University of Groningen
Shades of a blue heart
Moreira da Rocha de Miranda Az, Ricardo
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Publication date: 2018
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Moreira da Rocha de Miranda Az, R. (2018). Shades of a blue heart: An epidemiological investigation of depressive symptom dimensions and the association with cardiovascular disease. University of Groningen.
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Chapter 2
Cognitive/affective and
somatic/affective symptoms of
depression in patients with
heart disease and the
association with cardiovascular
prognosis
de Miranda Azevedo R, Roest AM, Hoen PW, de Jonge P. Cognitive/affective and somatic/affective symptoms of depression in patients with heart disease and their association with cardiovascular prognosis: A meta-analysis. Psychol Med. 2014:1-15.37
INTRODUCTION
Major depression is common in patients with heart disease, with a
prevalence of around 20% following acute myocardial infarction (MI)1.
However, the interpretation of the prognostic role of depression in patients with heart disease is still subject of debate. Two meta-analyses found that depression was related to a 2 to 2.5 fold increased risk of
mortality and cardiovascular events in MI and heart disease patients2,3.
Nevertheless, it has also been reported that adjustment for cardiovascular disease severity and other disease-specific risk factors was often
incomplete in individual studies4. Thus, it is unknown to what extent
depression is a truly independent prognostic risk factor, or one that is
confounded by cardiovascular disease severity4.
It has been hypothesized that the type of depression in patients
with heart disease is not the same as in the general psychiatric population.
Ormel and de Jonge5 suggested an integrative model in which two
prototypical forms of depression would comprise depression in patients with heart disease. These forms differ in terms of etiology and prognosis: a cognitive/affective subtype, marked by psychosocial vulnerability (e.g. avoidant coping, neuroticism, stress vulnerability) and a somatic/affective subtype, characterized by vascular disease [e.g. atherosclerosis, inflammation markers, sickness behavior, and deregulation of the hypothalamic-pituitary-adrenal (HPA) axis]. This model has been supported by findings from prospective longitudinal studies, which investigated specific dimensions of depressive symptoms and their association with
cardiovascular prognosis. Mostly, in these studies authors distinguished
two symptom dimensions: Cognitive/affective (e.g. pessimism, guilt, and self-dislike) and somatic/affective (e.g. insomnia, fatigue, and work difficulty) depressive symptoms6,7. However, other distinctions were made as well, such as including an appetitive dimension8. A significant association between somatic/affective symptoms of depression and cardiovascular mortality among MI patients, even after adjustment for
somatic health status, was reported by de Jonge et al8. By contrast,
cognitive/affective depressive symptoms were not predictive of adverse outcomes. The same pattern of findings was reported in other studies in
36
ABSTRACT
BACKGROUND AND OBJECTIVES: Several prospective longitudinal studies
have suggested that somatic/affective depressive symptoms, but not cognitive/affective depressive symptoms, are related to prognosis in patients with heart disease, but findings have not been consistent. The objective of this study was to investigate the association between cognitive/affective and somatic/affective symptoms of depression with cardiovascular prognosis in patients with heart disease using a meta-analytic -.
METHODS: A systematic search was performed in PUBMED, EMBASE, and
PsycInfo. Thirteen prospective studies on symptom dimensions of depression and cardiovascular prognosis fulfilled inclusion criteria summing a total of 11,128 subjects. The risk estimates for each dimension of depressive symptoms, demographic and methodological variables were extracted from the included articles. RESULTS: In least-adjusted analyses, both the somatic/affective (HR: 1.30, 95% CI = 1.19–1.41, p < .001) and the cognitive/affective (HR: 1.07, 95% CI = 1.00–1.15, p = .05) dimensions of depressive symptoms were associated with cardiovascular prognosis. In fully adjusted analyses, somatic/affective symptoms were significantly associated with adverse prognosis (HR: 1.19; 95%CI: 1.10–1.29; p < .001) but cognitive/affective symptoms were not (HR: 1.04; 95%CI: 0.97–1.12; p = .25). A one standard deviation (±1SD) increase in the scores of the somatic/affective dimension was associated with a 32% increased risk of adverse outcomes (HR Random, 1.32; 95% CI: 1.17–1.48; p < .001).
CONCLUSIONS: Somatic/affective depressive symptoms were more
strongly and consistently associated with mortality and cardiovascular events in patients with heart disease compared with cognitive/affective symptoms. Future research should focus on the mechanisms through which somatic/affective depressive symptoms may affect cardiovascular prognosis.
37
INTRODUCTION
Major depression is common in patients with heart disease, with a
prevalence of around 20% following acute myocardial infarction (MI)1.
However, the interpretation of the prognostic role of depression in patients with heart disease is still subject of debate. Two meta-analyses found that depression was related to a 2 to 2.5 fold increased risk of
mortality and cardiovascular events in MI and heart disease patients2,3.
Nevertheless, it has also been reported that adjustment for cardiovascular disease severity and other disease-specific risk factors was often
incomplete in individual studies4. Thus, it is unknown to what extent
depression is a truly independent prognostic risk factor, or one that is
confounded by cardiovascular disease severity4.
It has been hypothesized that the type of depression in patients
with heart disease is not the same as in the general psychiatric population.
Ormel and de Jonge5 suggested an integrative model in which two
prototypical forms of depression would comprise depression in patients with heart disease. These forms differ in terms of etiology and prognosis: a cognitive/affective subtype, marked by psychosocial vulnerability (e.g. avoidant coping, neuroticism, stress vulnerability) and a somatic/affective subtype, characterized by vascular disease [e.g. atherosclerosis, inflammation markers, sickness behavior, and deregulation of the hypothalamic-pituitary-adrenal (HPA) axis]. This model has been supported by findings from prospective longitudinal studies, which investigated specific dimensions of depressive symptoms and their association with
cardiovascular prognosis. Mostly, in these studies authors distinguished
two symptom dimensions: Cognitive/affective (e.g. pessimism, guilt, and self-dislike) and somatic/affective (e.g. insomnia, fatigue, and work difficulty) depressive symptoms6,7. However, other distinctions were made as well, such as including an appetitive dimension8. A significant association between somatic/affective symptoms of depression and cardiovascular mortality among MI patients, even after adjustment for
somatic health status, was reported by de Jonge et al8. By contrast,
cognitive/affective depressive symptoms were not predictive of adverse outcomes. The same pattern of findings was reported in other studies in
36
ABSTRACT
BACKGROUND AND OBJECTIVES: Several prospective longitudinal studies
have suggested that somatic/affective depressive symptoms, but not cognitive/affective depressive symptoms, are related to prognosis in patients with heart disease, but findings have not been consistent. The objective of this study was to investigate the association between cognitive/affective and somatic/affective symptoms of depression with cardiovascular prognosis in patients with heart disease using a meta-analytic -.
METHODS: A systematic search was performed in PUBMED, EMBASE, and
PsycInfo. Thirteen prospective studies on symptom dimensions of depression and cardiovascular prognosis fulfilled inclusion criteria summing a total of 11,128 subjects. The risk estimates for each dimension of depressive symptoms, demographic and methodological variables were extracted from the included articles. RESULTS: In least-adjusted analyses, both the somatic/affective (HR: 1.30, 95% CI = 1.19–1.41, p < .001) and the cognitive/affective (HR: 1.07, 95% CI = 1.00–1.15, p = .05) dimensions of depressive symptoms were associated with cardiovascular prognosis. In fully adjusted analyses, somatic/affective symptoms were significantly associated with adverse prognosis (HR: 1.19; 95%CI: 1.10–1.29; p < .001) but cognitive/affective symptoms were not (HR: 1.04; 95%CI: 0.97–1.12; p = .25). A one standard deviation (±1SD) increase in the scores of the somatic/affective dimension was associated with a 32% increased risk of adverse outcomes (HR Random, 1.32; 95% CI: 1.17–1.48; p < .001).
