The different roles of cardiovascular risk factors in men and women have recently been discussed . Many risk factors, including stress-related psychosocial coronary risk factors (e. g., social isolation, VE) have been reported to have a greater impact on CHD progression in men compared to women, especially in stressful psychosocial conditions . In line with these findings and with our hypothesis, we found a significant CAC x VE interaction for IMT only in the men. This association persisted after all adjustments, showing that age and traditional cardiovascular risk factors may have an additional harmful pressure in relation to atherosclerosis. The results of the three-way interactions analyses represent that the interaction between CAC and VE are statistically different between men and women. Our results imply that high VE significantly predicted high IMTs among the men with low CAC, but not among the women with low CAC or among the women or men with high CAC.
In the previous studies, we found the interactions of VE and acute stress reactivity/recovery with preclinical atherosclerosis only in the men , and a differential effect of VE in men compared to women . In addition, chronic stress has been shown to be associated with IMT only in men in the recent CRYF study . Furthermore, compared to women, men with high levels of cardiovascular risk factors have been found to demonstrate decreased elasticity and a significantly increased risk of structural atherosclerosis progression . Taken together, our current results imply that the effects on atherosclerosis are more pronounced in high vitally exhausted men with decreased CAC compared to women having the same levels of VE and CAC. These findings are in line with the concept of the female sex hormone's (estrogen) protective role in connection with atherosclerosis progression . Vital exhaustion belongs to one of the types of prolonged (chronic) stress. Chronic psychological stress has often been linked to estrogens in women. Thus, preventive role of estrogen on depression-like behavior has been found in the latest research when estrogen therapy has been applied on the animal depression model . On the other hand, estrogens have been reported to decrease total cholesterol and LDL-cholesterol levels [50, 51]. A vasodilatory effect of estrogens on the walls of vessels has been shown, and, in addition, the atheroprotective effect via inhibition of smooth-muscle cell proliferation . Moreover, estrogens have been found to decrease arterial stiffness , therefore, estrogens may increase arterial compliance (high arterial compliance is an indicator of good arterial elasticity, whereas high arterial stiffness indicates impaired arterial elasticity). Our findings are also in accordance with the idea of men's decreased stress coping , as well as with the response-to-injury model of atherosclerosis development .
The possible mechanism explaining the interactions of VE and CAC on atherosclerosis progression could be participation of the HPA axis  and the sympathetic-parasympathetic balance  in stress-related vascular disease development, possibly by triggering endothelial dysfunction , which can be related to structural alterations of the arterial walls , increasing the sensitivity of the vasculature to the harmful influence of risk factors and contributing to the pathogenesis of the atherosclerotic process. In addition, proinflammatory [28–31] and procoagulant alterations [26, 27] have been found to play a role in VE and atherogenesis relations. Van der Ven and coauthors  have found that VE is associated with (1) increased levels of cytokines, (2) increased procoagulant activity and (3) multiple herpes virus infections. In addition, elevated levels of both serum cytokines concentrations and tumor necrosis factor alpha have recently been reported to be associated with VE in patients with cardiovascular risk factors . Increased cytokines levels have also been reported in patients, who are exhausted after percutaneous coronary intervention . It has been shown earlier, that cytokines may affect the brain and evoke the sense of life discomfort and feelings of fatigue and tiredness [55–57]. On the other hand, the relationship between endothelial dysfunction and inflammatory processes in the walls of vessels, which can foster atherosclerosis development, have recently been reported in the CRYF study . Endothelial dysfunction has been considered to be an earlier indicator for the structural changes of the arterial walls . Reduced arterial compliance reflects structural abnormalities/alterations of the walls of vessels, which are associated with the diseases and/or age . In addition, the associations between VE and body mass index, suggested that reducing VE levels can play a role in reducing the prevalence of obesity have recently been found in ARIC study . On the other hand, it has been demonstrated in the CRYF study, that young adults (aged 24-39 years) with metabolic syndrome have increased carotid IMTs and decreased CAC . Possible links between obesity and VE , between metabolic factors and carotid atherosclerosis, which has been shown earlier , as well as between the metabolic syndrome and CAC  offer another potential explanation for the relations found between VE, CAC and carotid atherosclerosis.
