Circadian Misalignment and Cardiovascular Risk

Tracy Ashby, DO and Mariam Louis, MD, MSc, FCCP

1 University of Florida, Department of Medicine, 653 West Eighth Street, L20, Jacksonville, FL 32209, USA

Abstract All or ganisms, ranging from single-celled organisms to humans, demonstrate circadian rhythms that are near 24-h patterns that are present independent of environmental cues. Disruption of this process, calledc ircadian misalignment, is associated with deleterious health outcomes. The most extreme example of this misalignment is shift work,and there is evidence suggesting a strong association between shift work and certain cardiovascular outcomes. The outcomes of most studies include obesity, metabolic syndrome, hypertension, type 2 diabetes mellitus, atrial f brillation,and cardiovascular events. In this article we review the current literature with an emphasis on women ’ s cardiovascular health. The data are conf icting, and there is a paucity of robust evidence with regard to women’ s cardiovascular health and circadian misalignment. More studies are needed to better delineate the sex differences as well as the pathophysiology of the associations between circadian misalignment and cardiovascular diseases so that we can provide patients with more personalized care.

Keywords: shift work ; circadian misalignment ; metabolic syndrome ; cardiovascular ; women ; sex

Introduction

All organisms, ranging from single-celled or ganisms to humans, demonstrate circadian rhythms that are near 24-h patterns that are present independent of environmental cues. In humans, circadian rhythm is established centrally in the suprachiasmatic nucleus. However, peripheral rhythms exist in most cells and organs of the body. The orchestration of the circadian rhythm as a whole is a result of hormonal, neurologic, and behavioral input that is not entirely understood. Light, melatonin, and behaviors such as eating are cues, called zeitgeibers, that af fect the underlying circadian rhythms[ 1]. Disruption of these circadian rhythms, due to either intrinsic or extrinsic factors, has been associated with adverse physical and psychiatric consequences. Examples of intrinsic circadian factors include genetic mutations in numerous genes,such as the CLOCK gene, period genes, and cryptochrome genes [ 2]. Extrinsic factors, such as light(the strongest zeitgeiber), can also signif cantly impact circadian patterns. Circadian misalignment,def ned as inappropriate alignment of an individual’ s sleep-wake cycle with biological night, is an example of circadian disruption.

Shift work is the most well-known and well-studied form of circadian misalignment, and is therefore the focus of this article. However, other forms of circadian misalignment exist, including delayed(i.e., night owls) or advanced (i.e., early birds) sleepwake phase disorders, irregular sleep-wake rhythm disorder, transient misalignment related to daylight saving time, jet lag disorder, social jet lag (dif ferent sleep patterns on work days and days off work),and night eating syndrome [ 1, 3]. Shift work for the purpose of this article will be used interchangeably with circadian misalignment and is def ned as working outside normal work hours.

More than 20% of the population of the United States is engaged in shift work, and it is important to start understanding how this may affect health outcomes. Studies exploring the relationship between shift work and health consequences are often challenging because of the confounding psychosocial and behavioral aspects in addition to the physiologic elements. Nevertheless, it is well established that, in general, the overall health status of shift workers is poorer than that of those who work during the day. It is well recognized that shift workers may be at increased risk of developing gastrointestinal disorders, obesity, metabolic syndrome, hypertension, diabetes, cardiovascular disease, and psychiatric disease. Additionally, there seems to be a link to increased risk of colon and breast cancer. In evaluation of these disorders specif cally in women, the data are limited primarily to observational data. Here we review what is currently understood about circadian misalignment in women with respect to cardiovascular disease and outcomes.