CONCLUSIONS: Somatic/affective depressive symptoms were more
strongly and consistently associated with mortality and cardiovascular events in patients with heart disease compared with cognitive/affective symptoms. Future research should focus on the mechanisms through which somatic/affective depressive symptoms may affect cardiovascular prognosis.
39
METHODS Inclusion Criteria
The present study followed the Preferred Reporting Items for
Systematic reviews and Meta-Analyses (PRISMA) statement13 and the
Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) proposal
for reporting14. The inclusion criteria of the present study were derived
from four relevant characteristics of the studies, regarding to patient group, depressive symptoms, outcomes, and study design.
1. Type of patients: Patients had to be diagnosed with one of the following conditions: coronary heart disease (CHD), acute coronary syndrome, myocardial ischemia, congestive heart failure, or MI. Studies focusing on patients who underwent CABG surgery or cardioverter defibrillator implantation were included. One study with subjects with (suspected) myocardial ischemia of whom 39.3% had a history of
cardiovascular disease was also included15.
2. Measurement of depressive symptoms: Depressive symptoms had to be measured using valid and reliable instruments (interviews or self-reports), after being diagnosed with one of the conditions listed in inclusion criteria 1. Moreover, dimensions of n cognitive/affective and somatic/affective depressive symptoms had to be identified.
1. Prognostic outcomes: Endpoints had to contain cardiovascular mortality, all-cause mortality, or cardiovascular events (e.g. rehospitalization, stroke, congestive heart failure).
4. Study design: Studies had to be prospective (cohort or intervention study), with a minimum follow-up time of 12 months. Only
38
MI patients and patients with acute coronary syndrome7,9. However, two
studies in patients undergoing coronary artery bypass graft (CABG) surgery reported an association of cognitive/affective but not somatic/affective
symptoms of depression with cardiovascular mortality10 and recurrent
cardiovascular events11.
In a narrative review on this topic by Carney & Freedland (2012), although most studies reported that somatic/affective symptoms were stronger predictors of adverse cardiovascular prognosis than cognitive/affective symptoms, the authors state that it is not yet possible
to come to a conclusion12. Several sources of bias were suggested, such as
methodological inconsistencies across the studies (factor analytic technique and covariate adjustment), and response bias (social acceptability of reporting somatic/affective symptoms versus cognitive/affective symptoms of depression). Most importantly, however, the literature on this issue lacks of systematic approaches combining the
existing evidence. The aim of the current study was therefore to
investigate whether cognitive/affective and somatic/affective depressive symptoms are differentially associated with cardiovascular prognosis. We conducted a meta-analysis of prospective longitudinal studies assessing the association of cognitive/affective and somatic/affective depressive symptoms in patients with heart disease with cardiovascular prognosis.
39
METHODS Inclusion Criteria
The present study followed the Preferred Reporting Items for
Systematic reviews and Meta-Analyses (PRISMA) statement13 and the
Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) proposal
for reporting14. The inclusion criteria of the present study were derived
from four relevant characteristics of the studies, regarding to patient group, depressive symptoms, outcomes, and study design.
1. Type of patients: Patients had to be diagnosed with one of the following conditions: coronary heart disease (CHD), acute coronary syndrome, myocardial ischemia, congestive heart failure, or MI. Studies focusing on patients who underwent CABG surgery or cardioverter defibrillator implantation were included. One study with subjects with (suspected) myocardial ischemia of whom 39.3% had a history of
cardiovascular disease was also included15.
2. Measurement of depressive symptoms: Depressive symptoms had to be measured using valid and reliable instruments (interviews or self-reports), after being diagnosed with one of the conditions listed in inclusion criteria 1. Moreover, dimensions of n cognitive/affective and somatic/affective depressive symptoms had to be identified.
1. Prognostic outcomes: Endpoints had to contain cardiovascular mortality, all-cause mortality, or cardiovascular events (e.g. rehospitalization, stroke, congestive heart failure).
4. Study design: Studies had to be prospective (cohort or intervention study), with a minimum follow-up time of 12 months. Only
38
MI patients and patients with acute coronary syndrome7,9. However, two
studies in patients undergoing coronary artery bypass graft (CABG) surgery reported an association of cognitive/affective but not somatic/affective
symptoms of depression with cardiovascular mortality10 and recurrent
cardiovascular events11.
In a narrative review on this topic by Carney & Freedland (2012), although most studies reported that somatic/affective symptoms were stronger predictors of adverse cardiovascular prognosis than cognitive/affective symptoms, the authors state that it is not yet possible
to come to a conclusion12. Several sources of bias were suggested, such as
methodological inconsistencies across the studies (factor analytic technique and covariate adjustment), and response bias (social acceptability of reporting somatic/affective symptoms versus cognitive/affective symptoms of depression). Most importantly, however, the literature on this issue lacks of systematic approaches combining the
existing evidence. The aim of the current study was therefore to
investigate whether cognitive/affective and somatic/affective depressive symptoms are differentially associated with cardiovascular prognosis. We conducted a meta-analysis of prospective longitudinal studies assessing the association of cognitive/affective and somatic/affective depressive symptoms in patients with heart disease with cardiovascular prognosis.
41 mean or median time of follow-up, labels of depressive symptom dimensions, method to generate the symptom dimensions, covariates used in the multivariate analyses, end-points, effect estimates [e.g. hazard ratios (HRs) and odds ratios (ORs)] and occurrence of the end-point. To pool the studies, we selected the analyses with the lowest number of covariates for the least-adjusted models and with the highest number of covariates in the fully adjusted models. In cases where more than two dimensions of depressive symptoms were reported in one study, we selected the two dimensions most comparable to dimensions of the other studies. To check if the dimensions are similar with regard to individual items, we listed the way these symptoms loaded each dimension across the studies. Statistical Analyses The overall meta-analysis consisted of pooling the effect sizes (HRs
and ORs) for both cognitive/affective and somatic/affective symptoms dimensions. As not every study reported unadjusted results, we conducted least-adjusted and fully adjusted analyses. If the same study reported on multiple end-points, the hierarchy for inclusion in the overall analysis was: cardiovascular mortality, all-cause mortality, and cardiovascular events.
Heterogeneity was assessed with the I2 index: a value of 25% implies a
small degree of heterogeneity, a value of 50% a moderate degree, and 75% a large degree16. Because significant heterogeneity across methods of individual studies (different end-points, questionnaires and patient groups) was expected, a random-effects model was chosen a priori rather than a fixed-effects model, as the first takes into account the within- and between-study variation of the distribution17.
