Cardiovascular diseases (CVD), including coronary heart disease (CHD) and stroke, are still the major causes of death in European countries and account for 32% of all deaths (8). Besides classical risk factors, such as high blood pressure and cholesterol, depressive symptoms and physical inactivity have been associated with increased risk of CVD (14,27).
The first evidence for a relation between depression and CVD came from studies in patients with myocardial infarction (MI). These studies showed that about one third of post-MI patients had minor or major depression (13,31). In addition, these patients had a worse prognosis than patients who were not depressed after a MI (13). More recently, it has been hypothesized that depression not only leads to poor prognosis in patients with established CVD, but also increases the risk of CVD in apparently healthy persons. Recent reviews support the view that depression is a risk factor for CVD and cardiovascular mortality (14,32,39). The evidence comes not only from studies that used clinical diagnoses of depressive disorder, but also from studies that used questionnaires to estimate the presence and degree of depressive symptoms (14).
One of the hypotheses to explain the relationship between depression and CVD risk is that depressed persons adopt an unhealthy lifestyle. For instance, prospective studies indicate that depressed persons develop a more sedentary lifestyle and become less physically active (7,34). Physical inactivity may increase the risk of developing CVD in depressed subjects. Therefore, physical inactivity may be an intermediate factor in the relation between depressive symptoms and CVD. In addition, depression and physical inactivity may interact, possibly via atherosclerotic processes, in the development of CVD.
Although several population-based studies adjusted for physical activity in their analyses (1,17,24,36), they did so by adding this variable to the model in the same step as other covariates. Only two studies examined the independent effect of physical inactivity (sedentary behavior) on the relation between depressive symptoms and cardiovascular disease or mortality. One study observed that physical inactivity partly explained the relation between depression and cardiovascular mortality, and that there was no interaction between depression and physical inactivity (9). In contrast, the second study showed that depression did not explain the association between exercise and all-cause mortality and cardiovascular events (5). These studies were carried out in patients with CHD. It is not known what the role of depression and physical activity is in the origins of CVD, to what extent physical inactivity explains the association between depressive symptoms and cardiovascular mortality in subjects without prevalent CVD at baseline, and whether depressive symptoms and physical inactivity may interact in the development of CVD.
In the present study, we set out to determine the prospective independent and combined effects of depressive symptoms and physical inactivity on the 10-yr cardiovascular mortality in a population-based sample of European elderly men.
The FINE study.
The FINE (acronym for Finland, Italy, and the Netherlands Elderly) study is a prospective, population-based cohort study on risk factors and health in elderly men. The study design and measurements have been described in detail elsewhere (4). In brief, the FINE study started in 1984 as a continuation of the Seven Countries Study (SCS), which was originally initiated in 1958 by Keys as a cardiovascular risk factor survey among 12,763 middle-aged men (18). In total, 2285 men from Finland (N = 716), Italy (N = 682), and the Netherlands (N = 887) participated in the baseline examination of the study in 1985. Informed consent was obtained from all study participants. In 1985 in Finland, the research was approved by the ethics committee of the Kuopio University Hospital and in the Netherlands by the medical ethics committee of the University of Leiden. In Italy, an ethical committee at the local level approved the research. Data collection followed the international protocol used in previous surveys of the SCS (18). In 1989-1991, the second round of the FINE study took place. In this round, depressive symptoms were assessed. Mortality data were collected until the year 2000.
