Lifetime and 10-year risks of cardiovascular mortality in relation to risk factors in middle and old age: 50-year follow-up of the Whitehall study of London Civil Servants.

BACKGROUND: Cardiovascular disease (CVD)-related mortality has declined substantially in the United Kingdom (UK) in recent decades, but the continued relevance of conventional risk factors for prediction of CVD mortality throughout the life-course is uncertain. We compared the 10-year risks and lifetime risks of CVD mortality associated with conventional risk factors recorded in middle and old age. METHODS: The Whitehall study was a prospective study of 19,019 male London civil servants (mean age 52 years) when enrolled in 1967-1970 and followed-up for 50 years for cause-specific mortality. In 1997, 7044 (83%) survivors (mean age 77 years) were re-surveyed. The 10-year and lifetime risks of CVD mortality were estimated by levels of CVD risk factors recorded in middle-age and old-age, respectively. RESULTS: By July 2020, 97% had died (22%, 51% and 80% before age 70, 80 and 90 years, respectively) and 7944 of 17,673 deaths (45%) were from CVD. The 10-year and lifetime risks of CVD death increased linearly with higher levels of CVD risk factors recorded in middle-age and in old-age. Individuals in the top versus bottom 5% of CVD risk scores in middle age had a 10.3% (95% CI:7.2-13.4) vs 0.6% (0.1-1.2) 10-year risk of CVD mortality, a 61.4% (59.4-65.3) vs 31.3% (24.1-34.5) lifetime risk of CVD mortality and a 12-year difference in life expectancy from age 50 years. The corresponding differences using a CVD risk score in old-age were 11.0% (4.4-17.5) vs 0.8% (0.0-2.2) for 10-year risk and 42.1% (28.2-50.0) vs 30.3% (6.0-38.0) for lifetime risk of CVD mortality and a 6-year difference in life expectancy from age 70 years. CONCLUSIONS: Conventional risk factors remained highly predictive of CVD mortality and life expectancy through the life-course. The findings highlight the relevance of estimation of both lifetime risks of CVD and 10-year risks of CVD for primary prevention of CVD.

Interleukin-6 as a predictor of symptom resolution in psychological distress: a cohort study.

BACKGROUND: Elevated levels of interleukin-6 (IL-6) have been associated with the development of common mental disorders, such as depression, but its role in symptom resolution is unclear. METHOD: We examined the association between IL-6 and symptom resolution in a non-clinical sample of participants with psychological distress. RESULTS: Relative to high IL-6 levels, low levels at baseline were associated with symptom resolution at follow-up [age- and sex-adjusted risk ratio (RR) = 1.15, 95% confidence interval (CI) 1.06-1.25]. Further adjustment for covariates had little effect on the association. Symptomatic participants with repeated low IL-6 were more likely to be symptom-free at follow-up compared with those with repeated high IL-6 (RR = 1.21, 95% CI 1.03-1.41). Among the symptomatic participants with elevated IL-6 at baseline, IL-6 decreased along with symptom resolution. CONCLUSIONS: IL-6 is potentially related to the mechanisms underlying recovery from symptoms of mental ill health. Further studies are needed to examine these mechanisms and to confirm the findings in relation to clinical depression.

Job strain and the risk of severe asthma exacerbations: a meta-analysis of individual-participant data from 100 000 European men and women.

BACKGROUND: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. METHODS: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. RESULTS: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). CONCLUSIONS: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

Conflicts between work and family life and subsequent sleep problems among employees from Finland, Britain, and Japan.

PURPOSE: Research on the association between family-to-work and work-to-family conflicts and sleep problems is sparse and mostly cross-sectional. We examined these associations prospectively in three occupational cohorts. METHODS: Data were derived from the Finnish Helsinki Health Study (n = 3,881), the British Whitehall II Study (n = 3,998), and the Japanese Civil Servants Study (n = 1,834). Sleep problems were assessed using the Jenkins sleep questionnaire in the Finnish and British cohorts and the Pittsburgh Sleep Quality Index in the Japanese cohort. Family-to-work and work-to-family conflicts measured whether family life interfered with work or vice versa. Age, baseline sleep problems, job strain, and self-rated health were adjusted for in logistic regression analyses. RESULTS: Adjusted for age and baseline sleep, strong family-to-work conflicts were associated with subsequent sleep problems among Finnish women (OR, 1.33 (95 % CI, 1.02-1.73)) and Japanese employees of both sexes (OR, 7.61 (95 % CI, 1.01-57.2) for women; OR, 1.97 (95 % CI, 1.06-3.66) for men). Strong work-to-family conflicts were associated with subsequent sleep problems in British, Finnish, and Japanese women (OR, 2.36 (95 % CI, 1.42-3.93), 1.62 (95 % CI, 1.20-2.18), and 5.35 (95 % CI, 1.00-28.55), respectively) adjusted for age and baseline sleep problems. In men, this association was seen only in the British cohort (OR, 2.02 (95 % CI, 1.42-2.88)). Adjustments for job strain and self-rated health produced no significant attenuation of these associations. CONCLUSION: Family-to-work and work-to-family conflicts predicted subsequent sleep problems among the majority of employees in three occupational cohorts.

