Abstract
Study Objectives:
Previous studies have highlighted the importance of sleep patterns for human health. This study aimed to investigate the association of sleep timing with all-cause and cardiovascular disease mortality.
Methods:
Participants were screened from two cohort studies: the Sleep Heart Health Study (SHHS; n = 4,824) and the Osteoporotic Fractures in Men Study (n = 2,658). Sleep timing, including bedtime and wake-up time, was obtained from sleep habit questionnaires at baseline. The sleep midpoint was defined as the halfway point between the bedtime and wake-up time. Restricted cubic splines and Cox proportional hazards regression analyses were used to examine the association between sleep timing and mortality.
Results:
We observed a U-shaped association between bedtime and all-cause mortality in both the SHHS and Osteoporotic Fractures in Men Study groups. Specifically, bedtime at 11:00 pm and waking up at 7:00 am was the nadir for all-cause and cardiovascular disease mortality risks. Individuals with late bedtime (> 12:00 am) had an increased risk of all-cause mortality in SHHS (hazard ratio 1.53, 95% confidence interval 1.28–1.84) and Osteoporotic Fractures in Men Study (hazard ratio 1.27, 95% confidence interval 1.01–1.58). In the SHHS, late wake-up time (> 8:00 am) was associated with increased all-cause mortality (hazard ratio 1.39, 95% confidence interval 1.13–1.72). No significant association was found between wake-up time and cardiovascular disease mortality. Delaying sleep midpoint (> 4:00 am) was also significantly associated with all-cause mortality in the SHHS and Osteoporotic Fractures in Men Study.
Conclusions:
Sleep timing is associated with all-cause and cardiovascular disease mortality. Our findings highlight the importance of appropriate sleep timing in reducing mortality risk.
Citation:
Ma M, Fan Y, Peng Y, et al. Association of sleep timing with all-cause and cardiovascular mortality: the Sleep Heart Health Study and the Osteoporotic Fractures in Men Study. J Clin Sleep Med. 2024;20(4):545–553.
Keywords: bedtime, wake-up time, sleep midpoint, all-cause mortality, cardiovascular mortality
BRIEF SUMMARY
Current Knowledge/Study Rationale: A healthy sleep pattern is essential for maintaining health and preventing diseases. The association between bedtime, wake-up time, sleep midpoint, and all-cause and cardiovascular disease mortality remains to be fully elucidated, and this study investigated the association between sleep timing and all-cause as well as cardiovascular disease mortality using data from two large cohort studies.
Study Impact: Individuals with too early or too late sleep timing were prone to have a high all-cause and CVD mortality risk, especially in those with delayed sleep timing including bedtime > 12:00 AM, wake-up time > 8:00 AM, and sleep midpoint > 4:00 AM. We believe that our study makes a significant contribution to the literature because it highlights the importance of appropriate sleep timing in reducing mortality risk.
INTRODUCTION
As an important physiological function, a healthy sleep pattern is essential for maintaining health and preventing diseases.1,2 Observational studies have demonstrated an association between sleep disorders and obesity, diabetes, hypertension, major cardiovascular disease (CVD), and mortality.3–5 More than half of middle-aged and older individuals have sleep disorders.6 With the increasingly aging population globally, the number of health problems caused by sleep disorders is increasing worldwide.
Much of the previously conducted sleep research has focused on insomnia, sleep-disordered breathing, and sleep duration. Sleep timing (eg, bedtime, wake-up time, and sleep midpoint) is a noteworthy characteristic of sleep health. Previous studies have shown that sleep timing is associated with physical activity, cognitive function, depression, adiposity, type 2 diabetes, and CVD.7–10 However, the association between bedtime, wake-up time, sleep midpoint, and all-cause and CVD mortality remains to be fully elucidated.
In the present study, we sought to determine the sleep timing associated with reduced mortality in the general population. Therefore, we explored the role of sleep timing in all-cause and CVD mortality based on data from two cohort studies: the Sleep Heart Health Study (SHHS) and the Osteoporotic Fractures in Men Study (MrOS).
