Hopelessness, Depressive Symptoms, and Carotid Atherosclerosis in Women
The Study of Women’s Health Across the Nation (SWAN) Heart Study
Background and Purpose— Depression and hopelessness are associated with increased cardiovascular disease (CVD) morbidity and mortality; however, few studies have compared these constructs early in the atherogenic process, particularly in women or minorities.
Methods— This cross-sectional study examined associations of hopelessness and depressive symptoms with carotid artery intimal-medial thickening (IMT) in 559 women (62% white, 38% black; mean±SD age, 50.2±2.8 years) without evidence of clinical CVD from the Study of Women’s Health Across the Nation (SWAN) Heart Study. Hopelessness was measured by 2 questionnaire items; depressive symptoms were measured with the 20-item Center for Epidemiological Studies Depression Scale. Mean and maximum IMT were assessed by B-mode ultrasonography of the carotid arteries.
Results— Increasing hopelessness was significantly related to higher mean (P=0.0139) and maximum (P=0.0297) IMT in regression models adjusted for age, race, site, income, and CVD risk factors. A weaker pattern of associations was noted for depressive symptoms and mean (P=0.1056) and maximum (P=0.0691) IMT. Modeled simultaneously in a risk factor-adjusted model, hopelessness was related to greater mean IMT (P=0.0217) and maximum IMT (P=0.0409), but depressive symptoms were unrelated to either outcome (P>0.4). No interactions with race or synergistic effects of depressive symptoms and hopelessness were observed.
Conclusions— Among middle-aged women, higher levels of hopelessness are associated with greater subclinical atherosclerosis independent of age, race, income, CVD risk factors, and depressive symptoms.
Depression or depressive symptoms have been associated with increased risk of cardiovascular disease (CVD) morbidity and mortality, although evidence is equivocal.1 Recent investigations have examined depression or depressive symptoms in relation to subclinical CVD, including aortic and coronary calcification, carotid artery intimal-medial thickening (IMT), plaque prevalence, pulse-wave velocity, and endothelial function,2 with mixed results.3–6 Reasons for these inconsistent findings are unclear.
Increasingly, there is interest in determining whether specific features of depression are more atherogenic than others. Such an approach is consistent with research on Type A behavior that ultimately found hostility to be a particularly “toxic” component of that construct with regard to CV risk.7,8 Hopelessness may be 1 such toxic aspect of depression. Hopelessness refers to a negative cognitive style and feelings of futility regarding future goals and aspirations, and it frequently occurs in severe episodes of depression.9 It commonly is included in depressive symptoms checklists,10 and a subtype of depression with hopelessness as a critical feature is recognized.11 Nonetheless, hopelessness is not part of the diagnostic criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV-TR)12 and is not necessary to cause depression; indeed, individuals may experience feelings of hopelessness without meeting criteria for depression.13 Thus, hopelessness may be distinct from depression, a distinction that may be critical when assessing associated health effects. Hopelessness is strongly associated with CVD outcomes in men, independently of depressive symptoms14–16; little is known about its relation with CVD risk in women. Hopelessness has independently predicted clinical cardiovascular outcomes in women with known coronary artery disease,17 but its association with subclinical CVD in healthy women has not been studied.
We examined the cross-sectional association of hopelessness and depressive symptoms with carotid artery IMT in a community cohort of black and white women. Given the inconsistent literature relating depression to subclinical CVD and the emerging evidence showing strong associations between hopelessness and CV outcomes, we hypothesized that hopelessness and depressive symptoms would individually relate to carotid artery IMT, but when considered simultaneously, hopelessness would be more strongly related to IMT than depressive symptoms. Available data on several important CVD risk factors in the Study of Women’s Health Across the Nation (SWAN) allowed us to examine whether effects of hopelessness and depression on IMT were independent of these CVD risk factors. Secondarily, we examined whether associations differed between black and white women.