Circadian Misalignment and Metabolic Syndrome

An association between circadian disruption and metabolic syndrome may exist on the basis of the f ndings of epidemiologic studies, although a causal link cannot be inferred from current data. One of the f rst studies to evaluate this relationship included 27,485 workers in Sweden and found an increase in the incidence of obesity, elevated levels of triglycerides, decreased HDL level, and impaired glucose tolerance among shift workers [ 4]. When adjusted for age and socioeconomic status, the odds ratios(ORs) for BMI, obesity, and elevated levels of triglycerides were 1.39 (95% conf dence interval [CI]1.25- 1.55), 1.26 (95% CI 1.03 - 1.53), and 1.13 (95%CI 1.02 - 1.25), respectively, for women, compared with 1.44 (95% CI 1.27 - 1.64), 1.15 (95% CI 0.96 -1.38), and 1.12 (95% CI 1.01 - 1.24), respectively, for men. In another study, conducted in China [ 5], with 26,382 workers (1 1,783 men and 14,599 women),with a total of 9088 shift workers, long-term shift work was associated with metabolic syndrome without adjustment for any confounding factors. In female workers, every 10-year increase in shift work was associated with 10% (95% CI 1 - 20%) higher odds of metabolic syndrome. However, a meta-analysis by Canuto et al. [ 6] found a positive association between shift work and metabolic syndrome in eight of ten studies after control for sociodemographic and behavioral factors. However, only three studies included sleep duration as a confounder, and these studies had discordant results. Canuto et al. concluded that there was insuff cient evidence regarding the association between shift work and prevalent metabolic syndrome when the confounders are taken into account. A more recent literature review by Proper et al. [ 7] in 2016 found that shift work seems to be associated with body weight gain, risk of overweight, and impaired glucose tolerance. However,overall, the lack of high-methodological-quality studies and inconsistency in f ndings led to insuff -cient evidence in assessment of the relation between shift work and other metabolic risk factors.

One of the largest confounding factors is the sleep deprivation that might be associated with shift work. In studies evaluating sleep deprivation and energy expenditure in humans, 24 - 40 h of sleep deprivation resulted in increased total daily ener gy expenditure. However, food intake also increased with sleep deprivation, which may be a major factor contributing to weight gain through behavioral and hormonal changes. Studies have demonstrated increases in ghrelin, leptin, and insulin levels after sleep deprivation [ 8]. Additional contributing factors are believed to play a role, including the timing of food intake and light exposure. Shift workers tend to have poorer eating and exercise habits, but these are not poor enough to solely explain the increased risk of obesity in this group. Shift work has also been identif ed as a predictor of abdominal obesity,and working night shift is associated with higher BMI, shorter sleep, and higher caloric intake [ 9], all factors known to impact metabolic syndrome.

While it appears that shift work may be associated with metabolic syndrome in both men and women,more high-quality longitudinal studies that provide information on the shift work schedule are needed to better understand the association and the role of sex.

Circadian Misalignment and Type 2 Diabetes Mellitus

Serum glucose and insulin levels are known to be affected by sleep. The mechanism by which sleep deprivation and sleep disruption lead to increased incidence of type 2 diabetes mellitus (DM2) remains to be fully elucidated, but sympathetic activation by intermittent hypoxia, changes in cortisol levels,increased oxidative stress, increased inf ammation,and changes in levels of adipokines have all been implicated [ 10]. Robust data exist showing that long-term sleep deprivation leads to an increased incidence of DM2 [ 11]. Even a single night of partial sleep restriction is suff cient to reduce insulin sensitivity. Sleep restriction to 4 h in bed compared with 8.5 h resulted in increased endogenous glucose production in healthy individuals [ 12]. Extending sleep duration by as little as 1 h per night was shown to improve glucose metabolism [ 8].

There is evidence that circadian misalignment is also associated with incident DM2. Laboratory studies evaluating the metabolic effect of forced circadian misalignment showed higher postprandial levels of glucose and insulin [ 13]. In an attempt to distinguish the effects of sleep deprivation from the ef fects of circadian misalignment, Leproult et al. [ 14] found that sleep restriction to 5 h in bed for 8 days reduced insulin sensitivity compared with the baseline in both circadian-aligned and circadian-misaligned conditions. In women,no signif cant difference was found in insulin and glucose metabolism in the circadian-aligned and circadian-misaligned conditions. In contrast, in the larger group of men, the relative decrease in insulin sensitivity following circadian misalignment was nearly twice as large (- 58%) as compared with that in the aligned condition ( - 32%, P = 0.01). Despite the greater decrease in insulin sensitivity following circadian misalignment, the beta-cell response was similar in the two experimental conditions.

