Patients with rheumatoid arthritis are at increased risk for myocardial infarction. It has been hypothesized that mental stress-induced cardiovascular reactions may play a role in the triggering of myocardial infarction. Cardiovascular activity was measured during rest, stress, and recovery in rheumatoid arthritis patients with high systemic inflammation (C-reactive protein>8mg/l), rheumatoid arthritis patients with low systemic inflammation (C-reactive protein≤8mg/l), and osteoarthritis patients. Systemic vascular resistance increased only in rheumatoid arthritis patients with high systemic inflammation. Heart rate and mean arterial pressure increased during the stress task in all groups. Thus, acute cardiovascular events in rheumatoid arthritis patients may be related to stress-induced increases in systemic vascular resistance, particularly in patients with high levels of systemic inflammation.

Exaggerated blood pressure (BP) response to exercise is a strong predictor of cardiovascular disease, although the mechanisms remain unknown. The purpose was to examine the association between systemic markers of vascular inflammation and exercise blood pressure (BP) responses. Participants were 191 healthy men and women (aged 45–59 years). Blood pressure was measured at baseline and during 8 min of steady state cycling ergometry exercise (at 50 W). Markers of vascular inflammation (fibrinogen, von Willebrand factor antigen, tumour necrosis factor-α, interleukin-6 [IL-6], C-reactive protein [CRP]) were measured at baseline together with other traditional risk factors including central adiposity, smoking, alcohol, and habitual physical activity. CRP (β = 0.30, p < 0.001), IL-6 (β = 0.25, p = 0.001), and fibrinogen (β = 0.14, p = 0.04) were associated with exercise systolic BP. The association with CRP remained significant after adjustment for age, sex, resting BP, and other risk factors. Other independent predictors of exercise BP included resting BP, female gender, waist–hip ratio, lower employment grade, and low physical activity level. In summary, central adiposity and vascular inflammatory processes may underlie exaggerated BP responses to acute exercise.

Mental stress has been identified as a trigger of myocardial infarction (MI), with inflammation and vascular responses to mental stress independently implicated as contributing factors. This study examined whether inflammation moderates the vascular responses to mental stress. Eighteen healthy male participants completed a stress task under two counter balanced conditions. In the exercise condition, a morning bout of eccentric exercise (12×5 repetitions of unilateral eccentric knee extension at 120% intensity of concentric one repetition maximum) was used to increase levels of inflammatory-responsive cytokines during an afternoon stress session scheduled 6h later. In the control condition, participants sat and relaxed for 45min, 6h prior to the afternoon stress session. Forearm blood flow, calf blood flow (measured in the leg which completed the exercise task), blood pressure, heart rate and cardiac output were assessed at rest and in response to mental stress. As expected, interleukin-6 was higher (p=.02) 6h post exercise, i.e., at the start of the stress session, as compared to the no-exercise control condition. Mental stress increased forearm blood flow, calf blood flow, blood pressure, heart rate, and cardiac output in both conditions (p’s<.001). Stress-induced calf blood flow was attenuated in the exercise condition compared to the control condition (p<.05) which was not the case for forearm blood flow. This study found that the inflammatory response to eccentric exercise attenuated the vascular responses to mental stress locally at the site of eccentric exercise-induced inflammation. The observed impairment in vascular responses to stress associated with increased levels of inflammation suggests a mechanism through which inflammation might increase the risk for MI.

The Salmonella typhi vaccination induces transient increases in inflammatory-responsive cytokines and molecules. For instance, it causes small, mild increases in interleukin-6 (IL-6) within a few hours and C-reactive protein (CRP) within 24h. No study has charted either the time course of the inflammatory response to this vaccine or any associated changes in mood, physical symptoms, and cardiac function. In a blinded crossover experimental design, eight participants received the S. typhi vaccine (vaccination condition) and a saline (control condition) injection on two separate days, at least one week apart. Blood samples and mood ratings were collected at 0, 4, 5, 6, 7, 8 and 24h post-injection, physical symptoms and pain were assessed at 4–8 and 24h post-injection, and cardiovascular function was recorded until 8h post-injection. Repeated measures analyses of variance and polynomial trend analyses compared the timecourse of the response patterns between the two conditions. Whereas there were no temporal changes in the control condition, the vaccination increased granulocytes, IL-6, TNF-α, and CRP (all p’s<.05). Specifically, the granulocytes, IL-6 and TNF-α peaked after 6–8h while CRP peaked after 24h. This vaccine-induced mild inflammatory response was not accompanied by any changes in mood or cardiovascular activity. We also found that participants tended to report more pain in the injected limb in the vaccination condition (p<.07). In sum, our study charted the timecourse of key inflammatory-responsive markers following S. typhi vaccination and identified the timing of their modest peaks. It is worth noting that changes in these markers were not accompanied by any notable changes in mood or cardiovascular activity, and thus the S. typhi vaccination is a suitable method to induce increases in inflammatory-responsive markers, without altering mood or cardiovascular parameters.

Background
Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention.
Methods
Within 2850 Netherlands Study of Depression and Anxiety (NESDA) participants, we evaluated the explaining impact of biological stress systems (i.e., the hypothalamic–pituitary–adrenal [HPA] axis, autonomic nervous system [ANS] and inflammation) and lifestyle factors (i.e., tobacco and alcohol use, and physical activity) on adverse associations of anxiety and depression severity and TCA use with high and low-density lipoprotein cholesterol, triglycerides, body mass index and waist circumference. Through linear regression analyses, percentual change (%Δ) in β was determined and considered significant when %Δ>10.
Results
The inflammatory marker C-reactive protein had the most consistent impact (explaining 14–53% of the associations of anxiety and depression severity and TCA use with lipid and obesity levels), followed by tobacco use (explaining 34–43% of the associations with lipids). The ANS mediated all associations with TCA use (explaining 32–61%). The HPA axis measures did not explain any of the associations.
Conclusions
Increased dyslipidemia and (abdominal) obesity risk in patients with more severe anxiety disorders and depression may be partly explained by chronic low-grade inflammation and smoking. TCAs may increase metabolic risk through enhanced sympathetic and decreased parasympathetic ANS activity. That the HPA axis had no impact in our sample may reflect the possibility that the HPA axis only plays a role in acute stress situations rather than under basal conditions.

