Depressive Symptoms and Carotid Artery Intima-Media Thickness in Young Adults: The Cardiovascular Risk in Young Finns Study MARKO ELOVAINIO, PHD, LIISA KELTIKANGAS-JA¨ RVINEN, PHD, MIKA KIVIMA¨ KI, PHD, LAURA PULKKI, PHD, SAMPSA PUTTONEN, MSCI, TARJA HEPONIEMI, PHD, MARKUS JUONALA, MD, JORMA S. A. VIIKARI, MD, PHD, AND OLLI T. RAITAKARI, MD, PHD Objective: Depression and coronary heart disease are often comorbid conditions, but the mechanism behind this link is largely unknown. We tested the hypothesis that a high level of depressive symptoms in healthy young adults would be related to more prevalent preclinical atherosclerosis. Methods: We studied the association between depressive symptoms and carotid atherosclerosis in 1126 young adults (410 men and 716 women) as part of the ongoing population-based Cardiovascular Risk in Young Finns Study. The participants responded to a revised version of Beck’s Depression Inventory in 1992, 1997, and 2001. Carotid atherosclerosis was assessed by measuring the thickness of the common carotid artery intima-media complex with ultrasound in 2001. Cardiovascular risk factors were measured in childhood/adolescence (1980) and in adulthood (2001). Results: In men, high scorers of depressive symptoms in 2001 had higher carotid artery intima-media thickness (0.63 mm) compared with those with low or moderate scores on depressive symptoms (0.57 mm). This relationship (B ⫽ 0.08, F[1, 405] ⫽ 9.24, p ⫽ .003) persisted after adjustment for age and cardiovascular risk factors in adolescence and adulthood. Depression scores in 1992 and 1997 were not predictive of intima-media thickness. In women, no association was found between depressive symptoms and intima-media thickness. Conclusions: Depressive symptoms during early adulthood seem to be associated with higher levels of carotid intima-media thickness in men, but not in women. Key words: depression, atherosclerosis, CHD, psychosocial factors. LDL ⫽ low-density lipoprotein; HDL ⫽ high-density lipoprotein; CHD ⫽ cardiovascular heart disease; CRYF ⫽ Cardiovascular Risk in Young Finns; IMT ⫽ intima-media thickness; BDI ⫽ Beck’s Depression Inventory.

INTRODUCTION he association between unipolar depression and cardiovascular disease is well demonstrated (1,2). Many of the early reports have described how negative emotions precede heart attacks (3,4), and a growing body of epidemiological evidence shows that depression is a risk factor for the development of coronary heart disease (CHD) (5). In the study of Barefoot and Schroll (6), a high level of depressive symptoms predicted the subsequent occurrence of myocardial infarction and mortality in a 21-year follow up. Subjects with clinically manifest CHD suffer from depression more often than those without CHD (7–9). In a large Dutch study, relations were found between various negative psychological states and the occurrence of CHD (10). Despite the well-known association between depression and CHD, little is known about the mechanisms responsible for the link. The diagnosis of CHD may increase depressive symptoms, and depressive patients with CHD may have a worse outcome (23). In addition, direct pathophysiological

T

From the Department of Psychology, University of Helsinki, Helsinki, Finland (M.E., L. K-J., M.K. L.P., S.P., T.H.); STAKES (M.E.); the Institute of Occupational Health (M.K.); the Research Centre of Applied and Preventive Cardiovascular Medicine (M.J.), the Department of Medicine (J.S.A.V.), and the Department of Clinical Physiology (O.T.R.), University of Turku, Turku, Finland. Address correspondence and reprint requests to Olli T. Raitakari, MD, PhD, Department of Clinical Physiology, University of Turku, Kiinamyllynkatu 4 – 8, Turku FIN-20521, Finland. E-mail: [email protected] Received for publication August 23, 2004; revision received March 18, 2005. This study was financially supported by the Academy of Finland (grant no. 77841, 201888, 105195, 209514, and 209518), the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, the Yrjo¨ Jahnsson Foundation, government grants for the Turku University Hospital, the Finnish Foundation of Cardiovascular Research, the Lydia Maria Julin Foundation, and the Finnish Cultural Foundation. DOI: 10.1097/01.psy.0000170340.74035.23 Psychosomatic Medicine 67:561–567 (2005) 0033-3174/05/6704-0561 Copyright © 2005 by the American Psychosomatic Society