No significant FMD x VE interactions for IMT in the women or men were found. These results are in agreement with a recent findings that CAC is more closely related to coronary risk than FMD  and consistent with the idea that in some conditions arterial compliance/arterial stiffness may be a more sensitive and more effective risk marker than FMD [7, 62], because many risk factors can influence the elastic properties of vessels [7, 12, 63]. Indexes of arterial elasticity have been found to be highly important for identification of cardiovascular events risk and for determining the level of intervention . Thus, the predictive value of aortic stiffness on primary stroke in hypertensive patients has been shown . Future studies are needed to confirm the predictive values of arterial stiffness on cardiovascular events. In addition, patients at risk for cardiovascular events may benefit from earlier recognition of impaired arterial compliance and vascular abnormality. Earlier recognition and a reduction of arterial stiffening may decrease a risk and prevent cardiovascular events . Several non-invasive arterial elasticity tests have recently been created by various medical-research companies and some tests, such as measuring of arterial stiffness and arterial compliance, are under clinical evaluation.
Vital exhaustion was shown in the present study to exert an effect on IMT in the young men with impaired arterial elasticity. The distinction of VE from depression remains a subject of discussion. Exhaustion symptoms such as sleep alterations and feelings of weakness overlap with depressive symptomatology. It has been found in the comparative depression/vital exhaustion study that VE and depressive symptomatology correlated strongly (shared a common variance of 38%: ). However, a "depressed" mood, the key symptom of depression, is usually absent in exhausted individuals . Many studies have distinguished VE from depression, in that exhausted subjects have characterized by the absence of the main symptoms for depressive disorders: feelings of guilt, sadness, or feelings of worthlessness. Vitally exhausted subjects are typically characterized by demoralization, whereas the lowered self-esteem is a symptom of depression . In the study, which assesses the differences between depression and VE in 12640 participants from Hungary, most depressed subjects (77%: ) investigated have been found to be exhausted, but cognitive and mood disturbances, the important symptoms of depression, have been shown to be usually absent in exhausted subjects . In line with these findings and with  the depressive symptoms have been demonstrated to be a distinct from the concept of VE in 822 participants studied in Augsburg Cohort Study . In addition, depressive symptoms and VE have been presented to be differentially related to behavioral risk factors for cardiovascular diseases: VE has been associated with increased probability of cardiovascular disorders and history of cardiovascular treatment, whereas depressive symptomatology with increased risk for illegal drug uses, alcohol abuse, congenital disorders, disabilities and hostility . Finally, depression has typically considered to be a disease, whereas VE - a psychological state.
There are some limitations in the present study. First, we measured carotid IMT from the left carotid artery, not from the internal carotid artery. However, previous data support the use of the common carotid artery IMT in both studies of risk factor associations and cohort studies [68, 69]; the reproducibility of our measurements is comparable with other reports .
Second, we found relatively large within-subject long-term variation in FMD  and CAC measurements , which is in agreement with previous reports [70–72]; the long-term reproducibility of the carotid and brachial diameter measurements was very good, which suggests that much of the variation in CAC and FMD is due to physiological fluctuation. However, the large variability of FMD and CAC is a limitation.
The present analysis was conducted in participants aged 24 to 39. Our results cannot be generalized to older individuals with more definite atherosclerosis. Also, owing to the cross-sectional nature of the present study, it is impossible to make statements regarding atherosclerosis progress. We conducted several analyses, but not as many significant associations were found as was expected. Therefore, the possibility of a chance finding cannot be excluded. The CAC and VE interaction explains 0.5% of the variance in IMT in the men. This is a small amount, and we need to mention this point as an additional limitation of the study. Taking these limits into consideration, our results need to be viewed cautiously and replicated in future research.
The strength of our study is a comparatively large population-based sample. Furthermore, we were able to examine both men and women, which is important as it has been repeatedly shown that results related to cardiovascular diseases cannot be generalized from men to women or vice versa. Our study focused on young adults and brought important information on atherosclerosis development in a stage when clinical symptoms of carotid artery disease are rarely seen.