This sex difference has been also found in lar ger epidemiologic studies. Data regarding the increased risk of DM2 in women engaged in rotating shift work come from prospective cohort studies from the Nurses’ Health Study and Nurses’ Health Study II.An increased risk of DM2 was found, and the risk was higher in those with more years of rotating shift work, but was not signif cant after correction for BMI [ 15]. The hazard ratio per 5 years of shift work was 1.05 (95% CI 1.04 - 1.06) with correction for BMI. In contrast, in a meta-analysis looking at 12 studies with 28 independent reports involving 226,652 participants, the pooled adjusted OR for the association between ever exposure to shift work and DM2 risk for men was 1.37 (95% CI 1.20- 1.56)compared with 1.09 for women (95% CI 1.04 - 1.14)[ 16 ].

It is not clear why there is a sex dif ference in the risk of incident DM2 among shift workers, and further research is needed.

Circadian Misalignment and Systemic Arterial Hypertension

There have been many cross-sectional and longitudinal epidemiologic studies examining the relationship between sleep duration and hypertension.The studies have included diverse populations from around the world and have comprised age groups ranging from children to the elderly. The results have differed by age group, by sex, and whether the studies were cross-sectional or longitudinal.However, there is enough evidence to suggest that short sleep duration is associated with increased risk of hypertension [ 17].

The literature examining the relationship between circadian misalignment and hypertension, on the other hand, is somewhat controversial. For example, data regarding shift work hypertension in Asian males on rotating shift work in an industrial setting have established a clear increased risk of hyper-tension and increased risk with more years of shift work in this subgroup [ 18]. Cross-sectional data for 25,343 German autoworkers revealed that when the data were adjusted for confounders, shift work without nights (vs. day shifts) was signif cantly associated with hypertension (OR 1.15, 95% CI 1.02- 1.30). The total effect was mediated by BMI,physical inactivity, and sleep disorders [ 19]. With regard to women, during 16 years of follow-up(1991- 2007) of nurses in the Nurses ’ Health Study,the multivariable hazard ratio for incident hyper-tension among black women who worked rotating night shifts for more than 12 months in the previous 2 years compared with those working none was 1.81 (95% CI 1.14 - 2.87). By contrast, in whites, no increase in risk (hazard ratio 0.99, 95% CI 0.93 -1.06) was observed. In a secondary analyses, the multivariable hazard ratio for incident hypertension in black women who ever worked rotating night shifts was 1.46 (95% CI 1.07 - 1.99) compared with those never working rotating night shifts. In whites,there was no increase in risk (hazard ratio 0.97, 95%CI 0.93 - 1.01; Pinteraction＜ 0.01)[ 20 ].

To try to better delineate the relationship between circadian misalignment and shift work, a metaanalysis of 27 observational studies was under-taken recently [ 21]. The authors concluded that the pooled ORs of hypertension in shift workers in cohort and cross-sectional studies were 1.31 (95%CI 1.07 - 1.60) and 1.10 (95% CI 1.00 - 1.20), respectively. When the meta-analysis was restricted only to cohort studies involving rotating shift work, the pooled OR of hypertension in rotating shift workers was 1.34 (95% CI 1.08 - 1.67). The pooled OR of hypertension in night shift workers in cross-sectional studies was 1.07 (95% CI 0.85 - 1.35). The risk of hypertension was greatest for men engaged in rotating shift work, which is inconsistent with previously published data. This could be attributed to the increased number of men in the study, as of the 27 studies included, only half included women and men and four were studies of only women. This disparity underlies the diff culties associated with observational studies, as it is diff cult to control for confounding variables and changes in human behaviors.

Perhaps that best data available examining the relationship between circadian misalignment and hypertension come from laboratory studies. In controlled settings, several authors have demonstrated that circadian misalignment increases blood pressure in non - shift workers [ 22 , 23 ]. Scheer ’ s laboratory demonstrated a 3% increase in mean arterial blood pressure during wakefulness following forced desynchrony, or circadian misalignment. In the study by Morris et al. [ 23], following a short circadian misalignment, 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) were increased by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, + 5.6 mmHg; DBP, + 1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, + 1.6 mmHg; DBP, + 1.4 mmHg).In addition, there was an increase in the levels of inf ammatory markers such as tumor necrosis factor alpha, interleukin-6, and C-reactive protein.

