Published online before print April 24, 2008, doi: 10.1161/ATVBAHA.108.167239
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Do Psychological Factors Affect Inflammation and Incident Coronary Heart Disease
The Whitehall II Study
From the Department of Epidemiology and Public Health (H.N., A.S.-M., M.S., D.G., M.G.M., M.K.), University College London, United Kingdom; INSERM U687-IFR69 (H.N., A.S.-M.), Hôpital Paul Brousse, Villejuif Cedex, France; Hôpital Ste Périne (A.S.-M.), Centre de Gérontologie, Paris, France; Finnish Institute of Occupational Health (M.K.), Helsinki, Finland.
Correspondence to Hermann Nabi Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. E-mail H.Nabi{at}public-health.ucl.ac.uk
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Abstract |
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Objectives— The purpose of this study was to test whether psychological factors affect inflammation processes to an extent that increases the risk of coronary heart disease (CHD).
Methods and Results— We used data from 6396 civil servants (4453 men, 1943 women) from the Whitehall II Study, aged 35 to 55 years and free from clinically validated CHD at the start of the follow-up period. Two psychological factors were assessed at phase 1 (1985 to 1988) and phase 2 (1989 to 1990): negative affect and psychological distress. Inflammatory biomarkers (fibrinogen, high-sensitivity C-reactive- protein, interleukin-6) and 12 baseline covariates including biological and behavioral CHD risk factors, sociodemographic variables, and work stress were measured at phase 3 (1991 to 1993). Follow-up for CHD death, first nonfatal myocardial infarction, or definite angina occurring between phase 3 and phase 7 (2003 to 2004) was based on clinical records. Higher levels of inflammatory markers were associated with higher CHD incidence, with hazard ratios (HR) ranging from 1.31 to 2.37 in age-and sex-adjusted models. Higher levels of negative affectivity and psychological distress were not associated with greater concentrations of inflammatory markers. Negative affectivity (relative index of inequality=1.68, 95% confidence interval [CI] 1.20 to 2.36) and higher psychological distress exposure (HR=1.66, 95% CI 1.28 to 2.14) were associated with higher CHD incidence and these associations remained unchanged after adjustment for inflammatory markers.
Conclusions— Our findings suggest that psychological factors do not affect inflammation although they predict incident CHD.
Key Words: inflammation • psychological factors • coronary heart disease
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Introduction |
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The relationship between psychological factors and coronary heart disease has been studied extensively over the last 30 years.1,2 Although several studies have shown psychological factors to play a role in the development and prognosis of CHD outcomes,1–7 the mechanisms underpinning this association remain poorly understood. Recently, inflammatory markers have been posited as candidate pathophysiological mechanisms through which psychological factors influence CHD outcomes.8,9
Several inflammatory markers are associated with CHD risk. C-reactive protein (CRP), a robust nonspecific marker of systemic inflammation, has been found to predict future coronary events in asymptomatic populations.10 Similarly, circulating interleukin (IL)-6 levels, which are elevated in patients with acute coronary syndromes, predict future coronary events.11 In the nested case-referent PRIME study, plasma inflammatory markers including CRP, IL-6, and fibrinogen were associated with fatal/nonfatal CHD events.12
Prior literature provides some support for the associations between psychological factors and these inflammation markers. For example, clinical depression,8,9,13 vital exhaustion,14 irrational beliefs,15 cynical distrust, chronic stress,9 anger, hostility, and depressive symptoms16 were found to be associated with higher levels of inflammatory markers in some studies, although other studies reported null findings.14,17,18 There is also emerging evidence to suggest that positive affect may be associated with reduced levels of inflammatory markers.19 However, all these prior studies were cross-sectional. At least 3 studies examined the contribution of inflammatory markers to the associations between psychological factors and CHD but the results of these studies13,20,21 were mixed.