To aid the interpretability of the pooled effect size, we performed a subgroup analysis of studies that calculated their risk statistic using ±1
standard deviation (±1 S.D.), rather than arbitrary values in the depressive
symptoms dimensions subscales. To calculate it, we used the following formula, where HRI is the hazard ratio associated with a symptom dimension i, SDi is the standard deviation of the symptom dimension score 40 studies presenting original data were included. Identification of Studies We used four strings of free terms that we screened for in titles and abstracts of studies available in the literature. The first string represented the patient group: Cardiac OR Heart OR Myocard*. The second string resembled depressive symptoms: Depress*. The third string described the dimensions of depressive symptoms: Somatic OR Cognitive OR Fatigue. The fourth and last string represented the outcomes: Mortality OR Prognos*. The literature search was performed in the following electronic databases:
EMBASE, PubMed and PsycINFO, following previous work2-4. The results of
this search included all studies previously reviewed by Carney and
Freedland12, validating our search strategy. No limits regarding to language
and year were applied. We also hand searched other systematic reviews and meta-analyses on the association between depression and heart disease. In case of two studies reporting on the same sample, we selected the one most comparable to the rest of the studies (based on the questionnaire used and the objectives of the study). The literature search was performed on 04-01-2013.
The selection of studies was performed by two independent raters (R.deM.A. and A.M.R.) in two steps. The first step consisted of screening titles and abstracts obtained from the systematic search. Potentially relevant studies were included in the second step, which consisted of full text reading. The level of agreement between raters was represented by the Cohen’s κ coefficient.
Data Extraction
The following data was extracted from the included studies: number of participants (sample size and percentage lost to follow-up), country, year of baseline assessment, percentage of males, mean age,
41 mean or median time of follow-up, labels of depressive symptom dimensions, method to generate the symptom dimensions, covariates used in the multivariate analyses, end-points, effect estimates [e.g. hazard ratios (HRs) and odds ratios (ORs)] and occurrence of the end-point. To pool the studies, we selected the analyses with the lowest number of covariates for the least-adjusted models and with the highest number of covariates in the fully adjusted models. In cases where more than two dimensions of depressive symptoms were reported in one study, we selected the two dimensions most comparable to dimensions of the other studies. To check if the dimensions are similar with regard to individual items, we listed the way these symptoms loaded each dimension across the studies. Statistical Analyses The overall meta-analysis consisted of pooling the effect sizes (HRs
and ORs) for both cognitive/affective and somatic/affective symptoms dimensions. As not every study reported unadjusted results, we conducted least-adjusted and fully adjusted analyses. If the same study reported on multiple end-points, the hierarchy for inclusion in the overall analysis was: cardiovascular mortality, all-cause mortality, and cardiovascular events.
Heterogeneity was assessed with the I2 index: a value of 25% implies a
small degree of heterogeneity, a value of 50% a moderate degree, and 75% a large degree16. Because significant heterogeneity across methods of individual studies (different end-points, questionnaires and patient groups) was expected, a random-effects model was chosen a priori rather than a fixed-effects model, as the first takes into account the within- and between-study variation of the distribution17.
To aid the interpretability of the pooled effect size, we performed a subgroup analysis of studies that calculated their risk statistic using ±1
standard deviation (±1 S.D.), rather than arbitrary values in the depressive
symptoms dimensions subscales. To calculate it, we used the following formula, where HRI is the hazard ratio associated with a symptom dimension i, SDi is the standard deviation of the symptom dimension score 40 studies presenting original data were included. Identification of Studies We used four strings of free terms that we screened for in titles and abstracts of studies available in the literature. The first string represented the patient group: Cardiac OR Heart OR Myocard*. The second string resembled depressive symptoms: Depress*. The third string described the dimensions of depressive symptoms: Somatic OR Cognitive OR Fatigue. The fourth and last string represented the outcomes: Mortality OR Prognos*. The literature search was performed in the following electronic databases:
EMBASE, PubMed and PsycINFO, following previous work2-4. The results of
this search included all studies previously reviewed by Carney and
Freedland12, validating our search strategy. No limits regarding to language
and year were applied. We also hand searched other systematic reviews and meta-analyses on the association between depression and heart disease. In case of two studies reporting on the same sample, we selected the one most comparable to the rest of the studies (based on the questionnaire used and the objectives of the study). The literature search was performed on 04-01-2013.
The selection of studies was performed by two independent raters (R.deM.A. and A.M.R.) in two steps. The first step consisted of screening titles and abstracts obtained from the systematic search. Potentially relevant studies were included in the second step, which consisted of full text reading. The level of agreement between raters was represented by the Cohen’s κ coefficient.
Data Extraction
The following data was extracted from the included studies: number of participants (sample size and percentage lost to follow-up), country, year of baseline assessment, percentage of males, mean age,
43
of a scatterplot displaying the effect sizes of individual studies on the horizontal axis and the standard error of the effect sizes on the vertical axis. If publication bias is absent, the display should be comparable to a funnel. In case it is asymmetrical, with studies apparently missing in the lower left side of the scatterplot, publication bias is likely to be present. Comprehensive Meta-Analysis version 2.2 was used to perform the analyses. 42 and Ui is the unit of the associated risk (e.g. per one-point increase in the symptom dimension score)18. ! !" !"!×!"!÷!!
Subgroup analyses were planned a priori and were based on: endpoints (all-cause mortality, cardiovascular mortality, and cardiovascular events), patient group (MI patients), assessment of depressive symptoms [Beck Depression Inventory (BDI)] and covariate adjustment (studies that adjust and studies that did not adjust simultaneously for both dimensions of depressive symptoms). Subgroup analyses were performed on fully adjusted results.
One study reported results for two independent arms (drug versus placebo), and it was therefore included twice (once for each arm). In one study, cognitive/affective and somatic/affective symptoms were included
as dichotomous variables19. To keep in line with the other studies, the
authors provided us with the results including both dimensions as continuous variables. As not every author reported their results with the risk associated to a 1 SD increase in the symptom dimension, we requested means and standard deviations for the dimensions that were not reported in the manuscripts. One author provided us with the means and SDs for
each dimension of depressive symptoms10.
To assess the agreement on symptom assignment to one of the two
dimensions a multi-rater kappa coefficient was estimated for the BDI-I20. In
order to get a conservative estimate, loss of appetite and weight loss were considered as cognitive/affective items for specific studies in which these items were excluded or included in a third dimension. Although loss of appetite and weight loss were not considered as cognitive/affective symptoms in any of the studies, we classified these items as cognitive/affective in these cases in order to avoid the possibility of overestimating the coefficient of agreement.
The possible presence of publication bias was examined using three
different approaches: visual assessment of the funnel plot, the Egger’s
43
of a scatterplot displaying the effect sizes of individual studies on the horizontal axis and the standard error of the effect sizes on the vertical axis. If publication bias is absent, the display should be comparable to a funnel. In case it is asymmetrical, with studies apparently missing in the lower left side of the scatterplot, publication bias is likely to be present. Comprehensive Meta-Analysis version 2.2 was used to perform the analyses. 42 and Ui is the unit of the associated risk (e.g. per one-point increase in the symptom dimension score)18. ! !" !"!×!"!÷!!
Subgroup analyses were planned a priori and were based on: endpoints (all-cause mortality, cardiovascular mortality, and cardiovascular events), patient group (MI patients), assessment of depressive symptoms [Beck Depression Inventory (BDI)] and covariate adjustment (studies that adjust and studies that did not adjust simultaneously for both dimensions of depressive symptoms). Subgroup analyses were performed on fully adjusted results.
One study reported results for two independent arms (drug versus placebo), and it was therefore included twice (once for each arm). In one study, cognitive/affective and somatic/affective symptoms were included
as dichotomous variables19. To keep in line with the other studies, the
authors provided us with the results including both dimensions as continuous variables. As not every author reported their results with the risk associated to a 1 SD increase in the symptom dimension, we requested means and standard deviations for the dimensions that were not reported in the manuscripts. One author provided us with the means and SDs for
each dimension of depressive symptoms10.