Depressive symptoms were measured using the Self-Rating Depression Scale (SDS), developed by Zung (40). This scale was developed to assess depression among patients admitted to a psychiatric hospital, but also for noninstitutionalized elderly (42), and it was found to be highly comparable among different countries (41). The reliability of the SDS is good in elderly men (Cronbach alpha = 0.75) (19) and has been validated repeatedly with other questionnaires on depressive symptoms, such as the CESD (r = 0.69) (11), the GDS (r = 0.59) (12), and the Hamilton depression scale (r = 0.80) (2). The questionnaire contains 20 either positively or negatively formulated items, based on clinical diagnostic criteria commonly used to diagnose depressive disorders. The answers on those items are coded on a four-point Likert-type scale varying from none or sometimes to most or always. Positive items on the absence of depressive symptoms were recoded, so that a higher score indicated more depressive symptoms. An index for the SDS was derived by dividing the sum of the answers by 80 times 100 (range 25-100), with a higher score indicating more depressive symptoms (42). The original clinical cutoff values are no depression (< 50), mild depression (50-59), and moderate to severe depression (≥ 60) (42). For the analyses, a continuous measure was used (per standard deviation; Finland SD = 10.6, Italy SD = 11.3, and the Netherlands SD = 9.6), and the SDS was categorized into country-specific tertiles. The cutoff values for the middle and high tertiles were 42 and 51 for Finland, 45 and 54 for Italy, and 39 and 46 for the Netherlands.
Physical activity was assessed with a self-administered validated questionnaire, designed for retired men (10). The questionnaire has a substantial 4-month test-retest correlation (r = 0.93) and has been validated against the doubly labeled water technique (r = 0.61) in a subsample of the Dutch cohort of the FINE study (37).The questionnaire consisted of items on the frequency, durations, and pace of walking and bicycling during the previous week, the average amount of time spent weekly on hobbies and gardening (in both summer and winter), and the average amount of time spent monthly on odd jobs and sports. Type of odd jobs, sports, and hobbies (e.g., dancing or fishing) were also assessed. The Finnish and the Italian questionnaires further contained items on farming in summer and winter. All types of activity with an intensity of > 2 kcal of energy expended per kilogram of body weight during 1 h (e.g., fishing and playing billiards), reflecting multiples of resting oxygen consumption, were summed to obtain the total duration of physical activity expressed in minutes per week (4). For the analyses, duration of physical activity was used as continuous variable (30 min·d−1) and categorized into country-specific tertiles. The cutoff values for the middle and high tertiles were 315 and 795 for Finland, 335 and 965 for Italy, and 308 and 675 for the Netherlands.
Cardiovascular end points.
Mortality data were collected during 10 yr of follow-up. In Finland, information on causes of death was obtained from the Finnish death register, whereas in Italy and the Netherlands information was obtained from hospital registries and/or general practitioners. One person from Finland, one from Italy, and one from the Netherlands were lost to follow-up. They were included in the analyses but were censored at the date of the examination round after which they were lost to follow-up. Coding of causes of death for all countries was done by one clinical epidemiologist who was blinded for the risk-factor status of the subject. Mortality from CVD was coded according to the International Classification of Diseases, ninth revision (ICD-9: 390-459). In the analyses, primary (N = 214) and secondary (N = 120) causes of death were combined, and 256 men died from CVD. Men who died from causes other than CVD (N = 215) were censored at date of death. Men who were still alive at the end of the study were censored at the last examination date.
The self-administered questionnaire contained questions on marital status, educational level, alcohol consumption, and smoking habits. Marital status was classified as living alone (unmarried, separated, or widowed) or together. Educational level was expressed as years of education. In Finland and Italy, habitual alcohol consumption was assessed with a self-administered questionnaire, whereas in the Netherlands it was assessed in the dietary survey. Men were classified as consumers or nonconsumers. According to their smoking habits, men were divided in nonsmokers and current smokers.
Body mass index (BMI) was calculated from weight and height (kg·m−2), which were measured while the participant was standing in light clothing without shoes. Arterial blood pressure was measured twice on the right arm after 5 min of rest, with the man in a supine position. In Finland and Italy, standard mercury sphygmomanometers were used, whereas in the Netherlands a random zero sphygmomanometer was used. The average of two readings of both systolic and diastolic blood pressure (fifth Korotkoff phase) was calculated. Venous blood samples (fasting in Finland and nonfasting in Italy and the Netherlands) were taken, and total and high-density lipoprotein (HDL) cholesterol (mM) were determined using standardized procedures according to the criteria of the World Health Organization's lipid reference laboratories in Prague, Czechoslovakia, or the U.S. Centers for Disease Control and Prevention in Atlanta, GA (20).