Subjects and Methods
Participants and Study Design
Participants were women from the Pittsburgh and Chicago sites of SWAN who completed an ancillary study of the natural history of subclinical atherosclerosis (SWAN Heart Study). SWAN, a multiethnic, community-based study of the menopausal transition, enrolled 3302 women in 1996 to 1997 from 7 clinical sites (Chicago, Ill; Pittsburgh, Pa; Boston, Mass; Detroit, Mich; Newark, NJ; Oakland, Calif; and Los Angeles, Calif). Women were eligible if they were age 42 to 52 years; had an intact uterus, at least 1 ovary, at least 1 menstrual period, and no use of reproductive hormones affecting ovarian or pituitary function in the past 3 months; were not currently pregnant or breast-feeding; and self-identified as non-Hispanic white or a member of the site-designated minority group: black (Chicago, Pittsburgh, Boston, Detroit), Hispanic (Newark), Chinese/Chinese-American (Oakland), and Japanese/Japanese-American (Los Angeles). Complete details of the SWAN study design, recruitment, and protocol have been published elsewhere.18
Women enrolled in the SWAN Heart Study from 2001 to 2003, coincident with their fourth or fifth annual SWAN visit for 93.8% of participants or with their sixth or seventh visit for the remainder. Participants were eligible for the SWAN Heart Study if they had at least 1 intact ovary, had no history of CVD, and were not currently taking antihypertensive or diabetes medications. Of the 608 women enrolled in the SWAN Heart Study, 559 had complete data on menopause status and IMT and provided data for the current analyses; population numbers in the analytic models varied on the basis of missing data for the Center for Epidemiological Studies Depression (CES-D) Scale (n=8) or the hopelessness scale (n=46). Comparing those included with those excluded from analyses showed no significant differences between women in terms of predictors, covariates, or outcomes (all P>0.3).
The research protocol was approved by each site’s institutional review board; all women provided written, informed consent.
Measurement of Hopelessness and Depressive Symptoms
Hopelessness was assessed with a 2-item scale,14 administered at the baseline SWAN Heart visit. Items were “The future seems to me to be hopeless, and I can’t believe that things are changing for the better” and “I feel it is impossible for me to reach the goals that I would like to strive for.” Responses to each item were on a 5-point scale (0=strongly agree, 1=somewhat agree, 2=cannot say, 3=somewhat disagree, and 4=strongly disagree), were reverse-scored, and were summed to create a hopelessness score (range, 0 to 8), with higher values indicating greater hopelessness. Scores on this measure have predicted CVD outcomes in men14–16 and form an assessment of hopelessness that appears distinct from closely related constructs like depression. In primary analyses, hopelessness scores were modeled continuously; in secondary analyses, a cutoff score (≥5) was used to identify women with higher hopelessness scores based on conceptualization of responses to the hopelessness items14–16 and taking into consideration the score distribution.
Depressive symptoms were assessed annually in SWAN by the CES-D Scale, which was developed for use in community samples.10 The 20-item scale measures the frequency of being bothered by depressive symptoms in the previous week on a scale of 0 (rarely) to 3 (most or all of the time). Item responses are summed for a total score (range, 0 to 60); higher scores indicate more depressive symptomatology. The CES-D score obtained at the SWAN visit coincident with the baseline SWAN Heart visit was used in analyses. CES-D scores were modeled continuously in primary analyses; in secondary analyses, a standard cutoff (≥16) was used to represent clinically significant depressive symptomatology.19
IMT was assessed by B-mode ultrasonography of the left and right carotid arteries with a Hewlett-Packard 5500 scanner (Hewlett-Packard, Andover, Mass) at the Chicago site and a Toshiba SSA-270A scanner (Toshiba American Medical Systems, Tustin, Calif) at the Pittsburgh site. Image quality was comparable between the 2 systems. Images were obtained from 4 locations each in the left and right carotid arteries: near and far walls of the distal common carotid artery (1 cm proximal to the carotid bulb), far walls of the carotid bulb (at the point where the near and far walls of the common carotid are no longer parallel, extending to the flow divider), and internal carotid artery (from the flow divider to 1 cm distal to this point). The lumen-intima interface and the media-adventitia interface were electronically traced across a 1-cm segment to generate a measure of IMT. One measurement was generated for each pixel, resulting in ≈140 measures for each segment. Average, minimum, and maximum values of these measures were recorded for each location; for analyses, the mean of the average readings and mean of the maximum readings were used.
