Psychological distress as a risk factor for coronary heart disease in the Whitehall II Study

Transcription

1 International Epidemiological Association 2002 Printed in Great Britain International Journal of Epidemiology 2002;31: Psychological distress as a risk factor for coronary heart disease in the Whitehall II Study Stephen A Stansfeld, a,b Rebecca Fuhrer, b Martin J Shipley b and Michael G Marmot b Background Psychiatric disorder and psychological distress are increasingly recognized as risk factors for coronary heart disease (CHD). Elucidation of the mechanisms of these associations has implications for prevention. This study aims to confirm the association between psychological distress and CHD and examine if it could be explained by other factors such as health behaviours, social isolation and low control at work. Methods A prospective occupational cohort study of London-based civil service employees (Whitehall II Study) with baseline data collected from with a 5-year follow-up. The participants were male and female middle-aged civil servants working in 20 Government Departments; 73% of eligible employees attended baseline screening. Psychological distress measured by the General Health Questionnaire (GHQ) at baseline was used to predict incidence of self-reported CHD and possible and probable electrocardiographic (ECG) abnormalities during follow-up. Results In men, baseline psychological distress was associated with an increased incidence of overall self-reported CHD (odds ratios [OR] = 1.83, 95% CI : ) and ECG abnormalities (OR = 1.51, 95% CI : ), after adjustment for age, employment grade and length of follow-up. In women, baseline psychological distress was also associated with an increased incidence of CHD (OR = 1.60, 95% CI : ), but not with ECG abnormalities. Adjustment for health behaviours, marital status, social networks and work characteristics reduced the risks for incident CHD by 12% in men and by 10% in women; for ECG abnormalities these adjustments increased the risk in men by 16% and had little effect in women. Conclusions The experience of psychological distress confers increased risk of CHD in men that is not explained by health behaviours, social isolation or work characteristics. The increased risk of CHD associated with psychological distress is not consistently demonstrated in women. Keywords Depression, anxiety disorders, coronary disease, epidemiology Accepted 9 August 2001 Psychological distress, particularly depression, is being increasingly recognized as a risk factor for incident coronary heart disease (CHD). 1 7 Depression is also associated with increased mortality risk following myocardial infarction. 8,9 Its emergence as a major CHD risk factor has been relatively recent although a Barts and the London, Queen Mary s School of Medicine and Dentistry, University of London, London, UK. b International Centre for Health and Society, Department of Epidemiology and Public Health, University College London Medical School, London, UK. Correspondence: Professor SA Stansfeld, Department of Psychiatry, Barts and the London, Queen Mary s School of Medicine and Dentistry, 3rd Floor, BMS Building, Mile End Road, London E1 4NS, UK. S.A.Stansfeld@qmw.ac.uk for some time it has been recognized as a background risk factor, 10 among a cluster of other psychosocial factors with a negative connotation, namely hostility, low control at work, negative life events and social isolation. 11 There has been little work exploring how these psychosocial factors might relate to the association between psychological distress and CHD risk. There are several potential pathways for the effect of psychological distress on CHD. First, psychological distress may be indirectly associated with CHD through associations with the adoption of unhealthy behaviours such as smoking, eating fatty foods or drinking alcohol excessively, or lack of exercise, 12 which in themselves increase the risk of CHD. Second, social 248

2 DISTRESS AND HEART DISEASE 249 isolation may be a behavioural consequence of psychological distress, and an intervening factor between psychological distress and CHD. 13 Third, psychological distress may be an outcome of exposure to situations of low perceived control both at work and home, associated with lower socioeconomic status. Thus, if low control at work predisposes to CHD, 14 psychological distress may either be an intervening factor on the pathway to CHD or an index of low control or low socioeconomic position related directly to CHD risk. Fourth, psychological distress may have a direct effect on CHD independent of these other behavioural and psychosocial factors, mediated either by neurohumoral activation related to catecholamine secretion or hypothalamic pituitary-adrenal axis activation and secondary metabolic disturbance. These negative mood states and environmental conditions might all act through a single pathway or these factors might have independent effects on CHD risk. This paper uses data