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Self-reported sleep duration, all-cause mortality, cardiovascular mortality and morbidity in Finland
Sleep Medicine 12 (2011) 215–221
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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Self-reported sleep duration, all-cause mortality, cardiovascular mortality and morbidity in Finland Erkki Kronholm a,⇑, Tiina Laatikainen b, Markku Peltonen b, Risto Sippola c, Timo Partonen d a
National Institute for Health and Welfare, Department of Chronic Disease Prevention, Turku, Finland National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland c National Institute for Health and Welfare, Department of Health, Functional Capacity and Welfare, Helsinki, Finland d National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland b
a r t i c l e
i n f o
Article history: Received 13 April 2010 Received in revised form 21 June 2010 Accepted 22 July 2010
Keywords: Sleep duration Epidemiology Total mortality Cardiovascular mortality Cardiovascular morbidity Population-based study
a b s t r a c t Objective: The U-shaped association of self-reported sleep duration with all-cause mortality is generally accepted. Findings on cardiovascular (CVD) mortality and morbidity are inconsistent. We aimed to further clarify the associations of the self-reported sleep duration with CVD mortality and morbidity. Methods: In two population based surveys in 1972 and 1977 the levels of coronary risk factors in Finland and habitual sleep duration were measured; 25,025 individuals were followed-up until 2006 by the national register data. The outcome variables were death (for any reason), CVD death, and non-fatal CVD event (non-fatal myocardial infarction or stroke). Participants with former non-fatal CVD event at baseline were excluded from CVD analyses, and socio-demographic and health-related confounders were considered in the final Cox proportional hazard models for both genders. Results: The U-shaped association of total mortality with self-reported sleep duration was confirmed in both genders. The association of CVD mortality with self-reported sleep duration was independent of pertinent cardiovascular risk factors in women. The highest CVD mortality risk was found in both extreme ends of sleep duration distribution (65 and P10 h sleepers). Conclusions: Sleep duration is an independent risk factor for CVD mortality and morbidity in women but not in men. The highest CVD mortality risk is associated with the extreme ends of sleep duration distribution. Thus, in epidemiological studies, combining adjacent (6 and 9 h) sleep duration groups with the extreme groups may partly mask the mortality risks, especially in the long run. Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction The original observational finding of the U-shaped association between self-reported sleep duration and all-cause mortality [1,2] was later confirmed in at least 12 studies [3–14] with only two studies failing to confirm the association [15,16]. The first meta-analysis [17] also supported a U-shaped association between sleep duration and all-cause mortality. Studies examining the relationship between sleep duration and specific death cause or ill health, like cardiovascular disease (CVD), have yielded less consistent results. CVD mortality and/or morbidity has been predicted by long sleep duration in five studies [5,18–21]; three studies found only short sleep as an independent ⇑ Corresponding author. Address: National Institute for Health and Welfare, Department of Chronic Disease Prevention, Peltolantie 3, FI-20720 Turku, Finland. Tel.: +358 2 331 6718; fax: +358 2 331 6720. E-mail addresses: erkki.kronholm@thl.fi (E. Kronholm), tiina.laatikainen@thl.fi (T. Laatikainen), markku.peltonen@thl.fi (M. Peltonen), risto.sippola@thl.fi (R. Sippola), timo.partonen@thl.fi (T. Partonen). 1389-9457/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2010.07.021
predictor [22–24], two studies found an independent U-shaped association [25,26], one study found a U-shaped association in men but only long sleep duration to be independently associated with CVD mortality in women [27], and two studies failed to confirm an independent association between sleep duration and CVD mortality [15,28]. The nature and mechanisms yielding the association between sleep characteristics and mortality risks are far from clear. Sleep duration may be a direct or indirect causal risk factor/predictor or merely a correlate of processes implicated in mortality. The independent statistical role of short sleep duration as a predictor of mortality or health risk has been more often decreased or abolished by controlling for pertinent risk factors when compared with the role of long sleep duration [23,29]. The factors predicting or influencing an individual’s sleep duration may vary, at least in quantity, between different countries or cultures [30,31]. This may modulate the association between sleep characteristics and health risks across different countries. For example, in the United States sleep duration may have decreased during the last decades more strikingly [32] than in Finland, at
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least at the level of the adult general population [33]. Therefore, replications of the results on sleep and health risks within the same society are needed. We wanted to clarify the associations of self-reported sleep duration with all-cause mortality and with cardiovascular mortality and morbidity in Finland during 1972–2006 using a representative population-based sample. 2. Methods 2.1. Participants In two cross-sectional population surveys in the province of North Karelia and Kuopio, Finland, in 1972 and 1977 the levels of coronary risk factors and habitual sleep duration were measured. For both surveys an independent 6.6% random sample of 26,389 people born during the period 1913–1947 was drawn from the population register. Thus, the age range of the 1972 sample was 25–59 years, and the 1977 sample 30–64 years [34]. In all, 24,025 individuals (11,714 men and 12,311 women) participated in the surveys. The participation rate was high in both surveys (in the 1972 survey 93.5% and in the 1977 survey 89.9%). Complete data were obtained from 11,373 men and 11,917 women (total of 23,290 participants, 88.3% of the original sample). The study protocols of the FINRISK Surveys were approved a priori by the ethical committee of National Public Health Institute. 2.2. Baseline data Participants completed a self-administered questionnaire, which covered mainly questions on socioeconomic factors, medical history, current health, health behaviour, and psychosocial factors. Trained nurses measured the participants’ height, weight, and blood pressure and took venous blood specimens to determine the serum cholesterol concentration. Smoking was assessed with a standard set of questions in the self-administered questionnaire (for a detailed description, see [35]). For this study the following baseline variables were included in the analyses. 2.3. Self-reported sleep duration (predictor variable) Sleep duration was assessed by the question ‘‘How many hours do you sleep on average per night?’’ As suggested by the results of previous studies [17], the very extreme ends of the sleep duration distribution may be associated most strongly with increased mortality risk. Therefore, the participants were divided into five groups according to their sleep duration (65, 6, 7–8, 9, P10 h). 2.4. Confounding variables The following potentially confounding variables were included in the analyses: sociodemographic factors (age, marital status, income, the frequency of social activities during a month) and health factors (body mass index [BMI], smoking, total cholesterol, triglycerides, and systolic blood pressure). 2.5. Follow-up data The cohorts were followed up until 2006. The outcome variables were death (for any reason), cardiovascular (CVD) death (death caused by myocardial infarction [MI] or stroke), and non-fatal CVD event (non-fatal MI or stroke). This information was obtained from the national Causes-of-Death register and the Hospital Discharge Register.