This paper uses prospective data from the Whitehall II Study, an occupational cohort study of middle-aged civil servants, to test the inflammation hypothesis by exploring the associations between psychological factors, inflammatory markers, and incident CHD.
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Methods |
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The Whitehall II Study was established in 1985 as a longitudinal study to examine the socioeconomic gradient in health and disease. Phase 1 took place during 1985 to 1988, and involved a clinical examination and a self-administered questionnaire among 10 308 (73%) civil servants (6895 men and 3413 women),22 aged 35 to 55 years at baseline, from 20 London based departments.
Measures
The psychological factors considered in this study are negative affect (NA) and psychological distress.
NA refers to "stable and pervasive individual differences in mood and self-concept characterized by a general disposition to experience a variety of aversive emotional states (distress, discomfort, hopelessness, anger, anxiety, etc).23 NA was assessed at phases 1 and 2 using the Bradburn Affect Balance Scale,24 a widely used measure of psychological well-being. The ABS consists of 10 items, among which 5 are used to assess NA (Cronbach 
=0.67). All items are formulated in general terms, asking the participant’s feelings during the last few weeks. The items are phrased to elicit responses of the pleasurable or unpleasurable character of an experience instead of the context of the experience. Responses are on a 4-point Likert scale from 0 (=not at all) to 3 (=a great deal). Scores for NA subscale range from 0 to 15, with higher score indicating higher NA. For each participant, we averaged the scores of the 5 items at phases 1 and 2 and for those with missing values at one phase we used information from only 1 phase.
Psychological distress was assessed at phases 1 and 2 with the General Health Questionnaire 30 (GHQ-30; Cronbach =0.93), a well-established screening questionnaire for minor psychiatric ill-health, suitable for population studies.25 Scores 
5 were used to define "caseness" for psychological distress; this criterion has been validated in the Whitehall II Study.26 The accumulation of exposure to psychological distress over the 2 measurement periods (phases 1 and 2) was assessed by adding together the number of times the participant was exposed. Three groups of cumulative exposure to psychological distress were then created: no exposure, exposure at 1 phase, exposure at both phases.
Inflammatory markers were assessed at phase 3 (1991 to 1993). Blood samples were collected after either an 8-hour fast (participants presenting to the clinic in the morning) or at least 4 hours after a light fat-free breakfast (participants presenting in the afternoon) and stored at –70°C until analysis. Fibrinogen was measured by an automated Clauss assay in a MDA-180 coagulator (Organon Teknika) using the manufacturer’s reagents and the International Fibrinogen Standard.17 CRP was measured using a high-sensitivity immunonephelometric assay in a BN ProSpec nephelometer (Dade BehringUK). IL-6 was measured using a high-sensitivity ELISA, 2-site, enzyme-linked immunosorbent assay (R & D Systems). To measure short-term biological variation and laboratory error, a repeat sample was taken from a subset of 150 participants for CRP and 241 for IL-6 (average elapsed time between samples was 32 [SD=10.5] days). Intra- and interassay coefficients of variation were 4.7% for CRP and 7.5% for IL-6. Test-retest reliability between samples, assessed with Pearson’s r correlation coefficients, was satisfactory, r=0.77 for CRP and r=0.61 for IL-6.
CHD incidence was assessed from phase 3 (1991 to 1993) to phase 7 (2003 to 2004), a mean follow-up of 11.1 years (SD=2.8). CHD included fatal CHD (defined by the International Classification of Diseases [ICD] 9 codes 410 to 414 or ICD 10 codes I20 to 25), first nonfatal myocardial infarction (MI), or first "definite" angina. Fatal CHD was assessed by flagging participants at the National Health Service Central Registry, which provided information on the date and cause of death. Potential nonfatal MI was ascertained by questionnaire items on chest pain (the World Health Organization Rose questionnaire27) and the physician’s diagnosis of heart attack. Confirmation of MI according to MONICA criteria (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease)28 was based on electrocardiograms, markers of myocardial necrosis, and chest pain history from the medical records. Angina was assessed based on participant’s reports of symptoms with corroboration in medical records or abnormalities on a resting ECG, an exercise ECG, or a coronary angiogram.
