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Psychosomatic Medicine 68:408-413 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

The Effects of Effort-Reward Imbalance on Inflammatory and Cardiovascular Responses to Mental Stress

Mark Hamer, PhD, Emily Williams, MSc, MS, Raisa Vuonovirta, MSc, Pierluigi Giacobazzi, PhD, E. Leigh Gibson, PhD and Andrew Steptoe, DPhil

From the Psychobiology Group, Department of Epidemiology and Public Health, University College London, UK (M.H., E.W., P.G., A.S.); Institute of Cancer Research, Royal Marsden Hospital, London, UK (R.V.); School of Human and Life Sciences, Roehampton University, Surrey, UK (E.L.G.).

Address correspondence and reprint requests to Mark Hamer, PhD, Psychobiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. E-mail: m.hamer{at}ucl.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: We examined the influence of effort-reward imbalance, a stressful feature of the work environment, on cardiovascular and inflammatory responses to acute mental stress.

Methods: Ninety-two healthy men (mean age, 33.1 yeasr) in full-time employment were recruited. Effort-reward imbalance was measured using a self-administered questionnaire. Blood, for the analysis of C-reactive protein (CRP) and von Willebrand factor (vWF) antigen, was sampled at baseline and 10 minutes after two mental stress tasks, whereas cardiovascular activity was measured throughout.

Results: Plasma CRP and vWF were significantly elevated following the stress period, and cardiovascular activity was increased during and after both tasks (p < .001). Multiple linear regression analysis adjusted for age, body mass index, and baseline levels revealed that men with higher effort-reward imbalance demonstrated greater CRP and vWF responses to the stress tasks but blunted cardiovascular responses. Inflammatory and cardiovascular responses to stress appeared to be unrelated.

Conclusions: These findings suggest that the association between chronic work stress and cardiovascular disease risk may be mediated in part by heightened acute inflammatory responsivity. These responses appear not to result from differences in sympathoadrenal activation.

Key Words: inflammatory response • acute mental stress • chronic work stress • C-reactive protein • Von Willebrand factor • cardiovascular disease risk

Abbreviations: ERI = effort-reward imbalance; CHD = coronary heart disease; IL = interleukin; CRP = C-reactive protein; vWF = von Willebrand factor; BMI = body mass index.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
There is substantial evidence that stress at work has damaging effects on health. Two models are commonly employed to define work stress, namely, the demand-control model (1) and the effort-reward imbalance (ERI) model (2). The ERI model provides a framework for understanding the process of coping under conditions of limited control and hypothesizes that a lack of reciprocity between costs and gains leads to a state of emotional distress. Thus, having a demanding but unstable job or achieving at a high level without any prospects of promotion are examples of ERI. A recent review of 45 empirical studies that examined the ERI model concluded that a combination of high effort and low reward was associated with poorer employee health (3). The association between ERI and poor health has been observed for physical health outcomes (mainly cardiovascular disease related), behavioral outcomes (sickness absence, smoking, and alcohol consumption), and psychological well-being (psychosomatic health symptoms and psychological well-being). For example, ERI has been associated with an increased risk of coronary heart disease (CHD) in prospective epidemiologic studies (4–6) and is a significant predictor of poor well-being and self-reported ill-health (7,8). Recent work has also focused on biological pathways that may mediate the relationship between work stress and cardiovascular risk, showing that ERI is associated with greater working day ambulatory blood pressure, heart rate, and lower vagal tone (9) and higher levels of LDL cholesterol and plasma fibrinogen (10).

Heightened cardiovascular responsivity to acute stress has been implicated in the development of cardiovascular diseases (11,12). The response to acute stress is thought to be dependent on individual traits and background exposure to chronic stress that is related to environmental features such as work stress. It is puzzling, therefore, that the one study to investigate acute reactivity found that high ERI was associated with blunted cardiovascular and neuroendocrine responses to a standard behavioral stress task (13). This finding was interpreted as a functional adaptation to excessive hypothalamic-pituitary-adrenal (HPA) and sympathetic stimulation (due to chronic work stress), which has been previously termed as the "inoculation effect" (14), but might also be regarded as a consequence of sustained allostatic load (15). The first aim of this study was to determine whether the inverse relationship between ERI and cardiovascular stress responsivity could be replicated.

