Atherosclerosis 231 (2013) 191e197

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Association of obstructive sleep apnoea with subclinical coronary atherosclerosis Gerhard Weinreich a, *, 1, Thomas E. Wessendorf a, 1, Timo Erdmann a, Susanne Moebus b, Nico Dragano c, Nils Lehmann b, Andreas Stang d, Ulla Roggenbuck b, Marcus Bauer e, Karl-Heinz Jöckel b, Raimund Erbel e, Helmut Teschler a, Stefan Möhlenkamp e, f, for the Heinz Nixdorf Recall (HNR) study group a

Department of Pneumology, Ruhrlandklinik, West German Lung Center, University Clinic Essen, Tüschener Weg 40, D-45239 Essen, Germany Institute for Medical Informatics, Biometry and Epidemiology, University Clinic Essen, Germany c Institute for Medical Sociology, University Clinic Düsseldorf, University of Düsseldorf, Germany d Institute of Clinical Epidemiology, Medical Faculty, University Halle-Wittenberg, Halle, Germany e Clinic of Cardiology, West-German Heart Center Essen, University Clinic Essen, Germany f Clinic of Cardiology, Stiftung Krankenhaus Bethanien, Moers, Germany b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 June 2013 Received in revised form 30 August 2013 Accepted 12 September 2013 Available online 24 September 2013

Background: Accumulating evidence suggests a role of obstructive sleep apnoea (OSA) as a risk factor for coronary atherosclerosis. This study aimed i) to assess the prevalence of OSA in the general population and ii) to analyse the association of this disorder with traditional cardiovascular disease risk factors and subclinical coronary atherosclerosis. Methods: In a cross-sectional analysis of the Heinz Nixdorf Recall study a subgroup of 1604 subjects (791 men, age 50e80 years) underwent OSA screening. Furthermore, coronary artery calcium (CAC) was measured. OSA was defined as apnoea-hypopnoea index (AHI)  15/h. Results: OSA was observed in 29.1% of men and 15.6% of women. In a multiple linear regression analysis adjusted for risk factors AHI was associated with CAC in men aged 65 years (estimated log-transformed increase of CAC ¼ 0.25, 95% confidence interval (CI) ¼ 0.001e0.50, p ¼ 0.051) and in women of any age (estimated log-transformed increase ¼ 0.23, 95% CI ¼ 0.04e0.41, p ¼ 0.02). Doubling of the AHI was associated with a 19% increase of CAC in men aged 65 years and with a 17% increase in women of any age. Conclusions: In the general population aged 50 years OSA is associated with subclinical atherosclerosis in men aged 65 years and in women of any age, independent of traditional cardiovascular risk factors. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

Keywords: Sleep-disordered breathing Obstructive sleep apnoea Coronary artery calcium Subclinical atherosclerosis Heinz Nixdorf Recall study

1. Introduction Sleep-disordered breathing (SDB) describes a group of disorders characterized by irregularities of respiration during sleep. The most common SDB is obstructive sleep apnoea (OSA), characterized by recurrent narrowing or closing of the upper airway due to the sleep related reduction of muscle tone. The reported prevalence of OSA ranges from 7 to 25% in men and from 2 to 11% in women [1e3]. Compared with the general population, OSA is more frequent in cohorts with hypertension (30e83%) [4,5], diabetes (23e58%) [6,7],

* Corresponding author. Tel.: þ49 201 433 4633; fax: þ49 201 433 1995. E-mail address: [email protected] (G. Weinreich). 1 Both authors contributed equally. 0021-9150/$ e see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2013.09.011

heart failure (12e53%) [8,9], ischaemic heart disease (30e58%) [10,11], and stroke (44e63%) [12,13]. Severe untreated OSA is associated with fatal and non-fatal cardiovascular events in comparison to healthy controls [14,15]. In the Sleep Heart Health Study, an association of OSA with incident coronary artery disease (CAD) independent of traditional cardiovascular disease (CVD) risk factors was observed in men 140/90 mmHg or use of antihypertensive medication. Body mass index (BMI) was calculated by dividing a subject’s weight in kilograms by the square of their height in metres. We used original BMI values and not categorized data. Participants were considered diabetic if they reported a physician diagnosis of diabetes or were taking anti-diabetic medication. Current smoking was defined as a history of continued cigarette smoking during the past year. Standard enzymatic methods were used to measure total cholesterol, LDL and HDL cholesterol, and triglycerides [17]. All subjects were

