Premature Coronary Artery Disease Is More Prevalent in People Who Go to Bed Late

Farzad Masoudkabir, MD, MPH1,2#; Zahra Mohammadi, PhD3#; Mohammad Alirezaei, MD4; Bahman Cheraghian, PhD5; Zahra Rahimi, PhD Student6; Pegah Roayaei, MD1; Mohammad Reza Naderian, MD7; Leila Danehchin, MD8; Yousef Paridar, MD9; Farhad Abolnezhadian, MD10,11; Ali Vasheghani-Farahani, MD1,2; Mohammad Noori, MD12; Seyed Ali Mard, MD13; Sahar Masoudi, MSc3; Ali Akbar Shayesteh, MD13*; Hossein Poustchi, MD, PhD3*


Introduction
Ischemic heart disease is the leading cause of death 1,2 and years of life lost 3 world-wide. Although most of the coronary artery disease (CAD) occurs in the elderly, it has been reported that 4-10% of individuals with CAD are younger than 45 years. 4 Despite numerous definitions and age cut-offs 5,6 for premature coronary artery disease (PCAD), it is clear that developing CAD in younger ages has extra burden on societies because of involving people in their more productive years of life. This problem is more prominent in Middle-Eastern countries and particularly Iran where PCAD is more prevalent than Western countries. 7 Hence, identifying the independent predictors of developing CAD at younger ages is of outmost importance to develop evidence-based preventive measures. [7][8][9][10] There is evidence that sleep behavior, including sleep duration and bedtime, as an important part of lifestyle has changed in the last decades and it has been reported that people sleep shorter 11,12 and go to bed later 13 than before. It has led researchers to investigate the probable effects on sleep behavioral changes of different aspects of health. Studies have demonstrated that sleep duration is associated with obesity, insulin resistance, metabolic syndrome, hyperlipidemia, diabetes mellitus, and also CAD. [14][15][16][17][18][19] Furthermore, bedtime, as an indicator for congruence of sleep and circadian rhythm, has a significant relationship with obesity, diabetes mellitus, and insulin resistance in childhood and adulthood. 15,[20][21][22] However, there is limited data regarding the possible association of bedtime in adults and presence of PCAD. Hence, we aimed to evaluate the relationship between late bedtime and PCAD in a large sample of participant in Khuzestan Comprehensive Health Study (KCHS).

Study Population
This study is a subset of the KCHS, which was conducted with the aim of evaluating the health status of the people from the Khuzestan province. The province, with 27 counties and a population of 4 909 285 people, is located in southwestern Iran. KCHS was founded by the National Institute for Medical Research Development (NIMAD) in cooperation with the Digestive Diseases Research Institute (DDRI), Jundishapur Medical University, Iran Blood Transfusion Organization, and Abadan, Dezful and Behbahan Faculties.

Sampling Method
KCHS was performed in the period of October 2016 to November 2019 and the samples were selected using the multi-stage random sampling method. Consequently, 30 101 individuals between 20-65 years of age who were residents of the Khuzestan province for at least one year were enrolled in the study. 23

Study Protocol
Those who fulfilled all the inclusion criteria were invited face-to-face by trained staff and those who were unwilling to participate at any stage of the study for any reason, and individuals with mental, psychological or physical disabilities who were not able to complete the questioning process were excluded from the study. After a comprehensive review of the study procedures, each participant signed an informed consent.
Trained nurses performed blood pressure and anthropometric measurements. Height (in centimeters) and weight (in kilograms) were measured. Then, body mass index (BMI) was calculated by dividing weight (in kilograms) by height (in meters squared). Blood pressure was measured with Riester sphygmomanometers, twice on each arm in a standard sitting state. The lower reading on the arm with a higher systolic blood pressure was considered as the participant's blood pressure.
Using self-designed questionnaires, data on demographic characteristics, and past medical history, including history of CAD, traditional risk factors of cardiovascular disease, habit history, and physical activity were collected. Moreover, participants were asked about the time when they go to bed routinely.
After 8-12 hours of overnight fasting, a venous blood sample of 15 milliliters was collected from each participant. Afterward, levels of parameters, including fasting blood sugar (FBS), urea, creatinine (Cr), triglyceride (TG), total cholesterol (Chol), and high-density lipoproteins cholesterol (HDL) were measured in serum samples. 22

Definitions
We defined late bedtime as bedtime after 1:00 AM. PCAD was defined as history of acute myocardial infarction (documented in hospital discharge summary) or obstructive CAD diagnosed by coronary angiography or computed tomography coronary angiography before 45 years in men and before 55 years in women.

