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CLINICAL RESEARCH Prevention and epidemiology

Work stress and coronary heart disease: what are the mechanisms? Tarani Chandola1*, Annie Britton1, Eric Brunner1, Harry Hemingway1, Marek Malik2, Meena Kumari1, Ellena Badrick1, Mika Kivimaki1, and Michael Marmot1

1Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK; 2Department of Cardiac and Vascular Sciences, St George’s University of London, London, UK

Received 1 August 2007; revised 14 November 2007; accepted 22 November 2007; online publish-ahead-of-print 23 January 2008

See page 579 for the editorial comment on this article (doi:10.1093/eurheartj/ehm641)

Aims To determine the biological and behavioural factors linking work stress with coronary heart disease (CHD).

Methods and results

A total of 10 308 London-based male and female civil servants aged 35 – 55 at phase 1 (1985 – 88) of the Whitehall II study were studied. Exposures included work stress (assessed at phases 1 and 2), and outcomes included behavioural risk factors (phase 3), the metabolic syndrome (phase 3), heart rate variability, morning rise in cortisol (phase 7), and incident CHD (phases 2 – 7) on the basis of CHD death, non-fatal myocardial infarction, or definite angina. Chronic work stress was associated with CHD and this association was stronger among participants aged under 50 (RR 1.68, 95% CI 1.17 – 2.42). There were similar associations between work stress and low physical activity, poor diet, the metabolic syndrome, its components, and lower heart rate variability. Cross-sectionally, work stress was associated with a higher morning rise in cortisol. Around 32% of the effect of work stress on CHD was attributable to its effect on health behaviours and the metabolic syndrome.

Conclusion Work stress may be an important determinant of CHD among working-age populations, which is mediated through indirect effects on health behaviours and direct effects on neuroendocrine stress pathways.

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Keywords Work stress † Autonomic nervous system † Myocardial infarction † Angina † Coronary heart disease

Psychosocial

Introduction Stress at work is associated with an increased risk of coronary heart disease (CHD) but the mechanisms underlying this association remain unclear.1 Work stress may affect CHD through direct acti- vation of neuroendocrine responses to stressors, or more indirectly through unhealthy behaviours which increase the risk of CHD, such as smoking, lack of exercise, or excessive alcohol consumption. One of the main axes of neuroendocrine stress responses is the auto- nomic nervous system (ANS). Repeated activation of the ANS is characterized by lowered heart rate variability, which has been associated with work stress among men in cross-sectional studies.2,3 Furthermore, work stress may affect dysregulation of the hypothalamic – pituitary – adrenal axis,4 which is associated with disturbances in the circadian rhythm of cortisol and the develop- ment of the metabolic syndrome.5,6

Accumulation of work stress is associated with higher risks of the metabolic syndrome,7 and incident obesity.8 However, there are few longitudinal studies examining the effect of cumulative work stress on other intermediate mechanisms, despite evi- dence that chronic stress predicts cardiovascular mortality and morbidity.9 It is important to examine cumulative exposures in order to show dose – response relations,10 which would con- tribute a causal understanding of the association between work stress and CHD. In addition, there is little longitudinal evi- dence on the mechanisms by which work stress affects CHD. Stronger associations between work stress and CHD risk among working-age populations would also increase the speci- ficity of this association.

This study addresses the following questions: 1 Is the accumu- lation of work stress associated with higher risks of incident CHD and risk factors? 2 Is this association stronger among

* Corresponding author. Tel: þ44 20 7679 5629, Fax: þ44 20 7813 0242. Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: [email protected].

European Heart Journal (2008) 29, 640–648 doi:10.1093/eurheartj/ehm584

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working-age populations? 3 Does work stress affect CHD directly through neuroendocrine mechanisms and/or indirectly through behavioural risk factors for CHD?