2.3. Electron-beam computed tomography (EBCT)

2.5. Statistical analysis Descriptive statistics are given as mean  standard deviation. Differences between groups were analysed using the Student’s ttest for either paired or unpaired comparisons as appropriate. The severity of OSA was determined as follows: no sleep apnoea (AHI < 5/h), mild sleep apnoea (AHI 5e14/h), moderate sleep apnoea (AHI 15e29/h), and severe sleep apnoea (AHI  30/h). The median and mean values of CAC score were compared among patients with increasing severity of OSA with the nonparametric KruskaleWallis test because of the non-Gaussian distribution of coronary calcium scores. Spearman correlation analysis was performed in order to study a trend of cardiovascular risk factor burden in the aforementioned OSA severity groups. Differences in proportions of current and former smokers were statistically evaluated using chi-square test. Since AHI values were lognormal distributed, we used a log transformation to obtain normally

G. Weinreich et al. / Atherosclerosis 231 (2013) 191e197

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Fig. 1. Subjects flow of the OSA screening in the Heinz Nixdorf Recall study. CVD: cardiovascular disease; PEP: primary end-point (incident coronary event).

distributed values. Univariate and multivariate multiple linear regression models were used for determining associations of logtransformed AHI after risk factor adjustment. Multiple linear regression was performed for providing associations with logtransformed CAC. Models were also built stratified on age 65 years versus age >65 years which provided similar numbers of subjects in the younger and older group. A p-value less than 0.05 denoted the presence of a statistically significant difference.

70

60

Men Women

OSA, defined by AHI  15/h, was observed in 29.1% of men and 15.6% of women (overall: 22.3%). The prevalence of OSA increased with age both in men and in women (Fig. 2). In comparison to participants who were included in the main analysis, differences were small to those individuals who did not undergo AHI screening. In order to analyse the possibility of a bias we compared eligible subjects with successful screening (n ¼ 1604) to eligible subjects without screening (n ¼ 1508). Unscreened subjects were older than those who were screened (64.2  7.6 vs. 63.5  7.4 years, p ¼ 0.009), had higher systolic blood pressure (134  20 vs. 133  19 mmHg, p ¼ 0.03), and LDL cholesterol (136  37 vs. 132  33 mg/dL, p ¼ 0.004). In unscreened participants use of blood pressure lowering drugs was higher (45.6 vs. 43.5%, p ¼ 0.01) and frequency of hypertension was higher (64.9% vs. 60.7%, p ¼ 0.002).

Prevalence (%)

50

3. Results

40

30

20

10

0 50-54

55-59

60-64

65-69

70-74

75-80

Age (years) Fig. 2. Prevalence of OSA (AHI  15/h) in men (N ¼ 791) and women (N ¼ 813). Prevalence is higher in men and increases with age.

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Furthermore, we compared eligible subjects with successful screening (n ¼ 1604) to eligible subjects with unsuccessful screening (n ¼ 459). Participants with an unsuccessful AHI screening were older (65.1  8.2 years vs. 63.5  7.4 years, p ¼ 0.01), were more often women (59.5% vs. 49.8%, p ¼ 0.001), had a lower BMI (27.9  4.2 kg/m2 vs. 28.3  4.9 kg/m2 vs., p ¼ 0.01), higher HDL-cholesterol values (63  18 mg/dL vs. 61  16 mg/dL, p ¼ 0.04) and were more frequently active smokers (20.7% vs. 16.2%, p ¼ 0.01).