mechanisms linking depression to CHD have been suggested (23). In the present study, we tested the hypothesis that a high level of depressive symptoms in young and healthy adults would be related to more prevalent preclinical atherosclerosis. The thickness of the common carotid artery intima-media complex (IMT) measured by ultrasound represents a marker of preclinical atherosclerosis. Increased IMT correlates with cardiovascular risk factors (11,12), the severity of coronary atherosclerosis (13) and predicts cardiovascular events (14 – 16). Previously, hopelessness has been related to increased progression of carotid IMT among middle-aged men (17), whereas negative feelings have been related to increased carotid IMT in hypertensive men (18). Jones and coworkers (19) showed that among middle-aged women, a lifetime history of major depression was associated with plaque but not with IMT. A relationship between arterial calcification and depression among elderly people has also been reported (20). In populations of young adults such as in our study, the noninvasive measurement of carotid IMT has been used as a surrogate marker of cardiovascular health (21–24), but the relationship between depression and preclinical atherosclerosis has previously not been tested (25). However, it has been shown that atherosclerosis begins already in childhood and develops silently in subsequent decades (23). Thus, it would be important to know whether the relationship between depression and atherosclerosis could be detected already at an early age. We prospectively assessed the relation between depressive symptoms and carotid IMT in a 9-year follow up in young healthy adults. To evaluate whether the contribution of depressive symptoms to carotid IMT is independent of cardiovascular risk factors, we took into account the effects of serum low-density lipoprotein (LDL) cholesterol levels, systolic blood pressure, body mass index, and smoking measured in childhood/adolescence and in adulthood. A stronger association would be expected among men than among women, because the female sex is shown to be better protected from early atherosclerosis. 561

M. ELOVAINIO et al. METHODS Subjects and Methods The participants were drawn from the ongoing population-based study, Cardiovascular Risk in Young Finns (CRYF) (26). In this prospective epidemiological study, a randomized sample of 3596 Finnish children and adolescents aged 3, 6, 9, 12, 15, and 18 years at baseline in 1980 were followed with repeated examinations through childhood/adolescence and into adulthood (23). Childhood/adolescent cardiovascular risk factors were measured in 1980. A total of 2370 responded to a survey questionnaire on psychosocial factors such as depressive symptoms in 1992, whereas 2149 responded in 1997. Of the original sample, 2229 participants were reexamined in 2001 by measuring depressive symptoms, adulthood cardiovascular risk factors, and carotid IMT. The number of participants who completed the revised version of Beck’s Depression Inventory (27,28) was 1496 in 1992, 1533 in 1997, and 1731 in 2001. The sample with complete data (IMT measured in 2001 and depression measured in 1992, 1997, and 2001) consisted of 410 men and 716 women who were 3 to18 years of age at the baseline in 1980 (Fig. 1). Those who had a diagnosis of diabetes mellitus were excluded from the study sample. Compared with the eligible population at the baseline of the CRYF study, the participants in the present study were more often women (47% versus 64% female, ␹2 ⫽ 110.24, df ⫽ 1, p ⬍ .001), but other differences in childhood/ adolescence variables were small and statistically insignificant.

Carotid Artery Studies Ultrasound studies were performed using Sequoia 512 ultrasound mainframes (Acuson, CA) with 13.0-MHz linear array transducers. The studies were performed between September 2001 and January 2002. The left carotid artery was scanned by ultrasound technicians following a standardized protocol (23). In brief, a magnified image was recorded from the angle showing the greatest distance between the lumen–intima interface and the media– adventitia interface. A moving scan with a duration of 5 s, which included the beginning of the carotid bifurcation and the common carotid artery was

recorded and stored in digital format on optical discs for subsequent offline analysis. The digitally stored scans were manually analyzed by a single reader who was blind to the details of subjects. The analyses were performed using ultrasonic calipers. From the 5-s clip image, the best quality end-diastolic frame was selected (incident with the R-wave on a continuously recorded electrocardiogram). From this image, at least 4 measurements of the common carotid far wall were taken approximately 10 mm proximal to the bifurcation to derive a mean carotid IMT. To reduce observer bias, the sonographers were instructed to specifically scan the common carotid in the angle showing the greatest IMT. We have reported a 6.4% between-visit coefficient and a 5.2% between-observer coefficient of variation in the IMT measurements (23).