There is increasing interest in the role of stress-induced inflammatory responses in relation to cardiovascular disease risk (16). For example, our group has recently demonstrated that interleukin (IL)-6 responses to an acute laboratory stress task are associated with an increase in ambulatory blood pressure in a 3-year prospective study (17). Stress-induced procoagulant changes have also been implicated in a biobehavioural pathway to CHD (18). However, little attention has been given to the effect of chronic work stress on inflammatory and procoagulant responses to acute stressors. We therefore examined the effect of ERI on stress-induced inflammatory responses. We measured two inflammatory markers, C-reactive protein (CRP) and von Willebrand factor (vWF). CRP is an acute-phase reactant synthesized in the liver and is consistently associated with future CHD (19,20). We have previously demonstrated that healthy middle-aged men and patients with documented coronary artery disease show stress-induced increases in CRP (21), and CRP responses have also been described in patients with rheumatoid arthritis (22). VWF is released from vascular endothelial cells and platelets and promotes thrombus formation by stimulating platelet aggregation and adherence to damaged vessel walls. It is consistently associated with future CHD (23) and also increases in response to acute psychological stress (18,24). We hypothesized that ERI would be positively associated with the magnitude of stress-induced CRP and vWF responses.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants
Ninety-two healthy, nonsmoking men who were all engaged in full-time employment were recruited. The study was conducted between February 2003 and September 2004. All participants gave full informed consent to participate in the study, and ethical approval was obtained from the UCLH committee on the Ethics of Human Research.

ERI
ERI was assessed with scales previously used in the Whitehall II prospective epidemiological study (4). Effort was assessed with five items (e.g., "Do you have to work very intensively?"), each of which was rated on a 4-point scale ranging from 0 (often) to 3 (never/almost never). Reward was assessed with seven items (e.g., "How satisfied are you with your usual take home pay"), with responses ranging from very dissatisfied to very satisfied. Mean scores on each component were computed and scaled from 0 to 100, with higher scores reflecting greater effort and greater rewards. ERI was calculated as effort divided by reward. A score of 1 represents a perfect balance of effort and rewards, with higher scores reflecting disproportionate effort.

Procedures
All testing was performed in the morning, in a quiet, air-conditioned room. At the beginning of the session, weight and height were recorded for the calculation of body mass index (BMI), and the first blood sample was drawn from the antecubital fossa. Participants then rested for 10 minutes while baseline blood pressure and heart rate were measured continuously using a Finapres instrument (TNO Biomedical Instrumentation, Amsterdam, The Netherlands). Following the baseline period, participants were required to complete two psychologically demanding tasks that have been regularly used in previous studies (24,25). The first was a 3-minute role-play speech task, where the participants were asked to respond to one of three stressful situations that included the threat of unemployment, a shoplifting accusation, and an incident in a nursing home involving a close relative. These role plays were randomly assigned to participants and during the speech task participants were instructed to speak into a video camera. The second task was 5 minutes of mirror tracing, involving the tracing of a star with a metal stylus, which could only be seen in a mirror image (Lafayette Instruments, Lafayette, IN). A loud beep was emitted by the apparatus each time the stylus came off the star to signal a mistake, and performance comparisons with peers were made in order to introduce an element of competition. Ratings of perceived stress and relaxation were obtained on a 7-point scale from 1 = low to 7 = high at baseline, following each task and on recovery. The second blood sample was drawn 10 minutes posttask, and recovery heart rate and blood pressure were then monitored for a further 5 minutes.