History of MI was obtained using the London School of Hygiene and Tropical Medicine questionnaire (29), verified by information from general practitioners or hospital registries. A clinical history of stroke, heart failure and diabetes was based on a doctor's conclusion using questionnaire information and the results of the physical examination.
Depressive symptoms were measured during the second round of the FINE study, between October 1989 and November 1991, when in total 1416 men (82%) participated of the 1734 men still alive. Of these, 909 (64%) were free of CVD and diabetes. Thus, a study sample of 909 men remained for analysis: 268 men from Finland, 261 men from Italy, and 380 men from the Netherlands.
To enlarge power and to prevent bias from missing values in a selective group of respondents a single imputation procedure in SPSS version 12.0.1 was used. We imputed missing values on the items of the SDS (on average 7%), physical activity (3%), and the other covariates (on average 2%). All information of the baseline examination in 1990 and follow-up examinations was used to fill in missing values.
Frequency distributions are given for categorical variables for each country. Means and standard deviations were computed for continuous baseline variables, and medians and 10th to 90th percentiles for continuous variables with a skewed distribution. Differences between countries were tested with ANOVA, Kruskal-Wallis (in case of skewed distribution), or χ2 test.
Cross-sectional associations between depressive symptoms and physical activity at baseline were examined with multiple linear regression analyses. Depression was the independent variable (tertiles) and physical activity was the dependent variable, and adjustments were made for demographics and lifestyle factors. Robust standard errors were calculated to account for the violation-of-normality assumption.
Cox proportional hazard analyses were performed to estimate the prospective association between a decrease in physical activity with 30 min·d−1 and cardiovascular mortality. Analyses were adjusted for potential confounding or intermediated factors such as age (as the time scale), country (Finland vs the Netherlands and Italy vs the Netherlands), years of education, living alone (yes vs no), current smoking (no vs yes), alcohol consumption (yes vs no), BMI (kg·m−2), systolic blood pressure (mm Hg), and total and HDL cholesterol levels (mM).
The prospective associations between depressive symptoms (per SD) and cardiovascular mortality were estimated using Cox proportional hazard models. In the first model, hazard ratios were adjusted for confounding or intermediated factors such as age, country, years of education, living alone, current smoking, alcohol consumption, BMI, systolic blood pressure, and total and HDL cholesterol levels. In the second model, additional adjustment was made for duration of physical inactivity (continuously) to examine the extent to which physical inactivity could be an intermediate or confounding factor in the relation between depression and cardiovascular mortality. The percent reduction was calculated by one minus the estimate of depressive symptoms in the model with physical inactivity divided by the estimate of depressive symptoms in the model without physical activity. Accompanying confidence limits were also calculated (21).
Finally, we investigated whether depressive symptoms and physical inactivity interacted on the risk of cardiovascular mortality. To examine the biological interaction-that is, whether the combined risk of depressive symptoms and physical inactivity is larger then the sum of the separate risks-interaction should depart from additivity rather than from multiplicativity (which examines the statistical interaction). Therefore, interaction was examined on an additive scale (30). Dummy variables were created for the combination of tertiles of depressive symptoms with tertiles of physical activity. Subjects with depressive symptoms in the low tertile and duration of physical activity in the high tertile served as the reference group. Departure from additivity was calculated using the formula for the relative excess risk attributable to interaction (RERI = RR(AB) − RR(A) − RR (B) + 1) (30), and a 95% confidence limit was calculated (15). All analyses were repeated within strata of country.
All analyses were performed with the SAS statistical software package (version 9.1.2) and SPSS (version 12.0.1). Point estimates are given with corresponding 95% confidence intervals (CI).
At baseline, the average depression score was highest in Italy (49.6; SD = 11) and lowest in the Netherlands (43.2; SD = 10). Men in Italy were older, more physically active, and had higher HDL cholesterol levels than men in Finland and the Netherlands, whereas men in the Netherlands had higher levels of education, were more likely to smoke, had lower systolic and diastolic blood pressure, and had higher total cholesterol levels compared with those in Finland and Italy (P < 0.05) (Table 1).