from a prospective occupational cohort study, the Whitehall II Study, of middle-aged civil servants to test whether the increased CHD risk associated with psychological distress can be explained by health-related behaviours and psychosocial factors: social isolation and low control at work. Our prior hypothesis was that psychological distress, independently of other negatively-connoted risk factors, would be associated prospectively with increased CHD risk. Psychological distress measured by the General Health Questionnaire (GHQ) at Phase 1 ( ), was used to predict the incidence of CHD over a 5-year period. Method Sample The Whitehall II Study was set up in 1985 to investigate the causes of the social gradient in morbidity and mortality and included work characteristics and social networks as potential explanations of this gradient. All male and female civil servants, aged between 35 and 55 years in 20 London-based civil service departments were invited to a screening examination, including measurement of blood pressure, an electrocardiogram (ECG) and a blood sample (Phase 1: ). The overall response rate was 73% (74% for men and 71% for women). The true response rates are likely to be higher as around 4% of those on the list of employees moved before the study and thus were ineligible for inclusion. Altogether civil servants were examined at baseline 6895 men (67%) and 3413 women (33%). A postal questionnaire was carried out in 1989 (Phase 2) and the participants had a further screening examination (Phase 3: ). The length of follow-up between Phase 1 and Phase 3 was 5.3 years on average (range ). Data on psychosocial factors, health behaviours and medical history were collected by self-report questionnaire at all three phases. Details of the screening examination are reported elsewhere. 15 Of the participants at baseline, had data on psychological distress at baseline. Of these, 582 men and 313 women had self-reported CHD at baseline and were excluded. Of the 9294 participants, a further 139 were excluded because of missing CHD data at Phase 1. Participants were only included if they had complete CHD data at Phase 2 and Phase 3. Thus 2383 participants (1516 men and 867 women) did not complete questionnaires for either Phase 2 or 3 and 199 had uninterpretable data and were also excluded. The remaining 6573 participants (4538 men, 2035 women) were free of CHD at baseline and had incident self-reported CHD status available at Phase 2 or Phase 3. Similarly, 414 men and 239 women had an abnormal ECG data at baseline and were excluded. There were 7503 participants (5238 men and 2265 women) with baseline psychological distress measures who had a normal ECG reading at baseline and on whom incident ECG data were available; the number of participants available with complete data on covariates was 6269 (4374 men, 1895 women) for incident CHD analyses and 7081 (5040 men, 2041 women) for the incident ECG analyses. Employment grade The Civil Service identifies 12 non-industrial grades on the basis of salary. There is a steep increment in salaries from an annual salary in 1987 of between in the clerical and office support grades to between the unified grades 1 6. Besides the steep increment in salaries there were also marked differences in socioeconomic indicators (education, housing tenure, car ownership and father s occupation) by grade of employment. 15 Psychological distress Psychological distress was measured at each of the three phases by the 30-item GHQ 16 which was validated against the Clinical Interview in a sub-sample. 17 A threshold of 4/5 on the GHQ was chosen on the basis of receiver operating characteristic analysis. At this threshold the sensitivity of the GHQ was 73% and specificity was 78% against the Clinical Interview Schedule. The GHQ is a well-established screening questionnaire for nonpsychotic psychological distress, largely depression, suitable for use in general population studies. All those scoring 0 4 on the GHQ at Phase 1 were considered non-cases and those scoring 5+ were considered cases. Coronary heart disease and risk factors Three self-reported indicators of CHD were combined into a single measure of self-reported incident CHD: angina pectoris, severe pain across the chest that lasted half an hour or more from the London School of Hygiene Chest Pain Questionnaire, 18 and doctor-diagnosed ischaemia (i.e. a participant s report that a doctor had diagnosed or suspected a heart attack or angina pectoris). To be included as a new case, a participant had to have been free of disease at Phase 1, but to respond positively to one or more of the categories at Phase 2 or Phase 3. A separate measure of ECG abnormalities (i.e. incident ECG abnormalities) at Phase 3 was used as an objective indicator of new CHD. Incident ECG abnormalities included the presence of Q waves with Minnesota codes 1 1 to 1 2 (probable ischaemia); any Q wave with codes 1 1 to 1 3, S-T or T waves (codes 4 1 to 4 4 or 5 1 to 5 3) or left bundle branch block (code 7 1 1) (possible ischaemia). For each of these outcomes, subjects who were positive at Phase 1 were excluded from analyses. Coronary risk factors Coronary risk factors and health-related behaviours were measured in standard ways: smoking status (never, former, current, pipe or cigars only [men only]), body-mass index (kg/m 2 ), and physical activity ( 1 h vigorous activity per week, 1 h vigorous activity but 1 h moderate activity per week, 1 h vigorous or moderate activity per week). Alcohol intake was