Blood Assays
Peripheral blood was collected in EDTA-coated tubes and spun at room temperature. Plasma blood samples were frozen at –80°C until assay. High-sensitivity (hs) CRP was determined using a high-sensitivity enzyme immunoassay kit (BioCheck, Inc., CA) that was performed in duplicate. Intra- and inter-assay variability of the assay was 4.1% and 2.5% respectively. vWF antigen was determined using a double-sandwiched antibody enzyme immunoassay (DakoCytomation Ltd., UK).

Statistical Analysis
Mean values for blood pressure and heart rate were computed for the last 5-minute of the baseline period, the stress tasks, and a 5-minute recovery period. Responses to tasks were analyzed with repeated-measures analysis of variance, using four levels (baseline, speech, mirror task, recovery), with post hoc comparisons using Tukey's HSD. Change (reactivity) scores were calculated by subtracting mean values during stress tasks from the baseline values. The majority of healthy individuals have circulating CRP values below 3 µg/ml (26), and values between 3 and 10 µg/ml or >10 µg/ml may represent ongoing low-grade inflammation or an acute inflammatory reaction to infection. Therefore, individuals with hsCRP values >3 µg/ml at baseline were identified as outliers and removed from the CRP analyses. hsCRP values were not normally distributed and a log transformation was performed. Analysis of hsCRP was conducted on 74 participants, whereas difficulties with blood sampling led to five individuals being dropped from the vWF analyses. Multiple linear regression analysis was used to examine relationships between ERI (predictor variable) and physiological function at rest and in response to tasks (dependent variable). Inflammatory factors, such as CRP and vWF, are strongly associated with BMI and age (27), so these factors were included as covariates in the regression models. Significant effects in these regression analyses were illustrated by dividing the sample into effort-reward tertiles.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Descriptive Statistics
The characteristics of the 92 participants are summarized in Table 1. It can be seen that the participants were aged 33.1 years on average, were predominantly white, married, and well educated. Efforts and rewards were well balanced on average, but ERI ranged widely from a minimum of 0.35 to maximum of 2.33.


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  		TABLE 1. Characteristics of the Sample (n = 92) (Mean ± SD)

 

Psychobiological Responses to Mental Stress
A main effect for time was observed with all three hemodynamic variables (systolic pressure F(3,270) = 320, p = .001; diastolic pressure F(3,270) = 328, p = .001; and heart rate F(3,270) = 158, p = .001). Further analysis, using Tukey's HSD, indicated that all hemodynamic variables increased in response to both stress tasks and blood pressure was still elevated during recovery in relation to baseline (see Table 2). There were also significant increases in hsCRP of 10.3% (t(1,73) = 3.5, p = .001) and vWF of 4.9% (t(1,86) = 2.8, p = .01) following the stress tasks. A main effect for time was also observed for both psychological variables (ratings of perceived stress F(3,273) = 102, p = .001 and relaxation F(3,273) = 116, p = .001). Subjective stress increased and relaxation fell during the tasks, returning to baseline levels in the recovery period.


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  		TABLE 2. Psychophysiological Responses to Mental Stress Tasks (Mean ± SEM)

 

Psychobiological Responses in Relation to ERI
The relationship between ERI and biological measures at rest and in response to laboratory stress is summarized in Table 3. There were no relationships between ERI and baseline levels of blood pressure, heart rate, hsCRP, or vWF. Stress reactivity in systolic pressure, diastolic pressure, and heart rate was inversely associated with ERI. Thus, larger cardiovascular stress responses were recorded in participants with lower ERI after controlling for age, BMI, and baseline levels of cardiovascular function. This inverse relationship is illustrated for systolic pressure and heart rate in Figure 1. It can be seen that participants in the highest ERI tertile showed markedly reduced systolic pressure responses, while these were greater in the lowest ERI tertiles.


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  		TABLE 3. Relationship Between Effort-Reward Imbalance and Biological Stress Responses

 

Figure 19
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  		Figure 1. The effect of effort-reward imbalance on systolic pressure (upper panel) and heart rate (lower panel) responses to speech and mirror tracing (MT) stressors.