Inflammation is associated with poorer vascular function, with evidence to suggest that inflammation can also impair the vascular responses to mental stress. This study examined the effects of vaccine-induced inflammation on vascular responses to mental stress in healthy participants. Eighteen male participants completed two stress sessions: an inflammation condition having received a typhoid vaccination and a control (non-inflamed) condition. Tumor necrosis factor-alpha and interleukin-6 (p’s<.001) increased following vaccination, confirming modest increases in inflammation. Mental stress increased blood flow, blood pressure, heart rate, and cardiac output in both conditions (all p's<.001), but the blood flow response to stress was attenuated having received the vaccination compared to the control condition (p's<.05). These results further implicate the interaction between inflammation and the vasculature as a mechanism through which stress may trigger myocardial infarction.

Objectives Dysregulated biological stress systems and adverse life events, independently and in interaction, have been hypothesised to initiate chronic pain. We examine whether (1) function of biological stress systems, (2) adverse life events, and (3) their combination predict the onset of chronic multisite musculoskeletal pain.
Methods Subjects (n=2039) of the Netherlands Study of Depression and Anxiety, free from chronic multisite musculoskeletal pain at baseline, were identified using the Chronic Pain Grade Questionnaire and followed up for the onset of chronic multisite musculoskeletal pain over 6 years. Baseline assessment of biological stress systems comprised function of the hypothalamic-pituitary-adrenal axis (1-h cortisol awakening response, evening levels, postdexamethasone levels), the immune system (basal and lipopolysaccharide-stimulated inflammation) and the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, respiratory sinus arrhythmia). The number of recent adverse life events was assessed at baseline using the List of Threatening Events Questionnaire.
Results Hypothalamic-pituitary-adrenal axis, immune system and autonomic nervous system functioning was not associated with onset of chronic multisite musculoskeletal pain, either by itself or in interaction with adverse life events. Adverse life events did predict onset of chronic multisite musculoskeletal pain (HR per event=1.14, 95% CI 1.04 to 1.24, p=0.005).
Conclusions This longitudinal study could not confirm that dysregulated biological stress systems increase the risk of developing chronic multisite musculoskeletal pain. Adverse life events were a risk factor for the onset of chronic multisite musculoskeletal pain, suggesting that psychosocial factors play a role in triggering the development of this condition.

Objective
The current study examined whether (a) Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were associated with dysregulation of stress-related mechanisms, and (b) whether ADHD symptoms interact with affective disorders in their association with dysregulated stress-related mechanisms.
Methods
Data were obtained from 2307 subjects participating in the Netherlands Study of Depression and Anxiety. Stress-related mechanisms were reflected by the following biomarkers: (1) hypothalamic-pituitary-adrenal axis indicators (salivary cortisol awakening curve, evening cortisol, cortisol suppression after a 0.5mg dexamethasone suppression test (DST)); (2) autonomic nervous system measures (heart rate, pre-ejection period, respiratory sinus arrhythmia); (3) inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha); (4) brain-derived neurotrophic factor. ADHD symptoms were measured using Conners’ Adult ADHD Rating Scale and used both dichotomous (High ADHD symptoms (yes/no)) and continuous (Inattentive symptoms, Hyperactive/Impulsive symptoms, and the ADHD index).
Results
Regression analyses showed associations between High ADHD symptoms, Inattentive symptoms, the ADHD index and a higher cortisol awakening curve, between Hyperactive/Impulsive symptoms and less cortisol suppression after DST, and between Inattentive symptoms and a longer pre-ejection period. However, the associations with the cortisol awakening curve disappeared after adjustment for depressive and anxiety disorders. No associations were observed between ADHD symptoms and inflammatory markers or BDNF. ADHD symptoms did not interact with affective disorders in dysregulation of stress-related mechanisms.
Conclusion
Some associations were observed between ADHD symptoms, the HPA-axis, and the pre-ejection period, but these were mostly driven by depressive and anxiety disorders. This study found no evidence that ADHD symptomatology was associated with dysregulations in inflammatory markers and BDNF. Consequently, ADHD symptoms did not confer an added risk to the disturbances of stress-related mechanisms in an – already at-risk – population with affective disorders.

Depressive and anxiety disorders have shown to be associated to premature or advanced biological aging and consequently to adversely impact somatic health. Treatments with antidepressant medication or running therapy are both found to be effective for many but not all patients with mood and anxiety disorders. These interventions may, however, work through different pathophysiological mechanisms and could differ in their impact on biological aging and somatic health. This study protocol describes the design of an unique intervention study that examines whether both treatments are similarly effective in reducing or reversing biological aging (primary outcome), psychiatric status, metabolic stress and neurobiological indicators (secondary outcomes).

Background
Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive.
Methods
In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood.
Results
Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems’ activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β = .088, p =  .007; AUCi, β = .084, p =  .010), cumulative HPA-axis markers (β = .115, p =  .001), C-reactive protein (β = .055, p = .032), interleukin-6 (β = .053, p =  .038), cumulative inflammation (β = .060, p =  .020), and cumulative markers across all systems (β = .125, p =  .0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases.
Conclusion
While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health.