Covariates
Sociodemographic measures included age and sex from the phase 1 questionnaire. Observer-assigned ethnicity from phase 1 was used where self-reported ethnicity from Phase 5 was missing. Socioeconomic position (SEP) was assessed by British civil service grade of employment at phase 1.
Conventional risk factors for CHD assessed at phase 1 included smoking status (never, ex, and current), hypertension (systolic and diastolic blood pressure >140/90 mm Hg, or treatment for hypertension), blood cholesterol (6.2 mmol/L), exercise (1.5 or <1.5 hours of moderate or vigorous exercise/wk), daily fruit and vegetable intake (yes/no), alcohol consumption in units of alcohol consumed per week (low=<22 for men and <15 for women, moderate=22 to 51 for men and 15 to 35 for women, or high=>51 for men and >35 for women), body mass index (BMI) (<18.5, 18.5 to 24.9, 25 to 29.9, or 30 kg/m2), and self-reported diabetes. For behavioral risk factors, missing values at phase 1 were replaced by information at phase 2.
Psychosocial stress at work measured at phases 1 and 2, using the self-administrated job strain model questionnaire29 including scales of psychological job demands, decision latitude, and social support at work. Three groups of exposure to iso-strain30 were then created: no exposure, exposure at 1 phase, exposure at both phases.
Statistical Analyses
For all analyses, inflammatory marker concentrations were logarithmically transformed as their distribution was skewed. NA scores were standardized using the fractional rank procedure. It is computed by ranking the NA measure on a scale from the lowest, which is 0, to the highest, which is 1. Each participant is given a score on the scale equal to the cumulative midpoint of the number of participants who had the same NA score.
Differences in NA scores and inflammatory markers concentrations and differences in exposure to psychological distress as a function of covariates were assessed using 1-way ANOVA and a 
2 test, respectively.
The relationships between psychological factors (NA and psychological distress) at phases 1 and 2 and levels of inflammatory markers at phase 3 were modeled using linear regression stratified by sex and age groups. Linear regression coefficients using standardized values for inflammatory markers were calculated for 1 standard deviation increase in the standardized NA score and for a unit increase in the cumulative exposure to psychological distress. In the first model coefficients stratified by sex and age groups were adjusted for the exact time between phase 2 and 3 for each participant and for ethnicity because ethnicity is known to influence the distribution of the inflammatory markers.31 In the second model, statistically significant coefficients (P<0.05) in model 1 were additionally adjusted for SEP, psychological stress at work, smoking, alcohol consumption, exercise, daily fruit and vegetable intake, hypertension, BMI, and cholesterol.
The relationship between inflammatory markers and CHD incidence was assessed using 5 serially adjusted Cox regression models. Initial adjustment was made for sex and age. Subsequent models additionally adjusted for ethnicity and employment grade, conventional CHD risk factors, and psychosocial stress at work.
The relationship between psychological factors (NA and psychological distress) and incident CHD was modeled using the relative index of inequality (RII) for NA and hazard ratio (HR) for psychological distress in Cox regression analysis. The RII is a regression-based measure that summarizes the association between 2 variables.32 Here the RII is modeled using the ranked NA scores. The RII is the hazard ratio for CHD comparing the extremes of NA distribution, but it is estimated using the data on all scores and is weighted to account for the distribution of NA scores. An RII of 2 for instance indicates a doubling of the hazard of CHD for individuals with the highest NA scores compared to those with the lowest scores.
Finally, mediated effects of inflammation (psychological factors
inflammationCHD) were tested by examining whether the following 4 criteria were met. First, psychological factors should be associated with inflammatory markers (potential mediator). Second, the potential mediator should predict incident CHD. Third, psychological factors should predict CHD and finally, this association should be significantly attenuated after adjustment for the inflammatory markers. Failure to meet all these criteria suggests that the effects on inflammation do not explain the association between psychological factors and CHD.
