. However, longitudinal studies showing 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 o15 events?h-1 did not differ significantly from those with an AHI ,5 events?h-1 when it came to the risk 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-up within 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]. In patients with CAD, concomitant sleep apnoea also increases the risk of adverse outcome, including mortality [136, 137]. The lack of randomised controlled interventional trials clearly limits the evidence level, as untreated patients have either not been compliant with prescribed therapy or have, for some reason, not been selected for effective treatment. In addition, clinical mortality studies might be biased, as patients under treatment for some other serious morbidity might also

61

E. LINDBERG

In stratified analyses: Significant only in males ,60 years"

BMI: body mass index; EDS: excessive daytime sleepiness; AHI: apnoea/hypopnoea index. #: reference: ": adjusted HR 2.7 (1.64.5); +: adjusted HR 2.09 (95% CI 1.313.33).

No significant interaction with age, sex or EDS

All-cause mortality

In stratified analyses the adjusted HR was only significant in males ,70 yrs+

be more likely to be referred for an evaluation of sleep apnoea, leading to an overestimation of mortality in this group. However, in studies designed to investigate mortality in patients with OSAS, results have diverged, as no increase in mortality was reported in some of the works. When investigating elderly populations, no association was found between apnoea/ hypopnoea scores in two prospective studies [138, 139], while in another study a significant association was seen only in females [140]. Furthermore, in a prospective study, LAVIE et al. [132] found that the apnoea index was a predictor of excess mortality in the fourth and fifth decade but not in elderly males. This is in accordance with the results from of a population-based study from Uppsala in Sweden where males aged 3069 yrs were investigated by postal questionnaire and followed up for mortality over 10 yrs [141]. Snoring males, who also reported excess daytime sleepiness, had a significant increase in mortality but the age-adjusted relative risk decreased with increasing age and was no longer significant after the age of 50 yrs. Snoring alone had no impact on mortality in any of the age groups (table 2). The impact of OSA on mortality in population-based cohorts has recently been analysed in the Wisconsin Study [143], as well as in the Sleep Heart Health Study [144], and both reported a decrease in survival with increasing OSA severity (table 2). After adjusting for potential confounders including anthropometric variables and comorbidity, participants with an AHI o30 events?h-1 had an adjusted hazard ratio for all-cause mortality of 3.0 (95% CI 1.46.3) [143] and 1.46 (1.141.86) [141], respectively, compared with those with an AHI ,5 events?h-1. Similar results were obtained for

Table 2. Population-based studies designed to investigate the relationship between sleep-disordered breathing (SDB) and mortality

EPIDEMIOLOGY OF OSA

Follow-up Sample period size n yrs

3100

1522

L INDBERG [141]

62

P UNJAB [143]

First author [Ref.]

Y OUNG [142]

Sleep Heart Health Study

Sample of 3100 males in Uppsala, Sweden

Wisconsin Sleep cohort

Population

8.2

10

18

6441

Mean age Age, BMI, sex, 62.911.0 race, smoking, diabetes, blood pressure, cardiovascular disease

Confounders

Age yrs

3069

3060

Age, BMI, hypertension, heart disease, diabetes Age, BMI, sex

No snoring or EDS# Snoring no EDS EDS no snoring Snoring and EDS AHI 0,5# AHI 5,15 AHI 15,30 AHI o30 AHI 0,5# AHI 5,15 AHI 15,30 AHI o30

Marker of SDB

0.93 (0.801.08) 1.17 (0.971.42) 1.46 (1.141.86)

1.1 (0.81.5) 1.1 (0.61.9) 1.8 (1.22.5)

Adjusted HR (95% CI)

1.6 (0.92.8) 1.4 (0.63.3) 3.0 (1.46.3)

cardiovascular mortality in both studies and the exclusion of subjects treated for sleep apnoea did not change the results. However, when the 6,441 participants in the Sleep Heart Health Study were stratified by age and sex, the adjusted hazard ratios for severe sleep apnoea only remained significant in males aged ,70 yrs, while no excess mortality was found for participants aged .70 yrs. Among females aged ,70 yrs, the number of subjects with severe sleep apnoea was lower and the adjusted hazard ratio for mortality did not reach statistical significance (1.76, 95% CI 0.773.95) [143]. In addition 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 total health burden of this might be enormous. As OSA is associated with conditions that account for the leading causes of mortality in adults, it is a challenge to the scientific society to determine what cut-off limit for AHI that can be deemed reasonable 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 diagnostic criteria for the sleep apnoea syndrome [144] should be offered treatment to improve quality of life and avoid consequences such as traffic and job accidents. However, there are about four times that number who are asymptomatic but have an AHI .5 events?h-1. Available epidemiological data suggests, regardless of daytime symptoms, that an AHI .30 events?h-1 is followed by an increase in mortality while the cut-off limit for the risk of developing hypertension is much lower. Among middle-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 corresponding prevalence in non-sleepy habitual snorers are 9 and 38%, respectively [9]. If it will turn out in the future 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 then fulfil the treatment criteria.

Statement of Interest
None declared.

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