Association between occupational stress and asymptomatic cerebrovascular disease: A cross-sectional magnetic resonance imaging study

INTRODUCTION

Cerebrovascular disease (CVD) encompasses a group of disorders involving disrupted cerebral blood flow and vascular integrity. In recent decades, it has been recognized as a socially significant disease because it significantly reduces the quality of life of those affected, particularly younger people in their working years. Globally, stroke is the second most widespread cause of death (6.6 million people) and disability (loss of 143 million years of full health – DALYs).^[1] Most of the studies addressing the risk factors (RFs) for acute stroke describe a greater prevalence of asymptomatic CVD (ACVD), which is sometimes referred to as a silent CVD, a subclinical disease, or a latent CVD.^[2] Studying ACVD is critical, as it precedes symptomatic stroke, predicts dementia, and offers opportunities for early prevention.^[3] ACVD refers to subclinical brain lesions detectable by neuroimaging in individuals without prior clinical symptoms of stroke or transient ischemic attack (TIA). These lesions typically include white matter hyperintensities (WMH), silent lacunar infarcts, cerebral microbleeds, and mild brain atrophy and are associated with increased risk of future stroke, cognitive decline, and vascular dementia.^[3] The development of modern neuroimaging and vascular evaluation techniques led to the early detection of various conditions related to ACVD, such as atherosclerosis of the carotid arteries with intima-media thickening, ulcerations of atheromatous plaques, asymptomatic carotid artery stenoses, asymptomatic cerebral infarctions, ischemic lesions in deep white matter, and some brain atrophy.^[4]

A large number of studies investigate the relation between modifiable and non-modifiable RFs and CVD, but very little is known about the impact of occupational stress (OS) and other profession-related factors on ACVD. The overall contribution of the occupational RFs to cerebrovascular risk decreases with age, but the total exposure during a person’s lifetime might be significant depending on the specifics of the profession. Nevertheless, the occupational RFs might have a significant effect on younger adults.^[5] Numerous reports are proving the negative relationship between OS,^[6] longer working hours, work overload,^[7] and psychosomatic factors^[8] and the risk of ACVD.

OS negatively affects both mental and physical health, leading to reduced productivity, efficiency, work capacity, and job satisfaction.^[9] OSors are a group of various factors (socioeconomic, family- or group-related, work-related), which have an additive effect and could lead to the development of various symptoms of a psychosomatic nature, and if those factors have long enough persistence, they can lead to somatic disorders.^[8] According to the National study of working conditions in Bulgaria, from 2010, around 40% of workers complain of stress at the workplace, with the most affected sectors being education, health care, humanitarian work, content creation and information dissemination, and telecommunications. Prolonged stress response activation impairs physiological adaptability, contributing to disease development. This negatively impacts arterial blood pressure control, serum lipid levels, the coagulation system, and glucose metabolism, whereas the overall effect of these processes is stimulation of the atherosclerotic process in the body and, respectively, increased risk of cardiovascular and CVD.^[10] Psychological OS is considered one of the most persistent workplace-related RFs. It is subdivided into two primary subtypes: psychological demand (tight deadlines, mental workload, and obligations) and work control (skills and decision-making authority). Higher psychological demand and worse work control are proven to lead to higher stress, and vice versa, resulting in the establishment of a pathological cycle associated with increased risk of ACVD.^[11]

Unlike symptomatic stroke, ACVD is largely unstudied in relation to workplace exposures, representing a gap this study addresses. The present study aims to evaluate the influence of the occupational factors contributing to increased OS and its contribution to the general risk of ACVD.

To the best of our knowledge, this is one of the first studies to explore the relationship between OS and MRI-detected ACVD among a working-age population in Eastern Europe and in Bulgaria. This regional and demographic specificity, combined with detailed occupational stratification, adds unique value to the existing literature.