 

The reverse pattern was observed for the markers of inflammation. In this case, there was a positive association between ERI and the stress-induced increase in hsCRP (p = .046) and vWF (p = .043) after adjusting for age, BMI, and baseline levels. Figure 2 illustrates these effects, showing greater hsCRP and vWF responses with increasing tertiles of ERI. The stress-induced increase in hsCRP adjusted for covariates was more than five times greater in the high compared with low ERI tertile.


Figure 29
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  		Figure 2. The effect of effort-reward imbalance on C-reactive protein and von Willebrand factor responses to mental stress. Values are mean ± SEM adjusted for age, BMI, and baseline levels.

 

We further examined the relationship between the two components of ERI and biological stress responses in order to discover if the effect of ERI was due to effort or reward alone. There were no significant associations between either effort or reward in isolation and any biological measure. Two effects approached significance, namely, the relationships between job effort and systolic (p = .053) and diastolic blood pressure (p = .051) responses to stress, after adjusting for age, BMI, and baseline levels. However, these effects were weaker than were the associations with the combined ERI measure.

We tested the relationship between cardiovascular and inflammatory stress responses using product-moment correlations. There was no relationship between hsCRP responses and either baseline or stress responses in systolic pressure or heart rate. There was a negative association between diastolic pressure and hsCRP responses that approached significance (r = –0.21, p = .073). However, when diastolic pressure stress responsivity was included in the model predicting hsCRP responses, the association with ERI remained significant (p = .033). Stress-induced changes in vWF were not related to stress-related blood pressure or heart rate changes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The aim of the present study was to investigate the impact of ERI on inflammatory and cardiovascular responses to mental stress. The present findings corroborate previous research that has demonstrated ERI is associated with blunted cardiovascular responses to mental stress (13). The results are not consistent with the hypothesis that chronic work stress promotes heightened cardiovascular reactivity to acute stress. The literature relating background stress levels with acute responses is mixed, with recent life events being associated with both increased (28) and reduced (29) cardiovascular responses. Gump and Matthews (30) reviewed the evidence for the influence of background life stressors on stress reactivity and found that six studies reported a positive association between ongoing stressors and reactivity, whereas four reported a negative association. Our group previously found that chronic work stress conceptualized with the demand-control model predicted increased blood pressure responses to uncontrollable tasks (31). ERI evidently has the reverse effect, so would appear to operate through different pathways. Siegrist et al. (13) have suggested that heightened reactivity in the early stages of exposure is followed by attenuated reactivity with chronic exposure, although this pattern does not appear to apply to the inflammatory responses studied here. Nevertheless, others have also shown divergent patterns across different indices of reactivity, for example, greater daily hassles, were associated with greater immune reactivity but not cardiovascular reactivity (32).

It is therefore possible that the impact of ERI on cardiovascular risk is mediated partly through inflammatory processes. If these responses are typical of patterns present in everyday life, then people experiencing high ERI will show repeated enhancement of vascular inflammatory pathways that could accelerate the development of cardiovascular disease. Little is known about the consistency of individual differences in inflammatory stress responses, although recent studies have shown a lack of habituation in IL-6 and vWF responses to repeated testing (33,34), suggesting that they may be stable characteristics of the individual. The precise mechanisms by which acute stress may alter proinflammatory activity is unclear, although mental stress up-regulates nuclear factor-{kappa}B (35) and IL-1ß gene expression (36), both of which are important pathways in the production of a number of inflammatory proteins.

Previously, it has been found that acute increases in vWF can be stimulated by sympathetic nervous system activation (37). The lack of an association between cardiovascular activation and inflammatory responses in this study suggests that the relationship between ERI and heightened inflammatory response was not mediated by sympathoadrenal pathways but through other mechanisms. Previous research has demonstrated a link between ERI and blunted neuroendocrine responses to mental stress (13), and this may be relevant to proinflammatory responses. Kunz-Ebrecht et al. (38) demonstrated that plasma IL-6 and IL-1ra responses to mental stress were higher in a cortisol nonresponder group compared with responders. Also, among chronically stressed parents of cancer patients, the suppression of IL-6 production by dexamethasone was significantly reduced compared with parents of healthy children (39). This evidence therefore suggests that glucocorticoid resistance and lower neuroendocrine activation may impair the response of the immune system to anti-inflammatory signals.