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Results |
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Of the 8608 participants with no history of clinically validated CHD at phase 3, 100% and 99.8% had the NA and the GHQ-30 scores, respectively. Fibrinogen, CRP, and IL-6 data were available for a total of 6856 (79.6%), 6938 (80.6%), and 6892 (80.1%) participants, respectively. Among the 6396 participants with complete data on these markers and all covariates, 435 first CHD events were documented between phases 3 and 7. The participants excluded were more likely to be female, older, and to be in the lowest employment grade and nonwhite (P<0.001).
As shown in Tables 1 and 2
, sex, age, and several behavioral risk factors were associated with higher scores of both NA and exposure to psychological distress; similar factors were associated with higher concentrations of fibrinogen, CRP and IL-6.
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Table 3 shows the associations between psychological factors and inflammatory markers. In analyses stratified by age groups and sex and adjusted for ethnicity and the exact time between phase 2 and phase 3 (Model 1), only 2 of the 48 associations were statistically significant, ie, higher NA and psychological distress exposure were associated with reduced concentration of IL-6 in women aged 50 to 54 (β=–0.118, P=0.01) and in women aged 55 to 64 (β=–0.010, P=0.03), respectively. Only the former association remained after further adjustment for potential confounding variables (Model 2), in contrast to the inflammation hypothesis predicting that higher NA is related to higher inflammation levels.
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As expected all inflammatory markers were associated with higher incidence of CHD (Table 4). Table 5 shows that higher NA (RII=1.68, 95% CI 1.20 to 2.36) and exposure to psychological distress twice (HR=1.66, 95% CI 1.28 to 2.14) were associated with higher CHD incidence in age-sex-ethnicity-adjusted models. These associations persisted after additional adjustment for other potential confounding factors and were little affected by adjustment for inflammatory factors. Thus, the criteria for mediated effects were not met.
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Sensitivity Analysis
Data on psychological distress (but not on negative affect) were also available at phase 3. To further explore the association of exposure to psychological distress overtime and inflammatory biomarkers, we performed additional analyses stratified by sex and age groups. In these analyses, exposure to psychological distress was from phase 1 to phase 3 (ie, the phase at which the inflammatory markers were assessed). Four groups of cumulative exposure to psychological distress were then created: no exposure, exposure at 1 phase, exposure at 2 phases, and exposure at 3 phases. As shown in Table 6, there is no strong evidence for an association between exposure to psychological distress overtime (phases 1 to 3) and higher levels of inflammatory markers. These results are broadly consistent with the main analysis.
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Discussion |
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In this study of a well-characterized occupational cohort, negative affectivity, psychological distress, and all inflammatory markers predicted incident CHD, but there was no evidence of an association between these psychological factors and increased levels of inflammation. This suggests that inflammatory biomarkers are unlikely to be an important mediator for the associations observed between psychological factors and CHD.
Association Between Psychological Factors and Inflammatory Markers
The lack of association between psychological factors and greater concentrations of inflammatory markers is in line with several prior studies.14,17,33 A recent meta-analysis34 of 6 large scale studies conducted in the general population on depression and CRP concluded that the evidence for this relationship is weak. Our results show some unexpected associations between higher NA and reduced IL-6 concentration in women as in a recent study18 conducted in a sample of 984 outpatients with stable CHD. In that study, mean levels of CRP, fibrinogen, and IL-6 appeared to be lower rather than higher in depressed participants.