METHODS
Study sample
The SHHS was a multicenter, community-based cohort study (ClinicalTrials.gov Identifier: NCT00005275). Participants in the SHHS were middle-aged and older individuals. All participants completed sleep habit questionnaires at baseline (1995–1998) and were followed up for more than 10 years to observe adverse events.11,12 The study protocol was approved by the institutional review board of each participating institution. Data quality assurance and control systems were strictly used to screen the raw data during data collection. All the participants provided written informed consent. Subjects were excluded if (1) follow-up data were missing (n = 777), (2) bedtime and wake-up time data were missing (n = 101), or (3) circadian reversal was present (n = 102). Ultimately, 4,824 participants were included in the study.
The MrOS was a community-based cohort study that recruited 5,994 men from six centers across the United States between 2000 and 2002.13,14 The study was approved by the local institutional review board, and all participants provided written informed consent. A total of 3,135 men were recruited from the MrOS cohort to assess sleep disorder outcomes among older men. Subjects were excluded if they (1) lacked polysomnography data (n = 224) and (2) had missing mortality data (n = 253). In total, 2,658 participants were included in this study.
Data collection
Sleep timing, including bedtime and wake-up time, was obtained from sleep habit questions including “what time do you usually fall asleep and wake up” in SHHS and “during the past month, what time do you usually go to bed and wake up” in MrOS. Sleep midpoint was defined as the midpoint between bedtime and wake-up time. Shift workers were defined as having bedtime between 4:00 am and 6:00 pm or wake-up time between 12:00 pm and 4:00 am. In line with previous studies,15,16 bedtime was further categorized as ≤10:00 pm, 10:01 pm–12:00 am, and > 12:00 am, while wake-up time was categorized as ≤ 6:00 am, 6:01 am–8:00 am, and > 8:00 am. The sleep midpoints were divided into the following categories: ≤ 2:00 am, 2:01 am–4:00 am, and > 4:00 am.
Data on baseline characteristics, including age, sex, race, body mass index, smoking status, alcohol use, diabetes mellitus, hypertension, benzodiazepine use, lipid-lowering medication use, medical history (myocardial infarction, congestive heart failure, stroke/cerebrovascular disease, chronic bronchitis, and chronic obstructive pulmonary disease), apnea-hypopnea index, and percent time below oxygen desaturation 90%, were obtained from the SHHS and MrOS. In SHHS, insomnia symptoms were defined as difficulty falling asleep, maintaining sleep and/or early morning awakenings, and taking sleeping pills.17 In addition, insomnia symptoms were defined as difficulty falling asleep, maintaining sleep and/or early morning awakenings, and previously diagnosed by a doctor in MrOS.
Outcomes
In this study, the outcomes of interest were all-cause and CVD mortality rates. Deaths from any cause in the SHHS were identified and confirmed through follow-up interviews, hospital records, and community observations. All MrOS participants were contacted by postcard and/or telephone to survey CVD and all-cause deaths. Detailed information about the SHHS and MrOS follow-up has been described previously.18–20 The follow-up time was defined as the time interval between baseline and the participant’s death or end of follow-up.
Statistical analysis
The baseline characteristics of SHHS and MrOS in the dead and alive groups are represented as numbers (percentages) and mean ± SD for categorical and continuous variables, respectively. A restricted cubic spline Cox proportional hazards regression model was used to assess the existence of a nonlinear association between sleep timing and mortality. The model was adjusted for age; sex; race; body mass index; smoking status; alcohol use; diabetes mellitus; hypertension; apnea-hypopnea index; percent of sleep time SpO2 is below 90%; insomnia symptom; sleep duration; benzodiazepine use; lipid-lowering medication use; and history of myocardial infarction, congestive heart failure, stroke/cerebrovascular disease, chronic obstructive pulmonary disease, and chronic bronchitis. Five knots (5.0th, 27.5th, 50.0th, 72.5th, and 95.0th percentiles) were used in the restricted cubic spline analysis. Moreover, multivariable Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence intervals (CI) for different sleep timing categories (bedtime, wake-up time, and sleep midpoint) for all-cause and CVD mortality. All statistical analyses were performed using the SPSS software package (version 24.0; IBM Corp., Armonk, NY, USA) and R, version 3.6.3 (R Core Team, Vienna, Austria). Statistical significance was defined as a two-tailed P value of < .05.