3 250 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY measured in units per week and subdivided into categories: none, 1 14, 15 21, 22+ units, with the highest two categories being combined in women. A healthy diet consisted of wholemeal, granary or wheatmeal bread, skimmed or semi-skimmed milk, and fresh fruits or vegetables at least once daily. An unhealthy diet consisted of other types of bread and milk and less frequent consumption of fresh fruit and vegetables. Eating habits were coded from 0 (unhealthy diet) to 3 (healthy diet). Psychosocial work characteristics Job control and psychological job demands based on two of the dimensions in Karasek s Job Content Instrument 19 were measured by a self-completion questionnaire at Phase 1. Fifteen items deal with decision authority and skill discretion and these were combined into an index of decision latitude. Social networks The social network measures were summarized by a scale that measured the network beyond the household; this includes both frequency of contact and number of contacts with friends and relatives and participation in social groups. 20 Statistical analysis The longitudinal relations between psychological distress and subsequent CHD incidence were examined using logistic regression. This allowed the effects of psychological distress (GHQ caseness) to be expressed as odds ratios (OR) with their 95% CI relative to non-cases. In all analyses we controlled for the confounding effects of age and employment grade and also included a term for each individual s length of follow-up between Phase 1 and Phase 3. In order to assess the confounding effects of other factors, we selected the subset of subjects without any missing values and fitted further models just on these subjects. The magnitude of the confounding effects was assessed by calculating the proportion of the excess risk (OR minus 1.0) explained when fitting these terms in the model. The associations of GHQ caseness and the other factors on CHD incidence among this subset of subjects were compared, where possible, with the associations among the subjects who had been excluded because of missing values. These two datasets showed similar associations for most of the factors. Results A quarter of men and nearly a third of women scored above the threshold on the GHQ at baseline and were considered possible cases of psychiatric disorder manifesting significant psychological distress (Table 1). These percentages only differed minimally when analyses were restricted to those with incident data. reported more incident CHD events at follow-up than men although ECG abnormalities were more common in men than women (Table 1). Psychological distress at Phase 1 was associated with increased risk of new reports of CHD at Phase 2 or Phase 3 in both men and women, adjusting for age, employment grade and length of follow-up (Table 2). General Health Questionnaire caseness at baseline increased the odds of CHD by 83% in men and 60% in women (Table 2). In men, GHQ caseness was also associated with the development of new possible and probable ECG abnormalities at Phase 3 (Table 2). This was not found in women, where, if anything, psychological distress at Phase 1 was associated with lower risk of ECG abnormalities at Phase 3. Table 1 Percentages (number of occurrences/number of subjects) of General Health Questionnaire (GHQ) caseness at baseline, self-reported incident coronary heart disease (CHD) and possible or probable incident electrocardiographic (ECG) abnormalities Outcomes Incident CHD at Phase 2 or Phase (400/4538) 12.4 (252/2035) Possible or probable incident ECG abnormalities at Phase (163/5238) 2.5 (57/2265) Phase 1 exposures GHQ caseness Cases all subjects 25.3 (1727/6838) 30.3 (1017/3351) Subjects with incident CHD data 24.5 (1110/4538) 29.7 (605/2035) Subjects with incident ECG data 25.6 (1343/5238) 31.7 (728/2265) Table 2 Odds ratio a (95% CI) for self-reported incident coronary heart disease (CHD) and possible or probable incident electrocardiographic (ECG) abnormalities by General Health Questionnaire (GHQ) caseness at Phase 1 Incident CHD at Phase 2 or Phase 3 (400 men: 252 women) b GHQ caseness Non-case Case 1.83 ( ) 1.60 ( ) Possible or probable incident ECG abnormalities at Phase 3 (163 men: 57 women) b GHQ caseness Non-case Case 1.51 ( ) 0.67 ( ) a Odds ratios are adjusted for age, grade of employment and length of follow-up. b Figures show the numbers of men and women with the event.