between log-transformed AHI and log-transformed CAC score in men aged 65 years (Table 3b). Doubling of the AHI was associated with a 19% (95% CI ¼ 0.0008 to 42%) increase of CAC in men aged 65 years and with a 17% (95% CI ¼ 3e33%) increase in women of any age. Furthermore, age, hypertension, LDL cholesterol, lipidlowering medications, former and current smoking vs. never smoking were independently associated with CAC both in men and in women. 4. Discussion

3.1. Risk factors in OSA severity groups and associations with AHI The risk factor distribution was studied according to the severity of OSA as shown in Table 1a and b for men and women. The risk factor burden generally increased with OSA severity in men and women except for diabetes. Lipid values showed heterogeneous findings among men and women. In men the extent of CAC was much higher than in women. In univariate analysis age, BMI, systolic blood pressure, blood pressure lowering medications, hypertension were significantly associated with AHI in both sexes, whereas LDL cholesterol was significantly associated only in men, HDL cholesterol, lipid-lowering medications and current smoking only in women (Table 2a). In multiple regression analysis in men the association with AHI remained for age, BMI and LDL cholesterol. In women age and BMI were associated with AHI (Table 2b). 3.2. Associations with CAC score In multiple linear regression analysis adjusted for age and other risk factors, log-transformed AHI was independently associated with a log-transformed CAC score in women of any age (Table 3a). After stratification by age we found an independent association

To our knowledge, this is the first study investigating the association between obstructive sleep apnoea (OSA) and subclinical coronary artery calcium (CAC) in a large population-based study of men and women. This study provides some novel findings and confirms observations of previous studies. First, OSA as defined by AHI  15/h, is common (22%) in the general population aged 50e80 years. The prevalence is higher in men than in women and increases with age. Second, among traditional CVD risk factors, age, BMI and LDL cholesterol showed associations with the AHI in men. Age and BMI were independently associated with the AHI in women. Third, we observed an association of the severity of OSA, as defined by AHI, with the CAC score independent of traditional risk factors in men aged 65 years and in women of any age. The prevalence of SDB in the general population reported so far is both age- and sex-dependent [1e3]. Prevalence estimates range from 7 to 25% for men and from 2 to 11% for women. The wide range of estimates might be explained by a different age distribution among the different studies. In the Sleep Heart Health Study age ranged from 40 to 98 years, in the Wisconsin Sleep Cohort Study from 30 to 60 years, in a Pennsylvania study from 20 to 99 years, and in a Spain study from 30 to 70 years. Our study population is

Table 1 CVD risk factor distribution among OSA severity groups in men (a) and women (b). In general, risk factor burden increases with OSA severity in both sexes. a Men

AHI < 5/h

AHI 5e14/h

AHI 15e29/h

AHI  30/h

p-value

N Age (years) BMI (kg/m2) Systolic BP (mmHg) BP lowering medications (%) Hypertension (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Lipid-lowering medications (%) Diabetes mellitus (%) Current smoker (%) Former smoker (%) CAC score (median [Q1/Q3])

209 61.9  6.9 27.6  3.6 135.2  18.6 38.8 58.9 216.1  35.8 124.8  32.4 55.4  14.7 18.2 12.9 23.0 45.9 49 [0/311]

327 63.4  7.4 28.4  3.5 138.4  18.0 47.4 70.3 220.5  36.4 132.8  31.5 52.7  11.9 19.9 12.8 17.7 52.6 83 [7/381]

176 65.1  7.3 28.6  3.7 138.2  20.4 51.7 71.0 222.4  38.8 130.1  32.1 54.2  14.7 23.9 14.7 16.5 51.7 134 [21/444]

79 65.9  7.7 30.2  3.9 140.8  20.4 56.7 79.8 223.1  43.9 135.4  38.7 52.1  11.0 19.0 10.1 17.7 51.9 165 [31/439]

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Association of obstructive sleep apnoea with subclinical coronary atherosclerosis.

Accumulating evidence suggests a role of obstructive sleep apnoea (OSA) as a risk factor for coronary atherosclerosis. This study aimed i) to assess t...
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