Long working hours and symptoms of anxiety and depression: a 5-year follow-up of the Whitehall II study.

BACKGROUND: Although long working hours are common in working populations, little is known about the effect of long working hours on mental health. METHOD: We examined the association between long working hours and the onset of depressive and anxiety symptoms in middle-aged employees. Participants were 2960 full-time employees aged 44 to 66 years (2248 men, 712 women) from the prospective Whitehall II cohort study of British civil servants. Working hours, anxiety and depressive symptoms, and covariates were measured at baseline (1997-1999) followed by two subsequent measurements of depressive and anxiety symptoms (2001 and 2002-2004). RESULTS: In a prospective analysis of participants with no depressive (n=2549) or anxiety symptoms (n=2618) at baseline, Cox proportional hazard analysis adjusted for baseline covariates showed a 1.66-fold [95% confidence interval (CI) 1.06-2.61] risk of depressive symptoms and a 1.74-fold (95% CI 1.15-2.61) risk of anxiety symptoms among employees working more than 55 h/week compared with employees working 35-40 h/week. Sex-stratified analysis showed an excess risk of depression and anxiety associated with long working hours among women [hazard ratios (HRs) 2.67 (95% CI 1.07-6.68) and 2.84 (95% CI 1.27-6.34) respectively] but not men [1.30 (0.77-2.19) and 1.43 (0.89-2.30)]. CONCLUSIONS: Working long hours is a risk factor for the development of depressive and anxiety symptoms in women.

Incidence and prognosis of angina pectoris in South Asians and Whites: 18 years of follow-up over seven phases in the Whitehall-II prospective cohort study.

BACKGROUND: Whether the higher coronary mortality in South Asians compared with White populations is due to a higher incidence of disease is not known. This study assessed cumulative incidence of chest pain in South Asians and Whites, and prognosis of chest pain. METHODS: Over seven phases of 18-year follow-up of the Whitehall-II study (9,775 civil servants: 9,195 White, 580 South Asian), chest pain was assessed using the Rose questionnaire. Coronary death/non-fatal myocardial infarction was examined comparing those with chest pain to those with no chest pain at baseline. RESULTS: South Asians had higher cumulative frequencies of typical angina by Phase 7 (17.0 versus 11.3%, P < 0.001) and exertional chest pain (15.4 versus 8.5%, P < 0.001) compared with Whites. Typical angina and exertional chest pain at baseline were associated with a worse prognosis compared with those with no chest pain in both groups (typical angina, South Asians: HR, 4.67 and 95% CI, 2.12-0.30; Whites: HR, 3.56 95% CI, 2.59-4.88). Baseline non-exertional chest pain did not confer a worse prognosis. Across all types of pain, prognosis was worse in South Asians. CONCLUSION: South Asians had higher cumulative incidence of angina than Whites. In both, typical angina and exertional chest pain were associated with worse prognosis compared with those with no chest pain.

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-<5 g per day), the multivariable odds ratios of CRC were 1.16 (95% confidence interval (95% CI): 0.88, 1.53) for non-drinkers, 0.91 (95% CI: 0.67, 1.24) for drinkers with 5-<15 g per day, 0.90 (95% CI: 0.65, 1.25) for drinkers with 15-<30 g per day, 1.02 (95% CI: 0.66, 1.58) for drinkers with 30-<45 g per day and 1.19 (95% CI: 0.75, 1.91) for drinkers with >or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium.

The association of cognitive performance with mental health and physical functioning strengthens with age: the Whitehall II cohort study.