Multiple linear regression analyses, adjusted for age, country, and living alone, showed that men in the middle and high tertiles of depressive symptoms were less physically active (722 min·wk−1; 95% CI, 642-802; and 562 min·wk−1; 95% CI, 466-658, respectively) compared with men in the low tertile of depressive symptoms (919 min·wk−1; 95% CI, 823-1015) (Fig. 1). Additional adjustment for education, current smoking, and alcohol consumption did not change these estimates.
After 10 yr of follow-up, 471 (52%) of the 909 men had died. Two hundred fifty-six men (28%) had died from CVD. The total number of person-years was 6550, and the mean follow-up duration was 7.2 yr (SD = 3.1). A decrease in physical activity with 30 min·d−1 showed an increased risk of cardiovascular mortality with 9% (95% CI, 1.04-1.14), after adjusting for age. Additional adjustment for demographic and cardiovascular risk factors did not change this risk.
An increase in depressive symptoms with 1 SD was associated with a 42% higher risk of cardiovascular mortality (95% CI, 1.26-1.60), after adjusting for age, country, education and living alone. Adjustment for current smoking, alcohol consumption, BMI, systolic blood pressure, and total and HDL cholesterol did not change this risk. After additional adjustment for physical inactivity, the risk decreased to some extent (9%; 95% CI, 0.01-0.18), but an independent risk remained (HR = 1.37; 95% CI, 1.21-1.56). There were no significant differences between countries. Analyses with the primary death causes showed the same estimates, with wider confidence intervals (results not shown).
Figure 2 shows the combined effect of depressive symptoms and physical inactivity on cardiovascular mortality adjusted for age, country, education, and living alone. Men with more depressive symptoms (high tertile) and a low level of physical activity (low tertile) had an increased risk of cardiovascular mortality (HR = 4.22; 95% CI, 2.56-6.91) in comparison with men with few depressive symptoms (low tertile) and a high level of physical activity (high tertile). The HR for nondepressed but inactive men was 1.69 (95% CI, 0.89-3.18) and was 2.06 (95% CI, 1.12-3.80) for the depressed and active men. The excess risk of cardiovascular mortality that could be attributed to the interacting effect of depressive symptoms and physical inactivity was 4.22 − 1.69 − 2.06 + 1 = 1.47 (95% CI, −0.17 to 3.11). The proportion of cardiovascular mortality among men with more depressive symptoms and low physical activity that could be attributable to the interaction of these factors was 1.47/4.22 = 33%. There were no differences for the combined effects between countries (results not shown).
The results of this study show that depressive symptoms in elderly men are associated with a lower level of physical activity, and that depressive symptoms (HR = 1.42 per SD increase) and physical inactivity (HR = 1.09 per 30-min decrease) both increase the risk of cardiovascular mortality. However, physical inactivity does not materially explain the relation between depressive symptoms and cardiovascular mortality. Instead, depressive symptoms and physical inactivity may interact to increase the risk of cardiovascular mortality (excess risk 1.47).
The major strengths of this study are its prospective design with a long follow-up period, and the almost 100% complete mortality follow-up that minimizes the possibility of bias attributable to selective loss to follow-up. Also, this is the first study that examines the independent and combined effects of depressive symptoms and physical inactivity on cardiovascular mortality in initially healthy older men. In addition, physical activity was measured with a questionnaire specifically designed for older men, and different types and duration of activity were assessed in detail. This will have made misclassification less likely.
Some methodological limitations of the current study also need to be considered. First, the selective participation of healthier respondents may have led to a dilution of the observed associations. Second, in an observational study, the possibility of residual confounding can never be excluded. We tried to minimize this possibility by adjusting for many known classical cardiovascular risk factors in the analyses. Third, it could be argued that depressive symptoms and physical inactivity are markers of subclinical CVD, thus reflecting reversed causality. We tried to minimize this possibility by excluding men with prevalent CVD at baseline. In addition, in a previous paper we have shown that reversed causality was unlikely, because exclusion of subjects who died within the first 5 yr of follow-up, and who were more likely to have had asymptomatic CVD, did not change the risk estimate of depressive symptoms for cardiovascular mortality (17). Fourth, because we assessed depressive symptoms at a single point in time, we do not know the extent to which changes in the severity of depressive symptoms over time influenced CVD mortality risk. Fifth, it could be argued that our findings may not be generalized to women. However, previous studies show that the association between depression and CVD, as well as the association between physical activity and CVD, do not differ between men and women. Therefore, we have no reason to assume that the results of the present study do not apply to older women.