Methods

Study sample and design The Whitehall II study conducted in 1985 – 88 (phase 1) recruited 10 308 participants from 20 civil service departments in London. After initial participation, data collection was carried out in 1989 – 90 (phase 2), 1991 – 93 (phase 3), 1995 (phase 4), 1997 – 99 (phase 5), 2001 (phase 6), and 2002 – 04 (phase 7). Phases 2, 4, and 6 were postal questionnaires, and phases 3, 5, and 7 also included a clinical examination. Full details of the clinical examinations are reported else- where.11 Ethical approval for the Whitehall II study was obtained from the University College London Medical School Committee on the ethics of human research. Informed consent was obtained from the study participants.

Assessment of work stress Self-reported work stress was measured by the job-strain question- naire.12 Participants report job-strain when their responses to the job demands questions are high and decision latitude ( job control) questions are low (defined as being above or below the median score for the measures of job demands and decision latitude). In addition, participants are said to have iso-strain when they report job- strain and are socially isolated at work (i.e. without supportive co- workers or supervisors).7,13,14 A cumulative measure of work stress was created by adding together the number of times the participant reported iso-strain at phases 1 and 2 (range 0 – 2), giving us a measure on the duration of exposure to work stress, although measured on two occasions only. Participants who lacked work stress data at either phase were assigned a missing value. The preva- lence of work stress (iso-strain) was lowest in the highest civil service grade.

Follow-up measurements CHD events included fatal CHD (ICD9 codes 410 – 414 or ICD10 I20 – 25) or incident non-fatal myocardial infarction (MI) from phases 2 – 7 (an average of 12 years of follow-up), with or without angina. Non-fatal MI was defined following MONICA criteria15 based on study electrocardiograms, hospital acute ECGs, and cardiac enzymes, and excluded participants with existing MI at phase 1 or 2. Incident angina was defined on the basis of clinical records and nitrate medi- cation use, excluding cases based solely on self-reported data without clinical verification and participants with definite angina at phase 1 or 2.

Biological risk factors for CHD included the ATPIII16 metabolic syn- drome measured at phase 3, its components (waist circumference: men .102 cm, women .88 cm; serum triglycerides: �150 mg/dL; HDL cholesterol: men ,40 mg/dL, women , 50 mg/dL; blood pressure: �130/�85 mmHg or on antihypertensive medication; fasting glucose: �110 mg/dL); morning rise in cortisol and low heart rate variability (both measured at phase 7).

For the evaluation of heart rate variability, 5 min of RR interval data were collected and analysed both in the time domain [standard devi- ation of all intervals between normal-to-normal sinus rhythm R waves (SDNN)] and in the frequency domains: low frequency 0.04 – 0.15 Hz (ms2) and high frequency 0.15 – 0.4 Hz (ms2). These measures

were log-transformed to obtain a more normal distribution for the regression analyses.

For the evaluation of cortisol, participants were asked to provide samples of saliva collected at waking and 30 min after waking. Partici- pants were asked to record time of waking. Samples were posted back and stored at 2808C for subsequent hormone analysis. Cortisol was measured as previously described.17 Morning rise in cortisol was calculated as the difference between cortisol levels at waking and 30 min after waking.

Behavioural risk factors (at phase 3) for CHD included alcohol, smoking, activity, and diet. Alcohol consumption in the previous week was categorized into non-drinker, recommended (1 – 14 units for women/1 – 21 units for men), and unsafe (14þ units for women/ 21þ units for men). Cigarette smoking categories were non- smoker, ex-smoker, 1 – 9 cigarettes/day, 10 – 19 cigarettes/day, and 20þ cigarettes/day. Physical activity was measured by self-reported frequency of moderate activities (3þ times a week, at least once a week, at least once a month, never). Diet was measured by self- reported fruit or vegetable consumption (less than weekly, less than daily, and at least daily). For logistic regression analyses, these health behaviours were coded into binary variables of current vs. never/ ex-smokers, unsafe drinkers vs. non/recommended limit drinkers, less than daily fruit/vegetable consumption vs. daily, and no physical activity vs. some activity.

Missing data and statistical methods There were 10 308 civil servants who participated in the baseline (phase 1) study. By phase 7, of the 9692 participants still alive, 6484 attended the clinical examination, 71% on whom we measured heart rate variability. Of those participants who were asked to collect saliva samples, 90.1% (n ¼ 4609) returned samples. Some samples were not assayed for technical reasons. Participants taking corticoster- oid medication were excluded from analysis (n ¼ 236). Any partici- pants taking the first sample more than 10 min after waking were excluded from analysis (n ¼ 634), this is the commonly used cut-off when investigating daytime cortisol levels, as the cortisol awakening response is already substantially under way.

A missing value on the work stress measure could indicate that the data were not available at a particular phase, the participant dropped out, or the participant was not in employment. There were 7721 par- ticipants who were still in employment at phase 2 with work stress data at phases 1 and 2. Out of these participants, 98% had follow-up data on incident CHD, 86 – 90% had information on health behaviours and the metabolic syndrome at phase 3, 45 – 49% had information on heart rate variability and cortisol at phase 7.

Cox proportional hazard regression models were used to model the association between the cumulative work stress measures (from phases 1 and 2) and incident CHD events (from phases 2 to 7), adjusted for age, sex, and employment grade, smoking history, total cholesterol, and hypertension (systolic blood pressure .140 and diastolic blood pressure .90, or on antihypertensive medication). Logistic/linear regression models were then used to model the association between cumulative work stress and binary/continuous CHD risk factors. Finally, Cox proportional hazard regression models were used again to examine the reduction in the hazard ratios of cumulative work stress on CHD, adjusted for potential inter- mediate pathways (health behaviours and the metabolic syndrome). Heart rate variability and cortisol could not be examined as potential mediators, as they were not measured in the first few phases of data collection. All statistical significance testing used a two-sided test at the 0.05 significance level. As the main exposure (work stress) con- sisted of two pairwise comparisons (no report vs. one report, and

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no report vs. two reports), Bonferroni corrected P-values (a conservative statistical adjustment to adjust for multiple comparisons) are reported to reduce the risk of type 1 errors. Some of the analyses were strati- fied by age-group if there was a significant interaction between age and work stress.

Results The distribution of all the variables in the analysis is shown in Table A1. Table 1 displays the hazard ratios of incident CHD by cumulative measures of work stress from phases 1 and 2. Greater reports of work stress were associated with a higher risk of CHD. This was true for both major CHD events (fatal events and MI) and definite angina. Although reporting bias may lead to a spurious association between self-reports of stress and angina pectoris,18 the estimated risks of MI and definite angina were similar and so further analyses combined these two CHD outcomes.

There was a significant interaction between age and two reports of work stress (P ¼ 0.04), so the analysis is stratified by age group. Among younger participants (aged 37 – 49 at phase 2), there was a clear dose – response association between greater reports of work stress and higher risks of incident CHD events. Among older par- ticipants (aged 50 – 60), there was little association between work stress and CHD. Stratifying by employment status at phase 5 revealed similar effects (analysis not shown).

Table 2 shows the association of work stress (measured at phases 1 and 2) with the metabolic syndrome, its components, and health behaviours (all from phase 3) among younger (aged under 50) respondents in the Whitehall II cohort. Greater reports of work stress were associated with poorer health beha- viours in terms of eating less fruit and vegetables and less physical activity. In addition, work stress was associated with not drinking any alcohol (which increased the risk of CHD, Table A2). Work stress was also associated with the overall metabolic syndrome and four of its five components. Adjusting for health behaviours only slightly reduced the association between work stress and the overall metabolic syndrome.

Table 3 shows the association between work stress (at phases 1 and 2) and low heart rate variability (at phase 7), and morning rise in cortisol (at phase 7) for participants at all ages (there was no sig- nificant interaction between age and work stress). Greater reports of work stress were associated with lower heart rate variability in terms of lowering of the total variance and low- and high- frequency components. There was little association with morning rise in cortisol. However, additional cross-sectional analysis at phase 7 between work stress and cortisol revealed significantly elevated morning rise in cortisol among those reporting work stress (P , 0.05). All the analyses in Table 3 were adjusted for age, sex, employment grade, hypertension, total cholesterol, smoking, and other health behaviours.

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Table 1 Hazard ratios (95% confidence intervals) of incident coronary heart disease events (phases 2 – 7) by cumulative work stress (phases 1 – 2), age group: the Whitehall II study with an average follow-up of 12 years

Case definition and sample Work stress

Linear trend P-value

No report One report Two reports

All CHD—all ages 1.00 1.23 (0.90 – 1.68) 1.33 (1.04 – 1.69) 0.01

P-valuea 0.19 0.02

P-valueb 0.37 0.04

Cases/n 416/6052 38/497 68/779

CHD death or MI—all ages 1.00 1.18 (0.75 – 1.87) 1.56 (1.12 – 2.17) 0.01

P-valuea 0.47 0.01

P-valueb 0.94 0.02

Cases/n 242/6285 24/522 43/818

Definite angina—all ages 1.00 1.34 (0.93 – 1.93) 1.43 (1.07 – 1.90) 0.01

P-valuea 0.11 0.02

P-valueb 0.23 0.03

Cases/n 337/6276 35/523 57/819

All CHD—age 37 – 49 at baseline 1.00 1.40 (0.88 – 2.22) 1.68 (1.17 – 2.42) ,0.01

P-valuea 0.16 ,0.01

P-valueb 0.32 0.01

Cases/n 174/3912 22/346 38/509

All CHD—age 50 – 60 at baseline 1.00 1.09 (0.68 – 1.77) 1.13 (0.79 – 1.63) 0.47

P-valuea 0.71 0.51

P-valueb 1.00 1.00

Cases/n 258/2314 19/170 33/300

Hazard ratios are adjusted for age, sex, employment grade, hypertension, total cholesterol, and smoking history. aP-value adjusted for age, sex, employment grade, hypertension, total cholesterol, and smoking. bBonferroni corrected P-value adjusted for age, sex, employment grade, hypertension, total cholesterol, and smoking.

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Table 4 displays the hazard ratios of incident CHD for the younger respondents (aged under 50) by work adjusted for beha- vioural risk factors and the metabolic syndrome. There was a 16% reduction in the hazard ratios when behavioural risk factors were adjusted for, and a similar reduction when adjusting for the overall metabolic syndrome. Adjusting for both health behaviours and the metabolic syndrome reduced the work stress – CHD association by �32%.

Discussion Cumulative work stress is a risk factor for CHD and neuroendo- crine stress responses, especially among the younger, working-age population. Around 32% of the effect of work stress on CHD can be explained by the effect of work stress on health behaviours (low physical activity and poor diet in particular) and the metabolic syndrome.

The association between work stress and CHD was stronger among employees younger than 50 and those still in employ- ment. This is in agreement with previous age group analyses of work stress19 and is consistent with the fact that more robust work stress – CHD associations have been found in studies employing younger20,21 than older cohorts.22,23 Among older employees, the impact of work stress might be attenuated because of a healthy worker survivor bias. Retirement during the follow-up removes work stress and this exposure mis- classification may also reduce the effect of work stress. Further- more, an increasing number of other age-related causes of CVD may eclipse the effect of work stress as these other causes figure into both the numerator and the denominator of the ratio.

An important case – control study (INTERHEART24) of 11 119 patients with a first MI and 13 648 age- and sex-matched con- trols in 52 countries found that ‘permanent’ stress at work was associated with over twice the odds of MI compared with those reporting no stress at work. However, few studies have been able to move from demonstrating associations to causality. This article builds on the INTERHEART and other studies by advancing a causal understanding of this association in terms of dose – response associations, establishing the plausibility of this association in terms of underlying biological and behavioural

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Table 2 Odds ratios (95% confidence intervals) of health behaviours (phase 3) and metabolic syndrome (phase 3), by cumulative work stress (phases 1 – 2): Whitehall II respondents aged under 50 at phase 2

Model 1 Model 2 Cases/n

Health behaviours

Less than monthly fruit/vegetable

No report of work stress

1.00 42/3575

One report 1.10 (0.43 – 2.84) 5/316

Two reports 2.12 (1.07 – 4.18) 11/461

No alcohol consumption

No report of work stress

1.00 558/3581

One report 1.24 (0.92 – 1.67) 66/316

Two reports 1.42 (1.11 – 1.82) 101/461

No physical activity

No report of work stress

1.00 377/3581

One report 1.07 (0.74 – 1.55) 37/316

Two reports 1.33 (1.00 – 1.78) 66/460

Current smoker

No report of work stress

1.00 464/3580

One report 1.27 (0.93 – 1.73) 56/316

Two reports 1.11 (0.84 – 1.47) 68/460

Metabolic syndrome

High waist

No report of work stress

1.00 1.00 231/3292

One report 1.29 (0.84 – 1.99) 1.24 (0.81 – 1.92) 26/283

Two reports 1.51 (1.08 – 2.13) 1.46 (1.03 – 2.06) 45/426

High fasting glucose

No report of work stress

1.00 1.00 570/3201

One report 1.02 (0.74 – 1.42) 1.05 (0.76 – 1.47) 48/269

Two reports 1.40 (1.08 – 1.80) 1.43 (1.10 – 1.85) 89/410

High triglycerides

No report of work stress

1.00 1.00 802/3308

One report 1.18 (0.89 – 1.57) 1.16 (0.87 – 1.54) 78/280

Two reports 1.33 (1.06 – 1.69) 1.30 (1.03 – 1.65) 119/425

HDL cholesterol

No report of work stress

1.00 1.00 597/3308

One report 1.21 (0.89 – 1.63) 1.17 (0.86 – 1.59) 61/280

Two reports 1.32 (1.03 – 1.68) 1.26 (0.98 – 1.62) 95/425

Hypertension

No report of work stress

1.00 1.00 1182/3332

One report 0.87 (0.67 – 1.13) 0.88 (0.67 – 1.14) 93/285

Two reports 1.13 (0.91 – 1.39) 1.13 (0.91, 1.40) 159/430

Continued

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Table 2 Continued

Model 1 Model 2 Cases/n

ATPIII metabolic syndrome

No report of work stress

1.00 1.00 357/3308

One report 1.33 (0.93 – 1.91) 1.33 (0.93 – 1.91) 39/280

Two reports 1.72 (1.30 – 2.29) 1.69 (1.26 – 2.25) 69/425

Logistic regression odds ratios in model 1 are adjusted for age, sex, and employment grade; logistic regression odds ratios in model 2 are additionally adjusted for health behaviours.

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mechanisms, and demonstrating the specificity of this association among working-age populations.

There are relatively few studies which have found associations between work stress and (un)healthy behaviours. Work stress is associated with smoking and exercise,25 whereas fatty food intake increases under stressful conditions.26 Work stress has also been linked with problem drinking, although in this cohort, non-drinkers had the highest risk of CHD (and were more likely to report work stress).

Previous cross-sectional analysis from the Whitehall II study has shown low control at work is associated with poor autonomic function,2 and neuroendocrine activation during the working day.4 Longitudinal analyses from the study have shown that work stress is related to CHD,14 the metabolic syndrome,7 and predicts weight gain and incident obesity.8 This study adds to the literature by showing a linear association between work stress and CHD events, the components of the metabolic syndrome, and lower heart variability. In addition, �16% of the effect of work stress on CHD can be explained by the effect of work stress on the metabolic syndrome. As there was little reduction in the associ- ation between work stress and the metabolic syndrome after adjusting for health behaviours, work stress may directly affect neuroendocrine stress mechanisms independently of health

behaviours, resulting in increased risks of the metabolic syndrome. Direct biological stress-effects are additionally possible through acute work-related stressors triggering MI in susceptible individ- uals,27 a possibility which is consistent with the relatively small effect attenuation after adjustment for metabolic components and the fact that the association between work stress and CHD diluted in individuals who stopped work during follow-up. Heart rate variability and cortisol were not measured in the early phases of the study, so their role as a potential mediator of the work stress – CHD association could not be examined. However, adjusting for health behaviours did not change the association between work stress and (low) heart rate variability, suggesting a direct effect on the ANS and neuroendocrine function, rather than indirect effects through health behaviours. The association between work stress and the heart rate variability components suggests that work stress leads to vagal withdrawal and sympath- etic saturation indicating a prevalence of sympathetic mechanisms leading to cardiac electrical instability.28

Cumulative work stress did not predict a greater cortisol awa- kening response. However, there was a cross-sectional association between work stress and greater cortisol awakening response. A lag period of around 12 years between exposure (work stress) and disturbances in the circadian rhythm of cortisol may not be optimal for the detection of the hypothesized neuroendocrine effect.

The Whitehall II cohort is a sample of primarily office-based white-collar workers. There were few manual workers in the cohort. It is possible that the mechanisms underlying the associ- ation of work stress with CHD may differ in manual workers, although there is little evidence for this hypothesis.29 Previous research has suggested that the effect of work stress on cardiovas- cular is less consistent among women.30 The Whitehall II cohort is predominantly male (67%), although gender-stratified analysis revealed similar estimates of work stress on CHD among younger men and women. Missing data is a common problem all cohort studies face. Non-responders at the later clinical examin- ations were more likely to report work stress, consume less alcohol, have poor diets and high cholesterol, come from lower employment grades, be smokers, physically inactive, and obese, resulting in an underestimation of these effects in the analyses. The results on the heart rate variability and cortisol are less robust compared with the other outcomes due to the greater non- response at phase 7. The metabolic syndrome has been criticized as a purely artificial construct,31 not contributing any further infor- mation over its component risk factors, although recent results suggest otherwise.32 This article acknowledges this debate on the metabolic syndrome and presents results on the syndrome itself as well as its components. There may be unmeasured con- founders which may ‘cause’ the association between work stress and CHD, such as other sources of stress and personality type.

This study adds to the evidence that the work stress – CHD association is causal in nature.10 We demonstrate, within a popu- lation of office staff largely unexposed to physical occupational hazards, a prospective dose – response relation between psycho- social stress at work and CHD over 12 years of follow-up. We confirm, during the same exposure period, the plausibility of the proposed pathways involving behavioural mechanisms,

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Table 3 Regression coefficients (95% confidence intervals) of heart rate variability (phase 7) and morning rise in cortisol (phase 7), by cumulative work stress (phases 1 – 2): Whitehall II respondents, all ages

All ages n

Log of low frequency power

No report of work stress 0.00 2769

One report 20.09 (20.23 to 0.04) 211

Two reports 20.14 (20.25 to 20.02) 310

P-value for linear trend ,0.01

Log of high frequency power

No report of work stress 0.00 2769

One report 20.05 (20.21 to 0.11) 211

Two reports 20.14 (20.27 to 0.00) 310

P-value for linear trend ,0.05

Log of SD of NN intervals

No report of work stress 0.00 2769

One report 20.05 (20.12 to 0.01) 211

Two reports 20.05 (20.10 to 0.00) 310

P-value for linear trend ,0.05

Morning rise in cortisol

No report of work stress 0.0 2368

One report 0.00 (21.85 to 1.85) 169

Two reports 20.60 (22.11 to 0.91) 274

P-value for linear trend 0.45

All models are adjusted for age, sex, employment grade (phase 1), total cholesterol (phase 1), hypertension (phase 1), smoking history (phase 1), and other health behaviours (phase 3). In addition, morning rise in cortisol is adjusted for waking up time.

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neuroendocrine and autonomic activation, and development of risk factor clustering, represented by the metabolic syndrome.1,2,6,7

Further, those who are older (and are more likely to be retired and less exposed to work stress) are less susceptible to the work psy- chosocial effect, presenting a coherent pattern in our findings. This study demonstrates that stress at work can lead to CHD through direct activation of neuroendocrine stress pathways and indirectly through health behaviours.

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.

Conflict of interest: none declared.

Funding The Whitehall II study has been supported by grants from the Medical Research Council; Economic and Social 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 (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D. and Cathe- rine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. M.M. is supported by an MRC Research Professorship, H.H. by a public health career scientist award from the Department of Health, and M.K. by the Academy of Finland (grant 117 604).

Appendix 1

Table 4 Hazard ratios of incident all coronary heart disease events (phases 3 – 7) by cumulative work stress (phases 1 – 2) adjusted for health behaviours (phase 3) and metabolic syndrome (phase 3): Whitehall II respondents aged under 50 at phase 2

Model 1 þAll health behaviours

No report 1.00 1.00 140/3408

One report 1.52 (0.93 – 2.48) 1.43 (0.87 – 2.34) 18/292

Two reports 1.56 (1.02 – 2.37) 1.47 (0.97 – 2.25) 26/434

P-value for linear trend 0.02 0.04

þMetabolic syndrome

No report 1.00 1.00 144/3419

One report 1.48 (0.90 – 2.41) 1.44 (0.88 – 2.36) 18/294

Two reports 1.61 (1.06 – 2.43) 1.51 (1.00 – 2.29) 27/439

P-value for linear trend 0.01 0.03

þHealth behaviours and metabolic syndrome

No report 1.00 1.00 136/3265

One report 1.41 (0.84 – 2.37) 1.27 (0.75 – 2.15) 16/275

Two reports 1.56 (1.02 – 2.39) 1.38 (0.90 – 2.13) 25/416

P-value for linear trend 0.03 0.11

Model 1 is adjusted for age, sex, and employment grade.

Table A1 Distribution of the variables in the analysis

Sex

Men 3413

Women 6895

Age group (phase 1)

35 – 39 2811

40 – 44 2663

45 – 49 2107

50 – 56 2727

Cigarette smoking (phase 1)

Never smoker 5062

Ex-smoker 3274

0 – 9 cigarettes/day 540

10 – 19 cigarettes/day 774

20 or more cigarettes/day 418

Missing 240

Moderate exercise (phase 3)

Three times/week or more 1284

One to two times/week 3695

One to three times/month 2290

Never/hardly 1042

Missing 2000

Current smoker (phase 3)

Non-smoker 7168

Smoker 1145

Missing 1995

Continued

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Appendix 2

Table A1 Continued

Fruit/vegetable consumption (phase 3)

Less than daily 8198

Daily or more 112

Missing 1998

High waist (phase 3)

Normal 7258

Male .102 cm or female .88 cm 737

Missing 2313

High waist (phase 3)

Normal 7258

Male .102 cm or female .88 cm 737

Missing 2313

High glucose (phase 3)

Normal 6006

�110 mg/dL 1603

Missing 2699

High blood pressure (phase 3)

Normal 4823

High BPa 3351

Missing 2134

Employment grade (phase 1)

High 3028

Middle 4943

Low 2337

Total cholesterol (phase 1)

,5.2 mmol/L 2510

5.2 – 6.2 mmol/L 4006

.6.2 mmol/L 3718

Missing 74

Hypertension (phase 1)

Normotensive 9461

Systolic BP .140 mmHg/diastolic BPa .90 mmHg 832

Missing 15

ISO-strain (phase 1 – 2)

No report 6363

One report 529

Two reports 829

Missing 2587

Alcohol consumption (phase 3)

Low 1625

Moderate 5399

High 1288

Missing 1996

High triglycerides (phase 3)

Normal 5770

�150 mg/dL 2252

Missing 2286

Low HDL (phase 3)

Normal 6477

Male ,40 mg/dL, female ,50 mg/dL 1542

Missing 2289

Continued

Table A1 Continued

Metabolic syndrome (phase 3)

No syndrome 6897

Metabolic syndrome 1125

Missing 2286

Heart rate variability (phase 7) n ¼ 4095

Morning rise in cortisol (phase 7) n ¼ 3490

aIncludes those on antihypertensive medications.

Table A2 Hazard ratios of incident all coronary heart disease events (phases 3 – 7): Whitehall II respondents aged under 50 at phase 2

Employment grade

High 1.00

Middle 1.14 (0.84 – 1.56)

Low 1.65 (1.04 – 2.60)

Work stress

No reports of work stress 1.00

One report 1.55 (0.97 – 2.46)

Two reports 1.62 (1.10 – 2.40)

Waist circumference

Normal 1.00

High waist 2.04 (1.35 – 3.09)

Triglycerides normal 1.00

High triglycerides 1.93 (1.44 – 2.59)

Glucose tolerance normal 1.00

Glucose intolerance 1.35 (0.96 – 1.89)

HDL cholesterol

Normal 1.00

Low 2.03 (1.50 – 2.74)

Blood pressure

Normal 1.00

High blood pressure/antihypertensive medication 2.16 (1.63 – 2.87)

Overall metabolic syndrome

No syndrome 1.00

Three or more MS components 2.52 (1.82 – 3.49)

Reported fruit/vegetable consumption

Daily or more 1.00

Less than daily 2.38 (1.12 – 5.06)

Physical activity

Three times/week or more 1.00

One to two times/week 1.51 (0.93 – 2.46)

One to three times/month 1.91 (1.15 – 3.16)

Never 2.16 (1.20 – 3.90)

Continued

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Table A2 Continued

Alcohol consumption in the last week

Non-drinker 1.00

Safe alcohol limits 0.62 (0.43 – 0.88)

Unsafe alcohol limits 0.71 (0.46 – 1.11)

Cigarette smoker

Non-smoker 1.00

Ex-smoker 1.04 (0.75 – 1.44)

1 – 9 cigarettes/day 2.15 (1.24 – 3.72)

10 – 19 cigarettes/day 1.39 (0.74 – 2.60)

20þ cigarettes/day 3.06 (1.71 – 5.49)

Hazard ratios are adjusted for age and sex.

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CLINICAL VIGNETTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

doi:10.1093/eurheartj/ehm436 Online publish-ahead-of-print 16 October 2007

Pulmonary thromboembolism and ‘temporary’ patent foramen ovalis: ischaemic stroke due to paradox embolism Gianfranco Aprigliano*, Maksim Llambro, and Angelo Anzuini

Department of Cardiology, Santa Rita Clinical Institute, Via Catalani 4, 20131 Milan, Italy * Corresponding author. Tel: þ39 02 23933020, Fax: þ39 02 23933087, Email: [email protected], [email protected]

An 80-year-old woman was admitted to the orthopaedic department of our hospital for elec- tive right hip prosthesis implantation after recent fracture of the right femore. The first day after surgery, the patient became symptomatic for dyspnoea. Haemo-gas analysis showed hypoxia with hypocapnia. Slight elevation of D-dimer (14.5 mcg/mL) and normal ECG was found out. An echocardiogram revealed right ventricle (RV) dilatation with free wall hypokinesis and massive tricuspidal valve regurgitation secondary to pulmonary hypertension (Panel A). A floppy interatrial septum was also evidenced. Lower limb echo-Doppler showed left iliac vein throm- bosis. Based on this evidence, pulmonary angio- graphy was performed and bilateral thromboembolism diagnosed (Panels B and C). Loco-regional pulmonary thrombolysis and low molecular weight heparin at full dosage were started. During the second day, the patient became symptomatic for left-side emiparesis and afasia. Sovra-aortic trunks duplex scan, colour flow Doppler, and CT brain scan were negative. Transoesophageal echocardiography revealed a floppy aneurismatic interatrial septum (Type C), patent foramen ovalis with right to left shunt in basal conditions and positive micro bubble test (Panel D). Forty-eight hours later, the patient repeated the CT brain scan, showing major ischaemic stroke in right temporal lobe (Panel E). Subsequently, a caval filter was placed. One month later, a transoesophageal echocardiogram revealed aneurismatic floppy interatrial septum without right to left shunt even after Valsalva manoeuvre, and normal pulmonary pressure (Panel F). It seems plausible that the unexpected increase of pulmonary pressure secondary to pulmonary thromboembolism opened the foramen ovalis permitting right to left embolism.

Panel A. Transthoracic echocardiogram showing severe tricuspidal insufficiency. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; TV, tricuspidal valve.

Panel B. The red arrow points to massive embolism of the right pulmonary artery (RPA).

Panel C. The red arrow points to massive embolism of left pulmonary artery (LPA).

Panel D. Transoesophageal echocardiogram showing patent foramen ovalis with right-to-left shunting (red arrow).

Panel E. CT brain scan showing ischaemic area in the right temporal lobe (red arrow).

Panel F. Transoesophageal echocardiogram showing floppy interatrial septum without evidence of right-to-left shunting after Valsalva manoeuvre.

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