2.6. Data analysis and statistical methods The differences in baseline characteristics between sleep duration groups were tested with Chi-Square or Kruskal–Wallis tests or by ANOVA. Mortality during the follow-up was analysed by Kaplan–Meier failure curves for total and CVD mortality separately in men and women. Regarding CVD events, participants with former CVD history (former non-fatal MI and/or stroke based on the Hospital Discharge Register and self-reports) were excluded from analyses. Hazard Ratios (HR) for mortality and morbidity were analysed by Cox proportional hazard models separately in men and women. Three steps were taken in calculating HRs: (1) unadjusted, (2) adjusted for age, and (3) adjusted for age, smoking, BMI, systolic blood pressure, and total cholesterol. All the analyses were made using SAS version 9.1.3. 3. Results Baseline characteristics of the participants across self-reported night sleep duration are given in Table 1. In both genders there was a statistically significant U-shaped association between sleep duration and the following factors: age, total cholesterol, and systolic blood pressure. There was a U-shaped association of BMI and triglycerides with sleep duration only in women. The statistically significant association of smoking with sleep duration, however, was not U-shaped in women. In women the lowest frequency of smokers was found in 9 h sleepers and the highest in 6 h sleepers, but extremely short sleepers did not differ from mid-range sleepers. For the CVD mortality and morbidity analyses, 806 participants (522 men and 284 women) who had had former CVD event (infarction or stroke) when examined at baseline, were excluded. The exclusions revealed, as expected, a statistically significant Ushaped association with sleep duration (Table 1). 3.1. Total mortality Total morality during 35 years by sleep duration groups is presented in Figs. 1 and 2 and Table 2. The highest mortality rate per 1000 person years was found in extremely short sleepers (65 h) for both genders. In men also extremely long sleepers (P10 h) showed a similar mortality rate to extremely short sleepers. The mortality in 9 h sleepers did not practically differ from the reference group (7–8 h sleepers). The adjustment for age alone attenuated the HR estimates, except the HRs for 9 h sleepers, which were increased and in women became statistically significant (Table 2). The adjustment for age, smoking, systolic blood pressure and total cholesterol further continued the trend of attenuating HR estimates; results showed that in men only extreme sleep groups had statistically significant HRs when compared with 7–8 h sleepers, but in women, even after adjustments, all short and long sleep duration groups showed significant hazard ratios when compared to 7–8 h sleepers. In addition, we analysed separately the mortality by sleep duration among the participants who were excluded from the CVD analysis because of their former CVD event history at baseline. It was found that sleep duration was not associated statistically significantly with unadjusted total mortality among the excluded participants either in men (Log rank p 0.83) or in women (Log rank p 0.23). Thus, the exclusion of the former CVD cases slightly augmented the predictive power of sleep duration in modelling total mortality. We also analysed total mortality across sleep duration groups separately for different age groups. We found a significant interaction between sleep duration and age groups in men, but not in wo-
20 (5.6)
men. In men the increased mortality risk was found in extremely short sleepers among young (25–39 years; HR 2.1; p < .01) and middle-aged (40–54 years; HR 1.8; p < .01) men, but not among men older than 55 years (HR 1.1; p ns). In men extremely long sleep duration was associated with significantly increased mortality risk in all age groups.
33 (2.5)
3.2. CVD mortality and morbidity Kaplan–Meier failure probability curves for CVD mortality are shown for men and women in Figs. 3 and 4. In Table 3 the CVD mortality during the follow-up by sleep duration is described among participants without CVD events at baseline. Table 4 gives the HRs for all CVD events and for MIs and strokes separately. Taken together these results indicate that in men self-reported sleep duration is not independently associated with the CVD event risk after adjustments for basic cardiovascular risk factors (age, smoking, systolic blood pressure and total cholesterol). On the contrary, in women self-reported sleep duration is independently associated with the CVD event risk. In fully adjusted models in women, especially fatal and non-fatal MIs were independently associated with deviant sleep duration. The association was stronger in long sleepers than in short sleepers. Fatal and non-fatal strokes were independently associated only with extremely long sleep (10 h or more) in the fully adjusted model for women.
39 (3.6) 29 (7.0)
163 (1.9)
3.33 2.50 5.56 1.69 1.00 2.53 2.94 0.83 3.58 6.00 1.68 6.95
1.41 0.54 1.86
28 (11.0) 53 (5.3) 333 (3.8) 48 (11.9) Number of excluded participants: (%)
60 (6.1)
8.66 2.36 11.02 4.38 1.10 5.28 3.34 0.63 3.81 4.90 1.63 6.13 8.40 4.20 11.85 Exclusion criteria Former infarction,% Former stroke,% Former CVD,%
Values are means ± standard deviation unless otherwise noted. Abbreviations: CVD, cardiovascular disease.
26.7 ± 5.6 15.1 6.8 ± 1.6 1.6 ± 1.0 143.1 ± 24.3 26.0 ± 4.7 9.8 6.7 ± 1.4 1.4 ± 0.8 143.6 ± 24.8 27.2 ± 5.1 17.6 6.8 ± 1.3 1.4 ± 0.9 148.2 ± 25.8 26.0 ± 4.0 57.0 6.8 ± 1.3 1.9 ± 1.2 149.3 ± 23.2 Health characteristics: BMI, kg/m2 Smoking ever,% Total cholesterol, mmol/l Triglycerides, mmol/l Systolic blood pressure, mmHg
25.8 ± 3.5 56.5 6.8 ± 1.3 1.9 ± 1.2 146.5 ± 20.4
25.8 ± 3.4 46.6 6.7 ± 1.3 1.8 ± 1.7 144.8 ± 19.1
25.8 ± 3.4 42.3 6.8 ± 1.3 1.9 ± 1.3 146.5 ± 20.8
26.2 ± 4.1 49.8 6.8 ± 1.4 1.9 ± 1.1 148.7 ± 21.0
28.0 ± 5.1 12.4 7.0 ± 1.4 1.7 ± 1.0 153.3 ± 27.1
26.0 ± 4.5 12.5 6.6 ± 1.4 1.3 ± 0.7 143.7 ± 23.8
43.7 ± 12.1 41.4 ± 10.8 47.2 ± 10.6 48.0 ± 10.8 Sociodemographic characteristics Age, years
43.9 ± 10.8
42.0 ± 10.3
41.7 ± 10.8
44.1 ± 11.5
50.5 ± 9.6
43.0 ± 10.3
10 or more 9
360 8746 1089 417
7–8 6 5 or less
254 1004 8731 405
979
217
4. Discussion
Number of participants:
Females
10 or more 9 7–8 6 5 or less
Males Sleep duration/day (hours)
Table 1 Baseline characteristics of the participants by daily sleeping hours. The national FINRISK study, 1972 and 1977 surveys.