Information on covariates was obtained at the SWAN Heart baseline visit unless otherwise noted. Age was self-reported and modeled continuously. Women self-identified as either black or white (referent). Body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, was modeled continuously. Systolic blood pressure (SBP), the average of 2 manual measurements after a seated, 5-minute rest, was modeled continuously. Four percent of women were missing BMI or SBP data at the SWAN Heart baseline visit, so their most recently available BMI or SBP values from a prior SWAN visit were used. Smoking status was dichotomized as current smokers versus nonsmokers (referent); for 54 women without concurrent smoking data, their most recently available information from a prior SWAN visit was used. Menopausal status was assessed annually in SWAN and was defined as premenopausal (bleeding in the last 3 months with no cycle irregularity in the previous 12 months), early perimenopausal (bleeding in the last 3 months with some change in cycle regularity in the last 12 months), late perimenopausal (bleeding >3 months ago but within the last 12 months), postmenopausal (no bleeding in the last 12 months), or undetermined (surgery or hormone use precluded determination of natural menopausal status). Annual household income was modeled categorically (<$20 000, $20 000 to <$35 000, $35 000 to <$50 000, $50 000 to <$75 000, and $75 000 or higher [referent]); the most recently available data from a prior SWAN visit was used for 78 women without concurrent income data. Self-reported highest level of education was categorized as high school diploma or less, some college, college degree, or postcollege (referent). Consistent with SWAN guidelines, site was a covariate in all analyses.
We used descriptive statistics to characterize our sample on age, BMI, SBP, menopausal status, education, income, smoking status, hopelessness, depressive symptoms, and mean and maximum IMT. We calculated 3 sets of linear-regression models to examine the relation of hopelessness and depressive symptoms with IMT. In the first set of models, covariates included age, race, and study site; hopelessness or depressive symptoms were modeled continuously in separate models. These models were repeated, adding covariates representing income, BMI, SBP, and smoking status to determine whether associations were independent of known CV risk factors. Third, hopelessness and depressive symptoms were modeled simultaneously in a risk factor-adjusted model.
The risk factor-adjusted model with hopelessness and depressive symptoms included simultaneously was repeated with both hopelessness by race and CES-D by race interaction terms to determine whether associations differed by race. Separate risk factor-adjusted models tested the hopelessness by CES-D interaction to determine whether these constructs had a synergistic effect on IMT and examined dichotomous hopelessness (<5 vs ≥5) or depression (<16 vs ≥16) scores in relation to IMT.
Covariates were selected on the basis of known associations with CVD. The SWAN Heart Study was designed primarily to assess the effect of menopausal status on subclinical CVD, so we examined univariate associations of status with our predictors and IMT; no significant relations were observed, so menopausal status was not included as a covariate. However, because hormone therapy potentially positively affects atherosclerosis, we repeated all models after excluding 30 women who reported hormone replacement therapy at the SWAN Heart baseline; results from these models were identical to results with the full sample reported in the Results. Income was significantly related to hopelessness, depressive symptoms, and IMT in preliminary univariate analyses (P<0.006), whereas education was not; therefore, we included income as a marker of socioeconomic status in our risk factor-adjusted models, but education was used for descriptive purposes only. Analyses were conducted in PC-SAS (version 9.13, SAS Institute, Cary, NC).
Baseline characteristics are shown in Table 1. At SWAN Heart baseline, women were ≈50 years old, most had completed at least some college, average SBP was 119 mm Hg, and mean BMI was 29.1 kg/m2.
As shown in Table 2, the minimally adjusted (“model 1”) and risk factor-adjusted (“model 2”) linear-regression models revealed that increasing hopelessness was associated with higher levels of mean and maximum IMT. Depressive symptoms showed similar, but marginally significant, associations with the outcomes.
With hopelessness and CES-D modeled simultaneously in a risk factor-adjusted model, hopelessness was significantly associated with higher mean and maximum IMT, whereas depressive symptoms were unrelated to IMT. As shown in Table 3, each 1-point higher hopelessness score was related to a 0.0061-mm greater mean IMT and a 0.0074-mm greater maximum IMT. Age, race, site, BMI, and SBP were significant covariates, whereas income and smoking status were nonsignificant.