4 DISTRESS AND HEART DISEASE 251 Younger men, less than 45 years, had a higher risk of new possible and probable ECG abnormalities than older men (men 45, OR = 2.03, 95% CI : ; men 45 OR = 1.20, 95% CI : ). Covariate factors were chosen as either confounding or mediating factors in the association between psychological distress and CHD on the basis of a prior association with CHD or depression in the research literature. Age-adjusted associations between GHQ caseness and the covariate factors are reported in Table 3. In men, divorce, current smoking status, moderate or little physical activity, low levels of social contacts, low decision latitude and high job demands were all significantly associated with GHQ caseness (Table 3). In women, divorce, high alcohol Table 3 Age-adjusted associations (odds ratios and 95% CI) of covariate factors with General Health Questionnaire caseness Marital status (6819M/3333W) a Married Single 1.10 ( ) 1.15 ( ) Divorced 1.95 ( ) 1.33 ( ) Widowed 1.17 ( ) 1.06 ( ) Smoking (6812M/3334W) a Non-smoker Ex-smoker 1.13 ( ) 1.12 ( ) Pipe/cigar only 1.27 ( ) Current smoker 1.28 ( ) 1.05 ( ) Physical activity (6818M/3308W) a Moderate 1.15 ( ) 1.05 ( ) Little/None 1.32 ( ) 1.02 ( ) Diet (6771M/3288W) a Good Moderately good 0.96 ( ) 0.88 ( ) Moderately poor 1.09 ( ) 0.82 ( ) Poor 1.05 ( ) 1.86 ( ) Body mass index (6826M/3349W) a Per 5 kg/m ( ) 0.95 ( ) Alcohol intake (6786M/3313W) a Non-drinker ( ) ( ) ( ) ( ) ( ) Social networks (6777M/3310W) a Medium 1.35 ( ) 1.11 ( ) Low 1.39 ( ) 1.41 ( ) Decision latitude (6806M/3291W) a Medium 1.24 ( ) 0.99 ( ) Low 1.55 ( ) 1.11 ( ) Job demands (6826M/3318W) a Low Medium 1.34 ( ) 1.34 ( ) High 2.23 ( ) 2.69 ( ) a Figures show the numbers of men (M) and women (W). intake, low social contacts, and high job demands were all significantly associated with GHQ caseness. Age-adjusted associations between covariates at baseline and self-reported incident CHD at follow-up are reported in Table 4. In men, current smoking, lack of physical activity, higher body mass index, low social networks and low control at work were associated significantly (P 0.05) with increased coronary risk. In women, widowhood, higher body mass index, medium and low decision latitude and high job demands were associated with increased coronary risk. In men, moderate alcohol intake and, in women, single status, were associated with reduced coronary risk. In relation to incident possible/probable ECG Table 4 Age-adjusted associations (odds ratios and 95% CI) of covariate factors with self-reported incident coronary heart disease Marital status (4528M/2025W) a Married Single 1.28 ( ) 0.69 ( ) Divorced 1.02 ( ) 1.25 ( ) Widowed 0.63 ( ) 1.84 ( ) Smoking (4251M/2023W) a Non-smoker Ex-smoker 1.10 ( ) 0.80 ( ) Pipe/cigar only 1.26 ( ) Current smoker 1.72 ( ) 1.17 ( ) Physical activity (4527M/2017W) a Moderate 1.25 ( ) 1.03 ( ) Little/None 1.74 ( ) 1.08 ( ) Diet (4498M/2003W) a Good Moderately good 1.10 ( ) 1.02 ( ) Moderately poor 1.16 ( ) 0.96 ( ) Poor 1.28 ( ) 1.25 ( ) Body mass index (4530M/2034W) a Per 5 kg/m ( ) 1.15 ( ) Alcohol intake (4506M/2015W) a Non-drinker ( ) ( ) ( ) ( ) ( ) Social networks (4510M/2019W) a Medium 1.05 ( ) 0.97 ( ) Low 1.26 ( ) 0.94 ( ) Decision latitude (4519M/2004W) a Medium 1.13 ( ) 1.79 ( ) Low 1.65 ( ) 1.74 ( ) Job demands (4529M/2017W) a Low Medium 0.70 ( ) 1.01 ( ) High 0.90 ( ) 1.43 ( ) a Figures show the numbers of men (M) and women (W).