Overall, the magnitude of circadian misalignment and the risk of hypertension are not yet clear from available epidemiologic data. In addition, on the basis of the data to date, questions remain unanswered regarding the risk to women and especially African-American women with regard to hypertension and circadian misalignment.

Circadian Misalignment and Cardiovascular Events

While some speculate that the increased risk of cardiovascular disease (CVD) is associated with the higher prevalence of hypertension and metabolic syndrome,there is a small amount of data suggesting a robust association between shift work disorder and CVD.

One of the largest bodies of evidence comes from a meta-analysis by Vyas et al. [ 24] examining shift work and cardiovascular events that included 34 studies with more than 2 million people. They reported that shift work was associated with an increased risk of myocardial infarction (risk ratio 1.23, 95% CI 1.15 - 1.31, I2= 0) and ischemic stroke(risk ratio 1.05, 95% CI 1.01 - 1.09, I2= 0). The risk of coronary events was also increased (risk ratio 1.24, 95% CI 1.10 - 1.39), albeit with signif cant heterogeneity across studies ( I2= 85%). A more recent meta-analysis that included only studies published from 2006 onward found that the risk of any CVD event was 17% higher among shift workers than among day workers [ 25]. The risk of coronary heart disease morbidity was 26% higher (risk ratio 1.26, 95% CI 1.10 - 1.43, I2= 48.0%). Additionally,a dose-response association was found in which after the f rst 5 years of shift work there was a 7.1%increase in the risk of CVD events for every additional 5 years of exposure (95% CI 1.05- 1.10).

The relationship between shift work and cardiovascular events in women per se was recently examined with data from the Nurses ’ Health Study [ 26].As with the study by Torquati et al. [ 25], there was a dose response with increased risk of coronary artery disease and duration of shift work. Specif cally, the risk was 12% for less than 5 years of shift work, 19%for 5 - 9 years of shift work, and 27% for 10 years or more of shift work. In this study, when participants with hypertension, elevated cholesterol levels, or DM2 were excluded at the baseline and throughout follow-up, a signif cant dose-response relationship between rotating night shift work and coronary heart disease risk was observed in the Nurses ’Health Study but not in the Nurses ’ Health Study II,which includes a younger cohort. The authors also noted that the risk decreased after cessation of shift work. This is an important f nding that needs to be further investigated, as it offers possible insight into risk modif cation and possible disease reduction.

Although the association between circadian misalignment and cardiovascular events is suggested by the available data, evidence for the underlying cause is sparse. Levels of inf ammatory markers such as C-reactive protein, tumor necrosis factor alpha, interleukin-6, cholesterol, and homocysteine are found to be elevated in shift workers and are suspected to play a role in the increased risk of CVD [ 27]. In addition, oxidative stress, increased cortisol levels, endothelial dysfunction, and platelet dysfunction likely play a role. Therefore, while there exist robust data showing an association between circadian misalignment and cardiovascular disease in men and women, more longitudinal data are needed as well as studies looking at the pathophysiology of this relationship.

Conclusion

Current opinion is that the increased risk of obesity,hypertension, CVD, and DM2 in circadian misalignment is multifactorial, with physiologic, social,psychologic, sleep, and eating patterns all likely contributing. The data we have so far indicate circadian misalignment is robustly associated with increased obesity and cardiovascular events in women, with a dose-response relationship for the latter. There is a weaker association between shift work and DM2 and metabolic syndrome in women and conf icting data regarding shift work and hypertension. The differences and disparities in conclusions are a result of numerous confounders, including methodological differences in studies, the def nition of shift work,human behaviors, and sleep deprivation. Prospective and longitudinal studies are needed to address the limitations of the current body of literature.

In addition, experimental and interventional studies are needed to address optimal interventions and treatments for circadian misalignment. It seems termination of shift work reverses or attenuates some of adverse consequences. Also, behavioral modif -cations regarding the timing of eating, diet, weight loss, sleep patterns, and light exposure have been proposed as possible interventions. Pharmacologic agents such as melatonin, stimulants, and hypnotics have also been studied as potential treatments for shift work disorder. However, it is unclear if these interventions have any ef fect on diminishing the deleterious effects observed with circadian misalignment. These concepts may play a role in future treatment strategies.

Conflict of Interest

The authors declare that they have no conf icts of interest.