BACKGROUND: Cognitive performance has been associated with mental and physical health, but it is unknown whether the strength of these associations changes with ageing and with age-related social transitions, such as retirement. We examined whether cognitive performance predicted mental and physical health from midlife to early old age. METHOD: Participants were 5414 men and 2278 women from the Whitehall II cohort study followed for 15 years between 1991 and 2006. The age range included over the follow-up was from 40 to 75 years. Mental health and physical functioning were measured six times using SF-36 subscales. Cognitive performance was assessed three times using five cognitive tests assessing verbal and numerical reasoning, verbal memory, and phonemic and semantic fluency. Socio-economic status (SES) and retirement were included as covariates. RESULTS: High cognitive performance was associated with better mental health and physical functioning. Mental health differences associated with cognitive performance widened with age from 39 to 76 years of age, whereas physical functioning differences widened only between 39 and 60 years and not after 60 years of age. SES explained part of the widening differences in mental health and physical functioning before age 60. Cognitive performance was more strongly associated with mental health in retired than non-retired participants, which contributed to the widening differences after 60 years of age. CONCLUSIONS: The strength of cognitive performance in predicting mental and physical health may increase from midlife to early old age, and these changes may be related to SES and age-related transitions, such as retirement.

Performance of existing risk scores in screening for undiagnosed diabetes: an external validation study.

AIM: To compare the performance of nine published strategies for the selection of individuals prior to screening for undiagnosed diabetes. METHODS: We conducted a validation study, based on a cross-sectional analysis of 6990 participants of the Whitehall II study, an occupational cohort of civil servants in London. We calculated sensitivity, specificity and the area under the receiver operating characteristic (ROC) curve, indicative of the ability of a risk score to correctly identify those with undiagnosed diabetes. RESULTS: The prevalence of unknown diabetes was 2.0%. At a set level of sensitivity (0.70), the specificity of the different scores ranged between 0.41 and 0.57. A reference model, based solely on age and body mass index had an area under the ROC curve of 0.67 [95% confidence interval (CI): 0.62, 0.72]. Four scores had a lower area under the ROC curve (lowest ROC AUC: 0.62; 95% CI: 0.58, 0.67) compared with the reference model, while the other five scores had similar areas (highest ROC AUC: 0.68; 95% CI: 0.63, 0.72). All ROC curve areas were lower than those reported in the original publications and validation studies. CONCLUSIONS: Existing risk scores for the detection of undiagnosed diabetes perform less well in a large validation cohort compared with previous validation studies. Our study indicates that non-invasive risk scores require further refinement and testing before they can be used as the first step in a diabetes screening programme.

Do the Joint British Society (JBS2) guidelines on prevention of cardiovascular disease with respect to plasma glucose improve risk stratification in the general population? Prospective cohort study.

AIMS: British guidelines on vascular disease prevention recommend adding a random (casual) blood glucose measurement to a lipid profile in those aged > or = 40 years. To assess this recommendation, we compared the predictive value of a risk model based on the Framingham risk score alone to one which additionally included information on fasting blood glucose, with respect to incident coronary heart disease (CHD) over 11 years. METHOD: Men and women aged 40-63 years in Whitehall II were followed up for incident CHD: death/non-fatal myocardial infarction; angina confirmed by doctor diagnosis or electrocardiogram (ECG) and all first events. Fasting blood glucose was specified as a continuous variable or categorized by World Health Organization (WHO) 1999 glycaemic status (normal glucose tolerance, impaired fasting glucose or newly diagnosed diabetes). RESULTS: The hazard ratio for incident CHD was 1.10 (95%CI 1.09; 1.12) in men and 1.13 (1.10; 1.17) in women per percentage point increase in Framingham risk. The excess risk remained unchanged in models which added glycaemic status or continuous fasting glucose. The area under the receiver operating characteristic (ROC) curve for the Framingham score and incident coronary heart disease [0.70 (0.68; 0.73)] did not change when glycaemic status or fasting glucose was added to the prediction model. Reclassification with these modified models improved discrimination based on the Framingham score alone when glycaemic status was added, net reclassification improvement 2.4% (95% CI 0.2%; 4.6%), but not when fasting glucose was added. CONCLUSION: Better detection of unrecognized diabetes is a valuable consequence of including a random blood glucose in a vascular risk profile. Our results suggest that this strategy is unlikely to improve risk stratification for CHD.

Cumulative exposure to high-strain and active jobs as predictors of cognitive function: the Whitehall II study.