Depressive Symptoms Depressive symptoms were assessed by using a revised version of Beck’s Depression Inventory (BDI) (27,28). The original version of the BDI is a 21-item questionnaire that offers 4 alternative statements for each item. In the present study, the subjects were asked to rate a single statement (e.g., “I often feel sad”) on a 5-point scale ranging from totally disagree (1) to totally agree (5). The 21 items chosen were each the second mildest statement of the items in the original BDI, and they were selected because they have been suggested as the most effective ones to measure depression in the normal population (29,30). The items tap into negative mood, sadness, pessimism, decreased functioning such as indecisiveness and work inhibition, and somatic problems such as insomnia and fatigue. Cronbach’s ␣ reliability for the modified BDI was 0.89 in 1992, 0.91 in 1997, and 0.92 in 2001. The mean score of all items formed a general depressive symptoms index. The correlation between depressive levels of 1992 and 1997 was 0.60 ( p ⬍ .001), between 1992 and 2001 0.53 ( p ⬍ .001), and between 1997 and 2001 0.62 ( p ⬍ .001). Scores for depressive symptoms were used both as continuous and dichotomous variables. The respondents with a mean depression score in the highest decile (mean score ⬎3) were classified into a multiple depressive symptoms group separately in each of the measurement years, whereas others were classified into a fewer depressive symptoms group. The resultant proportions approximate the actual prevalence of severe depression in European populations (6.61% in men and 10.05% in women) (31).

Cardiovascular Risk Factors The risk variables measured in adolescence (in 1980) included LDL cholesterol, body mass index, and systolic blood pressure. The risk factors measured in 2001 were LDL cholesterol, body mass index, systolic blood pressure, and smoking. Smoking status was assessed by a questionnaire. Those smoking on a daily basis were classified as smokers. Body mass index was calculated as weight (kg)/height2 (m2). Height was measured with a wall-stationed statiometer and weight with digital scales. All measurements of lipid levels were performed in duplicate in the same laboratory. Standardized enzymatic methods were used for measuring levels of serum total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol. The LDL cholesterol concentration was calculated by the Friedewald formula (32). Blood pressure was measured with a standard mercury sphygmomanometer in 1980 and with a random zero sphygmomanometer in 2001. The average of 3 blood pressure measurements was used in the statistical analysis. Details of the methods have been reported elsewhere (23). Systolic blood pressure was included into the analyses because it has previously been shown to predict IMT among young adults from 33 to 39 years (23).

Statistical Analysis

Figure 1. 562

Forming the final sample.

Correlation (Pearson) analyses and linear regression analyses were used to examine the univariate relationships between the measured variables. The multivariate relationships between dichotomized depressive symptom scores and carotid IMT were studied by linear regression analyses. All of the dichotomous depression variables measured in 1992, 1997, and 2001 were used as independent variables and the carotid IMT in 2001 was the dependent variable. Statistical models were adjusted for age, childhood/adolescent risk factors (LDL cholesterol, body mass index, and systolic blood pressure), and finally for adulthood risk factors (LDL cholesterol, body mass index, systolic blood pressure, and smoking status). Psychosomatic Medicine 67:561–567 (2005)

DEPRESSION AND CAROTID ATHEROSCLEROSIS TABLE 1. Characteristics of Study Participants (N ⴝ 1126) Mean (SD) Men (N ⫽ 410) Childhood risk factors Age in 1980, yr LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Adulthood risk factors LDL- cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Smoking statusa (%) Depressive symptoms in 1992 (% of cases) Depressive symptoms in 1997 (% of cases) Depressive symptoms in 2001 (% of cases) Carotid IMT, mm a

p

Women (N ⫽ 716)

10.4 (5.0) 3.26 (0.73) 17.7 (2.9) 113 (13)

10.5 (5.0) 3.40 (0.75) 17.7 (2.8) 112 (11)

.645 .007 .977 .100

3.38 (0.92) 25.4 (3.7) 121 (12) 23 5.6 7.1 6.8 0.59 (0.10)

3.12 (0.78) 24.3 (4.4) 112 (12) 17 8.8 10.8 10.6 0.57 (0.09)

.001 .001 .001 .001 .053 .042 .035 .001

Daily smokers (%).