RESULTS
Data on a total of 4,824 participants (mean [SD] age, 63.9 ± 11.1 years; 2,250 men and 2,574 women) were available from the SHHS cohort. Over a mean follow-up of 10.7 ± 3.0 years, 1,117 all-cause deaths, including 338 CVD deaths, were identified (Table 1). The MrOS cohort included 2,658 men in the final analysis. The mean age of participants in the MrOS (76.3 ± 5.5 years) was older than that of the SHHS participants. During an average of 10.4 ± 3.9 years follow-up, 1,461 all-cause deaths and 506 CVD deaths were observed (Table 2).
Table 1.
Baseline characteristics of SHHS in all-cause and CVD death.
| Characteristics | Total n = 4,824 | Alive (n = 3,707) | All-Cause Death (n = 1,117) | CVD Death (n = 338) |
|---|---|---|---|---|
| Age, year | 63.9 ± 11.1 | 61.0 ± 10.1 | 73.4 ± 8.8 | 75.6 ± 7.5 |
| Sex, n (%) | ||||
| Men | 2,250 (46.6) | 1,650 (44.5) | 600 (53.7) | 187 (55.3) |
| Women | 2,574 (53.4) | 2,057 (55.5) | 517 (46.3) | 151 (44.7) |
| Race, n (%) | ||||
| Caucasian | 4,207 (87.2) | 3,227 (87.1) | 980 (87.7) | 290 (85.8) |
| Non-Caucasian | 617 (12.8) | 480 (12.9) | 137 (12.3) | 48 (14.2) |
| Body weight, n (%) | ||||
| Obesity | 1,475 (30.7) | 1,177 (31.9) | 298 (26.7) | 83 (24.6) |
| Overweight | 2,041 (42.4) | 1,571 (42.5) | 470 (42.2) | 154 (45.6) |
| Normal | 1,294 (26.9) | 947 (25.6) | 347 (31.1) | 101 (29.8) |
| Smoking status, n (%) | ||||
| Current | 452 (9.4) | 346 (9.4) | 106 (9.4) | 22 (6.5) |
| Former | 2,126 (44.2) | 1,571 (42.5) | 555 (49.9) | 167 (49.6) |
| Never | 2,234 (46.4) | 1,780 (48.1) | 454 (40.7) | 148 (43.9) |
| Alcohol use, n (%) | 1,948 (43.2) | 1,557 (45.5) | 391 (36.1) | 102 (30.8) |
| Medical history, n (%) | ||||
| MI | 318 (6.6) | 155 (4.2) | 163 (14.6) | 79 (23.4) |
| CHF | 132 (2.7) | 38 (1.0) | 94 (8.4) | 41 (12.1) |
| Stroke | 147 (3.0) | 80 (2.2) | 67 (6.0) | 25 (7.4) |
| COPD | 56 (1.2) | 29 (0.8) | 27 (2.5) | 4 (1.2) |
| Chronic bronchitis | 270 (5.7) | 184 (5.0) | 86 (7.9) | 19 (5.7) |
| Diabetes mellitus | 350 (7.4) | 182 (5.0) | 168 (15.3) | 74 (22.1) |
| Hypertension | 1,937 (40.2) | 1,262 (34.0) | 675 (60.4) | 238 (70.4) |
| Lipid-lowering medication use, n (%) | 605 (12.6) | 447 (12.1) | 158 (14.2) | 57 (17.0) |
| Benzodiazepine use, n (%) | 273 (5.7) | 183 (4.9) | 90 (8.1) | 29 (8.6) |
| Insomnia symptom, n (%) | 187 (3.9) | 136 (3.7) | 51 (4.7) | 17 (5.0) |
| Sleep duration, h | 7.5 ± 1.1 | 7.5 ± 1.0 | 7.6 ± 1.3 | 7.6 ± 1.4 |
| Sleep timing | ||||
| Bedtime, pm | 11.0 ± 1.1 | 11.0 ± 1.0 | 11.1 ± 1.3 | 11.1 ± 1.3 |
| Wake-up time, am | 6.5 ± 1.1 | 6.5 ± 1.0 | 6.7 ± 1.2 | 6.7 ± 1.2 |
| Sleep midpoint, am | 2.7 ± 0.9 | 2.7 ± 0.9 | 2.9 ± 1.0 | 2.9 ± 1.0 |
| AHI, events/h | 10.1 ± 13.4 | 9.5 ± 12.8 | 12.4 ± 15.1 | 12.4 ± 14.2 |
| T90, % | 3.6 ± 10.6 | 2.8 ± 8.6 | 6.4 ± 15.3 | 6.4 ± 16.2 |
| Follow-up time, year | 10.7 ± 3.0 | 11.9 ± 1.7 | 6.9 ± 3.2 | 6.9 ± 3.3 |
Results are presented as mean ± SD or n (%).