To assess the agreement on symptom assignment to one of the two
dimensions a multi-rater kappa coefficient was estimated for the BDI-I20. In
order to get a conservative estimate, loss of appetite and weight loss were considered as cognitive/affective items for specific studies in which these items were excluded or included in a third dimension. Although loss of appetite and weight loss were not considered as cognitive/affective symptoms in any of the studies, we classified these items as cognitive/affective in these cases in order to avoid the possibility of overestimating the coefficient of agreement.
The possible presence of publication bias was examined using three
different approaches: visual assessment of the funnel plot, the Egger’s
45
Hence a total of 13 studies were included in the meta-analysis, providing data on 11,128 participants. The characteristics of these studies are displayed in Table 1. The results of the individual studies are presented in Table 2.
Dimensions of depressive symptoms
Among the 13 included studies, 10 used the BDI questionnaire to
measure symptoms of depression6-10,15,19,24-26. The following items were in
general found to represent a cognitive/affective dimension: sadness (80%), pessimism (90%), sense of failure (100%), dissatisfaction (70%), guilt (100%), self-punishment (100%), self-dislike (100%), self-accusations (100%), suicidal-ideation (100%), crying (70%), irritability (50%), social withdrawal (90%), indecisiveness (70%) and change in body image (50%). The individual symptoms (work difficulty, insomnia, fatigability, somatic preoccupation, and loss of libido) were considered somatic/affective symptoms in all studies that used the BDI. Loss of appetite was regarded as a somatic/affective symptom in 80% of the studies, but in one of the
studies it loaded higher on a third “appetitive” dimension8. The other study
used the same division proposed by de Jonge et al, therefore this item was
not included in the analyses19. The item weight loss was also regarded as
appetitive in one study8, was not included in another study19 and did not
load on either a cognitive/affective or somatic/affective dimension in two
studies9,24. The agreement on BDI symptom assignment to one of the two
dimensions across studies was moderate (κ= 0.60)20,27.
Only one study used the BDI-II11, and yielded a three-factor solution
(cognitive, affective, and somatic symptoms). Two studies28,29 assessed
depressive symptoms with the Patient Health Questionnaire (PHQ-9). In both studies, two dimensions were derived from previous knowledge
based on a confirmatory factor analysis on this questionnaire8: a cognitive
dimension consisting of the following symptoms: depressed mood, lack of
interest, worthlessness, concentration problems, and suicidal ideation.
Also, a somatic dimension consisting of appetite problems, sleeping
difficulties, psychomotor agitation/retardation, and fatigue.
44 RESULTS
A flow diagram of the literature search is displayed in Figure 1. The
agreement between raters was good to very good22. Cohen’s κ was 0.82 for
the first, and 0.79 for the second step. A total of 14 studies met our inclusion criteria. However, since authors of one study could not provide the confidence intervals (CIs) of the effect estimate, this study could not be
included in the analyses23.
45
Hence a total of 13 studies were included in the meta-analysis, providing data on 11,128 participants. The characteristics of these studies are displayed in Table 1. The results of the individual studies are presented in Table 2.
Dimensions of depressive symptoms
Among the 13 included studies, 10 used the BDI questionnaire to
measure symptoms of depression6-10,15,19,24-26. The following items were in
general found to represent a cognitive/affective dimension: sadness (80%), pessimism (90%), sense of failure (100%), dissatisfaction (70%), guilt (100%), self-punishment (100%), self-dislike (100%), self-accusations (100%), suicidal-ideation (100%), crying (70%), irritability (50%), social withdrawal (90%), indecisiveness (70%) and change in body image (50%). The individual symptoms (work difficulty, insomnia, fatigability, somatic preoccupation, and loss of libido) were considered somatic/affective symptoms in all studies that used the BDI. Loss of appetite was regarded as a somatic/affective symptom in 80% of the studies, but in one of the
studies it loaded higher on a third “appetitive” dimension8. The other study
used the same division proposed by de Jonge et al, therefore this item was
not included in the analyses19. The item weight loss was also regarded as
appetitive in one study8, was not included in another study19 and did not
load on either a cognitive/affective or somatic/affective dimension in two
studies9,24. The agreement on BDI symptom assignment to one of the two
dimensions across studies was moderate (κ= 0.60)20,27.
Only one study used the BDI-II11, and yielded a three-factor solution
(cognitive, affective, and somatic symptoms). Two studies28,29 assessed
depressive symptoms with the Patient Health Questionnaire (PHQ-9). In both studies, two dimensions were derived from previous knowledge
based on a confirmatory factor analysis on this questionnaire8: a cognitive
dimension consisting of the following symptoms: depressed mood, lack of
interest, worthlessness, concentration problems, and suicidal ideation.
Also, a somatic dimension consisting of appetite problems, sleeping
difficulties, psychomotor agitation/retardation, and fatigue.
44 RESULTS
A flow diagram of the literature search is displayed in Figure 1. The
agreement between raters was good to very good22. Cohen’s κ was 0.82 for
the first, and 0.79 for the second step. A total of 14 studies met our inclusion criteria. However, since authors of one study could not provide the confidence intervals (CIs) of the effect estimate, this study could not be
included in the analyses23.