MATERIALS AND METHODS

Participants in the present study are part of a cross-sectional, hospital-based case–control study evaluating the influence of several occupational characteristics on the risk of ACVD. We hypothesized that high OS, combined with long working hours and shift work, would be associated with MRI-detected cerebrovascular lesions. We conducted the present study from February 2019 to May 2022, in the Second Clinic of Neurology with ICU and Stroke Center at the University Hospital “St. Marina,” Varna Bulgaria . Ethical permission (Protocol No. 87/24.10.2019) was received from the ethics committee of the Medical University “Prof. Dr. Paraskev Stoyanov,” Varna, Bulgaria. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki and institutional ethical guidelines.

Included in this study were 151 consecutively recruited, employed patients hospitalized in our clinic who underwent brain magnetic resonance imaging (MRI) for non-acute neurological indications. Based on MRI findings, participants were classified into two groups: individuals with imaging features consistent with ACVD and a control group consisting of hospital-based, employed participants without MRI evidence of ACVD. The control group was not considered a healthy population but served as imaging-negative controls within a working-age cohort. All of the selected patients had at least one vascular RF but no history of a current or past cerebrovascular accident or TIA. Patients were consecutively recruited after undergoing MRI for non-acute stroke indications. The participants were separated into two groups according to the MRI findings: 41 patients with ACVD and 110 controls with normal MRI imaging. ACVD was defined as: Hyperintense white matter lesions with suspected vascular etiology, lacunar strokes, cerebral microhemorrhages, and brain atrophy.

We accepted the following inclusion criteria: age between 18 and 64 years; employment at the time of the study; presence of at least one vascular RF; conducted MRI of the head during hospitalization; and no history or clinical evidence of stroke or TIA.

Exclusion criteria were: Age under 18 or more than 65 years; being unemployed at the time of the study; absence of vascular RFs; positive history and clinical evidence of stroke or TIA; presence of changes on an MRI scan characteristic of other diseases of the nervous system; refusal to sign an informed consent.

All subjects were evaluated by a neurologist following a standardized protocol to ensure consistency in the collection of clinical and RF data. A locally developed structured questionnaire was used to collect demographic, social, and occupational data. Data on occupational RFs encompassed employment duration, occupational role, work pattern, nature of work activities, and potential physicochemical exposures.

All participants were evaluated for vascular RFs through a combination of medical history review and standardized clinical assessment, focusing on hypertension, diabetes mellitus, ischemic heart disease, and heart failure. Diagnoses were confirmed based on documented history, current pharmacological treatment, and clinical records. All assessments were performed in accordance with the current European and international clinical guidelines.

OS was assessed using the specific self-reporting questionnaire Workplace Stress Scale (WSS), originally developed by the American Institute of Stress. As no validated Bulgarian version was available at the time of the study, we used a translated version reviewed by two occupational health experts for linguistic accuracy and conceptual equivalence. Internal consistency in our sample was acceptable (Cronbach’s α = 0.76). This tool consists of 8 items rated in Likert scale ranging from 1 to 5 points. The WSS includes items on workload, deadlines (psychological demand), and autonomy, decision-making (control). The interpretation of WSS is according to the total sum of points as ≤15 – relatively calm; 16–20 – fairly low OS; 21–25 – moderate stress; 26–30 – severe stress; 31–40 – potentially dangerous level of OS.

All participants underwent brain MRI as part of their clinical evaluation to detect small vessel disease and other cerebrovascular changes. None of the individuals had a history of stroke, TIA, or clinical signs of cerebrovascular events. We used a Siemens Magnetom 3 Tesla (3T) scanner at University Hospital “St. Marina,” Varna. The standardized imaging protocol included axial T1-weighted sequences (TR: 1900 ms, TE: 2.44 ms), T2-weighted sequences (TR: 4840 ms, TE: 96 ms), fluid-attenuated inversion recovery (FLAIR) sequences (TR: 9000 ms, TE: 114 ms, TI: 2500 ms), and diffusion-weighted imaging with b-values of 0 and 1000 s/mm². All patients also underwent intracranial magnetic resonance angiography using a 3D time-of-flight (TOF-MRA) technique (TR: 21 ms, TE: 3.43 ms, flip angle: 20°, voxel size: 0.5 × 0.5 × 0.6 mm) to evaluate vascular abnormalities, including stenosis or tortuosity. MRI scans were independently reviewed by a certified neuroradiologist blinded to clinical and occupational data.