AHI = apnea-hypopnea index, CHF = congestive heart failure, COPD = chronic obstructive pulmonary disease, CVD = cardiovascular disease, MI = myocardial infarction, SHHS = Sleep Heart Health Study, T90 = percent time below oxygen desaturation 90%.
Table 2.
Baseline characteristics of MrOS in all-cause and CVD death.
| Characteristics | Total n = 2,658 | Alive (n = 1,197) | All-Cause Death (n = 1,461) | CVD Death (n = 506) |
|---|---|---|---|---|
| Age, year | 76.3 ± 5.5 | 73.6 ± 4.0 | 78.5 ± 5.5 | 79.0 ± 5.4 |
| Race, n (%) | ||||
| Caucasian | 2,422 (91.1) | 1,071 (89.5) | 1,351 (92.5) | 473 (93.5) |
| Non-Caucasian | 236 (8.9) | 126 (10.5) | 110 (7.5) | 33 (6.5) |
| Body weight, n (%) | ||||
| Obesity | 637 (24.1) | 282 (23.6) | 355 (24.4) | 134 (26.5) |
| Overweight | 1,369 (51.7) | 648 (54.2) | 721 (49.7) | 250 (49.4) |
| Normal | 642 (24.2) | 265 (22.2) | 377 (25.9) | 122 (24.1) |
| Smoking status, n (%) | ||||
| Current | 1,047 (39.4) | 505 (42.2) | 542 (37.1) | 185 (36.6) |
| Former | 1,557 (58.6) | 671 (56.1) | 886 (60.6) | 315 (62.2) |
| Never | 54 (2.0) | 21 (1.7) | 33 (2.3) | 6 (1.2) |
| Alcohol use, n (%) | 1,733 (65.4) | 817 (68.4) | 916 (63.0) | 307 (60.8) |
| Medical history, n (%) | ||||
| MI | 459 (17.3) | 138 (11.5) | 321 (22.0) | 142 (28.1) |
| CHF | 155 (5.8) | 32 (2.7) | 123 (8.4) | 64 (12.6) |
| Cerebrovascular disease | 297 (11.2) | 86 (7.2) | 211 (14.5) | 78 (15.4) |
| COPD | 132 (5.0) | 38 (3.2) | 94 (6.4) | 25 (4.9) |
| Chronic bronchitis | 129 (4.9) | 53 (4.4) | 76 (5.2) | 24 (4.7) |
| Diabetes mellitus | 336 (14.3) | 133 (12.4) | 203 (15.8) | 83 (18.2) |
| Hypertension | 1,323 (49.8) | 519 (43.4) | 804 (55.0) | 309 (61.1) |
| Lipid-lowering medication use, n (%) | 1,128 (42.4) | 527 (44.0) | 601 (41.1) | 236 (46.6) |
| Benzodiazepine use, n (%) | 124 (4.7) | 42 (3.5) | 82 (5.6) | 24 (4.7) |
| Sleep duration, h | 8.3 ± 1.2 | 8.2 ± 1.1 | 8.5 ± 1.2 | 8.5 ± 1.2 |
| Insomnia symptom, n (%) | 217 (8.2) | 86 (7.2) | 131 (9.0) | 52 (10.3) |
| Sleep timing | ||||
| Bedtime, pm | 10.7 ± 1.1 | 10.7 ± 1.0 | 10.6 ± 1.2 | 10.6 ± 1.2 |
| Wake-up time, am | 6.8 ± 1.2 | 6.7 ± 1.1 | 6.9 ± 1.2 | 7.0 ± 1.3 |
| Sleep midpoint, am | 2.8 ± 1.0 | 2.7 ± 0.9 | 2.8 ± 1.0 | 2.8 ± 1.1 |
| AHI, events/h | 11.8 ± 13.0 | 10.6 ± 11.9 | 12.7 ± 13.8 | 14.0 ± 14.4 |
| T90, % | 4.3 ± 9.9 | 3.2 ± 7.9 | 5.1 ± 11.2 | 5.4 ± 10.4 |
| Follow-up time, year | 10.4 ± 3.9 | 13.6 ± 0.3 | 7.9 ± 3.5 | 7.9 ± 3.6 |
Results are presented as mean ± SD or n (%).