Statistical Analysis
Mean ± standard deviations were calculated for continuous variables and were compared between two independent groups using Student's t-test. Categorical variables were compared using the chi-square test or Fisher's exact test, as appropriate, and were presented as absolute frequencies with percentages. Multivariate logistic regression analysis was used to evaluate the independent predictors of PCAD. Two-tailed P values were reported with significance defined at P ≤ 0.05.
As shown in Table 1, participants who reported to go to bed late were younger and were less likely to have hypertension and positive family history of PCAD than those who reported to go to bed before 1:00 AM. Meanwhile, those who reported to go to bed late were more likely to smoke cigarettes, and have obesity defined as BMI ≥ 30 kg/m 2 than those who reported to go to bed early.

Discussion
The main finding of our study was that late bedtime is independently associated with presence of PCAD. Despite numerous studies in children and adolescents evaluating the possible linkage of late bedtime and various aspects of health, 24 there is lack of data regarding adulthood sleep behavior and cardiovascular diseases. To the best of our knowledge, this is the first study to report the independent association of late bedtime and PCAD.
Our findings confirms and expands the previous studies reporting a significant association between late bedtime in childhood and adolescence with major risk factors of CAD including obesity, 25 BMI, 20,24,26 hypertension, 27,28 reduced insulin sensitivity, 15 and diabetes mellitus. 22 Although late bedtime might predispose the person to PCAD via increased risk of abovementioned risk factors, we observed that even after adjustment for all abovementioned risk factors, late bedtime was independently associated with PCAD. This observation signals for other mechanistic pathways for association of late bedtime and PCAD. There is evidence that sleep deprivation and circadian rhythm disruption may lead to oxidative stress in humans. 29,30 Sleep deprivation and restricted sleep times are also associated with increased plasma levels of proinflammatory cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α). [31][32][33][34] Irwin et al demonstrated that sleep loss induces spontaneous monocytic expression of IL-6 and TNF-α and of signal transducer and activator of transcription (STAT) family proteins, which together map the dynamics of sleep loss on the molecular signaling pathways that regulate inflammatory and other immune responses. 35 Given the pivotal role of oxidative stress and inflammation in initiation and progression of coronary atherosclerosis, 2 it might be concluded that late bedtime contributes to PCAD through induction of inflammation and oxidative stress.
Although multiple studies have been performed on health impacts of late bedtime, there is no agreement regarding the definition of late bedtime and various studies have chosen different times. In contrast with our study, Yan et al 22 and Sasaki et al 36 chose going to bed after 12:00 AM as late bedtime. It seems reasonable to consider bedtime as a continuous variable and invoke receiver operating characteristics curve analysis for choosing an optimal cutoff time as late bedtime. Furthermore, it has been shown that systematic changes in the output of the human circadian pacemaker happen in the aging process 37 ; so, allocating age-related cut-offs for future studies seems reasonable.
Our study has some limitations that should be mentioned. One of the limitations is that we evaluated sleep behavior through self-reported questionnaires. Studies that evaluated the correlation of objective and subjective sleep duration, have reported a weak 20 to moderate correlation. [38][39][40] Another limitation is that we did not evaluate some sleep relating factors, such as sleep quality and insomnia which can potentially confound the association of bedtime and PCAD. 41 In this study, 64.1% of  the participants were female while according to the latest census in 2016, only 49.3% of residents in the Khuzestan province had female sex. Although this is a common selection bias in studies with volunteer participation, its probable impact on results should be acknowledged. Finally, due to the cross-sectional design of the study, a causal relationship cannot be inferred. Large-scale prospective cohort studies should elucidate the exact role of sleep behavior on developing CAD prematurely.
In conclusion, our study demonstrated a significant independent association between going to bed after 1:00 AM and PCAD. This finding supports the importance of bedtime in health. Future prospective studies should examine the possible causal relationship of late bedtime and PCAD.