Shift Work and Early Arterial Stiffness: A Systematic Review

Shift work is a way of organizing rotating schedules throughout the day. This can include 1–3 shifts for the same person on a rotational basis with other workers. Schedules that include night work have been associated with cardiovascular risk, mainly due to circadian misalignment. This systematic review sought to determine whether shift work is a risk factor for increased arterial stiffness. A systematic review of different databases was performed, using the following keywords: work shift, night work, arteriosclerosis, vascular stiffness, arterial stiffness, pulse wave velocity, and their Medical Subject Headings. We selected and analyzed 11 articles regarding pulse wave velocity as an indicator of arterial stiffness. Two studies identified higher levels of arterial stiffness in shift workers compared to day workers, while two studies found the opposite. In addition, four studies found no differences in arterial stiffness between shifts, two studies associated shorter sleep duration with arterial stiffness, and one study observed that physical activity could prevent adverse cardiovascular outcomes in shift workers. The findings are heterogeneous and preclude any robust conclusions. However, the present review points to the need for further studies to investigate arterial stiffness in shift workers, with greater control for confounding factors and longitudinal design.


Introduction
Shift work is an organizational form of working time, established to maintain the uninterrupted operation of workplaces through workers engaging in work schedules on a rotational basis [1,2]. Shift work is not a recent form of work organization, having existed since antiquity. This is characterized by work activity in shifts with a rotating pattern, clockwise or counterclockwise. It can involve shifts that start very early in the morning and may include part of the night or the whole night [3]. Worldwide production on a large scale and a practically uninterrupted, 24/7 basis, has led to the expansion of working hours beyond daytime hours, making shift work schedules increasingly common. Shift work can take the form of a rotating system incorporating three shifts (morning, afternoon, and night) on every day of the week, including weekends [4]. Workers engaged in shift work that includes night work have altered exposure to natural light and dark, which misaligns circadian rhythms [1]. Thus, night shift work has adverse health effects, predisposing workers to the development of metabolic and mental disorders and non-communicable chronic diseases, especially cardiovascular diseases (CVD) [5,6].
CVDs are one of the leading causes of death in Western countries. In the young and economically active population, 10-20% of total deaths are due to CVD associated with work characteristics [7]. One of the most widely acknowledged mechanisms for cardiovascular disease in shift workers is psychological stress [8]. Stress resulting from circadian misalignment and inversion of wake and sleep schedules can promote hypersecretion of cortisol and catecholamines, triggering hemodynamic and cardiovascular disorders [9,10]. Another hypothesis for the high risk of CVD among shift workers is that the inversion of the sleep-wake cycle due to night work may cause circadian disruption in blood pressure control mechanisms [11].
Arterial stiffness is an early, independent marker of increased risk of CVD and allcause mortality [12]. The study of arterial stiffness has been increasing in the cardiovascular field. Arteries tend to lose elasticity naturally with senescence (aging) or stiffen earlier from prolonged exposure to harmful conditions such as blood pressure, hyperglycemia, inflammation, and oxidative stress [13,14]. Arterial stiffness has been significantly associated with arteriosclerosis and future cardiovascular outcomes in the general population and in patients with various diseases, even with adjustments for multiple confounders regarding cardiovascular risk [15,16].
There are several methods to measure arterial stiffness, with pulse wave velocity being the gold standard for expressing this phenomenon. The oscillometric method, which is non-invasive and the most used in clinical practice, allows the evaluation of central blood pressure parameters, arterial stiffness, and vascular functionality simultaneously [17,18].
There are few studies that have analyzed arterial stiffness in shift workers. Some studies have shown an association of night work with vascular changes that are predictive of CVD. There was an observed greater thickness of the intima-media layer of carotid arteries in young night workers [19]. Vascular alterations have also been observed in individuals with long work hours [20]. A study that analyzed atherosclerotic risk, using measures of pulse wave velocity (PWV) in rotating shift workers showed that, regardless of the type of rotation, shift workers had more health problems and a higher heart rate than day workers [21]. The repercussions arising from shift work and long hours likely trigger arterial stiffness and might culminate in early vascular aging in young individuals. Thus, the aim of this systematic review was to summarize the results of studies investigating whether shift work predisposes individuals to arterial stiffness and consequently a higher risk of cardiovascular diseases.