5 252 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Table 5 Association (odds ratios and 95% CI) of covariate factors with possible/probable electrocardiographic abnormalities Marital status (5224M/2254W) a Married Single 0.95 ( ) 1.01 ( ) Divorced 1.29 ( ) 0.55 ( ) Widowed 1.01 ( ) Smoking (5520M/2252W) a Non-smoker Ex-smoker 0.95 ( ) 0.80 ( ) Pipe/cigar only 1.08 ( ) Current smoker 1.64 ( ) 0.94 ( ) Physical activity (5224M/2246W) a Moderate 1.02 ( ) 1.24 ( ) Little/None 0.77 ( ) 0.89 ( ) Diet (5188M/2226W) a Good Moderately good 1.04 ( ) 0.59 ( ) Moderately poor 1.02 ( ) 0.53 ( ) Poor 1.02 ( ) 0.66 ( ) Body mass index (5230M/2264W) a Per 5 kg/m ( ) 1.05 ( ) Alcohol intake (5204M/2243W) a Non-drinker ( ) ( ) ( ) ( ) ( ) Social networks (5198M/2237W) a Medium 0.96 ( ) 0.87 ( ) Low 0.81 ( ) 0.75 ( ) Decision latitude (5214M/2228W) a Medium 1.16 ( ) 0.80 ( ) Low 1.17 ( ) 1.21 ( ) Job demands (5228M/2244W) a Low Medium 0.98 ( ) 0.92 ( ) High 0.78 ( ) 1.15 ( ) a Figures show the numbers of men (M) and women (W). abnormalities, current smoking and higher body mass index were related significantly to increased risk in men but not women where there were no clear associations (Table 5). Could these associations between psychological distress and incidence of CHD be explained by existing risk factors for CHD, namely health-related behaviours, social isolation or work characteristics? The risk of new reports of CHD at Phase 2 or Phase 3 by GHQ caseness at Phase 1 is changed minimally after adjusting for health behaviours in men and women (Table 6). Adjustment for marital status, social networks and work characteristics made only about a 5% change in men but reduced the excess risk by about a quarter in women. Full adjustment for health behaviours, marital status, social networks and work characteristics simultaneously, in addition to age, employment grade and length of employment reduces the excess risk of new reports of CHD by about 10% in men and by just under a quarter in women. In men, considering an objective index of CHD, possible and probable ECG abnormalities, adjustment for health behaviours minimally diminished the risk associated with psychological distress of developing ECG abnormalities by Phase 3 (Table 7). Adjustment for marital status, social networks and work characteristics simultaneously increased the risk, with the OR for ECG abnormalities being 1.54 (P = 0.016). In women there was no statistically significant increased risk of ECG abnormalities either before or after adjustment for the risk factors. In general, there is a clear increased risk of CHD associated with psychological distress in men which is not explained by other known psychosocial risk factors for CHD. There was no change in the pattern of results when these analyses were repeated on a dataset with no missing observations for both self-reported CHD and ECG abnormalities. Discussion Psychological distress at baseline is predictive of self-reported incident CHD and possible and probable ECG abnormalities in men. The associations are less robust in women and are absent for ECG abnormalities. Health-related behaviours, social networks and control at work, despite associations with psychological distress and some associations with CHD, explain only a small part of the association between psychological distress and CHD. It is possible that associations between psychological distress and self-reported outcomes like angina pectoris and severe pain Table 6 Odds ratios a (95% CI) for self-reported incident CHD at Phase 2 or Phase 3 associated with General Health Questionnaire caseness at Phase 1 Adjustments (388 events/4374 subjects) (231 events/1895 subjects) Age, length of follow-up 1.90 ( ) 1.52 ( ) Age, grade, length of follow-up + grade 1.91 ( ) 1.59 ( ) grade + health behaviours b 1.87 ( ) 1.59 ( ) grade + marital status, work characteristics c 1.87 ( ) 1.44 ( ) grade + marital status, social network, work characteristics 1.86 ( ) 1.46 ( ) grade + all of the above factors 1.83 ( ) 1.46 ( ) a Odds ratio are adjusted for age, grade of employment and length of follow-up. b Health behaviours = physical activity, smoking status, alcohol intake, diet, body mass index. c Work characteristics = decision latitude, job demands.