Some prior studies have suggested that psychological factors, particularly depression, are associated with greater inflammation concentrations.8,9,13–16,35 However, all these studies are cross-sectional, making it impossible to determine the temporal sequence between these factors and inflammatory processes. Furthermore, the causal direction between psychological factors and inflammatory markers remains unclear as previous research also suggests that circulating IL-6 levels, for example, can produce symptoms of depression, anorexia, weight loss, malaise, anhedonia, and sleep disturbances.36,37 In our study psychological factors were assessed before the inflammatory markers, allowing a more accurate test for the mediation hypothesis. We were able to assess the association between cumulative exposure to psychological distress over time and inflammatory markers measured at the end of the exposure period. Here again, we found no evidence for an association between greater exposure to psychological distress and greater inflammation concentrations. Thus, our results suggest that psychological factors, measured concurrently or before the measurement of inflammation, have no robust association with the inflammatory markers examined.
We were also able to assess, within the same study, 2 major psychological factors, 1 a psychological trait (negative affectivity) and the other a psychological state (psychological distress) in relation to 3 important inflammatory markers. The lack of consistent association between these psychological factors and increased inflammatory markers concentrations suggests that the observed results were unlikely to be attributable to chance. The large sample size of our well-characterized cohort followed more than 12 years allowed us to control for relevant potential confounders.
Inflammatory Markers as Mediators of the Associations Between Psychological Factors and CHD
Few prior studies have tested the mediating role of inflammatory markers in the association between psychological factors and CHD. In a nested case-referent study13 of 889 (304 cases and 585 controls) middle-aged men from Belfast and France, inflammatory markers were positively associated with depressive mood and both were associated with CHD. The association between depressive mood and CHD remained unchanged after adjustment for inflammatory markers, suggesting that inflammatory markers are unlikely mediators of this association. In another study21 conducted in women with suspected coronary ischemia, inflammation was independently correlated with depression; however, it played a minor role in modulating the association between depression and cardiovascular events. In both studies, it was not possible to judge whether depressive mood preceded or was the consequence of higher inflammation as the relationships were cross-sectional. In a case-control study among 47 cases and 22 controls hospitalized for depression20 adjustment for inflammatory markers showed a moderate influence on the association between depression and CHD, suggesting that inflammation partly explained the association. However, inflammatory markers were measured 3 months after the first acute myocardial infarction which might have influenced their levels. In addition, only 17 to 20 cases and 11 to 13 controls had full data on inflammatory markers, and therefore the authors could have found the mediation pattern by chance.
Study Limitations
The present findings should be considered within the context of the study limitations. First, our cohort of civil servants did not include blue-collar workers and unemployed individuals and is thus not representative of the general population, which may limit the generalizability of our findings. Secondly, we used inflammatory markers assessed at 1 point in time at phase 3 and did not examine the effects of change in their levels. However, there is evidence to suggest that levels of these inflammatory markers are relatively stable over extended period.38 Longitudinal studies have found that levels of CRP were stable over time,39,40 when measurements were not made in a short period (2 to 3 weeks) after an infection.
Conclusion
Our prospective study suggests that major inflammatory markers, such as proinflammatory cytokines (IL-6) and acute phase reactants (CRP and fibrinogen), do not mediate the association between psychological factors, measured by negative affect and psychological distress, and CHD incidence in a large cohort of men and women initially free of diagnosed CHD. The inflammation hypothesis is not supported principally because of the lack of an association between psychological factors and inflammatory markers. The importance of our null finding is that it eliminates a strong candidate mechanism for the association between psychological factors and CHD. However, because results from any single epidemiological study may not provide conclusive evidence, additional prospective studies in other populations and with other psychological factors should be done.
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Acknowledgments |
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Sources of Funding
H.N. and M.K. are supported by the Academy of Finland (grant 117604). A.S.-M. is supported by a European Young Investigator Award from the European Science Foundation. M.M. is supported by an MRC Research Professorship. M.J.S. is supported by the British Heart Foundation. The Whitehall II study is supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging, US, NIH; Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. The funding agencies played no role in the design, conduct, data management, analysis, or manuscript preparation related to this article. H.N. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Disclosures
None.
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Footnotes |
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Original received February 11, 2008; final version accepted April 12, 2008.
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