An increased level of vWF in response to mental stress has been demonstrated in previous studies (18,24). However, this is the first study to our knowledge that has demonstrated an acute increase in circulating CRP immediately following a period of mental stress in healthy individuals. Veldhuijzen van Zanten et al. (22) recently demonstrated that acute mental combined with postural stress increased circulating CRP in rheumatoid arthritis patients with high disease activity but not in patients of lower disease status with lower baseline CRP. Previous work in our laboratory has demonstrated small increases (4.3%) in CRP 2 hours following two behavioral stress tasks in a sample of healthy men and CAD patients, although no measures were taken immediately after the stress period (21).

The rise in plasma levels of CRP in humans after an acute inflammatory stimulus is thought to reflect increased synthesis by hepatocytes. Induction of CRP in hepatocytes is principally regulated at the transcriptional level by the cytokine IL-6 and may be enhanced by IL-1ß (40). However, given that previous studies have demonstrated a delayed rise in IL-6 following stress (41,42), it is unlikely that the acute release of CRP observed in the present study is via a hepatic pathway. Another possible explanation for the acute release of CRP is via extrahepatic synthesis. For example, CRP is also known to be synthesized in smooth muscle cells within human coronary arteries (43), neurons, atherosclerotic plaques, lymphocytes, and monocytes (44,45), although the mechanisms regulating synthesis at these sites is largely unknown. The acute stress-induced rise in vWF is consistent with the evidence that mental stress is associated with transient endothelial dysfunction and platelet activation (46).

There is considerable debate as to whether CRP is purely a marker of CHD or if it plays a causal role in the etiology of disease (47). In vitro evidence has demonstrated direct prothrombotic and inflammatory effects of CRP (48–50). Recent in vivo data from humans have demonstrated similar effects (51), although questions have been raised suggesting that endotoxin contamination and not CRP itself is responsible for these findings. Furthermore, evidence from Mendelian randomization epidemiologic studies does not support a causative role of CRP (52), whereas transgenic studies of overexpression of human CRP have demonstrated no influence on the development of atherosclerosis in mice (53). Therefore, whether or not repeated stress-induced increases in CRP are clinically significant in themselves or are merely markers of inflammatory responses remains to be seen. In contrast, because vWF promotes thrombus formation by stimulating platelet aggregation and adherence of platelets to damaged vessel walls (54–56), it may have more direct significance to long-term health outcomes.

The limitations of this study should be recognized. We investigated a sample of healthy, nonsmoking, predominantly white men, so do not know whether findings would generalize to women, ethnic minorities, or to individuals who smoke. A nonstress control group was not employed in the present study, and therefore we cannot categorically state that the observed changes in CRP and vWF were as a result of the mental stress tasks. However, we have previously observed no significant changes in plasma CRP with repeated blood sampling over a 2-hour resting period (41).

In summary, our results show that in healthy men ERI was associated with a higher stress-induced inflammatory response but blunted cardiovascular activation during acute mental stress. These findings may help provide a link between work stress and CHD risk, and future research should aim to examine the mechanisms that mediate the relationship between chronic work stress and heightened inflammatory responses.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

This research was supported by the Biotechnology and Biological Sciences Research Council, Unilever Research, and by the British Heart Foundation. We are grateful to Bev Murray and Kesson Magid for their participation in data collection and data processing.

DOI:10.1097/01.psy.0000221227.02975.a0


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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M. Hamer, G. J. Molloy, and E. Stamatakis
Psychological distress as a risk factor for cardiovascular events: pathophysiological and behavioral mechanisms.
J. Am. Coll. Cardiol., December 16, 2008; 52(25): 2156 - 2162.
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