WMH were evaluated using the Fazekas scale, which is a validated semi-quantitative visual grading method. The scale ranges from Grade 0 (no WMH), Grade 1 (punctate foci), Grade 2 (beginning confluence of lesions), to Grade 3 (large confluent areas). This classification provides an estimate of WMH burden, which reflects the severity of cerebral small vessel disease. In our study, WMH grading served as a key imaging endpoint to identify asymptomatic cerebrovascular changes associated with OS and vascular RFs. This widely used visual grading system provides a reliable and standardized method for assessing WMH burden and reducing inter-rater variability.

The study design was an unmatched case-control, incorporating both categorical and continuous variables. Descriptive statistics were applied to characterize demographic, clinical, and occupational data. Continuous variables were presented as means with standard deviations (mean ± standard deviation), while categorical variables were expressed as absolute frequencies and percentages. Comparative analyses between the ACVD group and controls were conducted as follows:

• Independent samples t-tests were used to compare continuous variables, assuming normal distribution

• Chi-square tests, Fisher’s exact test, and cross-tabulations were employed to evaluate differences in categorical variables across groups.

Associations between OS levels and various occupational or vascular RFs were assessed using Spearman’s rank correlation coefficients (rho [ρ]). Residual confounding from unmeasured lifestyle and socioeconomic factors cannot be excluded.

To identify predictors of MRI-detected asymptomatic cerebrovascular changes, binary logistic regression analysis was conducted with age included as a covariate to control for its confounding effect on ACVD and white-matter hyperintensities. The results were reported as odds ratios (OR) with corresponding 95% confidence intervals (CI). An OR greater than 1 was interpreted as indicating increased risk. A two-tailed P < 0.05 was considered statistically significant for all analyses.

All statistical analyses were performed using IBM Statistical Package for the Social Sciences Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA) and Jamovi Version 2.2.0.

This study was designed as a pilot, exploratory, hospital-based case–control study intended to generate hypotheses regarding the association between OS and ACVD.

RESULTS

The study included 41 patients with MRI-confirmed features of ACVD and 110 unmatched controls with normal MRI and no ACVD findings. The mean age of the ACVD patients was 54.6 ± 6.7, as for the control group - 48.6 ± 7.9. Gender distribution and education level did not significantly differ between the two groups [Table 1].

A statistically significant difference was found between the two patient groups regarding vascular RFs. Patients with MRI-detected changes showed a significantly higher prevalence of hypertension (P = 0.004), diabetes mellitus (P = 0.011), heart failure (P = 0.016), and ischemic heart disease (P < 0.001). Among participants with hypertension, diabetes mellitus, and ischemic heart disease, a higher relative risk for silent brain infarctions was calculated.

We examined the patients in terms of occupational RFs – work experience, work schedule, total number of working hours per week, and working posture. The distribution of patients between the two groups revealed a statistically significant difference in terms of work experience (P = 0.032) and total weekly working hours (P < 0.001). Weekly working hours were significantly higher among patients with asymptomatic MRI changes than among controls (48.41 ± 6.26 vs. 44.45 ± 3.85; P < 0.001). A higher relative risk for the occurrence of MRI changes was calculated in patients working more than 55 h/week [Table 2].

The measurement of the OS using the WSS found significantly higher stress in the patients with ACVD. The average WSS result for the patients’ group was 21.34 ± 5.47, whereas for the controls, 19.08 ± 4.29 (P = 0.009).

OS subcategory analysis revealed that severe stress was present in 31.7% of ACVD patients versus 7.4% of controls, demonstrating a statistically significant association between higher stress levels and asymptomatic cerebrovascular changes (P < 0.001). In contrast, most patients from the control group were in the “low level of stress” category – 44.5%, and just 29.3% of patients with ACVD (P = 0.019). Detailed information regarding the distribution of the participants according to their OS is presented in Table 3.