6 DISTRESS AND HEART DISEASE 253 Table 7 Odds ratios a (95% CI) for possible or probable incident electrocardiographic abnormalities at Phase 3 associated with General Health Questionnaire caseness at Phase 1 Adjustments (158 events/5040 subjects) (56 events/2041 subjects) Age, length of follow-up 1.48 ( ) 0.68 ( ) Age, length of follow-up + grade 1.49 ( ) 0.70 ( ) grade + health behaviours b 1.47 ( ) 0.68 ( ) grade + marital status, work characteristics c 1.53 ( ) 0.67 ( ) grade + marital status, social network, work characteristics 1.55 ( ) 0.68 ( ) grade + all of the above factors 1.54 ( ) 0.66 ( ) a Odds ratio are adjusted for age, grade of employment and length of follow-up. b Health behaviours = physical activity, smoking status, alcohol intake, diet, body mass index. c Work characteristics = decision latitude, job demands. across the chest are confounded by negative affectivity, socalled plaintive set, influencing questionnaire response style 21 in which there is a tendency to report negatively on both risk factors and outcomes. This might explain why the association between psychological distress and self-reported CHD is stronger than the association between psychological distress and ECG abnormalities. Nevertheless, the GHQ is a measure of relatively transient psychological distress in most cases and is not a trait measure of neuroticism that might contribute to a negative response style which, for the purpose of this argument, would have had to remain stable over a 5-year follow up period. It is harder to argue that the association between psychological distress and a patho-physiological indicator of CHD, i.e. possible and probable ECG abnormalities, is all due to negative affectivity. Although negative affectivity might influence psychological distress it cannot influence the measurement of ECG abnormalities in a cohort study. At baseline there was no association between high GHQ scores and ECG abnormalities, 22 although angina pectoris was associated with higher GHQ scores. This could be due to some selection out of the baseline sample of people with both psychological distress and CHD from among eligible participants, but does not support psychological distress as a consequence of ECG abnormalities in the absence of accompanying symptoms. Another possibility might be that psychological distress is an indicator of low socioeconomic position and that the association between psychological distress and CHD could be explained through an association with socioeconomic position. This seems unlikely as GHQ scores do not show a strong association with socioeconomic position measured by employment grade 17 and although the confounding might relate to another indicator of social position, employment grade is a precise indicator of income and status in the Civil Service. Additionally, adjustment for employment grade had little effect on the magnitude of the association between CHD and psychological distress. In order to take this work further it is necessary to understand what the GHQ is measuring that increases the risk of CHD. It is possible that the GHQ is identifying fatigue and malaise indicating subclinical cardiac illness, which might be an antecedent of overt CHD. On the contrary, the 30-item GHQ was originally derived from the 60-item GHQ in order to eliminate contamination by physical illness. Also the GHQ was developed to screen for psychiatric disorder and scores on the GHQ are correlated with clinical psychiatric disorder and depression. 17,23,24 It might be that although the GHQ is not measuring subclinical physical illness it is identifying psychological distress that has arisen as a consequence of subclinical physical illness although this seems unlikely in the relatively young population at baseline in whom those with existing CHD were excluded from these analyses and in whom younger men were more at risk of CHD related to psychological distress than older men. If it is accepted that a psychological factor rather than physical illness-related factor is the key element of increased risk, it is still not clear from our analyses whether it might be depressive symptoms or depressive illness that are responsible for increased CHD risk. A recent study suggests that experience of clinical depressive illness is associated with increased CHD risk 25 and this seems plausible as major depressive illnesses are associated with raised cortisol levels 26 and physical symptoms, and might be expected to be associated with metabolic disturbance increasing coronary risk. Nevertheless, most studies have found that less severe depression, namely depressive symptoms, is predictive of CHD. The GHQ screens for both depressive illness and lesser levels of both depression and anxiety. It may be that persistence of depressive symptoms over long periods of time is more important in the pathogenesis of CHD than shorter episodes of severe depressive illness. Anda 2 has suggested that both severity of depression, and chronicity may be important in determining CHD risk. If psychological distress increases CHD risk through long-term pathophysiological processes such as atherosclerosis then it would seem likely that distress may be a marker for a persistent trait such as hopelessness 7 or pessimism 27 which have been linked to increased mortality risk. A shorter term risk associated with psychological distress would be more in keeping with underlying processes such as increased susceptibility to arrhythmia s or influences on thrombogenesis or inflammation. Health-related behaviours, particularly smoking, 28 alcohol use, high fat diet and lack of exercise have been associated both with psychological distress and CHD. The plausible hypothesis that the effects of psychological distress are mediated though health behaviours is not supported by our results. Similarly, in another longitudinal study depression predicted CHD but was not associated with physical activity or smoking. 25 Social isolation, measured by social network analysis predicts CHD morbidity and mortality in many studies. 29 Low social support has also been related to decreased survival postmyocardial infarction. 30,31 Depression and social relations have