AHI = apnea-hypopnea index, CHF = congestive heart failure, COPD = chronic obstructive pulmonary disease, CVD = cardiovascular disease, MI = myocardial infarction, MrOS = Osteoporotic Fractures in Men Study, T90 = percent time below oxygen desaturation 90%.
Sleep timing and mortality in SHHS
As shown in Figure 1 and Figure 2, there was a nonlinear association between sleep timing and all-cause and CVD mortality. In the restricted cubic spline analysis, we observed a U-shaped association between bedtime and all-cause (Poverall association < .001; Pnonlinear association < .001) as well as CVD mortality (Poverall association < .001; Pnonlinear association < .001) after adjusting for potential confounders. Bedtime at 11:00 pm and sleep midpoint at 3:00 am were associated with the lowest risk of all-cause and CVD mortality. Unlike the pattern seen for bedtime, only late (and not early) wake-up time was associated with an increased risk of mortality (Figure 1 and Figure 2).
Figure 1. Multivariable Cox proportional hazard ratio for all-cause mortality based on restricted cubic spline analysis of sleep timing in the Sleep Heart Health Study (SHHS) cohort and Osteoporotic Fractures in Men Study (MrOS) cohort.
(A) Bedtime and all-cause mortality in SHHS. (B) Wake-up time and all-cause mortality in SHHS. (C) Sleep midpoint and all-cause mortality in SHHS. (D) Bedtime and all-cause mortality in MrOS. (E) Wake-up time and all-cause mortality in MrOS. (F) Sleep midpoint and all-cause mortality in MrOS.
Figure 2. Multivariable Cox proportional hazard ratio for cardiovascular disease (CVD) mortality based on restricted cubic spline analysis of sleep timing in the Sleep Heart Health Study (SHHS) cohort and Osteoporotic Fractures in Men Study (MrOS) cohort.
(A) Bedtime and CVD mortality in SHHS. (B) Wake-up time and CVD mortality in SHHS. (C) Sleep midpoint and CVD mortality in SHHS. (D) Bedtime and CVD mortality in MrOS. (E) Wake-up time and CVD mortality in MrOS. (F) Sleep midpoint and CVD mortality in MrOS.
Multivariable Cox regression analysis was performed to explore the relationship between different sleep timing categories and mortality rates (Table 3). Both bedtime > 12:00 am (HR 1.53, 95% CI 1.28–1.84, P < .001) and ≤ 10:00 pm (HR 1.23, 95% CI 1.05–1.44, P = .011) were associated with all-cause mortality. Similar results were observed for bedtime and CVD mortality (Table 4). Participants with a wake-up time > 8:00 am had a high risk of all-cause mortality (HR 1.39, 95% CI 1.13–1.72, P = .002). However, no significant association was found between wake-up time and CVD mortality. A delay in the sleep midpoint (> 4:00 am) also predicted all-cause (HR 1.39, 95% CI 1.14–1.69, P = .001) as well as CVD mortality (HR 1.43, 95% CI 1.01–2.01, P = .041) (Table 3 and Table 4).
Table 3.
HRs and 95% CIs for sleep timing (bedtime, wake-up time, sleep midpoint) associated with all-cause mortality.