In secondary analyses to determine whether associations of hopelessness or depressive symptoms with IMT differed by race, all interactions were nonsignificant (mean IMT: hopelessness by race P=0.844, CES-D by race P=0.161; maximum IMT: hopelessness by race P=0.260, CES-D by race P=0.124). Separate risk factor-adjusted models showed no interaction between hopelessness and depressive symptoms for mean (P>0.81) or maximum (P>0.96) IMT. Four percent of women had a high hopelessness score (≥5), and 20% of women had a high CES-D score (≥16). In separate risk factor-adjusted models, women with high hopelessness scores had greater mean (estimate=0.066, P=0.0008) and maximum (estimate=0.068, P=0.012) IMT values than did more hopeful women, whereas depressed and nondepressed women did not differ on mean (P>0.4) or maximum (P>0.5) IMT.
This study examined the associations of depressive symptoms and hopelessness with carotid atherosclerosis in a cohort of healthy black and white women. As hypothesized, higher levels of hopelessness were associated with more IMT, whereas depressive symptoms were not, independent of important CVD risk factors, when these constructs were considered simultaneously. Findings are consistent with previous studies reporting that hopelessness relates to CVD in men14–16 and clinical outcomes in women with documented coronary artery disease.17 To our knowledge, this is the first study to report the association of hopelessness with subclinical CVD among healthy women.
The clinical significance of our findings is highlighted by considering the magnitude of difference in IMT observed with increasing hopelessness: each 1-point higher hopelessness score related to a 0.0061-mm higher mean IMT and a 0.0074-mm higher maximum IMT (Table 3). Thus, a 2-SD difference in hopelessness score would relate to a 0.0195-mm difference in mean IMT and a 0.0237-mm difference in maximum IMT. Moreover, women with high hopelessness scores had ≥0.06-mm greater levels of both mean and maximum IMT values than did women with lower hopelessness scores. These differences are potentially clinically significant. Average annual change in common carotid artery IMT over 10 years among black and white women in the Atherosclerosis Risk in Communities study was 0.008 to 0.009 mm20; other studies report that IMT increases by 0.01 to 0.03 mm per year.21 Such small incremental differences in IMT are associated with increasing CV risk21 as well as incident CVD and stroke.22
Mechanisms linking hopelessness with subclinical atherosclerosis need to be elucidated. Age, BMI, and resting SBP were significant covariates, yet none diminished the relation of hopelessness with IMT. Similarly, the relation of hopelessness with IMT was independent of smoking and income (nonsignificant in the multivariable models) and race (significantly related to mean IMT, marginally related to maximum IMT). Effects of hopelessness have been robust, independent of behavioral, biologic, and demographic characteristics,14–17 indicating that other mechanisms should be considered. Animal studies show that exposure to learned helplessness and uncontrollable stressors – analogs to hopelessness in humans – triggers autonomic, inflammatory, and neuroendocrine alterations23,24 that can potentiate atherogenesis. Alterations in serotonergic function centrally and peripherally may contribute to mood alterations, including depression and hopelessness, and exacerbate CVD risk.25 Significant positive associations of whole-blood serotonin with hopelessness have been reported in a cohort of older women and men,26 but whole-blood serotonin was unrelated to IMT in that cohort.27 Hopelessness likely operates through multiple pathways to influence atherosclerotic risk; future work should focus on several potential mediating mechanisms.
This study raises the question of how hopelessness and depressive symptoms are related. DSM-IV-TR diagnostic criteria for depression do not include hopelessness,12 but consistent evidence for a hopelessness subtype of depression exists,11 and hopelessness commonly is included in depressive symptom checklists, such as the CES-D. Moreover, severe depression often is accompanied by feelings of hopelessness. In our study, the correlation between the 2-item measure of hopelessness and the 20-item CES-D was small but statistically significant (r=0.27, P<0.0001); the association of the single CES-D item, “I felt hopeful about the future,” with the hopelessness scale also was small (r=−0.31, P<0.0001). The correlation of the hopelessness scale with the CES-D is strikingly similar to its association with other depressive symptom checklists.28 It is clear that this measure captures feelings of futility or loss of hope that do not map directly onto other depressive symptoms. Moreover, our pattern of findings suggests hopelessness confers unique risk of CVD.