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The main results of this study yielded by a relatively large cohort representative of the Finnish adult general population with a long (29–34 years) follow-up period showed that CVD mortality and morbidity were associated with sleep duration. Increased unadjusted CVD risk was found in both short sleeper groups (extremely short 65 h, and 6 h sleepers) as well as in extremely long sleepers (P10 h) in both genders when compared with mid-range (7–8 h) sleepers. The association, however, was found to be independent of pertinent cardiovascular risk factors only in women. An important finding was also that 9 h sleepers did not differ in their CVD risk when compared with mid-range sleepers. Our study is the second to have examined the association of sleep duration to total mortality in Finland. In the previous Finnish study [13] fully-adjusted HRs for all-cause mortality were, for short (<7 h) sleep, 1.26 among men and 1.21 among women. For long (>8 h) sleep they were 1.24 and 1.17, respectively. Our present results confirm these earlier results, adding the importance of analysing the sleep duration distribution more accurately. In our fully adjusted models we found the highest risks (1.32 and 1.25 for males and females, respectively) in the extremely short (65 h) and (1.61 and 1.62 for males and females, respectively) in the long (P10 h) sleepers. Total mortality was slightly increased also in 6 and 9 h sleepers but only in women. The existing literature, which often uses a coarse scale of sleep duration combining all individuals sleeping <7 h into short sleepers and >8 h into long sleepers, may thus partly mask the health risks associated with sleep duration, especially at the long run. The results of a recent German study [22] are in agreement with this conclusion. A limiting factor in some previous studies has been the relatively small number of participants, which alongside a relatively short follow-up time has lead to the small number of incident cases, particularly in the extremely short and long sleepers. For example, in a recent German study [22] CVD events in 65 h sleepers affected 8.7% of men and 6.2% of women; in P9 h sleepers the corresponding figures were 9.6% and 3.5%. We followed our cohorts for 29–34 years and CVD events in 65 h sleepers affected 24.9% of men and 24.7% of women; in P9 h sleepers the
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role of genetic factors that may underlie the association of sleep duration and health risks is clearly warranted. 4.1. Gender differences
Fig. 1. Total mortality (Kaplan–Meier failure probability plot) in men during 35 years of follow-up. The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Fig. 2. Total mortality (Kaplan–Meier failure probability plot) in women during 35 years of follow-up. The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
corresponding figures were 19.5% and 17.9%, increasing the reliability of our results. In this context, it is intriguing that the cumulative differences between groups of increased mortality rate and the reference group increased quite consistently across the whole follow-up period. But if the difference in mortality rates between the sleep groups were directly caused by sleep duration (strong causality hypothesis), this would not have been self-evident. In this case the changes in self-reported sleep duration (approximately in one-third of the adults over a relatively short [6-year] follow-up period [13]) should in the long run lead to diminishing death rate differences between baseline-defined sleep duration groups. Because this was not found, we are inclined to think that the self-reported sleep duration per s may not be a direct causal factor underlying the mortality differences between sleep groups. In a previous study Gangwisch and co-workers [14] discussed that if sleep durations were very stable during an individual’s lifespan, then progressively older age groups would have increasingly lower percentages of subjects belonging to groups of sleep duration with increased death risk. But the opposite is observed in epidemiological studies. One possible interpretation suggested by them [14] would be that the sleep duration functions as a surrogate marker of approaching death. Our results do not allow us to confirm or to falsify their hypothesis. Alternatively it is also possible that there may be some constant factor (probably a genetic one) influencing both the penetration of the sleep duration phenotype and health risks. This would explain the constant predictive information entered into the baseline sleep duration estimates. This conclusion is of course speculative and further study of the possible
In our fully adjusted models we found an increased risk of total mortality in both genders among extremely short and long sleepers and, in addition, in women also among 6 and 9 h sleepers. But the risk of CVD mortality was increased only in women. These results suggest that specific mortality causes may be differently associated with sleep duration among genders. To our knowledge, there are ten previous studies where the association of baseline sleep duration with future CVD mortality and/or incidence have been analysed separately in both genders. The results have been mixed. The increased independent risk in short sleepers was found among both genders in 4 studies [23,24,26,27] and only among women in one study [22]. The increased independent risk in long sleepers was found in both genders in 4 studies [18– 20,26] and only among women in one study [27]. In 2 studies [15,28] the increased risk was not found in either gender. There are several methodological reasons which may have caused this inconsistency, e.g., use of a coarse scale of sleep duration [15,18,19,28], only few large (>10,000) samples [20,26,27], and follow-up years from 4 to 19 years. In addition, two studies [19,20] were restricted to only elderly individuals (P64 years). Thus, not unexpectedly, in a recent meta-analysis none of the gender-specific pooled RRs for cardiovascular-related mortality associated with short sleep were statistically significant, and among long sleepers for both males and females, the pooled RRs for cardiovascular mortality were elevated, although not significantly [17]. Given the relatively large representative sample, the long follow-up periods and a design that allowed for an assessment of the levels of coronary risk factors, we feel that our results add reliability to the conclusion of an increased independent cardiovascular risk associated with sleep duration in women. The increased total mortality associated with sleep duration in men was not explained by CVD mortality, suggesting a further analysis on other specific mortality causes associated with sleep duration among men is needed. The importance of these results is emphasised by the fact that the mortality in middle aged men due to cardiovascular diseases was among the highest in the world in Finland in the early 1970s and has thereafter dramatically decreased so far by 80% in the middle-aged population [35,36]. Although the first Finnish cross-sectional observation about the association between self-reported sleep duration and history of angina pectoris and myocardial infarction among men was published already in 1982 [37], there so far have been no previous Finnish studies that analysed sleep duration-related CVD mortality/morbidity against this background. 4.2. Age Concerning total mortality, we found only one significant interaction between sleep duration and age suggesting that in men the sleep duration associated total mortality risk is increased among the extremely short sleepers of 25–54 years of age. The previous Finnish study [13] analysed the same age groups but used a more coarse sleep duration scale. They found that among the short sleepers the mortality risk was increased in all age groups among men. The increased risk for long sleep was found in the oldest age group (55 years or more) among men. The discrepancy between these two studies is probably explained by the coarse sleep duration scale in Hublin and co-workers, study [13] which may have partially masked the sleep duration associated mortality risk, especially in the long sleepers.
29.9 383 38,426 10.0 (9.0, 11.0) 1.01 (0.89) 1.16 (<.05) 1.18 (<.01) 29.9 2507 255,837 9.8 (9.4, 10.2) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 160 9605 16.7 (14.3, 19.4) 1.51 (<.01) 1.66 (<.01) 1.62 (<.01)
219
Fig. 3. Cardiovascular mortality (Kaplan–Meier failure probability plot) in men during 35 years of follow-up (former CVD cases excluded). The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Fig. 4. Cardiovascular mortality (Kaplan–Meier failure probability plot) in women during 35 years of follow-up (former CVD cases excluded). The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Adjusted for age, smoking, systolic blood pressure, and total cholesterol.
4.3. Mechanisms (hypothetical pathways between sleep and mortality/morbidity)
**
24.0 160 5483 29.2 (25.0, 34.1) 1.86 (<.01) 1.72 (<.01) 1.61 (<.01) 29.8 451 25,906 17.4 (15.9, 19.1) 1.05 (0.38) 1.08 (0.11) 1.10 (0.07) 22.4 283 8438 33.5 (29.8, 37.7) 2.17 (<.01) 1.37 (<.01) 1.32 (<.01) Total mortality Median follow-up, years Number of deaths, n Person years, years Rate per 1000 person years (95% confidence interval) Hazard ratio, unadjusted (p) Hazard ratio, adjusted for age (p) Hazard ratio, fully adjusted** (p)
29.8 530 24,125 22.0 (20.2, 23.9) 1.35 (<.01) 1.19 (<.01) 1.09 (0.07)
29.8 3817 230,187 16.6 (16.1, 17.1) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 239 10,674 22.4 (19.7, 25.4) 2.50 (<.01) 1.35 (<.01) 1.25 (<.01)
29.8 458 29,704 15.4 (14.1, 16.9) 1.65 (<.01) 1.15 (<.05) 1.14 (<.05)
1305 8746
360
9h 7–8 h
1089
6h
417 254 1004 405 Number of individuals: n
979
8731
65 h P10 h 7–8 h 6h 65 h
Sleep duration, men
Table 2 Total mortality by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006.