All regression models on depressive symptoms and IMT were made separately for men and women. As the first step, the carotid IMT measured in 2001 was regressed on age and depressive symptoms measured in 1992. Age and depressive symptoms in 1997 were used in the second step, and similarly, depressive symptoms in 2001 were used in the third step. In the fourth step, age and depressive symptoms in 1992, 1997, and 2001 were simultaneously entered as independent variables in the model. Additionally, other risk factors measured in 1980 and in 2001 were added into the fully adjusted regression model. We examined whether depressive symptoms in 1992, 1997, and/or 2001 adjusted for age, depressive symptoms from prior years, and risk factors during childhood and adulthood were associated with carotid IMT. The statistical tests were performed with Statistical Analysis System version 8.01, and statistical significance was inferred at a 2-tailed p value of ⬍.05.

RESULTS The characteristics of study subjects are shown in Table 1. The proportion of those who were highly depressed was greater in women than in men in each year. There were statistically significant differences between men and women in LDL cholesterol level in 1980 and in 2001. Similarly, body mass index and systolic blood pressure were significantly

higher in men. Men were also more often smokers than women (Table 1). Tables 2 and 3 presents the univariate relationships (zero order correlations) between depressive symptoms and other variables. Both continuous and dichotomous depressive symptoms variables were used. In men, body mass index in childhood/adolescence was related to depressive symptoms in 2001. Body mass index in adulthood was related only to the continuous depressive symptoms variable in 2001. Age and adulthood systolic blood pressure were associated with the dichotomous depressive symptoms variable in 1997. In men, IMT was related to both continuous and dichotomous depressive symptoms variables in 2001 (Table 2). In women, body mass index in adulthood was related to variables for continuous depressive symptoms in 1992 and in 2001 and to the variable for dichotomous depressive symptoms in 2001. Smoking was associated with continuous depressive symptoms variables in 1992 and in 1997. In women,

TABLE 2. Correlation Coefficients Between Childhood and Adulthood Factors and Linear and Dichotomous Depression Scores in Men (N ⴝ 841 to 1764) Linear Depression Scores

Age, yr Childhood risk factors LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Adulthood risk factors LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Smoking status, % Thickness of intima media, mm

Dichotomous Depression Scores

1992

1997

2001

⫺0.02

0.05

⫺0.02 0.05 0.00

⫺0.01 0.06 ⫺0.00

0.04 0.11** 0.01

⫺0.01 0.02 0.01

⫺0.04 0.02 ⫺0.01

⫺0.05 0.09 0.02 0.01 ⫺0.03

⫺0.02 0.00 ⫺0.03 ⫺0.03 ⫺0.04

0.04 0.012* 0.05 0.06 0.08***

0.00 0.00 ⫺0.04 ⫺0.01 0.00

⫺0.02 ⫺0.04 ⫺0.06*** ⫺0.02 ⫺0.01

0.07

1992 0.02

1997 0.07***

2001 0.06 0.00 0.06*** 0.02 0.05 0.04 ⫺0.01 0.02 0.08***

* p ⬍ .001, ** p ⬍ .01, *** p ⬍ .05. Psychosomatic Medicine 67:561–567 (2005)

563

M. ELOVAINIO et al. TABLE 3. Correlation Coefficients Between Childhood and Adulthood Factors and Linear and Dichotomous Depression Scores in Women (N ⴝ 1215 to 1832) Linear Depression Scores 1992 Age, yr Childhood risk factors LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Adulthood risk factors LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Smoking status, % Thickness of intima media, mm

Dichotomous Depression Scores

1997

2001

1992

1997

2001

⫺0.09**

⫺0.02

⫺0.01

0.01

⫺0.03

0.02

⫺0.04 ⫺0.02 0.00

⫺0.01 0.00 ⫺0.01

0.00 0.06 0.01

⫺0.02 0.02 ⫺0.01

0.00 ⫺0.03 ⫺0.02

0.01 0.03 ⫺0.01

⫺0.02 0.10* 0.02 0.06*** 0.00

⫺0.05 0.00 ⫺0.00 0.08** ⫺0.03

0.04 0.17* 0.03 0.08 0.01

⫺0.03 0.03 0.02 0.04 ⫺0.01

⫺0.03 ⫺0.00 ⫺0.03 0.04 ⫺0.03

0.05 0.15* 0.03 0.04 0.01

* p ⬍ .001, ** p ⬍ .01, *** p ⬍ .05.