| Sleep Timing | SHHS | MrOS | ||||||
|---|---|---|---|---|---|---|---|---|
| Univariable Analysis | Multivariable Adjusted | Univariable Analysis | Multivariable Adjusted | |||||
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| Bedtime | ||||||||
| > 12:00 am | 1.76 (1.49–2.09) | <0.001 | 1.53 (1.28–1.84) | < .001 | 1.25 (1.12–1.39) | <0.001 | 1.27 (1.01–1.58) | .038 |
| ≤ 10:00 pm | 1.45 (1.26–1.67) | <0.001 | 1.23 (1.05–1.44) | .009 | 1.09 (0.89–1.33) | 0.423 | 1.08 (0.95–1.23) | .222 |
| 10:01 pm–12:00 am | 1 | 1 | 1 | 1 | ||||
| Wake-up time | ||||||||
| > 8:00 am | 2.04 (1.68–2.48) | <0.001 | 1.39 (1.13–1.72) | .002 | 1.51 (1.29–1.77) | <0.001 | 1.18 (0.98–1.42) | .076 |
| ≤ 6:00 am | 0.97 (0.86–1.10) | 0.638 | 1.09 (0.94–1.25) | .254 | 0.99 (0.88–1.11) | 0.885 | 1.12 (0.98–1.28) | .090 |
| 6:01 am–8:00 am | 1 | 1 | 1 | 1 | ||||
| Sleep midpoint | ||||||||
| > 4:00 am | 1.90 (1.58–2.29) | <0.001 | 1.39 (1.14–1.69) | .001 | 1.36 (1.13–1.64) | 0.001 | 1.24 (1.01–1.52) | .038 |
| ≤ 2:00 am | 1.10 (0.95–1.27) | 0.216 | 1.12 (0.96–1.30) | .159 | 1.10 (0.98–1.25) | 0.115 | 1.11 (0.97–1.26) | .132 |
| 2:01 am–4:00 am | 1 | 1 | 1 | 1 | ||||
Multivariable adjusted by age, sex, race, BMI, smoking status, alcohol use, diabetes mellitus, hypertension, AHI, T90, benzodiazepine use, lipid-lowering medication use, history of MI, CHF, stroke/cerebrovascular disease, COPD, and chronic bronchitis, insomnia symptom, and sleep duration.
AHI = apnea-hypopnea index, BMI = body mass index, CHF = congestive heart failure, 95% CI = 95% confidence interval, COPD = chronic obstructive pulmonary disease, HR = hazard ratio, MI = myocardial infarction, MrOS = Osteoporotic Fractures in Men Study, SHHS = Sleep Heart Health Study, T90 = percent time below oxygen desaturation 90%.
Table 4.
HRs and 95% CIs for sleep timing (bedtime, wake-up time, sleep midpoint) associated with CVD mortality.
| Sleep Timing | SHHS | MrOS | ||||||
|---|---|---|---|---|---|---|---|---|
| Univariable Analysis | Multivariable Adjusted | Univariable Analysis | Multivariable Adjusted | |||||
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| Bedtime | ||||||||
| > 12:00 am | 2.16 (1.62–2.87) | <0.001 | 1.70 (1.24–2.34) | .001 | 1.10 (0.78–1.56) | 0.574 | 1.26 (0.85–1.86) | .247 |
| ≤ 10:00 pm | 1.49 (1.14–1.93) | 0.003 | 1.28 (0.96–1.71) | .098 | 1.37 (1.14–1.65) | 0.001 | 1.15 (0.94–1.42) | .179 |
| 10:01 pm–12:00 am | 1 | 1 | 1 | 1 | ||||
| Wake-up time | ||||||||
| > 8:00 am | 2.12 (1.50–3.02) | <0.001 | 1.25 (0.85–1.84) | .257 | 1.73 (1.33–2.24) | <0.001 | 1.19 (0.88–1.60) | .261 |
| ≤ 6:00 am | 1.00 (0.79–1.25) | 0.972 | 1.17 (0.91–1.51) | .226 | 1.03 (0.84–1.26) | 0.775 | 1.25 (1.00–1.56) | .052 |
| 6:01 am–8:00 am | 1 | 1 | 1 | 1 | ||||
| Sleep midpoint | ||||||||
| > 4:00 am | 2.08 (1.51–2.88) | <0.001 | 1.43 (1.01–2.01) | .041 | 1.54 (1.13–2.08) | 0.006 | 1.27 (0.90–1.79) | .178 |
| ≤ 2:00 am | 1.05 (0.81–1.38) | 0.704 | 1.10 (0.84–1.46) | .486 | 1.31 (1.07–1.60) | 0.008 | 1.36 (1.10–1.68) | .004 |
| 2:01 am–4:00 am | 1 | 1 | 1 | 1 | ||||
Multivariable adjusted by age, sex, race, BMI, smoking status, alcohol use, diabetes mellitus, hypertension, AHI, T90, benzodiazepine use, lipid-lowering medication use, history of MI, CHF, stroke/cerebrovascular disease, COPD, and chronic bronchitis, insomnia symptom, and sleep duration.