Blacks had significantly greater mean IMT than did whites in our cohort; however, no significant interactions with hopelessness or depressive symptoms were observed. Other reports from SWAN Heart have observed racial differences. CES-D scores were significantly related to aortic calcification among black participants only in a multivariable model,29 but hopelessness was not included in those analyses. Aortic calcification and IMT represent structural changes to the vasculature and are considered early markers of the atherosclerotic disease process in women30; however, these 2 indices are only modestly correlated in SWAN (r=0.2, P<0.001) and may represent differing underlying processes.31,32
Our study has several strengths. The SWAN Heart Study focused on community-dwelling women, thus enhancing generalizability of findings. We used state-of-the-art assessments of IMT in a well-characterized cohort of women. Finally, we controlled for important CVD risk factors to demonstrate the independent associations of hopelessness and depressive symptoms with IMT.
Limitations include the cross-sectional nature of the data. It remains to be seen whether hopelessness influences atherosclerotic progression in women. Also, SWAN women are relatively healthy, and the majority came from middle- or upper-middle income households; it is unknown whether similar associations would be observed in women with more adverse CV profiles or who experience greater socioeconomic disadvantage, for example, or who differ in other ways from our cohort.
In conclusion, this study demonstrates that hopelessness is a strong and significant correlate of subclinical atherosclerosis in black and white women, independent of depressive symptoms and known CVD risk factors. Further research is needed to understand mechanisms that may mediate this association and to determine whether hopelessness predicts accelerated progression of atherosclerosis in women.
Appendix: Study Sites and Investigators
Clinical Centers: University of Michigan, Ann Arbor-MaryFran Sowers, PI; Massachusetts General Hospital, Boston, Mass-Robert Neer, PI 1994–1999; Joel Finkelstein, PI 1999-present; Rush University, Rush University Medical Center, Chicago, Ill-Lynda Powell, PI 1994–2009; Howard Kravitz, PI 2009-present; University of California, Davis/Kaiser-Ellen Gold, PI; University of California, Los Angeles-Gail Greendale, PI; University of Medicine and Dentistry, New Jersey Medical School, Newark-Gerson Weiss, PI 1994–2004; Nanette Santoro, PI 2004-present; and University of Pittsburgh, Pittsburgh, Pa-Karen Matthews, PI.
NIH Program Office: NIA, Bethesda, Md-Marcia Ory, 1994–2001; Sherry Sherman 1994-present; NINR, Bethesda, Md-Program Officers.
Central Laboratory: University of Michigan, Ann Arbor-Daniel McConnell (Central Ligand Assay Satellite Services).
Coordinating Center: New England Research Institutes, Watertown, Mass-Sonja McKinlay, PI 1995–2001; University of Pittsburgh, Pittsburgh, Pa-Kim Sutton-Tyrrell, PI 2001-present.
Steering Committee: Chris Gallagher, Chair, Susan Johnson, Chair.
We thank the study staff at each site and all of the women who participated in SWAN.
Sources of Funding
The SWAN has grant support from the NIH, Department of Health and Human Services, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women’s Health (ORWH), and the SWAN Heart Study was supported by the National Heart, Lung, and Blood Institute (NHLBI grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495, HL065581, and HL065591). The Chicago site of the SWAN Heart Study also was supported by the Charles J. and Margaret Roberts Trust. Ms Whipple and Dr Everson-Rose received support from the Program in Health Disparities Research, University of Minnesota Medical School. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, NHLBI, ORWH, or the NIH.
Authors T.T.L., K.S.-T., K.A.M., E.B.-M., L.H.P., and S.A.E.-R. were funded by the National Institutes of Health (NIH) for their roles as principle investigators or coinvestigators of SWAN and/or the SWAN Heart Study during the time this research was conducted.
Portions of these findings have been presented at the American Psychosomatic Society 65th Annual Scientific Meeting, Budapest, Hungary, March 2007, and the University of Minnesota’s Powell Center on Women’s Health 5th Annual Women’s Health Research Conference, Minneapolis, Minn, September 2008.
- Received April 24, 2009.
- Accepted May 6, 2009.
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