IMT was not related to any of the variables for depressive symptoms (Table 3). In men, the age-adjusted high depressive symptoms in 2001, as indicated with the dichotomous variable (multiple symptoms group), was directly related to carotid IMT in the univariate model (B ⫽ 0.04, F[1, 407] ⫽ 4.51, p ⫽ .034). Similarly, in men, a high level of depressive symptoms was associated with carotid IMT in the model additionally adjusted for previous levels of depressive symptoms (B ⫽ 0.08, F[1, 405] ⫽ 9.24, p ⫽ .003). The mean IMT in multiple symptoms depression group (highest 10%) in 2001 was 0.63 mm and 0.57 mm in others. In women, no statistically significant relations were detected between high levels of depressive symptoms and carotid IMT. The relationship between the continuous depressive symptoms score and IMT was not sta-

tistically significant in men (B ⫽ 0.008, F[1, 407] ⫽ 1.00, p ⫽ .319) nor in women (B ⫽ 0.002, F[1, 713] ⫽ 0.44, p ⫽ .508). The results of the regression analysis with other risk factors and with carotid IMT as the dependent variable are shown in Table 4. In men, the high level of depressive symptoms in 2001 was related to higher IMT after adjustment for age, level of depressive symptoms in 1992 and 1997, childhood/adolescence body mass index, LDL cholesterol, systolic blood pressure, adulthood body mass index, LDL cholesterol, systolic blood pressure, and smoking status (B ⫽ 0.078, F[1, 378] ⫽ 8.93, p ⫽ .002). In women, the additional adjustments did not affect the relationship between high levels of depressive symptoms and IMT. After adjustment for age, and mean scores of childhood/ adolescence and adulthood risk factors (body mass index, LDL cholesterol, and systolic blood pressure), a relationship

TABLE 4. Regression Coefficients (B) for Depressive Symptoms Predicting Carotid IMT in Men and Women. Adjusted for Age, LDL Cholesterol, Body Mass Index, and Systolic Blood Pressure in Childhood/Adolescent (in 1980) and for LDL Cholesterol, Body Mass Index, Systolic Blood Pressure and Smoking Status in Adulthood at Follow up (in 2001) Men (N ⫽ 389)

Women (N ⫽ 689)

Independent Variables

Childhood risk factors Age, years LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Adulthood risk factors LDL-cholesterol, mmol/l Body mass index, kg/m2 Systolic blood pressure, mm Hg Smoking status, % Depressive symptoms in 1992a Depressive symptoms in 1997a Depressive symptoms in 2001a 2 R

B

F-value

B

F-value

0.147 0.00 0.004 0.001

17.22* 0.03 ns 0.48 ns 0.13 ns

0.147 0.000 0.000 0.007

0.22.7* 0.02 ns 0.06 ns 1.11 ns

0.004 0.034 0.046 0.013 0.020 0.024 0.076

0.50 ns 4.00*** 5.01*** 1.62 ns 0.01 ns 2.86 ns 8.93** 0.21

0.000 0.32 0.050 0.001 0.002 0.001 0.002

0.01 ns 4.98** 7.73** 0.18 ns 0.37 ns 0.08 ns 0.23 ns 0.13

Note. All the variables are included in the models simultaneously. * p ⬍ .001, ** p ⬍ .01, *** p ⬍ .05. a Depressive symptoms scores are dichotomized. 564

Psychosomatic Medicine 67:561–567 (2005)

DEPRESSION AND CAROTID ATHEROSCLEROSIS between a high level of depressive symptoms in 2001 and IMT was detected in men (B ⫽ 0.073, F[1, 378] ⫽ 8.63, p ⫽ .004) but not in women (B ⫽ 0.002, F[1, 678] ⫽ 0.35, p ⫽ .553). Similar results were found when using delta scores of childhood/adolescence and adulthood risk factors; the relationship between depressive symptoms in 2001 and IMT in men was statistically significant (B ⫽ 0.074, F[1, 378] ⫽ 8.48, p ⫽ .004). DISCUSSION We found that a high level of depressive symptoms was related to thicker carotid IMT in men at 24 to 39 years of age. This association persisted after adjustments for previous depressive status, age and cardiovascular risk factors measured in childhood/adolescence and adulthood. These findings suggest a pathophysiological link between depression and atherosclerosis. Our results do not, however, establish an etiological role of depression in the development of atherosclerosis among young and healthy adults. The present findings are in line with previous studies suggesting an association between depressive symptoms and increased carotid IMT. Everson and others (17) examined the association between high levels of hopelessness and progression of carotid atherosclerosis in over 900 Finnish middleaged men in the Kuopio Ischemic Heart Disease Study. They reported that high levels of hopelessness were associated with faster progression of carotid IMT during a 4-year follow up. Agewall and coworkers (18) observed that negative feelings (discontent) were related to an increase in the common carotid IMT in a 3-year follow up of 94 hypertensive men in Sweden. Increased level of anxiety, which often correlates with depressive symptoms, has also been associated with faster progression of carotid IMT (33). Prior evidence has consistently shown that emotional problems can contribute to the development of CHD (34), but studies on the possible mechanisms between CHD and depression are only beginning to emerge (25,35). Our results extend these prior observations by showing that a high level of depressive symptoms is associated with a sensitive marker of preclinical atherosclerosis already in young adults, independently of well-established risk factors for CHD. In the present study, the relationship between depressive symptoms and IMT was detectable in men but not in women. Previous studies on the relationship between depression or negative feelings and progression of IMT have been conducted among middle-aged or hypertensive men, whereas women have been almost totally ignored in these studies. The lack of association between depressive symptoms and atherosclerotic process in women should be verified in other studies. However, the subjects in the present study were fairly young, and it has been shown that atherosclerosis develops later in women than in men, because female sex seems to be a protective factor until menopause (probably because of estrogen) (36). In interpreting the present results, it is important to note some limitations. Although the Cardiovascular Risk in Young Psychosomatic Medicine 67:561–567 (2005)

Finns is a population-based longitudinal study with a large sample of 6 age cohorts, the present analysis was restricted to men and women aged 24 to 39 years at the time of the carotid IMT measurement. We did not measure carotid IMT at the baseline. Thus, it is possible that there are common pathophysiological processes behind the association between depressive symptoms and increased IMT or that depressive symptoms are affected by changes in IMT. Confounding factors responsible for the association may include smoking, obesity, elevated blood pressure, and high LDL cholesterol concentration, all of which have been associated with both depression and increased carotid atherosclerosis (2,23,37). However, the association between depressive symptoms and higher carotid IMT remained after adjusting for these cardiovascular risk factors measured in adolescence and in adulthood. There are, of course, other potential cofounders that were not measured in this study such as physical activity. According to our results, there was no relationship between continuous depressive symptoms and IMT, suggesting that only high levels of depressive symptoms contribute to the progression of early atherosclerosis. The measure of depressive symptoms used in this study was a revised version of the widely used Beck’s Depression Inventory, which was revised to be more effective in measuring depressive symptoms in the normal population (29). We dichotomized the depression measure to select a group with a substantial level of depressive symptoms, but we were not able to define a clinically significant cutoff point for the level of depression. Future studies need to investigate the effect of this relationship between the level of depression and IMT. In the present study, carotid IMT was determined from the left carotid artery approximately 10 mm distally below the carotid bulb. At least 4 measurements were obtained to assess mean and maximum carotid IMT. A more complex carotid IMT score involving both internal and common carotid observations might have better predictive value than either measure taken alone. By contrast, IMT of the common carotid artery has been shown to be easily visualized and a highly reproducible measurement, and previous validation data support its use in both studies of risk factor associations and in the cohort (38,39). The association between carotid and coronary atherosclerosis is only marginally increased when information of IMT from the internal carotid and carotid bulb are added to the common carotid IMT, supporting the view that the use of the common carotid IMT may be preferable for certain analyses (38). To our knowledge, this is the first prospective study that examined the association between depressive symptoms and carotid IMT in men and women in their early adulthood. Our results suggest that a high level of depressive symptoms may be directly related to early stages of the atherosclerotic process in men. Although the mechanisms underlying this association are still to be identified, several possibilities exist. These include abnormalities in platelet function, hypercortisolemia, elevated homocysteine levels, endothelial dysfunction, and reduced heart rate variability (25). Moreover, pathophysiological reactions that are typical in depression such as activated 565

M. ELOVAINIO et al. adrenosympathetic mechanisms, altered monoamine levels, and hyperactivity of the hypothalamic pituitary adrenal axis (40 – 42) could underlie the blood vessel abnormalities (43,44). It has also been shown that depression may be associated with heightened expression of inflammatory markers implicated in the pathogenesis of cardiovascular disease (45). Thus, depression may involve several potential pathophysiological mechanisms that could favor the development of atherosclerosis. We detected only a cross-sectional relationship between depressive symptoms and atherosclerosis. In older cohorts including subjects with more advanced atherosclerosis, depressive symptoms have predicted the progression of IMT (16 –18). Our findings raise the possibility that in early stages of the atherosclerotic process, depressive symptoms may act as a marker rather than a predictor of IMT. It is not highly probable that the thickness of the carotid IMT in our study would have reflected an adaptive response as suggested by Bots and others (46). In fact, they concluded that even when IMT of the common carotid artery is unlikely to represent local atherosclerosis, measurement of IMT (⬎0.60 mm) may be used as a marker for total burden of atherosclerosis present in the individual. Compared with other large arteries, atherosclerosis of the common carotid artery tends to develop relatively late in life, and lower degrees of common carotid IMT may indicate the presence of atherosclerosis elsewhere in the arterial system (46). In summary, the present study demonstrates that depressive symptoms are a marker of risk for higher IMT in young healthy men. This evidence provides support for the link between depressive symptoms and early stages of atherosclerosis. Future research needs to examine the mechanisms underlying the observed relationship.

12. 13.

14. 15. 16.

17.

18.

19. 20. 21. 22.

23.

REFERENCES 1. Aromaa A, Raitasalo R, Reunanen A, Impivaara O, Helio¨vaara M, Knekt P, Lehtinen V, Joukamaa M, Maatela J. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl 1994;377:77– 82. 2. Rugulies R. Depression as a predictor for coronary heart disease. A review and meta-analysis. Am J Prev Med 2002;23:51– 61. 3. Sigler LH. Acute myocardial infarction following an emotional disturbance. Am J Cardiol 1960;6:697– 8. 4. Pinckney MM. Acute myocardial infarction precipitated by severe emotional disturbance. Am J Cardiol 1961;7:759 – 60. 5. Hemingway H, Marmot M. Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. BMJ 1999;318:1460 –7. 6. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996; 93:1976 – 80. 7. Blackwood R, Mayou RA, Garnham JC, Armstrong C, Bryant B. Exercise capacity and quality of life in the treatment of heart failure. Clin Pharmacol Ther 1990;48:325–32. 8. Schleifer SJ, Macari-Hinson MM, Coyle DA, Slater WR, Kahn M, Gorlin R, Zucker HD. The nature and course of depression following myocardial infarction. Arch Intern Med 1989;149:1785–9. 9. Sihm I, Dehlholm G, Hansen ES, Gerdes LU, Faergeman O. Psychic vulnerability and type-A behavior among young Danish male survivors of acute myocardial infarction. Nord Psyktr Tidsk 1991;45:451– 6. 10. Appels A, Mulder P. Excess fatigue as a precursor of myocardial infarction. Eur Heart J 1988;9:758 – 64. 11. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and 566

24.

25. 26. 27. 28. 29. 30.

31.

32. 33.

follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis 1988;70:253– 61. Haapanen A, Koskenvuo M, Kaprio J, Kesa¨niemi YA, Heikkila¨ K. Carotid arteriosclerosis in identical twins discordant for cigarette smoking. Circulation 1989;80:10 – 6. Burke GL, Evans GW, Riley WA, Sharrett AR, Howard G, Barnes RW, Rosamond W, Crow RS, Rautaharju PM, Heiss G. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995; 26:386 –91. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96:1432–7. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991; 11:1245–9. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14 –22. Everson SA, Kaplan GA, Goldberg DE, Salonen R, Salonen JT. Hopelessness and 4-year progression of carotid atherosclerosis. The Kuopio Ischemic Heart Disease Risk Factor Study. Arterioscler Thromb Vasc Biol 1997;17:1490 –5. Agewall S, Wikstrand J, Dahlo¨f C, Fagerberg B. Negative feelings (discontent) predict progress of intima-media thickness of the common carotid artery in treated hypertensive men at high cardiovascular risk. Am J Hypertens 1996;9:545–50. Jones DJ, Bromberger JT, Sutton-Tyrrell K, Matthews KA. Lifetime history of depression and carotid atherosclerosis in middle-aged women. Arch Gen Psychiatry 2003;60:153– 60. Tiemeier H, van Dijck W, Hofman A, Witteman JC, Stijnen T, Brete MM. Relationship between atherosclerosis and late-life depression: Rotterdam study. Arch Gen Psychiatry 2004;61:369 –76. O’Leary DH, Polak JF. Intima-media thickness: a tool for atherosclerosis imaging and event prediction. Am J Cardiol 2002;90:18L–21L. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study. Circulation 2001;104: 2815–9. Raitakari OT, Juonala M, Ka¨honen M, Taittonen L, Laitinen T, Ma¨kiTorkko N, Ja¨rvisalo MJ, Uhari M, Jokinen E, Ro¨nnemaa T, Åkerblom HK, Viikari JS. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 2003;290:2277– 83. Li S, Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Berenson GS. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003; 290:2271– 6. Zellweger MJ, Osterwalder RH, Langewitz W, Pfisterer ME. Coronary artery disease and depression. Eur Heart J 2004;25:3–9. Åkerblom HK, Uhari M, Pesonen E, Dahl M, Kaprio EA, Nuutinen EM, Pietika¨inen M, Salo MK, Aromaa A, Kannas L. Cardiovascular risk in young Finns. Ann Med 1991;23:35–9. Beck AT, Steer RA. Manual for the Revised Beck Depression Inventory. San Antonio: TX: Psychological Corp; 1987. Katainen S. Temperament and Development. University of Helsinki; 1999. Nurmi J, Salmela-Aro K, Haavisto T. The strategy and attribution questionnaire: psychometric properties. Eur J Psychol Assess 1995;11: 108 –21. Katainen S, Ra¨ikko¨nen K, Keltikangas-Ja¨rvinen L. Adolescent temperament, perceived social support, and depressive tendencies as predictors of depressive tendencies in young adulthood. Eur J Person 1999;13: 183–207. Ayuso-Mateos JL, Vazquez-Barquero JL, Dowrick C, Lehtinen V, Dalgard OS, Casey P, Wilkinson C, Lasa L, Page H, Dunn G, Wilkinson G, ODIN Group. Depressive disorders in Europe: prevalence figures from ODIN study. Br J Psychiatry 2001;179:308 –16. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499 –502. Paterniti S, Zureik M, Ducimetiere P, Touboul PJ, Feve JM, Alperovitch Psychosomatic Medicine 67:561–567 (2005)

DEPRESSION AND CAROTID ATHEROSCLEROSIS

34. 35.

36. 37.

38.

39.

A. Sustained anxiety and 4-year progression of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 2001;21:136 – 41. Shapiro PA. Psychiatric aspects of cardiovascular disease. Psychiatr Clin North Am 1996;19:613–29. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002;90:1279 – 83. Manson JE. Post menopausal hormone therapy and atherosclerotic disease. Am Heart J 2002;128:1337– 43. Oren A, Vos LE, Uiterwaal CS, Gorissen WH, Grobbee DE, Bots ML. Change in body mass index from adolescence to young adulthood and increased carotid intima-media thickness at 28 years of age: the Atherosclerosis Risk in Young Adults study. Int J Obes Relat Metab Disord 2003;27:1383–90. Crouse JR III, Craven TE, Hagaman AP, Bond MG. Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation 1995;92:1141–7. Kanters SD, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke 1997;28:665–71.

Psychosomatic Medicine 67:561–567 (2005)

40. Matthews KA. Psychological perspectives on the type A behavior pattern. Psychol Bull 1982;91:293–323. 41. Sloan RP, Shapiro PA, Bagiella E, Bigger JT Jr, Lo ES, Gorman JM. Relationships between circulating catecholamines and low frequency heart period variability as indices of cardiac sympathetic activity during mental stress. Psychosom Med 1996;58:25–31. 42. Steptoe A. The assessment of sympathetic nervous function in human stress research. J Psychosom Res 1987;31:141–52. 43. Greenwald BS, Kramer-Ginsberg E, Krishnan RR, Ashtari M, Aupperle PM, Patel M. MRI signal hyperintensities in geriatric depression. Am J Psychiatry 1996;153:1212–5. 44. Lesser IM, Boone KB, Mehringer CM, Wohl MA, Miller BL, Berman NG. Cognition and white matter hyperintensities in older depressed patients. Am J Psychiatry 1996;153:1280 –7. 45. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers fro coronary heart disease. Am. J Cardiology 2002;90:1279 – 83. 46. Bots ML, Hofman A, Grobbee DE. Increased common carotid intimamedia thickness. Adaptive response or reflection of atherosclerosis? Findings from the Rotterdam study. Stroke 1997;28:2442–7.

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