Correlation analysis was performed on the full sample (n = 151) to explore relationships between occupational factors and perceived stress levels, as measured by the WSS. These variables were examined as potential contributors to stress, which may act as a modifying factor in ACVD.

We observed weak but statistically significant correlations between OS levels and selected occupational characteristics. Specifically, longer employment duration (Rho = 0.172, P = 0.036), longer weekly working hours (Rho = 0.244, P = 0.003), and shift work (Rho = 0.209, P = 0.010) were modestly associated with higher stress levels [Table 4]. These correlations were of small magnitude and should therefore be interpreted cautiously.

We investigated the correlation between stress levels and vascular RFs. We found a statistically significant correlation between stress levels and hypertension (Rho = 0.212, P = 0.009) [Table 5].

Correlation analysis demonstrated a modest association between higher OS levels and MRI-detected cerebrovascular changes (Rho = 0.179, P = 0.028); however, this association did not remain significant after adjustment for age in logistic regression analysis. In age-adjusted binary logistic regression analysis, OS was not identified as an independent predictor of MRI-detected cerebrovascular abnormalities (OR = 1.734; 95% CI: 0.492–1.093).

DISCUSSION

While our findings are consistent with prior research, the novelty of our study lies in its focus on a younger, actively working cohort and the integration of work stress variables with objective neuroimaging findings. In many cases, patients report non-specific, transient symptoms such as lightheadedness, presyncope, unexplained falls, or brief episodes of cognitive fog that are often overlooked or misattributed to fatigue or stress. However, such symptoms may reflect early cerebrovascular compromise, especially in individuals with vascular or occupational RFs.^[12] The relationship between hypertension and asymptomatic ischemic lesions has been established in numerous studies. Hypertension is considered one of the main RFs for ACVD, with its frequency increasing as the average blood pressure rises.^[13] Our study confirms these results, showing a statistically significant difference in the frequency of hypertension between the two groups, as well as a positive correlation (Rho = 0.263, P = 0.001). We calculated nearly twice the increased risk of asymptomatic lesions in patients with hypertension, which is consistent with previously reported data from the Rotterdam Scan Study.^[14] Our findings are in line with data on the frequency of hypertension among stroke patients in several European countries, including the United Kingdom, Greece, Croatia, and others.^[15-17]

A similar relationship is observed concerning the association between diabetes mellitus and ACVD. Diabetes mellitus is positively correlated with the presence of MRI changes (Rho = 0.206, P = 0.011) and nearly doubles the risk of ACVD in the studied patients. These results align with scientific reports indicating a higher frequency of lacunar infarcts and WMH in patients with diabetes mellitus.^[18,19] The findings regarding the prevalence of diabetes in stroke patients in Europe and Bulgaria are significantly higher than those in our study.^[16,17] This discrepancy can likely be explained by the lower average age of the patients in our study, as the incidence of diabetes increases with age.^[20]

Previous studies have reported a wide range in the prevalence of diagnosed heart failure among patients with asymptomatic infarcts and WMH, with estimates ranging from 10% to 24%.^[21] The observed prevalence of heart failure was 7.3%, which is lower than anticipated, potentially due to the younger mean age and lower comorbidity burden of our cohort. Despite this low percentage, it is significantly higher compared to the control group and correlates with the presence of asymptomatic MRI changes.

Various research groups have investigated the correlation between different manifestations of atherosclerosis and WMH. A positive relationship has been established with coronary,^[22] aortic,^[23] cerebral,^[3] carotid,^[24] and atherosclerosis in branches of the basilar artery and atherosclerosis in branches of the basilar artery.^[24,25] Increased cardiovascular risk and the presence of cardiovascular RFs increase the risk of asymptomatic cerebrovascular lesions. 17.1% of our patients with asymptomatic lesions reported a history of diagnosed coronary artery disease, which is statistically significantly higher than in the control group. The presence of coronary artery disease, as a clinical manifestation of coronary atherosclerosis, increases the risk of lesion development in our patients.