9h
Sleep duration, women
P10 h
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
The core question of how the aetiology of CVD is associated with sleep duration is still without a conclusive answer. Speaking in statistical terms [38], there exists a consensus that sleep duration is a ‘‘risk factor’’ for (i.e., significantly associated with) mortality and CVD morbidity [17]. Therefore, most studies have focused on attempting to discern if sleep duration is an ‘‘independent risk factor/predictor,’’ i.e., if it retains its statistical association with CVD mortality when other established risk factors for CVD mortality are included in the model. The results have been mixed. One reason for this may be that a problem of over-adjustment is not always considered. If sleep duration is a causal link in an aetiological pathway to a CVD event, an inference supported by several studies [39], then correcting for the previous CVD history or for other causal factors (like cholesterol, blood pressure and BMI) in the pathway between sleep and health might obscure an underlying effect of sleep duration [30]. In our fully adjusted models we found that among women (but not among men) sleep duration was an independent risk factor. Consequently, one may ask if the results for men are caused by an over-adjustment. We do not believe this is the case. First, in a separate analysis we found that sleep duration was not a significant predictor of mortality among individuals who had had non-fatal CVD events at baseline. Second, as discussed above, among individuals without former CVD events the cumulative differences between baseline-defined sleep groups in CVD mortality increased relatively constantly during the long follow-up period, indicating that the
220
Table 3 CVD mortality by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006. Sleep duration, men 6h
7–8 h
9h
P10 h
65 h
6h
7–8 h
9h
P10 h
Number of individuals: n
357
919
8398
951
226
388
1050
8583
1272
340
CVD mortality Median follow-up, years Number of event, n Person years, years Rate per 1000 person years (95% confidence interval) Hazard ratio, unadjusted (p) Hazard ratio, adjusted for age (p) Hazard ratio, fully adjusted** (p)
20.4 89 7146 12.5 (10.1, 15.3) 1.97 (<0.01) 1.18 (0.14) 1.20 (0.12)
26.6 198 21,094 9.4 (8.2, 10.8) 1.46 (<0.01) 1.25 (<0.01) 1.12 (0.16)
29.8 1356 208,028 6.5 (6.2, 6.9) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 143 23,149 6.2 (5.2, 7.3) 0.95 (0.54) 0.97 (0.74) 0.95 (0.58)
22.8 44 4782 9.2 (6.8, 12.4) 1.44 (0.02) 1.34 (0.06) 1.27 (0.14)
27.1 96 9312 10.3 (8.4, 10.3) 3.04 (<0.01) 1.51 (<0.01) 1.33 (0.01)
29.8 170 27,372 6.2 (5.3, 7.2) 1.77 (<0.01) 1.18 (0.06) 1.20 (0.04)
29.9 879 241,832 3.6 (3.4, 3.9) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.9 138 36,187 3.8 (3.2, 4.5) 1.04 (0.65) 1.23 (0.02) 1.20 (0.06)
29.8 61 8805 6.9 (5.4, 8.9) 1.95 (<0.01) 1.91 (<0.01) 1.76 (<0.01)
Adjusted for age, smoking, systolic blood pressure, and total cholesterol.
Table 4 Hazard ratios and their statistical significance (p) for fatal and non-fatal CVD events by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006. Adjustments
Sleep duration males 65 h
CVD events (806 former CVD cases excluded)
Infarcts (806 former CVD cases excluded)
Strokes (806 former CVD cases excluded)
Unadjusted Adjusted for age Fully adjusted* Unadjusted Adjusted for age Fully adjusted* Unadjusted Adjusted for age Fully adjusted*
1.62 1.09 1.12 1.66 1.14 1.18 1.60 1.04 1.07
(<0.01) (0.34) (0.20) (<0.01) (0.23) (0.14) (<0.01) (0.80) (0.67)
Significant fully adjusted HRs are shown in bold. Abbreviations: CVD, cardiovascular disease; BMI, body mass index; HR, hazard ratio. Adjusted for age, smoking, BMI, systolic blood pressure and total cholesterol.
*
Sleep duration females
6h 1.34 1.20 1.08 1.35 1.22 1.09 1.31 1.16 1.08
(<0.01) (<0.01) (0.17) (<0.01) (<0.01) (0.25) (0.01) (0.15) (0.47)
7–8 h
9h
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.01 1.04 1.03 1.07 1.10 1.08 0.91 0.95 0.96
(ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref)
(0.89) (0.50) (0.61) (0.37) (0.18) (0.30) (0.43) (0.63) (0.74)
P10 h
65 h
1.22 1.19 1.13 1.17 1.14 1.06 1.31 1.29 1.26
2.34 1.34 1.22 2.49 1.38 1.23 2.04 1.22 1.15
(0.10) (0.14) (0.34) (0.29) (0.37) (0.72) (0.21) (0.22) (0.30)
6h (<0.01) (<0.01) (0.03) (<0.01) (<0.01) (0.09) (<0.01) (0.16) (0.33)
1.54 1.13 1.13 1.63 1.17 1.19 1.46 1.09 1.08
(<0.01) (0.06) (0.06) (<0.01) (0.06) (0.04) (<0.01) (0.35) (0.44)
7–8 h
9h
P10 h
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.00 (0.95) 1.16 (0.02) 1.14 (0.05) 1.04 (0.61) 1.22 (0.17) 1.23 (0.02) 0.93 (0.47) 1.07 (0.48) 1.02 (0.88)
1.45 1.48 1.41 1.45 1.48 1.43 1.46 1.51 1.40
(ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref)
(<0.01) (<0.01) (<0.01) (0.01) (0.01) (0.01) (0.02) (0.01) (0.05)
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
**
Sleep duration, women
65 h
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
statistical predictive power of sleep duration has remained during the long follow-up. Together, these findings prompt us to consider a possibility that sleep duration may be a ‘‘non-causal risk factor/ proxy,’’ i.e., it is associated with some real constant causal factor but does not have a causal relationship with the CVD mortality. Here, we suggest that this stable factor is likely to be a genetic factor. Thus, extremely deviant sleep duration and increased CVD risk may both be expressions of the same genetic predisposition, at least in men. This hypothesis is in agreement with the results of the recent meta-analysis where there were no differences between the results when meta-analyses were conducted that included all studies and when including only those studies that considered comorbid conditions [17]. However, it is also evident that the expression of this supposed genetic predisposition may be modulated by several known risk factors such as gender [17], socioeconomic status [40–42], hypertension [24], anxiety and depression [43], making the association between sleep duration and CVD mortality/morbidity a very complex one. If this currently speculative hypothesis is true, it would be problematic to consider sleep duration as a therapeutic target for attempts to decrease CVD mortality in the general population. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2010.10.006.