Our results show an increased risk of cardiovascular mortality with more depressive symptoms in elderly men free of CVD at baseline. This is concordant with the risk estimates observed in other studies in the elderly (22,26,38). In addition, we observed a lower duration of physical activity to be associated with an increased risk of cardiovascular mortality, which is concordant with consistent reports of an inverse association between physical activity and coronary heart disease and cardiovascular mortality in the elderly (3,35). Following from the literature (7,34), we hypothesized that physical inactivity could be an intermediate or confounding factor in the relation between depressive symptoms and cardiovascular mortality. At baseline, men with more depressive symptoms were indeed less physically active. However, physical inactivity did not materially explain the association between depressive symptoms and cardiovascular mortality. We determined the 95% CI interval for the 9% reduction in the risk of depressive symptoms after adjusting for physical inactivity, which ranged from 0.01 to 0.18. Because of the relatively wide interval, the 9% reduction estimate is imprecise, and it is thus possible that there is no reduction at all. In addition, after adjusting for physical activity a strong independent effect of depressive symptoms remained. We therefore concluded that physical activity was not likely to be a mediator. Therefore, it is not likely that in older men physical inactivity is an intermediate or confounding factor in this relation. Other possible explanations for this relation could be dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, inflammation, platelet reactivity, and autonomic dysfunction (25).
The combined effects of physical activity and depression on cardiovascular mortality have not been investigated before in the elderly. Although the confidence interval indicated borderline significance, the results of the present study suggest that depression and physical inactivity interact on an additive scale, indicating that the combination of the two risk factors has a greater effect than the sum of the two separate effects. This is suggestive for a possible biological interaction between depression and physical inactivity. This indicates that, in addition to other classical risk factors, depression and physical inactivity are necessary, but not sufficient, factors in a proportion of CVD deaths (30).
What are the possible mechanisms through which this interaction may occur? It has been hypothesized that depression increases risk of CVD by dysregulation of the HPA axis, which may lead to atherosclerosis-inducing actions, such as injury of vascular endothelial cells, hypertension, hypercholesterolemia, and inflammation (25). Physical activity, on the other hand, might slow down the atherosclerotic process (27). The hypothesized antidepressive effects of physical activity include increased aerobic capacity (6), an increase in circulating concentrations of brain amines and beta-endorphin (28), increased feelings of mastery or self-efficacy (23), distraction, a reduction in negative thought patterns (16), and reduced activity of the HPA axis and decreased cortisol levels (33). One explanation for a possible interaction between depression and physical inactivity to increase CVD risk may be that depressed persons who are inactive are more prone to atherosclerotic processes than depressed persons who remain active. Another explanation may be that depressed persons may become less active (34) and that this inactivity may also lead to persistence or worsening of the depression, thereby increasing the risk of CVD even further.
In summary, the results of the present study show that physical inactivity does not explain the association between depressive symptoms and cardiovascular mortality, and depressive symptoms are associated with an increased risk, independent of physical activity and other CVD risk factors. However, the combination of depressive symptoms and physical inactivity may result in an excess risk of cardiovascular mortality, suggesting that a proportion of the cardiovascular mortality cases is dependent on the joint presence of depression and physical inactivity. Further research is needed to confirm these results and explain the possible underlying mechanisms.
This study was supported by grant number 2001b176 of the Netherlands Heart Foundation and previous grants of the National Institute on Aging, National Institutes of Health, Beshesda, Md, USA, The Academy of Finland, Finland and the Netherlands Prevention Foundation, The Hague, The Netherlands.
Conflict of interest: None
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