46 Tab le 1. O verv iew o f t he po ol ed st ud ies Fi rs t a ut ho r, ye ar Pat ie nt s N Me an age (y ea rs ) M al e (% ) N at io n an d ye ar o f s tudy Lo st to FU (% ) De pre ss iv e sy m pt om qu es tio nn ai re or in te rv ie w Sy m pt om di m en si on s Me th od us ed fo r asse ssi ng de pre ssi ve sy mp to m di m en si on FU (ye ars ) Endp oi nt s Be kk e-Ha ns en , 2 01 2 MI 2442 60 .8 56 .2 US A, 1996 N/ A BDI -I C vs . S PCA 2. 3* Ca rd iov as cu la r m or ta lit y, al l-c au se m or ta lit y an d ca rd iov as cu la r e ve nt s ( no n- fa ta l M I) Va n de n Br oe k 2011 IC D 591 62 .7 80 .7 Ne th er la nd s, 2003 8. 4 BDI -I C vs . S OD BS 3. 2 † Al l-c au se m or ta lit y and ca rd iov as cu la r m or ta lit y Tu lly , 201 1 CA BG 222 63 .0 83 .2 Au st ra lia , 1999 N/ A BDI -II AF v s. C v s. S C FA 4. 9 † Co m po sit e o f ca rd iov as cu la r e ve nt s a nd m or ta lit y (fa ta l o r n on fa ta l M I, un st ab le an gi na pe ct or is, re pe at re va sc ul ar iza tio n, he ar t fa ilu re , s us tai ne d ar rh yt hm ia , s tr oke o r ce re br ov as cu la r a cc id en t, le ft ve nt ric ul ar fa ilu re a nd m or ta lit y)
47 Ro es t, 2011 ACS 874 62 .0 65 .5 Ca na da , 1 997 1. 2 BDI -I C vs . S PCA 1. 0‡ Al l-c au se m or ta lit y Ho en , 20 10 CH D 1019 67 .0 82 .0 US A, 2000 < 1 PH Q -9 C vs . S Pr io r s tudy (C FA ) 6. 0‡ Co m po sit e of ca rd iov as cu la r ev en ts a nd m or ta lit y (h ea rt fa ilu re , M I, st ro ke , t ra ns ie nt isc he m ic at ta ck, o r d eat h) Co nn er ne y, 201 0 CA BG 309 63 .1 67 .0 US A, 1997 N/ A BDI -I C vs . S OD BS 9. 3 † Ca rd iov as cu la r m or ta lit y M ar te ns , 2 01 0 MI 419 59 .0 78 .0 Ne th er la nd s, 2003 0. 0 BDI -I C vs . S PCA 2. 8 Co m po sit e of ca rd iov as cu la r ev en ts (n on - fa ta l M I) an d m or tal ity Sc hi ffe r, 20 09 CH F 357 65 .6 71 .6 Ne th er la nd s, 2003 0. 0 BDI -I C vs . S Pr io r s tudy (C FA ) 3. 1 Al l-c au se m or ta lit y Li nk e, 2 00 9 S M IS 550 58 .4 0. 0 US A, 1996 12 .5 § BDI -I C vs . S PCA 5. 8 † Co m po sit e o f ca rd iov as cu la r e ve nt s an d m or ta lit y (c on ge st iv e he ar t fa ilu re , s tr ok e, M I a nd m or ta lit y) Sm ol de re n, 2 00 9 MI 2347 59 .1 ║ 67 .9 US A, 2003 0. 0 ¶ PH Q -9 C vs . S Pr io r s tudy (C FA ) 4. 0‡# Al l-c au se m or ta lit y and re ho sp ital iza tio n de Jo ng e, 2 00 6 MI 494 60 .6 81 .0 Ne th er la nd s, 1997 6. 4 BDI -I AP v s. C v s. S C FA 2. 5 Ca rd iov as cu la r m or ta lit y an d ca rd iov as cu la r e ve nt s (u ns ta bl e ang in a, re cur re nt M I, su st ai ne d ar rh yt hm ia , he ar t f ai lu re , p er ip he ra l ar te ria l d ise as e, ot he r ca rd iov as cu la r e ve nt s ne ed in g ho sp ita liz ati on )
49 Ta bl e 2. O ver vi ew o f t he of the a ss oc ia tions of c og ni tiv e/ af fe ct iv e and som at ic /a ffe ct iv e sy m pt om s of de pr es sion and ca rdi ov as cul ar pr og nos is. Fi rst a ut ho r Ad ju st m en t En dp oi nt s O ccu rr en ce o f en dp oi nt Po in t es tim at e (95% C I) Ad ju st m en t Po in t es tim at e (95% C I) Bek ke -H ans en Tr ea tm en t gr ou p All -c au se m or tal ity 13. 7% Co gn iti ve /a ffe ct iv e: HR: 0 .7 9 (0 .7 0-0. 90) † Tr ea tm en t g ro up , a ge , s ex , eth ni ci ty , m ari ta l s ta tu s, educ at ion, hous ehol d inc om e and low pe rc ei ve d soc ia l suppor t. Co gn iti ve /a ffe ct iv e: HR: 0 .9 4 (0 .8 3-1. 07) Som at ic /af fe ct iv e: HR: 1 .4 1 (1 .2 6-1. 58) † Som at ic /af fe ct iv e: HR: 1 .2 4 (1 .1 0-1. 40) Car di ov as cu lar m orta lity 8. 5% Co gn iti ve /a ffe ct iv e: HR : 0. 84 (0. 72 –0. 98) * Co gn iti ve /a ffe ct iv e: HR: 0 .9 9 (0 .8 4– 1. 16) Som at ic /af fe ct iv e: HR: 1 .3 6 (1 .1 8– 1. 58) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .0 3– 1. 41) N on -fa ta l M I (Ca rdi ov as cul ar ev ent ) 13. 8% Co gn iti ve /a ffe ct iv e: HR : 1. 00 (0. 90 –1. 13) † Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 –1. 18) Som at ic /af fe ct iv e: HR: 1 .3 0 (1 .1 6– 1. 46) † Som at ic /af fe ct iv e: HR : 1. 25 (1. 10 –1. 41) Tr ea tm en t gr ou p, a ge, se x, e th nic ity , m ar ita l st at us , e duc at ion, hous ehol d inc om e, lo w p er cei ved so ci al suppor t, hi st or y of CH F, LV EF an d pr ev ious M I. All -c au se m or tal ity 13. 7% Co gn iti ve /a ffe ct iv e: HR : 0. 95 (0. 84 –1. 09) Tr ea tm ent g roup , a ge , s ex , eth ni ci ty , m ari ta l s ta tu s, educ at ion, hous ehol d inc om e, lo w p er cei ved so ci al su pp or t, hi st or y of CH F, L VE F, pr ev ious M I, pul m ona ry di se as e, di abe te s, m al ig nanc y and re na l di se as e. Co gn iti ve /a ffe ct iv e: HR: 0 .9 3 (0 .8 2-1. 06 )† Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 1-1. 29) Som at ic /af fe ct iv e: HR: 1 .0 9 (0 .9 6-1. 24) † Car di ov as cu lar m orta lity 8. 5% Co gn iti ve /a ffe ct iv e: HR : 1. 00 (0. 85 –1. 18) Co gn iti ve /a ffe ct iv e: HR : 0. 98 (0. 83 -1. 16) * Som at ic /af fe ct iv e: HR: 1 .0 9 (0 .9 3– 1. 28) Som at ic /af fe ct iv e: HR : 1. 05 (0. 89 -1. 23) * N on -fa ta l M I (Ca rdi ov as cul ar ev ent ) 13. 8% Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 –1. 18) Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 -1. 18) † Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .0 7– 1. 37) So m ati c/ affe cti ve : HR: 1 .1 6 (1 .0 3-1. 