AHI = apnea-hypopnea index, BMI = body mass index, CHF = congestive heart failure, 95% CI = 95% confidence interval, COPD = chronic obstructive pulmonary disease, CVD = cardiovascular disease, HR = hazard ratio, MI = myocardial infarction, MrOS = Osteoporotic Fractures in Men Study, SHHS = Sleep Heart Health Study, T90 = percent time below oxygen desaturation 90%.
Sleep timing and mortality in the MrOS
A U-shaped association was observed between bedtime and all-cause mortality (Poverall association = .025, Pnonlinear association = .017). A nadir association was also observed between bedtime at 11:00 pm and all-cause mortality. In addition, both earlier and later sleep timings were associated with a high risk of all-cause and CVD mortality in patients with MrOS (Figure 1 and Figure 2).
Multivariable Cox regression showed that late bedtime > 12:00 am (HR 1.27, 95% CI 1.01–1.58, P = .038) were significantly associated with an increased risk of all-cause mortality (Table 3). Delaying sleep midpoint (> 4:00 am) was associated with all-cause mortality (HR 1.24, 95% CI 1.01–1.52, P = .038). In addition, earlier sleep midpoint had an increased risk of CVD mortality (HR 1.36, 95% CI 1.10–1.68, P = .004) (Table 4).
DISCUSSION
In the present study, we employed two-decade-long cohort studies to investigate the role of sleep timing in all-cause and CVD mortality. For both the SHHS and MrOS, a U-shaped association was observed between bedtime and all-cause mortality. In addition, participants with a wake-up time of > 8:00 am had an increased risk of all-cause mortality. Delaying the sleep midpoint was also associated with all-cause and CVD mortality in the two cohort studies.
Appropriate sleep timing, including bedtime and wake-up time, is an essential component of a healthy sleep pattern. Later or earlier sleep is associated with adverse health outcomes.7 Observational studies have demonstrated that individuals with later bedtimes are at risk of weight gain, obesity, type 2 diabetes, liver disease, mental disorders, and myocardial infarction.8,10,21–24 A recent large study showed that earlier and later bedtimes were associated with major CVD and mortality.15 Early bedtime has also been associated with a high risk of elevated blood pressure in adolescents.25 However, most previous studies have focused on linear relationships. According to a recent study, people in different regions or countries may have different sleep timing, sleep duration, and weekend sleep extension.26 We therefore examined the association between sleep timing and mortality in the SHHS and MrOS, respectively. In this study, we found a nonlinear association between sleep timing, including bedtime, wake-up time, sleep midpoint, and all-cause as well as CVD mortality. A U-shaped association was observed between bedtime and all-cause mortality in both the SHHS and MrOS cohorts. Importantly, individuals with a bedtime at 11:00 pm had the lowest risk of all-cause mortality and CVD mortality. The association between wake-up time and mortality differed from that between bedtime and mortality. A previous study showed that a delayed wake-up time is associated with a high incidence of congestive heart failure.8 The nadir of mortality risk for wake-up time was approximately 7:00 am in our analysis. Furthermore, only a later wake-up time (> 8:00 am) was consistently associated with a higher risk of all-cause mortality. These findings indicate that appropriate bedtime and wake-up times can reduce an individual’s risk of mortality.
The sleep midpoint, which is a common sleep timing variable, is the halfway point of the sleep period (between sleep onset and wake-up time). The midpoint of sleep becomes progressively later with increasing age until it reaches a plateau at the age of 17 years.27 In addition, the onset of dim light melatonin significantly correlates with the sleep midpoint.28 Several studies have investigated the effects of sleep midpoints on human health. Individuals with late sleep midpoints spend less time engaging in moderate to vigorous physical activity. Suh et al found that delaying the midpoint of sleep could impair cognitive function.29 However, there is little evidence regarding the relationship between sleep midpoint and mortality. A nonlinear association between the sleep midpoint and mortality was found in our study. Both earlier and later midpoints of sleep were associated with an elevated risk of all-cause and CVD mortality. However, delaying the sleep midpoint, especially after 4:00 am, significantly increased the risk of all-cause and CVD mortality in the SHHS cohort. Similar results were obtained in the MrOS cohort. These findings suggest that both early and late sleep timing could increase mortality risk, a relationship that is more pronounced with the latter.