7 254 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY been found to have independent effects on all-cause mortality in a French community study 32 suggesting that the risk of depression on mortality risk is not mediated by social isolation. It could be that low social support might precede psychological distress on the pathway to CHD. Although low social support may contribute to the causation of psychological distress and hence to CHD in this cohort, it does not seem to explain the association between psychological distress and CHD. Alternatively, psychological distress could be an antecedent of low social support but other analyses in this cohort do not support this. Although we have reported that low control in the workplace predicts CHD, 14 as well as psychiatric morbidity, 33 it does not seem to explain the psychological distress-chd association. Moreover, the effect of low control on CHD risk is independent of GHQ score. 34 The results reported in this paper suggest that psychological distress has an independent effect on CHD risk which is not explained by psychosocial risk factors for CHD. Why does this association between depression and CHD, also found in other studies, appear to be more consistent in men than women? 5 Recent reports from the NHANES I Study found that depressive symptoms predicted CHD incidence in both men and women. However, effects differed for mortality where depressive symptoms predicted CHD mortality in men but not in women. 6 Similarly, an increased all-cause mortality risk associated with neurotic depression was confined to men in the Amsterdam Study of the Elderly although increased mortality associated with psychotic depression was found in both men and women. 35 have a higher prevalence of depression in the general population and also a higher prevalence of angina pectoris and new CHD in this study, but a lower prevalence of ECG abnormalities. In women there are increased risks for the selfreport outcomes, but not for the ECG abnormalities. It may be that this discrepancy, and the higher rates of self-reported coronary outcomes in women, are the result of a greater tendency to symptom reporting with higher rates of false positive CHD outcomes than in men. 36 A further reason why women do not have increased coronary risk associated with depression may be due to pre-menopausal hormonal influences which exert a protective influence against CHD. However, it is paradoxical that during this period of the lifespan women have increased vulnerability to depression relative to men. Alternatively, women may deal more constructively with depression than men, talking about their feelings and seeking help which may neutralize the toxic potential of depression to cause CHD. Our study is limited by our current reliance on broad questionnaire measures of psychological distress and depression and selfreport measures of incident CHD, although ECG abnormalities provide an objective estimate of CHD. We are currently collecting hospital and general practitioner records of CHD events and are measuring depression by interview to address this. The GHQ as a non-specific screening tool for psychological distress could be a marker for early decline in physical functioning, which may be a risk factor for CHD. However, removal of prevalent cases of CHD from these prospective analyses makes this less likely. It is possible that health behaviours such as smoking and alcohol consumption assessed by self-report underestimate consumption and therefore underestimate risk. This may be especially the case for assessment of alcohol intake. Nevertheless, studies find agreement between some self-report and objective indices of health behaviours, for instance cotinine and smoking, 37 suggesting that certain of our self-report measures may be accurate indicators of behaviour. Although the Whitehall II cohort is an office-based occupational cohort there seems no reason why these results should not generalize to the population at large. Altogether, the results of this study support the existing evidence that psychological distress is a risk factor for CHD, in men, if not in women. Further research is needed to identify which aspects of psychological distress are toxic to the heart. Acknowledgements We thank all participating civil service departments and their welfare, personnel and establishment officers; the Occupational Health and Safety Agency; the Council of Civil Service Unions; all participating civil servants in the Whitehall II study; and all members of the Whitehall II study team. The work presented in this paper was supported by a grant from the Department of Health (Grant Number 121/5044). The Whitehall II study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; Economic and Social Research Council; US, NIH: National Heart Lung and Blood Institute (RO1-HL36310); US, NIH: National Institute on Aging (RO1-AG13196); US, NIH: Agency for Health Care Policy Research (RO1-HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. MM is supported by an MRC Research Professorship. KEY MESSAGES Psychological distress predicts electrocardiographic abnormalities suggestive of coronary heart disease (CHD) in men but not women. The association of psychological distress and CHD was not explained by health behaviours, social isolation or work characteristics. It is unclear what aspects of psychological distress may be associated with CHD risk.