Studies examining the relationship between asymptomatic manifestations of cerebrovascular disease and occupational factors are scarce. Longer work experience and prolonged working hours (>41 h/week) are associated with a higher incidence of cardiovascular diseases, including stroke.^[7,26] With increased work experience, there is also an increase in age-related RFs such as hypertension, diabetes, dyslipidemia, and others, as well as exposure to other factors such as OS, night shifts, and physical–chemical hazards. Longer work tenure, particularly beyond 30 years, was associated with a greater incidence of asymptomatic MRI changes in our cohort. We also found a higher risk of MRI lesions in patients with work experience between 20–30 years and 31–40 years compared to those with 10–20 years of work experience. Patients in the group with MRI changes showed statistically significantly higher weekly working hours. A systematic analysis by Kivimäki et al. in 2014 demonstrated a dose-dependent association between prolonged working hours and stroke risk.^[26] A summary of the data from the WHO and ILO in 2020 found sufficient evidence for an increased risk only when working >55 h/week, with weaker evidence for exposure to 41–48 h and 49–54 h/week,^[27] which our study also confirms.

We did not establish an influence of the work schedule (day, night, shift work) on the occurrence of MRI lesions. Previous studies, however, have shown that shift work is associated with a higher incidence of ischemic stroke and cerebrovascular mortality, particularly with prolonged night-shift exposure.^[28,29] One possible explanation is that shift work disrupts sleep–wake cycles, leading to circadian misalignment, reduced sleep quality, and hormonal dysregulation. These disturbances may elevate blood pressure, impair glucose metabolism, and increase metabolic risk, thereby indirectly contributing to cerebrovascular vulnerability. Larger cohort studies have demonstrated similar mechanisms linking night shift exposure with cardiovascular morbidity.^[30]

The type of working posture did not show a connection with the presence of MRI lesions, and no increased risk of lesion development was calculated. Hall et al. reported a higher frequency of CVD with a “standing” working posture, a result that our study could not confirm.^[31] Descriptive data from our study show a higher percentage of patients working in “forced postures” (19.5%) in the MRI lesion group. Such work conditions often involve reduced autonomy, limited recovery time, and increased fatigue, which may contribute to physical inactivity and elevated stroke risk.^[32]

Studies connecting professional stress levels with the early stages of CVD are scarce or absent. The studies that exist use different scales and methods to assess stress levels, with most establishing a higher stroke risk with exposure to high levels of professional stress.^[11,33] We found a statistically significantly higher mean score on the WSS in the group with MRI changes. Although the group differences in stress were significant, logistic regression did not support OS as an independent determinant of MRI-detected lesions. These findings suggest that OS may potentiate the effects of established vascular RFs, rather than operate as a standalone RF. Higher scores are associated with an increased risk of MRI lesions. Work-related stress is considered the most stressful occupational factor, encompassing two components: psychological demands (tight deadlines, mental load, and responsibilities) and job control (skills and decision-making authority). When working with high demands and low control, stress levels are high.^[26] In the group with MRI lesions, a higher frequency of stress-related factors was recorded. First, associated with high work stress (high workload, excessive information) and second, related to low job control (lack of control, mismatch between demands and capabilities, and inability to make independent decisions).

Age negatively impacts work ability, particularly in physical labor,^[34] reducing control over the work process and increasing professional stress.^[26] In our study, OS demonstrated statistically significant but weak correlations with work experience, weekly working hours, and shift work. Although these findings suggest a possible link between workplace conditions and stress perception, the small effect sizes indicate that the relationships are modest and not necessarily indicative of causal pathways. It is plausible that other unmeasured factors, such as socioeconomic status, job security, or sleep quality, may account for part of the observed associations. A study among the working population of Denmark found higher work stress linked to a lack of decision-making freedom and “managerial support” among night shift workers, compared to day shift workers.^[35] Ma et al. found higher stress levels among police officers working shift schedules,^[36] which aligns with our findings. Research in various countries and among different worker populations confirms the relationship between prolonged working hours and professional stress.^[37] It is believed that overtime and extended workweeks increase stress levels by increasing exposure to stress-inducing factors, reducing sleep and rest time, and subsequently disrupting the hypothalamic–pituitary–adrenal axis.^[37]

The pathophysiological and biochemical changes induced by stress negatively impact the onset and control of modifiable RFs for CVD. Our study only demonstrated a positive relationship between higher stress levels and hypertension in the patients examined. Numerous epidemiological studies have shown that prolonged exposure to professional stress positively impacts the onset of hypertension and increases blood pressure levels among workers.^[38,39] OS increases serum cortisol levels, and its secretion follows a circadian rhythm, with its concentration in saliva, urine, and blood reflecting stress levels from the previous minutes and hours.^[40] For this reason, several authors measure hair cortisol concentration due to its non-invasive nature and cumulative concentration.^[39] Hsu et al. were the first to establish a positive relationship between professional stress, hair cortisol concentration, and arterial hypertension. In our patients, we did not find a connection between higher professional stress levels and other RFs (diabetes, arrhythmias, heart failure, and coronary artery disease).^[5] The lack of data on these factors could be attributed to the smaller sample size and the absence of longitudinal follow-up studies.^[5]

Our study indicates an elevated risk of asymptomatic ischemic lesions among patients reporting higher levels of OS. Previous studies have linked stress to brain changes associated with atrophy affecting key regions such as the prelimbic, cingulate, insular, and retrosplenial cortices, as well as the somatosensory, motor, auditory, and perirhinal/entorhinal cortices, the hippocampus, dorsomedial striatum, nucleus accumbens, septum, bed nucleus of the stria terminalis, thalamus, and several brainstem nuclei.^[41] The study by Johnson et al. demonstrated a positive association between stressful life events and the progression of WMH, as well as depressive symptomatology.^[42] Occupational processes and the associated stress significantly elevate overall levels of perceived life stress and related events. This may explain the proportional relationship we observed between higher levels of OS and the volume of hyperintense white matter lesions in the experimental group, as assessed by the Fazekas scale. Longitudinal studies are needed to further investigate the impact of OS on the progression of asymptomatic brain lesions and RFs for CVD.

This study has several limitations that should be acknowledged. First, the relatively small sample size may limit the generalizability of the findings and reduce statistical power, particularly in subgroup analyses (e.g., work schedule, posture). Second, due to the cross-sectional nature of the study, causal relationships between OS and asymptomatic cerebrovascular lesions cannot be definitively established. Third, stress levels were assessed using a self-reported questionnaire, which may introduce response bias and does not capture physiological measures of stress. The use of the WSS in a hospitalized population may introduce recall bias, particularly for subjective items involving retrospective perceptions of workplace-related health effects. This limitation should always be considered when interpreting self-reported data. In addition, differences in the age and educational level, also unmeasured confounders such as socioeconomic status, sleep quality, mental health conditions, and medication adherence, could have influenced both stress levels and vascular health. Finally, the study did not include longitudinal follow-up, which would be necessary to assess the progression of MRI-detected lesions over time.

CONCLUSION

ACVD, including WMH, lacunar infarctions, and cerebral atrophy, is associated with an increased risk of stroke and cognitive decline. Our study identified higher OS levels in participants with MRI-detected lesions. However, OS was not independently associated with ACVD after adjustment for age. It also demonstrated modest correlations between stress and key vascular RFs, particularly hypertension and long working hours. Although higher OS scores were observed in participants with MRI-detected lesions, logistic regression did not support OS as an independent predictor. However, the findings suggest that OS may act as a potential modifier of vascular risk, potentially amplifying the impact of pre-existing comorbidities in working-age individuals. Among the occupational variables examined, longer weekly working hours, shift work, and prolonged work experience were associated with increased stress scores. These results underscore the need to consider workplace exposures in CVD prevention strategies, especially in populations with elevated vascular risk.

Longitudinal studies with larger cohorts are warranted to determine the causal pathways linking OS and subclinical cerebrovascular pathology and to assess whether targeted workplace interventions may mitigate long-term neurological risk.