OBJECTIVES: A high-strain job (a combination of high job demands and low job control) is expected to increase the risk of health problems, whereas an active job (high demands and high control) can be hypothesised to be associated with a greater capacity to learn. We tested associations between high-strain and active jobs and cognitive function in middle-aged men and women. METHODS: Data on 4146 British civil servants (2989 men and 1157 women) aged 35-55 years at baseline came from the Whitehall II study. Cumulative exposure to both high-strain and active jobs was assessed at phases 1 (1985-1988), 2 (1989-1990) and 3 (1991-1993). Cognitive performance was assessed at phases 5 (1997-1999) and 7 (2003-2004) using the following tests: verbal memory, inductive reasoning (Alice Heim), verbal meaning (Mill Hill), phonemic and semantic fluency. Analyses were adjusted for age, sex and employment grade. RESULTS: Longer exposure to high job strain and shorter exposure to active jobs were associated with lower scores in most of the cognitive performance tests. However, these associations disappeared on adjustment for employment grade. Phonemic fluency was an exception to this pattern. Associations between exposure to an active job and phonemic fluency at both follow-up phases were robust to adjustment for employment grade. However, there was no association between exposure to active jobs and change in phonemic fluency score between the follow-up phases after adjustment for employment grade. CONCLUSIONS: In these data, associations between cumulative exposure to high-strain or active jobs and cognition are largely explained by socioeconomic position.

Cigarette smoking and site-specific cancer mortality: testing uncertain associations using extended follow-up of the original Whitehall study.

BACKGROUND: The relation between cigarette smoking and several malignancies is still unclear. We examined the association of cigarette smoking with death attributed to 15 cancer sites, 7 of which are regarded as having an uncertain relation with tobacco. PATIENTS AND METHODS: The original Whitehall study is a prospective cohort of 17 363 London-based male government employees (age 40-69 years) who were examined in the late 1960s and then followed up for a maximum of 38 years. RESULTS: Following adjustment for demographic characteristics, risk factors, and prevalent disease, established positive cigarette smoking--cancer gradients were confirmed for carcinoma of the lung, stomach, pancreas, bladder, upper aero-digestive (including oesophagus), and liver, and for myeloid leukaemia. Among the cancers of uncertain relation with smoking, mortality rates for malignancy of the colon, rectum and prostate and for lymphatic leukaemia were elevated in current and/or former smokers. There was essentially no apparent relation between smoking and mortality from carcinoma of the brain or from lymphoma. CONCLUSION: In this study, cigarette smoking appears to be a risk factor for several malignancies of previously unclear association with tobacco use.

Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study.

Obesity has been implicated in the aetiology of liver disease. However, to date, evidence is largely drawn from cross-sectional studies, where interpretation is hampered by reverse causality, and from studies on clinical populations that have limited generalisability. In this prospective cohort study, data on body mass index (BMI) and covariates were collected at baseline on 18 863 male government employees (aged 40-69 years). Respondents were then followed up for a maximum of 38 years of age. Mortality surveillance gave rise to 13 129 deaths, 122 of which were due to liver disease (57 cancers; 65 non-cancers). In age-adjusted analyses, BMI was positively related to total liver disease mortality (hazards ratio per 1 s.d. increase in BMI; 95% confidence interval (CI): 1.36; 1.14, 1.62) in a graded fashion across the weight categories (P-value for trend: 0.01). The magnitude of this association was somewhat stronger for non-cancer liver disease deaths (1.47; 1.16, 1.86) than for cancer liver disease deaths (1.25; 0.96, 1.62). Excluding deaths in the first 10 years of follow-up somewhat strengthened the BMI-non-cancer liver disease association. Adjustment for socioeconomic position, other candidate confounders and mediating factors led to the modest attenuation of these associations. Further investigation in prospective cohort studies with more detailed data on liver disease, for instance using biochemical tests of liver function or hepatic ultrasonography, is warranted.

Low medically certified sickness absence among employees with poor health status predicts future health improvement: the Whitehall II study.

BACKGROUND: High sickness absence is associated with poor health status, but it is not known whether low levels of sickness absence among people with poor health predict future health improvement. OBJECTIVE: To examine the association between medically certified sickness absence and subsequent change in health among initially unhealthy employees. METHODS: 5210 employees (3762 men, 1448 women) whose self-rated health status remained stable (either good or poor) between data phases 1 and 2 were divided into three groups according to their rate of medically certified absences during this period (0 vs >0-5 vs >5 absence spells longer than 7 days per 10 person-years). Subsequent change in health status was determined by self-rated health at follow-up (phase 3). RESULTS: After adjustment for age and sex, there was a strong contemporaneous association between lower sickness absence and better health status. Among participants reporting poor health, low absence was associated with subsequent improvement in health status (odds ratio 2.66, 95% CI 1.78 to 4.02 for no absence vs >5 certified spells per 10 years). This association was only partially explained by known existing morbidity, socioeconomic position and risk factors. CONCLUSIONS: Low levels of medically certified sickness absence seem to be associated with positive change in health status among employees in poor health. Further research is needed to examine whether lower sickness absence also marks a more favourable prognosis for specific diseases.