Materials and Methods
This systematic review entailed a critical analysis of articles in the literature and was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The systematic review study was registered according to the international prospective register of systematic reviews [22], receiving PROSPERO number CRD42022336082. The approval of the Research Ethics Committee was not required because the study was a systematic review.

Search Strategy
The PICO strategy (population, intervention, control, and outcomes) was used to guide the research question (Table 1). Based on the question: "Does shift work lead to early arterial stiffness?", searches were initially carried out to define the Medical Subject Headings (MeSH) terms and to determine the inclusion and exclusion criteria, allowing a thorough search of the databases and analysis of articles, increasing the reliability of the study.

Eligibility
The search was carried out on the Cochrane, Embase, PubMed, Scielo, and Scopus databases, using the MeSH terms and inclusion and exclusion criteria described in Table 2.
The references listed in the articles included in the review were also analyzed to identify additional studies addressing the research question.
The terms selected for the search were organized as strings, according to the pattern of each database. The search was performed by two reviewers independently, who carefully read the title and abstract of the studies to identify potentially relevant articles that met the inclusion criteria established for this review: (1) quantitative articles related to shift work, including night shifts, and arterial stiffness; (2) original and research articles, longitudinal studies, cohort studies and case-control studies; and (3) available online with free access and as full text, regardless of publication date. Disagreements regarding the eligibility of articles were resolved by consulting a third researcher.

Results
A total of 140 articles were identified using the search strategy, comprising 10 on Cochrane, 28 on Embase, 10 on PubMed, 89 on Scielo, and 3 on Scopus databases. After the automated removal of duplicates (n = 41), 99 articles were selected for title and abstract screening. During the reading process, five duplicates and four records for clinical studies were detected and manually excluded. Of the remaining 90 articles, 79 were subsequently excluded for not meeting the inclusion criteria. The 11 remaining articles met the inclusion criteria and were selected. Therefore, after consensus between the two independent reviewers, 11 studies were included in this systematic review. A flow diagram of the study selection process based on PRISMA criteria is depicted in Figure 1.
This systematic review, including cross-sectional studies and cohort studies, revealed that there are only a few studies investigating shift work and arterial stiffness. The studies included in this review highlight that shift work can damage the physical and mental health of workers, and also increase the risk of cardiovascular disease.
The present systematic review only included studies involving humans, since no simulated studies in animal models were found. The first article investigating the association of shift work and arterial stiffness was published in 2010 [23], possibly due to the wider access to non-invasive techniques for assessing arterial stiffness ( Figure 2). This systematic review, including cross-sectional studies and cohort studies, revealed that there are only a few studies investigating shift work and arterial stiffness. The studies included in this review highlight that shift work can damage the physical and mental health of workers, and also increase the risk of cardiovascular disease.
The present systematic review only included studies involving humans, since no simulated studies in animal models were found. The first article investigating the association of shift work and arterial stiffness was published in 2010 [23], possibly due to the wider access to non-invasive techniques for assessing arterial stiffness ( Figure 2).  The characteristics of the selected articles are presented in Tables 3-5. In Table 3, data were tabulated by identifying the following variables: author and year of publication, country, study design, number of participants, gender and age, type of worker, exposure (type of shift work), and study duration or follow-up. Table 4 presents the objectives, collected data/methods, and assessment of arterial stiffness and groups. Finally, Table 5 describes the main results, confounder factors, and limitations of the studies.
Out of the eleven articles selected for this systematic review, five were cross-sectional The characteristics of the selected articles are presented in Tables 3-5. In Table 3, data were tabulated by identifying the following variables: author and year of publication, country, study design, number of participants, gender and age, type of worker, exposure (type of shift work), and study duration or follow-up. Table 4 presents the objectives, collected data/methods, and assessment of arterial stiffness and groups. Finally, Table 5 describes the main results, confounder factors, and limitations of the studies.
Out of the eleven articles selected for this systematic review, five were cross-sectional studies, three were cohort studies, and three were interventional studies. Eight of the studies were carried out on the European continent and three on the Asian continent. The studies included adult healthy populations and number of participants varied greatly. The article with the fewest participants included 19 individuals [24] and the largest 10.475 people [25]. Eight articles had a predominance of male participants [21,[23][24][25][26][27]29,31]. Females prevailed in the samples of three studies [28,30,32]. One study evaluated arterial stiffness in health professionals and observed that this indicator of arteriosclerosis did not differ statistically between men and women, despite the higher rate of work-life conflict in women [31].
The equipment used to assess pulse wave velocity (PWV) also varied widely. The methods used were: oscillometric [23][24][25][26][27]30,32] and waveform analysis [21,28,29,31]. The duration of the studies ranged from 8 weeks to 3 years. Considering PWV as an indicator of arterial stiffness, two articles identified higher PWV values in shift workers compared to day workers [23,25]. Some studies failed to identify any differences in arterial stiffness among workers on different shifts [21,27,30,32]. Conversely, two studies found higher PWV values in day workers than shift workers. Day workers who were older and had a higher BMI exhibited higher PWV values than night shift workers [26]. Another study observed significantly higher arterial stiffness values in day workers than in shift workers [29].
In the present review, two studies investigated the relationship between shorter sleep duration and arterial stiffness. In the study, short sleep (<6 h/day) and long working hours (>60 h/week) were non-linearly associated with arteriosclerosis [28]. However, another study observed a direct relationship between higher blood pressure levels and PWV related to short sleep episodes [24]. In a study evaluating the impact of physical activity as a preventive intervention against adverse cardiovascular outcomes in shift workers, was found that PWV values were negatively correlated with physical activity in both control and intervention groups [27].
In a study conducted to assess whether shift work, including long working hours and night shifts, was associated with the risk of developing CVD [26] it was observed that day workers had a higher PWV compared to shift workers. The results indicated that age and body mass index were positively associated with increased PWV, while a high level of physical activity had a protective effect on this indicator of arterial stiffness. Similarly, another study found that day workers had higher arterial stiffness rates than shift workers. Industrial workers on fixed day shifts had significantly higher levels of arterial stiffness when associated with smoking compared to shift workers [29].
Three of the studies included in this review observed no differences regarding arterial stiffness between shift workers compared to day workers. A study with metallurgists observed that PWV measurements were within the normal range and without statistically significant differences even when comparing shifts of fast rotation and clockwise direction with slow rotation and counterclockwise direction [21]. An intervention study involving physical exercise for eight weeks in industrial workers showed a reduction in blood pressure values in the intervention group [27].
The third study investigated the association between psychosocial stress and CVD risk in 576 medical staff in Taiwan [28]. PWV values were significantly higher in males, and after adjustment for gender, age, medical profession, working hours, type of work, depression, BMI, systolic and diastolic blood pressure, blood glucose, and cholesterol, only sleep duration < 6 h, and working hours > 60 h were significantly associated with an increased risk of atherosclerosis.
It is important to highlight the large differences regarding the shift schedules, professions, and workplaces in which the studies were performed.     The analyzes were of a transversal cut. There was no precise data on types of turns and direction of rotation. The number of valid measurements of vascular function was limited. Physical activity cannot be considered an adjustment.  [31] There was no association between WLC and incident hypertension or increased AS, but results stratified by gender resulted in a hazard ratio of 1.47 (95% CI 0.54-3.98) for incident CVD among women.
Depending on the model: sex, age, socioeconomic level, WLC (management position, NS and working hours/week), factors of private life, smoking, alcohol abuse and WHR.
Few incidents CVD were observed in the first five years among women. Selection bias may have occurred (healthy worker). They could not estimate the effect of private life roles interfering with work on cardiovascular health.

Matre et al. (2022) [24]
Shorter sleep duration was associated with higher BP and partly with higher PWV, indicating an increased risk of CVD with reduced sleep Analyzes involving PWV were adjusted for gender and age Sample size. Data not representative of the population. Sleep duration calculated by an actigraphy not validated against polysomnography. Wide divergence between actigraphy and diary data. BaPWV = brachial-ankle pulse wave velocity, PA = physical activity, WC = waist circumference, BP = blood pressure, BMI = body mass index, CHOL = total cholesterol, HDL = high-density lipoprotein cholesterol, LDL = low-density lipoprotein cholesterol, PWV = pulse wave velocity, HR = heart rate, WHR = waist-to-hip ratio, CVR = cardiovascular risk, FBG = fasting blood glucose, MI = myocardial infarct, SW = shift workers, DW = day workers, CVD = cardiovascular disease, IMT = intima media thickness, TGL = triglyceride, VFA = visceral fat area, CAVI = cardio-ankle vascular index, CCA = common carotid artery, IG = intervention group, CG = control group, NS = night shift, WLC = work-life conflicts.

Discussion
According to the studies retrieved in this review, there is no uniformity in the results observed for early arterial stiffness as a predictor of vascular aging in shift workers. The studies reviewed differed in terms of study design, follow-up time, method of assessing arterial stiffness, exposure to shift work and night work, as well as observed results. Some studies reported that factors such as short sleep duration, BMI, systolic and diastolic blood pressure, fasting blood glucose, cholesterol, and smoking were associated with the risk of early arterial stiffness [24,28].
A few studies found no direct association between work shifts and arterial stiffness [21,30,32], others reported higher levels of arterial stiffness in day workers [26,29] whereas some studies showed that this indicator of arteriosclerosis was higher in shift workers [23,25]. These contradictory findings are surprising since there is evidence that shift work is associated with several health problems, including effects deleterious effects on the cardiovascular and metabolic systems [33][34][35][36][37][38][39][40].
The findings of Skogstad et al. [26] and Sugiura et al. [29] may have occurred due to the limitations highlighted in the studies in relation to the heterogeneity of the sample and possible selection bias and not considering covariates related to CVD (unhealthy eating habits and alcohol intake). In addition, the day workers studied by Skogstad et al. [26] were mostly older and with higher BMI when compared to night workers. A systematic review with meta-analysis, for instance, found a 17% higher risk of cardiovascular events, and an almost 20% higher risk of cardiovascular disease mortality, in shift workers compared to day workers [32].
Although the association between shift work and cardiovascular diseases is well described in the literature, with the work shift being recognized as an independent factor for cardiovascular diseases, the pathophysiological mechanisms involved are still not fully elucidated [30]. A possible explanation for this relationship is that the reduced synthesis of melatonin in shift workers can promote increased pressure and thrombus formation, since when the hormone is released in the ideal concentration, it could contribute to reducing blood pressure and increasing of blood fluidity [41,42]. Evidence indicates that reduced sleep time alters physiological processes in the body, including changes in heart rate [43], changes in blood clotting [44,45] dysregulation of immunity [46], mental disorders [47], and risk of cardiometabolic diseases [48][49][50].
Of the studies exploring the association between work shifts and early arterial stiffness, two identified an association between the time of exposure to work shifts, in the last 10 years, and early arterial stiffness [23,25]. Moreover, the study found a positive relationship between shift work and arterial stiffness with 3% higher levels when associated with a cumulative number in the last 10 years of night shifts among the workers analyzed. When analyzing cumulative work shifts and overall years worked, the association with increased arterial stiffness was even greater, reaching 4% [25]. In line with these findings, a metanalytic study found a 7.1% higher risk of CVD incidence for every five years of night work [51]. Another systematic review with meta-analysis, based on prospective observational studies, indicated approximately 40% higher risk of coronary heart disease in workers engaged in long working hours [52]. In fact, the risk of CVD in shift workers has previously been reported in the literature.
The study evaluating whether intentional exercise before night shifts could improve the cardiometabolic profile of workers observed that 24 h blood pressure and PWV values remained practically unchanged before and after the period of intervention with exercise [32]. In this same line of research, another author assessed the impact of high-intensity exercise two hours before night work and observed subtle changes in blood pressure and PWV values, but these were not significant when compared to the control group throughout the study [30].
Studies about physical exercise and PWV among night workers might be interesting to investigate whether the activation of the circulatory and metabolic systems alleviates the circadian disruption observed in this population (in addition to glucose regulation and blood pressure regulation) [53].
One of the studies found in the review, investigating the impact of work-life conflicts on workers' health, with five years of follow-up, observed no association between worse work-life conflict and hypertension or increased arterial stiffness. However, gender stratification showed an increased risk for women [31]. López-Soto et al. [54] highlighted that women, when working in shifts, have more sleep disturbances than men, especially when they need to perform housework and care for small children, as they tend to restrict their rest time to perform the demands of home care. One of the most accepted mechanisms for the genesis of cardiovascular changes in shift workers is psychological stress. It is suggested that the stress triggered by circadian disruption, caused by exposure to shift work and routine instability, promotes hypersecretion of cortisol and catecholamines, contributing to changes in physiology [9,10].
Although the association between shift work and arterial stiffness has not been fully elucidated by the studies included in this review, findings showed there are risk factors involved in the etiology of arterial stiffness. Risk factors previously associated with shift work include high levels of cholesterol, uric acid, glucose, and potassium. Another aspect to be considered is that night shift work has been associated with an increased risk of chronic systemic inflammation, which potentiates cardiac risks [51,52].
The metabolic and physiological changes in circadian disruption can cause changes in lipid metabolism, represented by an increase in triglycerides, an increase in total cholesterol, and a reduction in high-density lipoprotein. In addition to the lack of control of the mechanisms of the hypothalamic-pituitary axis of hunger and satiety, triggered by increased resistance to leptin and insulin, predisposing to obesity [55,56]. These conditions are known to be involved in the etiology of health problems and can be potentiated by other predisposing factors such as family history, hypertension, diabetes, smoking, sedentary lifestyle, and inadequate diet [10].
Epidemiological studies have shown that there is an increased risk of cardiovascular diseases in individuals who work in shifts [56,57]. It has been suggested that this risk may be due to the stress generated by years of exposure to irregular shifts or due to the accumulation of classic cardiovascular risk factors that are more present in shift workers, including: smoking, low physical activity, overweight or dyslipidemias (triglycerides, total cholesterol, low-density lipoproteins-LDL above the normal limits and/or highdensity lipoproteins-HDL below the normal value) [55].
Matre et al. [24] and Chou et al. [23] identified an association between short sleep duration and arterial stiffness. It is suggested that this occurs because sleep deprivation can cause biological outcomes such as increased inflammation, and hormonal and metabolic changes, which disorganize the collagen and elastin fibers of the vascular wall [58] and may increase arterial stiffness [59]. The higher prevalence of CVD in individuals with sleep deprivation, which occurs during work shifts, may be associated with changes in circadian patterns, reduced vascular elasticity, and, consequently, increased arterial stiffness [5,60]. A systematic review with meta-analysis, for instance, found a 17% higher risk of cardiovascular events, and an almost 20% higher risk of cardiovascular disease mortality, in shift workers compared to day workers [61].
Several hypotheses have been suggested to explain the higher incidence and prevalence of CVD in shift workers. One of these hypotheses holds that night shift workers are less likely to adopt a healthy lifestyle [8]. The association between inadequate lifestyle and chronic sleep restriction may render professionals who work at night more exposed to endothelial dysfunction, loss of arterial elasticity, and vascular stiffness, which are early markers of CVD [62]. Another assumption underlying the increased risk of CVD seen in shift workers, especially night workers, is that exposure to work at night causes circadian disruption in blood pressure control mechanisms [11]. The repercussions of shift work on blood pressure can trigger arterial stiffness and possibly culminate in premature vascular aging. It is noteworthy that arterial stiffness is also naturally influenced by the age, genetics, and gender of the individual, being an early predictor of cardiovascular disease and target organ damage [62].
Findings on shift work and arterial stiffness remain heterogeneous, precluding any robust conclusions. Yet, the present review complements a growing body of evidence on the impact of shift work and the risk of atherosclerosis, which potentiates the emergence of cardiovascular disease. In addition, shift work, as cited in the articles reviewed, exposes workers to shorter sleep duration, artificial light at night, and both physical and mental stress. All these changes can misalign circadian rhythms, alter blood pressure regulatory mechanisms, and increase the risk of metabolic disorders, chronic inflammation, arterial stiffness, and cardiovascular outcomes. Occupations, different forms of organization of shift work, including night work or otherwise, weekly exposure dose, and cumulative exposure time over the years of night work are factors, which also play a role.
Due to the diversity of study designs and the conflicting results of the studies included in this review, it cannot be said that there is an association between shift work and arterial stiffness. There is a need for more studies with well-controlled, longitudinal methods and with samples that allow population inference so that robust evidence can be produced.

Conclusions
The studies included in this review evaluated arterial stiffness using different methods, obtained conflicting results, and do not allow us to state that shift work is an independent predictor of arterial stiffness. However, considering the papers just mentioned, there are many studies that show that different factors (sleep deprivation, circadian disruption, and lack of adoption of a healthy lifestyle) are capable to increment the prevalence of CVD. Further studies with a longitudinal design and control of confounding factors are needed to establish whether there is a causal relationship between shift work and arterial stiffness.