The possible mechanisms driving the association between sleep timing and mortality are not fully understood. Late sleepers have been shown to be prone to unhealthy dietary habits including overeating at dinner and consuming excess bedtime snacks.30,31 Previous studies have shown that late bedtime is associated with a high prevalence of obesity, diabetes, and CVD.8–10 People who go to bed late tend to have shorter sleep durations, which contributes to insufficient sleep.32 Moreover, individuals with a delayed wake-up time experience a relatively long period of light exposure, which might affect their circadian rhythm.33 Early and late sleep times may cause a misalignment between endogenous circadian rhythms and the external environment. Circadian disruption can decrease leptin and glucose tolerance, increase mean arterial pressure, and influence cortisol rhythms.34
This study has several strengths. We identified appropriate bedtimes and wake-up times to reduce all-cause and CVD mortality, which could help improve sleep patterns. Our findings were tested using multiple covariate adjustments and were consistent in two independent cohort studies. Shift work may have an impact on sleep quality and further lead to the occurrence of physical or mental diseases.35,36 In our study, we excluded participants with bedtimes between 4:00 am and 6:00 pm or wake-up times between 12:00 pm and 4:00 am to prevent the effect of shift work on the results. However, our study also had some limitations. Since sleep timing information was acquired from sleep habit questionnaires, it was difficult to avoid measurement errors and recall bias. With the development of smart wearable devices, it is possible to obtain objective sleep data over a long period of time. In addition, most participants from both the SHHS and MrOS groups were middle-aged and older Caucasians. Therefore, our findings may not extend to adolescents or to all ages and ethnic groups.
CONCLUSIONS
This study has established an important link between sleep timing and mortality. Bedtime at 11:00 pm and waking up at 7:00 am were associated with the lowest all-cause and CVD mortality risks. Individuals with earlier and later sleep times tended to have an increased risk of all-cause and CVD mortality. However, the association was even more pronounced for delayed sleep timing, especially in patients with a bedtime > 12:00 am, wake-up time > 8:00 am, and sleep midpoint > 4:00 am. Therefore, appropriate bedtime and wake-up times are important for implementing sleep-targeted interventions aiming to reduce mortality.
DISCLOSURE STATEMENT
All authors have approved this manuscript. Work for this study was performed at The First Affiliated Hospital of Xi’an Jiaotong University. This study was supported by the National Natural Science Foundation of China (No. 82201659) and the Natural Science Basic Research Program of Shaanxi (No. 2021JQ-395). The Sleep Heart Health Study was supported by National Heart, Lung, and Blood Institute cooperative agreements U01HL53916 (University of California, Davis), U01HL53931 (New York University), U01HL53934 (University of Minnesota), U01HL53937 and U01HL64360 (Johns Hopkins University), U01HL53938 (University of Arizona), U01HL53940 (University of Washington), U01HL53941 (Boston University), and U01HL63463 (Case Western Reserve University). The National Heart, Lung, and Blood Institute provided funding for the ancillary Osteoporotic Fractures in Men Study, “Outcomes of Sleep Disorders in Older Men,” under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. The National Sleep Research Resource was supported by the National Heart, Lung, and Blood Institute (R24 HL114473, 75N92019R002). The authors report no conflicts of interest.
ACKNOWLEDGMENTS
The authors thank the Brigham and Women’s Hospital for sharing datasets.
CRediT authorship contribution statement: Mingfang Ma: Conceptualization; Methodology; Visualization; Writing–original draft; Writing–review and editing. Yajuan Fan: Conceptualization; Validation; Funding acquisition; Writing–original draft. Yuan Peng: Validation; Visualization. Qingyan Ma: Validation. Min Jia: Visualization. Zhiyang Qi: Methodology; Software. Jian Yang: Methodology; Software. Wei Wang: Writing–review and editing. Xiancang Ma: Conceptualization; Writing–review and editing; Supervision. Bin Yan: Conceptualization; Formal analysis; Data curation; Methodology; Validation; Funding acquisition; Writing–review and editing; Supervision. All authors approved the final version of the report.
Data availability statement: The data in this study was obtained from SHHS datasets (https://sleepdata.org/datasets/shhs) and MrOS datasets (https://mrosdata.sfcc-cpmc.net).
ABBREVIATIONS
- CI
confidence intervals
- CVD
cardiovascular disease
- HR
hazard ratio
- MrOS
Osteoporotic Fractures in Men Study
- SHHS
Sleep Heart Health Study
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