8 DISTRESS AND HEART DISEASE 255 References 1 Carney RM, Freedland KE, Jaffe AS. Insomnia and depression prior to myocardial infarction. Psychosom Med 1990;52: Anda R, Williamson D, Jones D et al. Depressed affect, hopelessness, and the risk of ischaemic heart disease in a cohort of US adults. Epidemiology 1993;4: Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction and total mortality in a community sample. Circulation 1996;93: Hemingway H, Marmot M. Psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies. Br Med J 1999;318: Hippisley-Cox J, Fielding K, Pringle M. Depression as a risk factor for ischaemic heart disease in men: population based case-control study. Br Med J 1998;316: Ferketich AK, Schwartzbaum JA, Frid DJ, Moeschberger ML. Depression as an antecedent to heart disease among women and men in the NHANES I Study. Arch Intern Med 2000;160: Everson SA, Goldberg DE, Kaplan GA et al. Hopelessness and risk of mortality and incidence of myocardial infarction and cancer. Psychosom Med 1996;58: Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on six-month survival. JAMA 1993; 270: Frasure-Smith N, Lesperance F, Talajic M. Depression and 18 month prognosis after myocardial infarction. Circulation 1995;91: Booth-Kewley S, Friedman HS. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987;101: Williams RB, Barefoot JC, Blumenthal JA et al. Psychosocial correlates of job strain in a sample of working women. Arch Gen Psychiatry 1997;54: Ruuskanen JM, Ruoppila I. Physical activity and psychological wellbeing among people aged 65 to 84 years. Age Ageing 1995;24: Henderson S, Duncan-Jones P, McAuley H, Ritchie K. The patient s primary group. Br J Psychiatry 1978;132: Bosma H, Marmot MG, Hemingway H, Nicholson AC, Brunner E, Stansfeld SA. Low job control and the risk of coronary heart disease in the Whitehall II (prospective cohort) Study. Br Med J 1997;314: Marmot MG, Davey Smith G, Stansfeld SA et al. Health inequalities among British Civil Servants: the Whitehall II study. Lancet 1991; 337: Goldberg DP. Detecting Pychiatric Illness by Questionnaire. Maudsley Monograph 21. London: Oxford University Press, Stansfeld SA, Marmot MG. Social class and minor psychiatric disorder in British Civil Servants: a validated screening survey using the General Health Questionnaire. Psychol Med 1992;22: Rose G, McCartney P, Reid DD. Self-administration of a questionnaire on chest-pain and intermittent claudication. Br J Prev Soc Med 1977;31: Karasek R, Theorell T. Healthy Work: Stress, Productivity, and the Reconstruction of Working Life. New York: Basic Books, Stansfeld SA, Marmot MG. Deriving a survey measure of social support: the reliability and validity of the Close Persons Questionnaire. Soc Sci Med 1992;35: Chen PY, Spector PE. Negative affectivity as the underlying cause of correlations between stressors and strains. J Appl Psychol 1991;76: Stansfeld SA, Davey Smith G, Marmot MG. Association between physical and psychological morbidity in Whitehall II Study. J Psychosom Res 1993;37: Goldberg DP, Rickels K, Downing R, Hesbacher P. A comparison of two psychiatric screening tests. Br J Psychiatry 1976;129: Goldberg D, Williams P. A Users Guide to the General Health Questionnaire. Windsor: NFER-NELSON, Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men. Arch Intern Med 1998;158: Amsterdam JD, Maislin G, Gold P, Winokur A. The assessment of abnormalities in hormonal responsiveness at multiple levels of the hypothalamic-pituitary-adrenocortical axis in depressive illness. Psychoneuroendocrinology 1989;14: Engel GL. A life-setting conducive to illness. The giving up-given up complex. Ann Int Med 1968;69: Anda RF, Williamson DF, Escobedo LG, Mast EE, Giovino GA, Remington PL. Depression and the dynamics of smoking. A national perspective. JAMA 1990;264: Berkman LF, Syme SL. Social networks, host resistance and mortality: a nine-year follow-up of Alameda County residents. Am J Epidemiol 1979;109: Ruberman W, Weinblatt E, Goldberg JD, Chaudhary BS. Psychosocial influences on mortality after myocardial infarction. N Engl J Med 1984;311: Berkman LF, Leo-Summers L, Horwitz RI. Emotional support and survival after myocardial infarction. A prospective, population-based study of the elderly. Ann Intern Med 1992;117: Fuhrer R, Dufouil C, Antonucci TC, Shipley MJ, Helmer C, Dartigues JF. Psychological disorder and mortality in French Older Adults: do social relations modify the association? Am J Epidemiol 1999;149: Stansfeld SA, Fuhrer R, Shipley MJ, Marmot MG. Work characteristics predict psychiatric disorder: prospective results from the Whitehall II Study. Occup Environ Med 1999;56: Bosma H, Stansfeld SA, Marmot MG. Job control, personal characteristics and heart disease. J Occup Health Psychol 1998;3: Schoevers RA, Geerlings MI, Beekman ATF et al. Association of depression and gender with mortality in old age. Br J Psychiatry 2000; 177: Nicholson A, White I, MacFarlane P, Brunner E, Marmot M. Rose questionnaire angina in younger men and women: gender differences in the relationship to cardiovascular risk factors and other reported symptoms. J Clin Epidemiol 1999;52: Wilcox RG, Hughes J, Roland J. Verification of smoking history in patients after infarction using urinary nicotine and cotinine. Br Med J 1979;ii: