1 Danish Epidemiology Science Centre at the Institute of Preventive Medicine, University of Copenhagen, Denmark.
2 Present affiliation: Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
3 Copenhagen City Heart Study, Bispebjerg University Hospital, Denmark.
4 Department of Cardiology, Hvidovre University Hospital, Denmark.
5 Duke University Medical Centre, Durham, North Carolina, USA.
Correspondence: Eva Prescott, Hasselvej 58, DK-2720 Vanløse, Denmark. E-mail: prescott{at}dadlnet.dk
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Abstract |
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Methods The study base was 4084 men and 5479 women aged 2098 free of IHD examined in 19911993 in the Copenhagen City Heart Study. Events were ascertained through record linkage until 1998 for IHD and September 2000 for all-cause mortality. There were 483 first hospital admissions and deaths caused by IHD and 1559 deaths from all causes during follow-up.
Results The 17 items on the vital exhaustion questionnaire were frequently endorsed with prevalence ranging from 6 to 47 per cent, higher in women. All but 4 of the 17 items were significantly associated with IHD with significant relative risks (RR) ranging between 1.36 (95% CI: 1.08, 1.72) and 2.10 (95% CI: 1.63, 2.71). Associations with all-cause mortality were also observed, but were weaker. RR of both IHD and all-cause mortality increased with increasing item sum score and were similar in men and women. For IHD, RR reached a maximum of 2.57 (95% CI: 1.65, 4.00) for subjects endorsing >9 items. The similar RR for all-cause mortality was 2.50 (95% CI: 2.09, 2.99). Multivariate adjustment for biological, behavioural, and socioeconomic risk factors did not substantially affect the association for IHD but attenuated the association with all-cause mortality.
Conclusions Measures of fatigue and depression were common symptoms in this population sample and convey increased risk of IHD and of all-cause mortality. We propose this knowledge begin to be implemented in risk assessment in clinical practice.
Accepted 9 May 2003
Several prospective studies have shown associations between psychological measures and development of ischaemic heart disease (IHD).1 One such measure composed of items reflecting fatigue, hopelessness, and depression was labelled vital exhaustion2 and has been shown to prospectively predict IHD.3 Other studies have found single item measures of exhaustion to be associated with future IHD events and mortality.4,5 Although it has been argued that the vital exhaustion construct is distinct from depression6 there is undoubtedly considerable overlap.7 In a factor analysis of the vital exhaustion construct, items reflecting fatigue were especially important for the prediction of myocardial infarction.8
Previous studies of vital exhaustion and IHD have not been based on representative samples of the community. Furthermore, investigations of gender differences in the impact of symptoms of depression and fatigue on IHD have had mixed results.913 Therefore the generality of the phenomenon remains in question.
The aim of the present study was to describe the distribution of symptoms of fatigue and depression as defined in the vital exhaustion construct in a random sample of the general population, and to determine whether these symptoms prospectively predict IHD and all-cause mortality in both genders.
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Methods |
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Variables of interest
Cardiovascular risk factors were assessed by a self-administered questionnaire checked with the participant by trained staff, and by various laboratory tests.
Vital exhaustion was assessed using a 17-item questionnaire derived from the items used by Appels14 (items given in Table 1). Each item had the possible response categories yes, no, and I dont know. The latter was classified as a negative response and subjects with missing data on one or more of the items (n = 361) were excluded from analyses of the total vital exhaustion item score, leaving 9202 subjects. Summing positive responses constituted a vital exhaustion item score (range: 017) which was then grouped into four categories: 0, 14, 59, and >9 items positive. Cut-off points were arbitrarily chosen to facilitate exploration of a doseresponse relationship while keeping number of end-points in each category sufficient. Tobacco consumption was categorized as follows: never-smokers; ex-smokers; non-inhaling current smokers; and inhaling current smokers of 114, 1524, and
25 g tobacco per day. Current tobacco consumption was calculated from type of tobacco (cigarette, cheroot, cigar, pipe, or mixed) for current smokers by equating a cigarette to 1 g, a cheroot to 3 g, and a cigar to 5 g tobacco. Systolic and diastolic blood pressure was measured in a sedentary position after
5 minutes rest. Blood lipids were measured non-fasting. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). In the statistical analyses these continuous variables were divided into gender-specific quartiles. Two socioeconomic status variables were included: educational level, in three categories: <8 years of schooling (completed primary school); 811 years, and; >11 years, as well as household income in seven categories. Cohabitation was registered dichotomously as living along versus not living alone. Alcohol consumption was classified according to daily intake in: no daily consumption,
1 drink per day; 12; and >2 drinks per day, one drink containing 913 g alcohol. Physical activity in leisure time was classified into three categories as: sedentary; moderate activity <4 hours; and moderate activity >4 hours per week. Diabetes and family history of myocardial infarction were self-reported.
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Results |
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All survival analyses were repeated with exclusion of the first 2 years of follow-up to evaluate the effect of symptoms caused by pre-clinical cardiovascular disease. This reduced the number of IHD cases from 455 to 300 and number of deaths from 1430 to 1165 but did not change the results (not shown). This lessens the likelihood that we have observed a spurious association due to the elevation of exhaustion scores in severely ill respondents.