32) † 48 Abb re vi at io ns : AC S: A cu te C or on ar y Sy nd ro m e; A F: A ffe cti ve s ym pt om s of d ep re ss io n; A P: A pp eti tiv e sy m pt om s of d ep re ss io n; B DI -I: B ec k’s D ep re ss io n In ve nt or y ve rs io n I; BD I-II : Be ck ’s D ep re ss io n In ve nt or y ve rs io n II; C : C ogn iti ve /a ffe cti ve s ym pt om s of d ep re ss io n; C AB G : P at ie nt s w ho u nd er w en t a C or on ar y Ar te ry B yp as s Gr af t; CF A: C on fir m at or y Fa ct or an al ys is; C H D: C or on ar y He ar t D ise as e; C H F: C on ge sti ve H ea rt F ai lu re ; IC D: P ati en ts w ho u nd er w en t Im pl an ta bl e Ca rd iov er te r D ef ib ril la to r i m pl an ta tio n; M I: My oc ar di al In fa rc tio n; N /A : In fo rm ati on n ot a va ila bl e; O DB S: O rig in al d iv isi on a s pr op os ed by B ec k and S te er 2 4 ; P CA : Pr in cip al C om po ne nt A nal ys is; PH Q -9 : Pa tie nt H eal th Q ue sti onn ai re 9; S : So m ati c/ af fe cti ve s ym pt om s o f d ep re ss io n; S M IS : S us pe ct ed M yo ca rd ia l I sc he m ia . * M ea n fo r fo llow -up m or tal ity ; 2 .1 ye ar s fo r n on -fat al M I † Me di an ‡ N o sp ec ifi c sta tis tic s § Mi ss in g fo llo w -up, c ov ar ia te d at a or in co m pl et e BD I ║V al ue fo r p ati en ts w ith h ig h sc or e on s om ati c/ af fe cti ve s ym pt om s ¶ Da ta w as c om pl et e fo r m or ta lit y. T he p er ce nt age lo st to fo llo w -up fo r r eh os pi ta liz at io n w as 9 .0 % . # Va lue fo r m or ta lit y. T he fo llo w -up ti m e fo r r e-ho sp ita liz at io n w as o f 1 -y ea r. ** Mi ss ing d at a Fr as ur e-Smi th , 2003 MI 870 59 .4 74 .1 Ca na da , 1 991 2. 9 BDI -I C vs . S OD BS 5. 0‡ Ca rd iov as cu la r m or ta lit y Ir vi ne , 1 99 9 MI 634 63 .8 82 .8 Ca na da , 1 990 10 ** BDI -I C vs . S OD BS 2. 0‡ Ca rd iov as cu la r m or ta lit y
49 Ta bl e 2. O ver vi ew o f t he of the a ss oc ia tions of c og ni tiv e/ af fe ct iv e and som at ic /a ffe ct iv e sy m pt om s of de pr es sion and ca rdi ov as cul ar pr og nos is. Fi rst a ut ho r Ad ju st m en t En dp oi nt s O ccu rr en ce o f en dp oi nt Po in t es tim at e (95% C I) Ad ju st m en t Po in t es tim at e (95% C I) Bek ke -H ans en Tr ea tm en t gr ou p All -c au se m or tal ity 13. 7% Co gn iti ve /a ffe ct iv e: HR: 0 .7 9 (0 .7 0-0. 90) † Tr ea tm en t g ro up , a ge , s ex , eth ni ci ty , m ari ta l s ta tu s, educ at ion, hous ehol d inc om e and low pe rc ei ve d soc ia l suppor t. Co gn iti ve /a ffe ct iv e: HR: 0 .9 4 (0 .8 3-1. 07) Som at ic /af fe ct iv e: HR: 1 .4 1 (1 .2 6-1. 58) † Som at ic /af fe ct iv e: HR: 1 .2 4 (1 .1 0-1. 40) Car di ov as cu lar m orta lity 8. 5% Co gn iti ve /a ffe ct iv e: HR : 0. 84 (0. 72 –0. 98) * Co gn iti ve /a ffe ct iv e: HR: 0 .9 9 (0 .8 4– 1. 16) Som at ic /af fe ct iv e: HR: 1 .3 6 (1 .1 8– 1. 58) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .0 3– 1. 41) N on -fa ta l M I (Ca rdi ov as cul ar ev ent ) 13. 8% Co gn iti ve /a ffe ct iv e: HR : 1. 00 (0. 90 –1. 13) † Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 –1. 18) Som at ic /af fe ct iv e: HR: 1 .3 0 (1 .1 6– 1. 46) † Som at ic /af fe ct iv e: HR : 1. 25 (1. 10 –1. 41) Tr ea tm en t gr ou p, a ge, se x, e th nic ity , m ar ita l st at us , e duc at ion, hous ehol d inc om e, lo w p er cei ved so ci al suppor t, hi st or y of CH F, LV EF an d pr ev ious M I. All -c au se m or tal ity 13. 7% Co gn iti ve /a ffe ct iv e: HR : 0. 95 (0. 84 –1. 09) Tr ea tm ent g roup , a ge , s ex , eth ni ci ty , m ari ta l s ta tu s, educ at ion, hous ehol d inc om e, lo w p er cei ved so ci al su pp or t, hi st or y of CH F, L VE F, pr ev ious M I, pul m ona ry di se as e, di abe te s, m al ig nanc y and re na l di se as e. Co gn iti ve /a ffe ct iv e: HR: 0 .9 3 (0 .8 2-1. 06 )† Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 1-1. 29) Som at ic /af fe ct iv e: HR: 1 .0 9 (0 .9 6-1. 24) † Car di ov as cu lar m orta lity 8. 5% Co gn iti ve /a ffe ct iv e: HR : 1. 00 (0. 85 –1. 18) Co gn iti ve /a ffe ct iv e: HR : 0. 98 (0. 83 -1. 16) * Som at ic /af fe ct iv e: HR: 1 .0 9 (0 .9 3– 1. 28) Som at ic /af fe ct iv e: HR : 1. 05 (0. 89 -1. 23) * N on -fa ta l M I (Ca rdi ov as cul ar ev ent ) 13. 8% Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 –1. 18) Co gn iti ve /a ffe ct iv e: HR : 1. 05 (0. 93 -1. 18) † Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .0 7– 1. 37) So m ati c/ affe cti ve : HR: 1 .1 6 (1 .0 3-1. 32) † 48 Abb re vi at io ns : AC S: A cu te C or on ar y Sy nd ro m e; A F: A ffe cti ve s ym pt om s of d ep re ss io n; A P: A pp eti tiv e sy m pt om s of d ep re ss io n; B DI -I: B ec k’s D ep re ss io n In ve nt or y ve rs io n I; BD I-II : Be ck ’s D ep re ss io n In ve nt or y ve rs io n II; C : C ogn iti ve /a ffe cti ve s ym pt om s of d ep re ss io n; C AB G : P at ie nt s w ho u nd er w en t a C or on ar y Ar te ry B yp as s Gr af t; CF A: C on fir m at or y Fa ct or an al ys is; C H D: C or on ar y He ar t D ise as e; C H F: C on ge sti ve H ea rt F ai lu re ; IC D: P ati en ts w ho u nd er w en t I m pl an ta bl e Ca rd iov er te r D ef ib ril la to r i m pl an ta tio n; M I: M yo ca rd ia l I nf ar cti on ; N /A : In fo rm ati on n ot a va ila bl e; O DB S: O rig in al d iv isi on a s pr op os ed by B ec k and S te er 2 4 ; P CA : Pr in cip al C om po ne nt A nal ys is; PH Q -9 : Pa tie nt H eal th Q ue sti onn ai re 9; S : So m ati c/ af fe cti ve s ym pt om s o f d ep re ss io n; S M IS : S us pe ct ed M yo ca rd ia l I sc he m ia . * M ea n fo r fo llow -up m or tal ity ; 2 .1 ye ar s fo r n on -fat al M I † M ed ia n ‡ N o sp ec ifi c sta tis tic s § M iss in g fo llo w -up, c ov ar ia te d at a or in co m pl et e BD I ║V al ue fo r p ati en ts w ith h ig h sc or e on s om ati c/ af fe cti ve s ym pt om s ¶ Da ta w as c om pl et e fo r m or ta lit y. T he p er ce nt age lo st to fo llo w -up fo r r eh os pi ta liz at io n w as 9 .0 % . # Va lue fo r m or ta lit y. T he fo llo w -up ti m e fo r r e-ho sp ita liz at io n w as o f 1 -y ea r. ** M iss ing d at a Fr as ur e-Smi th , 2003 MI 870 59 .4 74 .1 Ca na da , 1 991 2. 9 BDI -I C vs . S OD BS 5. 0‡ Ca rd iov as cu la r m or ta lit y Ir vi ne , 1 99 9 MI 634 63 .8 82 .8 Ca na da , 1 990 10 ** BDI -I C vs . S OD BS 2. 0‡ Ca rd iov as cu la r m or ta lit y