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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
Self-reported sleep duration, all-cause mortality, cardiovascular mortality and morbidity in Finland Erkki Kronholm a,⇑, Tiina Laatikainen b, Markku Peltonen b, Risto Sippola c, Timo Partonen d a
National Institute for Health and Welfare, Department of Chronic Disease Prevention, Turku, Finland National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland c National Institute for Health and Welfare, Department of Health, Functional Capacity and Welfare, Helsinki, Finland d National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland b
a r t i c l e
i n f o
Article history: Received 13 April 2010 Received in revised form 21 June 2010 Accepted 22 July 2010
Keywords: Sleep duration Epidemiology Total mortality Cardiovascular mortality Cardiovascular morbidity Population-based study
a b s t r a c t Objective: The U-shaped association of self-reported sleep duration with all-cause mortality is generally accepted. Findings on cardiovascular (CVD) mortality and morbidity are inconsistent. We aimed to further clarify the associations of the self-reported sleep duration with CVD mortality and morbidity. Methods: In two population based surveys in 1972 and 1977 the levels of coronary risk factors in Finland and habitual sleep duration were measured; 25,025 individuals were followed-up until 2006 by the national register data. The outcome variables were death (for any reason), CVD death, and non-fatal CVD event (non-fatal myocardial infarction or stroke). Participants with former non-fatal CVD event at baseline were excluded from CVD analyses, and socio-demographic and health-related confounders were considered in the final Cox proportional hazard models for both genders. Results: The U-shaped association of total mortality with self-reported sleep duration was confirmed in both genders. The association of CVD mortality with self-reported sleep duration was independent of pertinent cardiovascular risk factors in women. The highest CVD mortality risk was found in both extreme ends of sleep duration distribution (65 and P10 h sleepers). Conclusions: Sleep duration is an independent risk factor for CVD mortality and morbidity in women but not in men. The highest CVD mortality risk is associated with the extreme ends of sleep duration distribution. Thus, in epidemiological studies, combining adjacent (6 and 9 h) sleep duration groups with the extreme groups may partly mask the mortality risks, especially in the long run. Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction The original observational finding of the U-shaped association between self-reported sleep duration and all-cause mortality [1,2] was later confirmed in at least 12 studies [3–14] with only two studies failing to confirm the association [15,16]. The first meta-analysis [17] also supported a U-shaped association between sleep duration and all-cause mortality. Studies examining the relationship between sleep duration and specific death cause or ill health, like cardiovascular disease (CVD), have yielded less consistent results. CVD mortality and/or morbidity has been predicted by long sleep duration in five studies [5,18–21]; three studies found only short sleep as an independent ⇑ Corresponding author. Address: National Institute for Health and Welfare, Department of Chronic Disease Prevention, Peltolantie 3, FI-20720 Turku, Finland. Tel.: +358 2 331 6718; fax: +358 2 331 6720. E-mail addresses: erkki.kronholm@thl.fi (E. Kronholm), tiina.laatikainen@thl.fi (T. Laatikainen), markku.peltonen@thl.fi (M. Peltonen), risto.sippola@thl.fi (R. Sippola), timo.partonen@thl.fi (T. Partonen). 1389-9457/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2010.07.021
predictor [22–24], two studies found an independent U-shaped association [25,26], one study found a U-shaped association in men but only long sleep duration to be independently associated with CVD mortality in women [27], and two studies failed to confirm an independent association between sleep duration and CVD mortality [15,28]. The nature and mechanisms yielding the association between sleep characteristics and mortality risks are far from clear. Sleep duration may be a direct or indirect causal risk factor/predictor or merely a correlate of processes implicated in mortality. The independent statistical role of short sleep duration as a predictor of mortality or health risk has been more often decreased or abolished by controlling for pertinent risk factors when compared with the role of long sleep duration [23,29]. The factors predicting or influencing an individual’s sleep duration may vary, at least in quantity, between different countries or cultures [30,31]. This may modulate the association between sleep characteristics and health risks across different countries. For example, in the United States sleep duration may have decreased during the last decades more strikingly [32] than in Finland, at
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least at the level of the adult general population [33]. Therefore, replications of the results on sleep and health risks within the same society are needed. We wanted to clarify the associations of self-reported sleep duration with all-cause mortality and with cardiovascular mortality and morbidity in Finland during 1972–2006 using a representative population-based sample. 2. Methods 2.1. Participants In two cross-sectional population surveys in the province of North Karelia and Kuopio, Finland, in 1972 and 1977 the levels of coronary risk factors and habitual sleep duration were measured. For both surveys an independent 6.6% random sample of 26,389 people born during the period 1913–1947 was drawn from the population register. Thus, the age range of the 1972 sample was 25–59 years, and the 1977 sample 30–64 years [34]. In all, 24,025 individuals (11,714 men and 12,311 women) participated in the surveys. The participation rate was high in both surveys (in the 1972 survey 93.5% and in the 1977 survey 89.9%). Complete data were obtained from 11,373 men and 11,917 women (total of 23,290 participants, 88.3% of the original sample). The study protocols of the FINRISK Surveys were approved a priori by the ethical committee of National Public Health Institute. 2.2. Baseline data Participants completed a self-administered questionnaire, which covered mainly questions on socioeconomic factors, medical history, current health, health behaviour, and psychosocial factors. Trained nurses measured the participants’ height, weight, and blood pressure and took venous blood specimens to determine the serum cholesterol concentration. Smoking was assessed with a standard set of questions in the self-administered questionnaire (for a detailed description, see [35]). For this study the following baseline variables were included in the analyses. 2.3. Self-reported sleep duration (predictor variable) Sleep duration was assessed by the question ‘‘How many hours do you sleep on average per night?’’ As suggested by the results of previous studies [17], the very extreme ends of the sleep duration distribution may be associated most strongly with increased mortality risk. Therefore, the participants were divided into five groups according to their sleep duration (65, 6, 7–8, 9, P10 h). 2.4. Confounding variables The following potentially confounding variables were included in the analyses: sociodemographic factors (age, marital status, income, the frequency of social activities during a month) and health factors (body mass index [BMI], smoking, total cholesterol, triglycerides, and systolic blood pressure). 2.5. Follow-up data The cohorts were followed up until 2006. The outcome variables were death (for any reason), cardiovascular (CVD) death (death caused by myocardial infarction [MI] or stroke), and non-fatal CVD event (non-fatal MI or stroke). This information was obtained from the national Causes-of-Death register and the Hospital Discharge Register.