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Discussion |
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There is considerable overlap in the symptoms of vital exhaustion and depression but in the absence of a standard measure of depression we cannot address the potential distinction empirically. However, the similarities suggest that the findings of this study are also relevant to the burgeoning literature on depressive symptoms and coronary disease.1
The adjusted risk of IHD was approximately doubled in those reporting vital exhaustion and fatigue. Similar hazard ratios were found in the previous prospective study of 3877 males.3 With the exception of a case-control study with very high RR associated with vital exhaustion,16 most other studies of vital exhaustion, fatigue, or depression have reported risks in the range reported here.3,5,12,13,1720
The ability of vital exhaustion to predict IHD events was evident in the data of both women and men as well as in all age groups. Although the effects of vital exhaustion in women have been investigated in a case-control study,21 this is the first demonstration of their importance in a sample of healthy women followed prospectively. To the extent that the symptoms of vital exhaustion overlap with those of depression, the findings of this study are relevant to the question of gender difference in the health impact of depressive symptoms.913 Furthermore, the prevalence of vital exhaustion as measured by individual items was higher in women than in men. Therefore the potential impact of these symptoms should be of special concern for women. The similarity of the associations with disease in men and women suggests that the higher prevalence in women cannot be put down to gender-related cultural differences in expression of emotions.
IHD can lead to depression and fatigue, and the possibility of reverse causality caused by sub-clinical disease at study entry was considered. Precautions were taken to reduce this risk: the study was prospective and subjects with pre-existing IHD based on self-reports and previous hospitalizations were excluded. Further, exclusion of the incident cases within the first 2 years of follow-up did not affect results. Residual confounding is another potential alternative explanation. However, adjustment for other risk factors had little impact on risk estimates for IHD. Another potential bias is the possibility that depressed and exhausted individuals might be more likely to seek care, thereby inflating the number of cases for those individuals. However, the presence of associations between vital exhaustion and hard end-points, IHD deaths and total mortality, argues against this as an alternative explanation for the results.
Several hypotheses have been proposed to explain the associations between these psychosocial factors and the development of IHD, among them increased platelet reactivity, lower heart rate variability, and increased atherogenesis. Depressed individuals have been shown to have impaired parasympathetic tone and thus lower heart rate variability, which likely results in higher blood pressure variability that could foster atherogenesis.2224 The role of psychosocial factors in atherogenesis is supported by the finding that hopelessness was associated with the progression of carotid atherosclerosis among men in the Kuopio ischaemic heart disease study, where it also predicted IHD and all-cause mortality independent of depression.25,26 However, vital exhaustion was not or only modestly related to severity of coronary artery disease in two studies of patients undergoing coronary angiography.27,28 Furthermore, vital exhaustion was not related to carotid intimae-medial wall thickness in 12 448 individuals free of coronary heart disease after adjustment for established risk factors,29 and a recent study could not confirm any association between either depression or hopelessness and coronary artery calcification measured by electron beam computed tomography in 630 young healthy subjects with low prevalence of depression and anxiety.30
Vital exhaustion did, however, predict new cardiac events in 127 patients after successful percutanerous transluminal coronary angioplasty.31 This may indicate that the biological link between fatigue and depression and IHD is mainly through increased thrombogenic activity. A small study found significantly higher plasminogen activator inhibitor in exhausted than in non-exhausted healthy men but no difference in other coagulation factors.32 Further studies are needed to verify associations between fatigue and depression and thrombolytic and thrombogenic factors.
The role of burden of infections has not yet been solved and it is possible that fatigue is a marker of frequent sub-clinical infections and of arterial inflammation. In one study vital exhaustion was positively associated with serological markers of inflammation: antibody titres against chlamydia pneumonia, cytomegalovirus, and interleukines (IL) 1' and IL6.33
We found a clear socioeconomic gradient in vital exhaustion. Psychosocial factors such as social isolation, lack of control at work, and hostility are more prominent in low social class groups, as are smoking, insulin resistance, and other risk factors.34 It has been proposed that psychosocial pathways may mediate the inverse association between socioeconomic status and IHD,1 perhaps involving the hypothalamic-pituitary-adrenal (HPA)-axis, a principal pathway activated as part of the physiological stress response, which has been linked to psychosocial factors.35,36 This would raise the possibility that depressive symptoms and fatigue might be markers of chronic stress and affected HPA-axis rather than causal factors.
Although still present, associations between depression and fatigue and all-cause mortality were weaker. This may indicate specificity of disease but also calls for analyses of other disease entities, in particular cancers. At present this study does not allow analyses of specific disease entities due to insufficient number of end-points.
In conclusion, these data show that symptoms of fatigue and depression are common in the general population, and confirm earlier observations that they convey a substantially increased risk of IHD and some mortality risk. Although the biological mechanisms relating fatigue and depressive symptomatology to IHD are not yet fully understood, we feel that depressive symptoms and fatigue should begin to become part of risk assessment in clinical practice.
KEY MESSAGES
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Acknowledgments |
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References |
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