51 H oen Ag e Com pos ite of car di ov as cu lar ev en ts and m or tal ity 39. 2% Co gn iti ve /a ffe ct iv e: HR: 1 .1 2 (1 .0 3-1. 21) Ag e, se x, di abe te s, hi st or y of M I, hi st or y of st ro ke , h ist or y of CH F, L VE F, B M I, s m ok in g, as pi rin us e, be ta -bl oc ke r us e, st at in us e and re ni n ang iot ens in sy st em inhi bi tor use . Co gn iti ve /a ffe ct iv e: HR: 1 .0 8 (0 .9 9-1. 17) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .1 1-1. 31) Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 5-1. 24) * Co nn er ney U na dj us te d Car di ov as cu lar m orta lity 20. 1% Co gn iti ve /a ffe ct iv e: HR: 1 .1 0 (1 .0 3-1. 17) * Ag e, se x, L VE F a nd di abe te s. Co gn iti ve /a ffe ct iv e: HR: 1 .1 0 (1 .1 0-1. 17) * Som at ic /af fe ct iv e: HR: 1 .0 8 (0 .9 9-1. 17) * Som at ic /af fe ct iv e: HR: 1 .0 7 (0 .9 8-1. 16) * M ar te ns U na dj us te d Com pos ite of car di ov as cu lar ev en ts and m or tal ity 11. 7% Co gn iti ve /a ffe ct iv e: HR: 1 .1 7 (0 .9 4-1. 44) * Cog ni tiv e/ af fe ct iv e sy m pt om s of de pr es sion and so m ati c/ affe cti ve sy m pto m s o f de pr es sion. . Co gn iti ve /a ffe ct iv e: HR: 1 .0 3 (0 .8 1-1. 32) *†‡ Som at ic /af fe ct iv e: HR: 1 .3 9 (1 .0 8-1. 79) * Som at ic /af fe ct iv e: HR: 1 .3 7 (1 .0 3-1. 82) † Pr ev io us M I an d LV EF Com pos ite of car di ov as cu lar ev en ts and m or tal ity 11. 7% Co gn iti ve /a ffe ct iv e: N /A Som at ic /af fe ct iv e: HR: 1 .3 1 (1 .0 2-1. 69) * 50 Va n de n Br oe k U na dj us te d All -c au se m or tal ity 16. 2% Co gn iti ve /a ffe ct iv e: HR: 1 .0 2 (0 .9 8-1. 07) † Ag e, se x, re la tions hi p, se conda ry pr ev ent ion, co ro nar y ar ter y di seas e, car di ac res yn chr on izat io n the ra py , L VE F <35 % , di abe te s, sm ok er , be ta -bl oc ke rs , ACE in hi bi to rs , app ro pr iat e shoc ks , in ap pr op riat e sh oc ks , co gn iti ve/ af fec tiv e sy m pt om s of de pr es sion and so m ati c/ affe cti ve sy m pto m s o f de pr es sion. Co gn iti ve /a ffe ct iv e: HR: 0 .9 7 (0 .9 1-1. 03) † Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 7-1. 20) † Som at ic /af fe ct iv e: HR: 1 .1 3 (1 .0 4-1. 23) † Car di ov as cu lar m orta lity 11. 7% Co gn iti ve /a ffe ct iv e: HR: 1 .0 2 (0 .9 7-1. 08) * Co gn iti ve /a ffe ct iv e: HR: 0 .9 3 (0 .8 7-1. 00) * Som at ic /af fe ct iv e: HR: 1 .1 8 (1 .1 0-1. 25) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .1 1-1. 33) * Tu lly Ag e, a ffe ct iv e sy m pt om s of de pr es sion, co gn iti ve sy m pt om s of de pr es sion , s om at ic sy m pt om s of de pr es sion, CH F, di abe te s, L VE F < 60 % , re na l di se as e and re spi ra tor y di se as e. Com pos ite of car di ov as cu lar ev en ts and m or tal ity . 29. 3% Affe cti ve : HR: 0 .7 6 (0 .5 5-1. 05) Cogni tiv e: HR: 1 .3 6 (1 .0 2-1. 82) * Som at ic : HR: 1 .1 8 (0 .8 2-1. 70) * Roe st Cog ni tiv e sy m pt om s of de pr es sion and som at ic sy m pt om s of de pr es sion Alll -c au se m or tal ity 5. 8% Co gn iti ve /a ffe ct iv e: HR: 0 .8 7 (0 .6 6-1. 16) * Ag e, d ia be te s, se x, K illip c la ss , pr ev ious M I c ogn iti ve/ af fec tiv e sy m pt om s of de pr es sion and so m at ic /af fec tiv e sy m pt om s of de pr es sion. Co gn iti ve /a ffe ct iv e: HR: 1 .0 7 (0 .7 5-1. 52) * Som at ic /af fe ct iv e: HR: 2 .0 1 (1 .5 2-2. 65) * Som at ic /af fe ct iv e: HR: 1 .9 2 (1 .3 6-2. 71) *
51 H oen Ag e Com pos ite of car di ov as cu lar ev en ts and m or tal ity 39. 2% Co gn iti ve /a ffe ct iv e: HR: 1 .1 2 (1 .0 3-1. 21) Ag e, se x, di abe te s, hi st or y of M I, hi st or y of st ro ke , h ist or y of CH F, L VE F, B M I, s m ok in g, as pi rin us e, be ta -bl oc ke r us e, st at in us e and re ni n ang iot ens in sy st em inhi bi tor use . Co gn iti ve /a ffe ct iv e: HR: 1 .0 8 (0 .9 9-1. 17) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .1 1-1. 31) Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 5-1. 24) * Co nn er ney U na dj us te d Car di ov as cu lar m orta lity 20. 1% Co gn iti ve /a ffe ct iv e: HR: 1 .1 0 (1 .0 3-1. 17) * Ag e, se x, L VE F a nd di abe te s. Co gn iti ve /a ffe ct iv e: HR: 1 .1 0 (1 .1 0-1. 17) * Som at ic /af fe ct iv e: HR: 1 .0 8 (0 .9 9-1. 17) * Som at ic /af fe ct iv e: HR: 1 .0 7 (0 .9 8-1. 16) * M ar te ns U na dj us te d Com pos ite of car di ov as cu lar ev en ts and m or tal ity 11. 7% Co gn iti ve /a ffe ct iv e: HR: 1 .1 7 (0 .9 4-1. 44) * Cog ni tiv e/ af fe ct iv e sy m pt om s of de pr es sion and so m ati c/ affe cti ve sy m pto m s o f de pr es sion. . Co gn iti ve /a ffe ct iv e: HR: 1 .0 3 (0 .8 1-1. 32) *†‡ Som at ic /af fe ct iv e: HR: 1 .3 9 (1 .0 8-1. 