Prostate cancer risk related to foods, food groups, macronutrients and micronutrients derived from the UK Dietary Cohort Consortium food diaries.

BACKGROUND/OBJECTIVES: The influence of dietary factors remains controversial for screen-detected prostate cancer and inconclusive for clinically detected disease. We aimed to examine these associations using prospectively collected food diaries. SUBJECTS/METHODS: A total of 1,717 prostate cancer cases in middle-aged and older UK men were pooled from four prospective cohorts with clinically detected disease (n=663), with routine data follow-up (means 6.6-13.3 years) and a case-control study with screen-detected disease (n=1054), nested in a randomised trial of prostate cancer treatments (ISCTRN 20141297). Multiple-day food diaries (records) completed by men prior to diagnosis were used to estimate intakes of 37 selected nutrients, food groups and items, including carbohydrate, fat, protein, dairy products, fish, meat, fruit and vegetables, energy, fibre, alcohol, lycopene and selenium. Cases were matched on age and diary date to at least one control within study (n=3528). Prostate cancer risk was calculated, using conditional logistic regression (adjusted for baseline covariates) and expressed as odds ratios in each quintile of intake (±95% confidence intervals). Prostate cancer risk was also investigated by localised or advanced stage and by cancer detection method. RESULTS: There were no strong associations between prostate cancer risk and 37 dietary factors. CONCLUSIONS: Prostate cancer risk, including by disease stage, was not strongly associated with dietary factors measured by food diaries in middle-aged and older UK men.

Injustice at work and incidence of psychiatric morbidity: the Whitehall II study.

BACKGROUND: Previous studies of organisational justice and mental health have mostly examined women and have not examined the effect of change in justice. AIM: To examine effects of change in the treatment of employees by supervisors (the relational component of organisational justice) on minor psychiatric morbidity, using a cohort with a large proportion of men. METHODS: Data are from the Whitehall II study, a prospective cohort of 10 308 white-collar British civil servants (3143 women and 6895 men, aged 35-55 at baseline) (Phase 1, 1985-88). Employment grade, relational justice, job demands, job control, social support at work, effort-reward imbalance, physical illness, and psychiatric morbidity were measured at baseline. Relational justice was assessed again at Phase 2 (1989-90). The outcome was cases of psychiatric morbidity by Phases 2 and 3 (1991-93) among participants case-free at baseline. RESULTS: In analyses adjusted for age, grade, and baseline physical illness, women and men exposed to low relational justice at Phase 1 were at higher risk of psychiatric morbidity by Phases 2 and 3. Adjustment for other psychosocial work characteristics, particularly social support and effort-reward imbalance, partially attenuated these associations. A favourable change in justice between Phase 1 and Phase 2 reduced the immediate risk (Phase 2) of psychiatric morbidity, while an adverse change increased the immediate and longer term risk (Phase 3). CONCLUSION: This study shows that unfair treatment by supervisors increases risk of poor mental health. It appears that the employers' duty to ensure that employees are treated fairly at work also has benefits for health.

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.

Self-reported economic difficulties and coronary events in men: evidence from the Whitehall II study.

BACKGROUND: Numerous studies have demonstrated social inequalities in coronary heart disease using a variety of measures of social position. In this study we examine associations between persistent economic difficulties and serious coronary events. Our aim is to assess whether these associations are (i) explained by other measures of socioeconomic status, and (ii) mediated by psychosocial, behavioural and biological factors. METHODS: The data come from 5021 middle-aged, white-collar men in the Whitehall II study. Self-reported household financial problems, measured at baseline (1985-88) and Phase 3 (1991-93), were used to construct a five-category score of persistent economic difficulties. Associations between economic difficulties and incident coronary events were determined over an average follow-up of 7 years. Other socioeconomic, psychosocial, behavioural and biological explanatory variables were obtained from the Phase 3 questionnaire and clinical examination. RESULTS: Age-adjusted Cox regression analyses demonstrated steep gradients in the incidence of coronary events with economic difficulties. The relative hazard between the bottom and the top of the difficulties hierarchy was 2.5 (95% confidence intervals (CI) 1.2-5.2) for fatal and non-fatal myocardial infarction (MI), 2.1 (1.3-3.6) for MI plus definite angina and 2.8 (1.9-4.2) for total coronary events. Adjustment for other markers of socioeconomic position, early life factors, psychosocial work environment characteristics and health-related behaviours had little effect, while adjustment for the biological factors reduced the association between difficulties and coronary events by 16-24%. CONCLUSION: We have demonstrated an economic difficulties gradient in coronary events in men that is independent of other markers of socioeconomic position and appears to be only partially mediated by well-known risk factors in mid-life.