2.6. Data analysis and statistical methods The differences in baseline characteristics between sleep duration groups were tested with Chi-Square or Kruskal–Wallis tests or by ANOVA. Mortality during the follow-up was analysed by Kaplan–Meier failure curves for total and CVD mortality separately in men and women. Regarding CVD events, participants with former CVD history (former non-fatal MI and/or stroke based on the Hospital Discharge Register and self-reports) were excluded from analyses. Hazard Ratios (HR) for mortality and morbidity were analysed by Cox proportional hazard models separately in men and women. Three steps were taken in calculating HRs: (1) unadjusted, (2) adjusted for age, and (3) adjusted for age, smoking, BMI, systolic blood pressure, and total cholesterol. All the analyses were made using SAS version 9.1.3. 3. Results Baseline characteristics of the participants across self-reported night sleep duration are given in Table 1. In both genders there was a statistically significant U-shaped association between sleep duration and the following factors: age, total cholesterol, and systolic blood pressure. There was a U-shaped association of BMI and triglycerides with sleep duration only in women. The statistically significant association of smoking with sleep duration, however, was not U-shaped in women. In women the lowest frequency of smokers was found in 9 h sleepers and the highest in 6 h sleepers, but extremely short sleepers did not differ from mid-range sleepers. For the CVD mortality and morbidity analyses, 806 participants (522 men and 284 women) who had had former CVD event (infarction or stroke) when examined at baseline, were excluded. The exclusions revealed, as expected, a statistically significant Ushaped association with sleep duration (Table 1). 3.1. Total mortality Total morality during 35 years by sleep duration groups is presented in Figs. 1 and 2 and Table 2. The highest mortality rate per 1000 person years was found in extremely short sleepers (65 h) for both genders. In men also extremely long sleepers (P10 h) showed a similar mortality rate to extremely short sleepers. The mortality in 9 h sleepers did not practically differ from the reference group (7–8 h sleepers). The adjustment for age alone attenuated the HR estimates, except the HRs for 9 h sleepers, which were increased and in women became statistically significant (Table 2). The adjustment for age, smoking, systolic blood pressure and total cholesterol further continued the trend of attenuating HR estimates; results showed that in men only extreme sleep groups had statistically significant HRs when compared with 7–8 h sleepers, but in women, even after adjustments, all short and long sleep duration groups showed significant hazard ratios when compared to 7–8 h sleepers. In addition, we analysed separately the mortality by sleep duration among the participants who were excluded from the CVD analysis because of their former CVD event history at baseline. It was found that sleep duration was not associated statistically significantly with unadjusted total mortality among the excluded participants either in men (Log rank p 0.83) or in women (Log rank p 0.23). Thus, the exclusion of the former CVD cases slightly augmented the predictive power of sleep duration in modelling total mortality. We also analysed total mortality across sleep duration groups separately for different age groups. We found a significant interaction between sleep duration and age groups in men, but not in wo-
20 (5.6)
men. In men the increased mortality risk was found in extremely short sleepers among young (25–39 years; HR 2.1; p < .01) and middle-aged (40–54 years; HR 1.8; p < .01) men, but not among men older than 55 years (HR 1.1; p ns). In men extremely long sleep duration was associated with significantly increased mortality risk in all age groups.
33 (2.5)
3.2. CVD mortality and morbidity Kaplan–Meier failure probability curves for CVD mortality are shown for men and women in Figs. 3 and 4. In Table 3 the CVD mortality during the follow-up by sleep duration is described among participants without CVD events at baseline. Table 4 gives the HRs for all CVD events and for MIs and strokes separately. Taken together these results indicate that in men self-reported sleep duration is not independently associated with the CVD event risk after adjustments for basic cardiovascular risk factors (age, smoking, systolic blood pressure and total cholesterol). On the contrary, in women self-reported sleep duration is independently associated with the CVD event risk. In fully adjusted models in women, especially fatal and non-fatal MIs were independently associated with deviant sleep duration. The association was stronger in long sleepers than in short sleepers. Fatal and non-fatal strokes were independently associated only with extremely long sleep (10 h or more) in the fully adjusted model for women.
39 (3.6) 29 (7.0)
163 (1.9)
3.33 2.50 5.56 1.69 1.00 2.53 2.94 0.83 3.58 6.00 1.68 6.95
1.41 0.54 1.86
28 (11.0) 53 (5.3) 333 (3.8) 48 (11.9) Number of excluded participants: (%)
60 (6.1)
8.66 2.36 11.02 4.38 1.10 5.28 3.34 0.63 3.81 4.90 1.63 6.13 8.40 4.20 11.85 Exclusion criteria Former infarction,% Former stroke,% Former CVD,%
Values are means ± standard deviation unless otherwise noted. Abbreviations: CVD, cardiovascular disease.
26.7 ± 5.6 15.1 6.8 ± 1.6 1.6 ± 1.0 143.1 ± 24.3 26.0 ± 4.7 9.8 6.7 ± 1.4 1.4 ± 0.8 143.6 ± 24.8 27.2 ± 5.1 17.6 6.8 ± 1.3 1.4 ± 0.9 148.2 ± 25.8 26.0 ± 4.0 57.0 6.8 ± 1.3 1.9 ± 1.2 149.3 ± 23.2 Health characteristics: BMI, kg/m2 Smoking ever,% Total cholesterol, mmol/l Triglycerides, mmol/l Systolic blood pressure, mmHg
25.8 ± 3.5 56.5 6.8 ± 1.3 1.9 ± 1.2 146.5 ± 20.4
25.8 ± 3.4 46.6 6.7 ± 1.3 1.8 ± 1.7 144.8 ± 19.1
25.8 ± 3.4 42.3 6.8 ± 1.3 1.9 ± 1.3 146.5 ± 20.8
26.2 ± 4.1 49.8 6.8 ± 1.4 1.9 ± 1.1 148.7 ± 21.0
28.0 ± 5.1 12.4 7.0 ± 1.4 1.7 ± 1.0 153.3 ± 27.1
26.0 ± 4.5 12.5 6.6 ± 1.4 1.3 ± 0.7 143.7 ± 23.8
43.7 ± 12.1 41.4 ± 10.8 47.2 ± 10.6 48.0 ± 10.8 Sociodemographic characteristics Age, years
43.9 ± 10.8
42.0 ± 10.3
41.7 ± 10.8
44.1 ± 11.5
50.5 ± 9.6
43.0 ± 10.3
10 or more 9
360 8746 1089 417
7–8 6 5 or less
254 1004 8731 405
979
217
4. Discussion
Number of participants:
Females
10 or more 9 7–8 6 5 or less
Males Sleep duration/day (hours)
Table 1 Baseline characteristics of the participants by daily sleeping hours. The national FINRISK study, 1972 and 1977 surveys.
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The main results of this study yielded by a relatively large cohort representative of the Finnish adult general population with a long (29–34 years) follow-up period showed that CVD mortality and morbidity were associated with sleep duration. Increased unadjusted CVD risk was found in both short sleeper groups (extremely short 65 h, and 6 h sleepers) as well as in extremely long sleepers (P10 h) in both genders when compared with mid-range (7–8 h) sleepers. The association, however, was found to be independent of pertinent cardiovascular risk factors only in women. An important finding was also that 9 h sleepers did not differ in their CVD risk when compared with mid-range sleepers. Our study is the second to have examined the association of sleep duration to total mortality in Finland. In the previous Finnish study [13] fully-adjusted HRs for all-cause mortality were, for short (<7 h) sleep, 1.26 among men and 1.21 among women. For long (>8 h) sleep they were 1.24 and 1.17, respectively. Our present results confirm these earlier results, adding the importance of analysing the sleep duration distribution more accurately. In our fully adjusted models we found the highest risks (1.32 and 1.25 for males and females, respectively) in the extremely short (65 h) and (1.61 and 1.62 for males and females, respectively) in the long (P10 h) sleepers. Total mortality was slightly increased also in 6 and 9 h sleepers but only in women. The existing literature, which often uses a coarse scale of sleep duration combining all individuals sleeping <7 h into short sleepers and >8 h into long sleepers, may thus partly mask the health risks associated with sleep duration, especially at the long run. The results of a recent German study [22] are in agreement with this conclusion. A limiting factor in some previous studies has been the relatively small number of participants, which alongside a relatively short follow-up time has lead to the small number of incident cases, particularly in the extremely short and long sleepers. For example, in a recent German study [22] CVD events in 65 h sleepers affected 8.7% of men and 6.2% of women; in P9 h sleepers the corresponding figures were 9.6% and 3.5%. We followed our cohorts for 29–34 years and CVD events in 65 h sleepers affected 24.9% of men and 24.7% of women; in P9 h sleepers the
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role of genetic factors that may underlie the association of sleep duration and health risks is clearly warranted. 4.1. Gender differences
Fig. 1. Total mortality (Kaplan–Meier failure probability plot) in men during 35 years of follow-up. The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Fig. 2. Total mortality (Kaplan–Meier failure probability plot) in women during 35 years of follow-up. The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
corresponding figures were 19.5% and 17.9%, increasing the reliability of our results. In this context, it is intriguing that the cumulative differences between groups of increased mortality rate and the reference group increased quite consistently across the whole follow-up period. But if the difference in mortality rates between the sleep groups were directly caused by sleep duration (strong causality hypothesis), this would not have been self-evident. In this case the changes in self-reported sleep duration (approximately in one-third of the adults over a relatively short [6-year] follow-up period [13]) should in the long run lead to diminishing death rate differences between baseline-defined sleep duration groups. Because this was not found, we are inclined to think that the self-reported sleep duration per s may not be a direct causal factor underlying the mortality differences between sleep groups. In a previous study Gangwisch and co-workers [14] discussed that if sleep durations were very stable during an individual’s lifespan, then progressively older age groups would have increasingly lower percentages of subjects belonging to groups of sleep duration with increased death risk. But the opposite is observed in epidemiological studies. One possible interpretation suggested by them [14] would be that the sleep duration functions as a surrogate marker of approaching death. Our results do not allow us to confirm or to falsify their hypothesis. Alternatively it is also possible that there may be some constant factor (probably a genetic one) influencing both the penetration of the sleep duration phenotype and health risks. This would explain the constant predictive information entered into the baseline sleep duration estimates. This conclusion is of course speculative and further study of the possible
In our fully adjusted models we found an increased risk of total mortality in both genders among extremely short and long sleepers and, in addition, in women also among 6 and 9 h sleepers. But the risk of CVD mortality was increased only in women. These results suggest that specific mortality causes may be differently associated with sleep duration among genders. To our knowledge, there are ten previous studies where the association of baseline sleep duration with future CVD mortality and/or incidence have been analysed separately in both genders. The results have been mixed. The increased independent risk in short sleepers was found among both genders in 4 studies [23,24,26,27] and only among women in one study [22]. The increased independent risk in long sleepers was found in both genders in 4 studies [18– 20,26] and only among women in one study [27]. In 2 studies [15,28] the increased risk was not found in either gender. There are several methodological reasons which may have caused this inconsistency, e.g., use of a coarse scale of sleep duration [15,18,19,28], only few large (>10,000) samples [20,26,27], and follow-up years from 4 to 19 years. In addition, two studies [19,20] were restricted to only elderly individuals (P64 years). Thus, not unexpectedly, in a recent meta-analysis none of the gender-specific pooled RRs for cardiovascular-related mortality associated with short sleep were statistically significant, and among long sleepers for both males and females, the pooled RRs for cardiovascular mortality were elevated, although not significantly [17]. Given the relatively large representative sample, the long follow-up periods and a design that allowed for an assessment of the levels of coronary risk factors, we feel that our results add reliability to the conclusion of an increased independent cardiovascular risk associated with sleep duration in women. The increased total mortality associated with sleep duration in men was not explained by CVD mortality, suggesting a further analysis on other specific mortality causes associated with sleep duration among men is needed. The importance of these results is emphasised by the fact that the mortality in middle aged men due to cardiovascular diseases was among the highest in the world in Finland in the early 1970s and has thereafter dramatically decreased so far by 80% in the middle-aged population [35,36]. Although the first Finnish cross-sectional observation about the association between self-reported sleep duration and history of angina pectoris and myocardial infarction among men was published already in 1982 [37], there so far have been no previous Finnish studies that analysed sleep duration-related CVD mortality/morbidity against this background. 4.2. Age Concerning total mortality, we found only one significant interaction between sleep duration and age suggesting that in men the sleep duration associated total mortality risk is increased among the extremely short sleepers of 25–54 years of age. The previous Finnish study [13] analysed the same age groups but used a more coarse sleep duration scale. They found that among the short sleepers the mortality risk was increased in all age groups among men. The increased risk for long sleep was found in the oldest age group (55 years or more) among men. The discrepancy between these two studies is probably explained by the coarse sleep duration scale in Hublin and co-workers, study [13] which may have partially masked the sleep duration associated mortality risk, especially in the long sleepers.
29.9 383 38,426 10.0 (9.0, 11.0) 1.01 (0.89) 1.16 (<.05) 1.18 (<.01) 29.9 2507 255,837 9.8 (9.4, 10.2) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 160 9605 16.7 (14.3, 19.4) 1.51 (<.01) 1.66 (<.01) 1.62 (<.01)
219
Fig. 3. Cardiovascular mortality (Kaplan–Meier failure probability plot) in men during 35 years of follow-up (former CVD cases excluded). The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Fig. 4. Cardiovascular mortality (Kaplan–Meier failure probability plot) in women during 35 years of follow-up (former CVD cases excluded). The National FINRISK Study, Finland, two cohorts in 1972 and 1977, followed-up to 2006.
Adjusted for age, smoking, systolic blood pressure, and total cholesterol.
4.3. Mechanisms (hypothetical pathways between sleep and mortality/morbidity)
**
24.0 160 5483 29.2 (25.0, 34.1) 1.86 (<.01) 1.72 (<.01) 1.61 (<.01) 29.8 451 25,906 17.4 (15.9, 19.1) 1.05 (0.38) 1.08 (0.11) 1.10 (0.07) 22.4 283 8438 33.5 (29.8, 37.7) 2.17 (<.01) 1.37 (<.01) 1.32 (<.01) Total mortality Median follow-up, years Number of deaths, n Person years, years Rate per 1000 person years (95% confidence interval) Hazard ratio, unadjusted (p) Hazard ratio, adjusted for age (p) Hazard ratio, fully adjusted** (p)
29.8 530 24,125 22.0 (20.2, 23.9) 1.35 (<.01) 1.19 (<.01) 1.09 (0.07)
29.8 3817 230,187 16.6 (16.1, 17.1) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 239 10,674 22.4 (19.7, 25.4) 2.50 (<.01) 1.35 (<.01) 1.25 (<.01)
29.8 458 29,704 15.4 (14.1, 16.9) 1.65 (<.01) 1.15 (<.05) 1.14 (<.05)
1305 8746
360
9h 7–8 h
1089
6h
417 254 1004 405 Number of individuals: n
979
8731
65 h P10 h 7–8 h 6h 65 h
Sleep duration, men
Table 2 Total mortality by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006.
9h
Sleep duration, women
P10 h
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
The core question of how the aetiology of CVD is associated with sleep duration is still without a conclusive answer. Speaking in statistical terms [38], there exists a consensus that sleep duration is a ‘‘risk factor’’ for (i.e., significantly associated with) mortality and CVD morbidity [17]. Therefore, most studies have focused on attempting to discern if sleep duration is an ‘‘independent risk factor/predictor,’’ i.e., if it retains its statistical association with CVD mortality when other established risk factors for CVD mortality are included in the model. The results have been mixed. One reason for this may be that a problem of over-adjustment is not always considered. If sleep duration is a causal link in an aetiological pathway to a CVD event, an inference supported by several studies [39], then correcting for the previous CVD history or for other causal factors (like cholesterol, blood pressure and BMI) in the pathway between sleep and health might obscure an underlying effect of sleep duration [30]. In our fully adjusted models we found that among women (but not among men) sleep duration was an independent risk factor. Consequently, one may ask if the results for men are caused by an over-adjustment. We do not believe this is the case. First, in a separate analysis we found that sleep duration was not a significant predictor of mortality among individuals who had had non-fatal CVD events at baseline. Second, as discussed above, among individuals without former CVD events the cumulative differences between baseline-defined sleep groups in CVD mortality increased relatively constantly during the long follow-up period, indicating that the
220
Table 3 CVD mortality by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006. Sleep duration, men 6h
7–8 h
9h
P10 h
65 h
6h
7–8 h
9h
P10 h
Number of individuals: n
357
919
8398
951
226
388
1050
8583
1272
340
CVD mortality Median follow-up, years Number of event, n Person years, years Rate per 1000 person years (95% confidence interval) Hazard ratio, unadjusted (p) Hazard ratio, adjusted for age (p) Hazard ratio, fully adjusted** (p)
20.4 89 7146 12.5 (10.1, 15.3) 1.97 (<0.01) 1.18 (0.14) 1.20 (0.12)
26.6 198 21,094 9.4 (8.2, 10.8) 1.46 (<0.01) 1.25 (<0.01) 1.12 (0.16)
29.8 1356 208,028 6.5 (6.2, 6.9) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.8 143 23,149 6.2 (5.2, 7.3) 0.95 (0.54) 0.97 (0.74) 0.95 (0.58)
22.8 44 4782 9.2 (6.8, 12.4) 1.44 (0.02) 1.34 (0.06) 1.27 (0.14)
27.1 96 9312 10.3 (8.4, 10.3) 3.04 (<0.01) 1.51 (<0.01) 1.33 (0.01)
29.8 170 27,372 6.2 (5.3, 7.2) 1.77 (<0.01) 1.18 (0.06) 1.20 (0.04)
29.9 879 241,832 3.6 (3.4, 3.9) 1.00 (ref) 1.00 (ref) 1.00 (ref)
29.9 138 36,187 3.8 (3.2, 4.5) 1.04 (0.65) 1.23 (0.02) 1.20 (0.06)
29.8 61 8805 6.9 (5.4, 8.9) 1.95 (<0.01) 1.91 (<0.01) 1.76 (<0.01)
Adjusted for age, smoking, systolic blood pressure, and total cholesterol.
Table 4 Hazard ratios and their statistical significance (p) for fatal and non-fatal CVD events by sleep duration. The national FINRISK study, 1972 and 1977 cohorts followed-up to 2006. Adjustments
Sleep duration males 65 h
CVD events (806 former CVD cases excluded)
Infarcts (806 former CVD cases excluded)
Strokes (806 former CVD cases excluded)
Unadjusted Adjusted for age Fully adjusted* Unadjusted Adjusted for age Fully adjusted* Unadjusted Adjusted for age Fully adjusted*
1.62 1.09 1.12 1.66 1.14 1.18 1.60 1.04 1.07
(<0.01) (0.34) (0.20) (<0.01) (0.23) (0.14) (<0.01) (0.80) (0.67)
Significant fully adjusted HRs are shown in bold. Abbreviations: CVD, cardiovascular disease; BMI, body mass index; HR, hazard ratio. Adjusted for age, smoking, BMI, systolic blood pressure and total cholesterol.
*
Sleep duration females
6h 1.34 1.20 1.08 1.35 1.22 1.09 1.31 1.16 1.08
(<0.01) (<0.01) (0.17) (<0.01) (<0.01) (0.25) (0.01) (0.15) (0.47)
7–8 h
9h
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.01 1.04 1.03 1.07 1.10 1.08 0.91 0.95 0.96
(ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref)
(0.89) (0.50) (0.61) (0.37) (0.18) (0.30) (0.43) (0.63) (0.74)
P10 h
65 h
1.22 1.19 1.13 1.17 1.14 1.06 1.31 1.29 1.26
2.34 1.34 1.22 2.49 1.38 1.23 2.04 1.22 1.15
(0.10) (0.14) (0.34) (0.29) (0.37) (0.72) (0.21) (0.22) (0.30)
6h (<0.01) (<0.01) (0.03) (<0.01) (<0.01) (0.09) (<0.01) (0.16) (0.33)
1.54 1.13 1.13 1.63 1.17 1.19 1.46 1.09 1.08
(<0.01) (0.06) (0.06) (<0.01) (0.06) (0.04) (<0.01) (0.35) (0.44)
7–8 h
9h
P10 h
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1.00 (0.95) 1.16 (0.02) 1.14 (0.05) 1.04 (0.61) 1.22 (0.17) 1.23 (0.02) 0.93 (0.47) 1.07 (0.48) 1.02 (0.88)
1.45 1.48 1.41 1.45 1.48 1.43 1.46 1.51 1.40
(ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref) (ref)
(<0.01) (<0.01) (<0.01) (0.01) (0.01) (0.01) (0.02) (0.01) (0.05)
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
**
Sleep duration, women
65 h
E. Kronholm et al. / Sleep Medicine 12 (2011) 215–221
statistical predictive power of sleep duration has remained during the long follow-up. Together, these findings prompt us to consider a possibility that sleep duration may be a ‘‘non-causal risk factor/ proxy,’’ i.e., it is associated with some real constant causal factor but does not have a causal relationship with the CVD mortality. Here, we suggest that this stable factor is likely to be a genetic factor. Thus, extremely deviant sleep duration and increased CVD risk may both be expressions of the same genetic predisposition, at least in men. This hypothesis is in agreement with the results of the recent meta-analysis where there were no differences between the results when meta-analyses were conducted that included all studies and when including only those studies that considered comorbid conditions [17]. However, it is also evident that the expression of this supposed genetic predisposition may be modulated by several known risk factors such as gender [17], socioeconomic status [40–42], hypertension [24], anxiety and depression [43], making the association between sleep duration and CVD mortality/morbidity a very complex one. If this currently speculative hypothesis is true, it would be problematic to consider sleep duration as a therapeutic target for attempts to decrease CVD mortality in the general population. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2010.10.006.
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