79) * Som at ic /af fe ct iv e: HR: 1 .3 7 (1 .0 3-1. 82) † Pr ev io us M I an d LV EF Com pos ite of car di ov as cu lar ev en ts and m or tal ity 11. 7% Co gn iti ve /a ffe ct iv e: N /A Som at ic /af fe ct iv e: HR: 1 .3 1 (1 .0 2-1. 69) * 50 Va n de n Br oe k U na dj us te d All -c au se m or tal ity 16. 2% Co gn iti ve /a ffe ct iv e: HR: 1 .0 2 (0 .9 8-1. 07) † Ag e, se x, re la tions hi p, se conda ry pr ev ent ion, co ro nar y ar ter y di seas e, car di ac res yn chr on izat io n the ra py , L VE F <35 % , di abe te s, sm ok er , be ta -bl oc ke rs , ACE in hi bi to rs , app ro pr iat e shoc ks , in ap pr op riat e sh oc ks , co gn iti ve/ af fec tiv e sy m pt om s of de pr es sion and so m ati c/ affe cti ve sy m pto m s o f de pr es sion. Co gn iti ve /a ffe ct iv e: HR: 0 .9 7 (0 .9 1-1. 03) † Som at ic /af fe ct iv e: HR: 1 .1 4 (1 .0 7-1. 20) † Som at ic /af fe ct iv e: HR: 1 .1 3 (1 .0 4-1. 23) † Car di ov as cu lar m orta lity 11. 7% Co gn iti ve /a ffe ct iv e: HR: 1 .0 2 (0 .9 7-1. 08) * Co gn iti ve /a ffe ct iv e: HR: 0 .9 3 (0 .8 7-1. 00) * Som at ic /af fe ct iv e: HR: 1 .1 8 (1 .1 0-1. 25) * Som at ic /af fe ct iv e: HR: 1 .2 1 (1 .1 1-1. 33) * Tu lly Ag e, a ffe ct iv e sy m pt om s of de pr es sion, co gn iti ve sy m pt om s of de pr es sion , s om at ic sy m pt om s of de pr es sion, CH F, di abe te s, L VE F < 60 % , re na l di se as e and re spi ra tor y di se as e. Com pos ite of car di ov as cu lar ev en ts and m or tal ity . 29. 3% Affe cti ve : HR: 0 .7 6 (0 .5 5-1. 05) Cogni tiv e: HR: 1 .3 6 (1 .0 2-1. 82) * Som at ic : HR: 1 .1 8 (0 .8 2-1. 70) * Roe st Cog ni tiv e sy m pt om s of de pr es sion and som at ic sy m pt om s of de pr es sion Alll -c au se m or tal ity 5. 8% Co gn iti ve /a ffe ct iv e: HR: 0 .8 7 (0 .6 6-1. 16) * Ag e, d ia be te s, se x, K illip c la ss , pr ev ious M I c ogn iti ve/ af fec tiv e sy m pt om s of de pr es sion and so m at ic /af fec tiv e sy m pt om s of de pr es sion. Co gn iti ve /a ffe ct iv e: HR: 1 .0 7 (0 .7 5-1. 52) * Som at ic /af fe ct iv e: HR: 2 .0 1 (1 .5 2-2. 65) * Som at ic /af fe ct iv e: HR: 1 .9 2 (1 .3 6-2. 71) *
53 Sm ol der en U na dj us te d All -c au se m or tal ity 18. 1% (O ve ra ll) Co gn iti ve /a ffe ct iv e: HR: 1 .0 1 (0 .8 9-1. 14) * Ag e, se x, ra ce , di abe te s, pr ior co ro nar y ar ter y di seas e, st ro ke , c hr on ic renal fai lu re, ch ro ni c lu ng di seas e, C HF, n on -sk in ca nc er , c ur re nt sm ok ing , BM I, m ari ta l s ta tu s, e du ca tio n, in su ran ce st at us , w or ki ng st at us , S T-el ev at ion AM I, LV EF ≤40% , h ear t r at e, an gi og rap hy , re va sc ul ar iza tion, pe rc ent a nd num be r of qua lit y of c ar e in di cat or s r ec ei ved Co gn iti ve /a ffe ct iv e: HR: 1 .1 0 (0 .9 7-1. 25) * Som at ic /af fe ct iv e: HR: 1 .2 2 (1 .0 8-1. 39) * Som at ic /af fe ct iv e: HR: 1 .0 7 (0 .9 4-1. 21) * Car di ov as cu lar ev ent s 36. 4% (O ve ra ll) Co gn iti ve /a ffe ct iv e: HR: 1 .0 1 (0 .9 3-1. 11) † Ag e, se x, ra ce , di abe te s, pr ior co ro nar y ar ter y di seas e, st rok e, c hr oni c re na l f ai lur e, ch ro ni c lu ng di seas e, C HF, n on -sk in ca nc er , c ur re nt sm ok ing , BM I, m ari ta l s ta tu s, e du ca tio n, in su ran ce st at us , w or ki ng st at us , S T-el ev at ion AM I, LV EF ≤40% , h ear t r at e, an gi og rap hy , re va sc ul ar iza tion, pe rc ent a nd num be r of qua lit y of c ar e in di cat or s r ec ei ved Co gn iti ve /a ffe ct iv e: HR: 1 .0 0 (0 .9 1-1. 09) † Som at ic /af fe ct iv e: HR: 1 .2 2 (1 .1 1-1. 33) † Som at ic /af fe ct iv e: HR: 1 .1 6 (1 .0 6-1. 29) † 52 Sc hi ffe r U na dj us te d All -c au se m or tal ity 18. 6% Co gn iti ve /a ffe ct iv e: HR: 1 .2 0 (0 .9 8-1. 46) *§ Ag e, L VE F, N YH A c la ss II I/ IV , sm ok ing , k idne y di se as e, ni tr at es, w or k st at us, co gn iti ve/ af fec tiv e sy m pt om s of de pr es sion and so m ati c/ affe cti ve sy m pto m s o f de pr es sion Co gn iti ve /a ffe ct iv e: HR: 1 .0 3 (0 .7 7-1. 37) * § Som at ic /af fe ct iv e: HR: 1 .4 0 (1 .1 2-1. 76) *§ Som at ic /af fe ct iv e: HR: 1 .2 6 (0 .9 2-1. 71) * § Lin ke Cog ni tiv e/ af fe ct iv e sy m pt om s of de pr es sion and so m at ic /af fec tiv e sy m pt om s of de pr es sion Com pos ite of car di ov as cu lar ev en ts and m or tal ity 16. 5% Co gn iti ve /a ffe ct iv e: HR: 0 .7 9 (0 .6 2-1. 02) * Cog ni tiv e/ af fe ct iv e sy m pt om s of de pr es sion, so m ati c/ affe cti ve sy m pto m s o f de pr es sion, ang iog ra phi c se ve rit y sco re s, pe rc ut ane ous co ro nar y int er ven tio n, C AB G , CH F, M I, cer eb ro vas cu lar di se as e and per iphe ra l vas cu lar d iseas e Co gn iti ve /a ffe ct iv e: HR: 0 .8 7 (0 .68 -1. 11) * Som at ic /af fe ct iv e: HR: 1 .7 1 (1 .3 6-2. 14) * Som at ic /af fe ct iv e: HR: 1 .6 3 (1 .2 8-2. 08) * Cog ni tiv e/ af fe ct iv e sy m pt om s of de pr es sion, so m at ic /af fec tiv e sy m pt om s of de pr es sion, ang iog ra phi c se ve rit y sco re s, pe rc ut ane ous co ro nar y int er ven tio n, CA BG , C HF , M I, cer eb ro vas cul ar di se as e, pe riphe ra l vas cu lar d iseas e educ at ion, ra ce , hi st or y of di abe te s a nd sm ok ing hi st or y. Com pos ite of car di ov as cu lar ev en ts and m or tal ity 16. 5% Co gn iti ve /a ffe ct iv e: HR: 0 .8 1 (0 .6 4-1. 03) * Cogni tive/ af fect ive: HR: 0 .8 7 (0 .6 8-1. 11) * Som at ic /af fe ct iv e: 1. 39 (1. 08 -1. 79) *
