Depressive disorders have been associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis has not been well described, particularly in women and minorities. The relation between repeated episodes of high depressive symptoms and coronary calcium (CAC) is unknown in women at midlife when depression is common. Participants in the Study of Women’s Health Across the Nation Heart study were assessed annually for depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D scale]) over 5 years before CAC assessment and classified as high (CES-D ≥16) or not. CAC, measured by computed tomography, was analyzed as a categorical variable using cumulative logit partial proportional odds models. In these middle-aged women free of CVD and diabetes (194 black, 334 white), high depressive symptoms over 5 years were common; 19% had 1, 9% had 2, and 11% experienced ≥3 episodes. CAC was low; 54% had no CAC, 25% had scores from 0 to 10, and 21% had CAC ≥10 Agatston score. After adjusting for CVD risk factors, women with ≥3 episodes were twice as likely to have significant CAC (≥10 Agatston units) than women with no depressive episodes (odds ratio 2.20, 95% confidence interval 1.13 to 4.28, p = 0.020) with no difference by race. Women with 1 or 2 episodes did not differ from women with no episodes. In conclusion, in healthy women aged 46 to 59 years without clinical CVD or diabetes, persistent depressive symptoms were significantly associated with elevated CAC scores, suggesting that they are more likely to have pathophysiological and behavioral effects on the development of subclinical CVD than does a single episode of elevated depressive symptoms.
Cardiovascular disease (CVD) in women increases substantially after the age of 45 years. Depression has been identified as a potential risk factor for CVD, and midlife women are particularly vulnerable to depressive mood. Coronary calcium (CAC) correlates with atherosclerosis and predicts clinical events, but results from past studies of depression and CAC have been inconsistent. Major depressive disorders have been linked to higher levels of CAC cross-sectionally and longitudinally, but depressive symptoms have been unrelated to CAC in cross-sectional studies. In an older cohort, a negative association was found between depressive symptoms and CAC level; women in the lowest quartile of depressive symptoms had the highest odds of CAC. In a younger cohort, high depressive symptoms, especially the subscale of depressive affect, were related to incident CAC. Whitehall II study participants with ≥2 episodes of high depressive symptoms at 3 times over a 10-year period were more likely to have high levels of CAC, but the effect was observed only in men. Higher levels of depressive symptoms at Study of Women’s Health Across the Nation (SWAN) Heart baseline were related to aortic calcification but not CAC in black women only and to progression of CAC in both black and white women. A history of recurrent major depression has also been related to CAC and CAC progression. However, recurrent depressive symptoms have not been investigated in relation to CAC level in a middle-aged biracial cohort of women. Therefore, we aimed to investigate whether persistently high levels of depressive symptoms are related to higher levels of CAC, whether this association varied by race, and whether this association was limited to certain subscales.
Methods
Baseline data were used from the SWAN Heart Study, an ancillary study of the SWAN. The aim of the parent SWAN study was to examine the natural history of the menopausal transition in 3,302 women from 5 ethnic backgrounds, recruited from 7 geographic sites in the United States. The SWAN Heart Study was conducted at the Chicago and Pittsburgh sites only which, by design, recruited non-Hispanic white and black participants. The institutional review boards at each site approved all protocols; all women provided written informed consent.
SWAN Heart began in 2001 to 2003, coincident with the year 4 through 7 annual SWAN examinations. A total of 608 participants were recruited (37% black). The analytic sample for the present study included 528 (87%) of the 608 SWAN Heart participants. The 80 exclusions were for clinical CVD (history of myocardial infarction, angina, intermittent claudication, cerebral ischemia, or revascularization, n = 11), for diabetes (n = 20), and for missing CAC scan (n = 49). There were no differences in the variables presented in Table 1 between those who were and were not in the analytic sample.
| Variable | Total (n=528) | CAC (Agatston units) | P-value ∗ | ||
|---|---|---|---|---|---|
| 0 (n=285) | > 0, < 10 (n=134) | ≥ 10 (n=109) | |||
| Age (years, mean [SD]) | 50.9 (2.9) | 50.5 (2.8) | 50.7 (2.9) | 52.1 (2.6) † ‡ | <.001 |
| Black | 194 (36.7%) | 88 (30.9%) | 58 (43.3%) † | 48 (44.0%) † | 0.005 |
| Economic hardship | 162 (30.7%) | 86 (30.2%) | 46 (34.3%) | 30 (27.5%) | 0.813 |
| Unmarried | 154 (29.2%) | 85 (29.8%) | 35 (26.1%) | 34 (31.2%) | 0.968 |
| Education | |||||
| ≤ High School | 91 (17.2%) | 44 (15.4%) | 25 (18.7%) | 22 (20.2%) | 0.062 |
| Some College | 154 (29.2%) | 77 (27.0%) | 42 (31.3%) | 35 (32.1%) | |
| College Degree | 282 (53.6%) | 164 (57.5%) | 67 (50.0%) | 52 (47.7%) | |
| Smoker | 89 (16.9%) | 55 (19.3%) | 16 (11.9%) | 18 (16.5%) | 0.285 |
| Post-menopausal | 143 (27.1%) | 73 (25.6%) | 30 (22.4%) | 40 (36.7%) ‡ | 0.072 |
| Hormone Therapy use | 25 (4.7%) | 12 (4.2%) | 7 (5.2%) | 6 (5.5%) | 0.771 |
| Family history of CVD | 352 (66.7%) | 179 (62.8%) | 100 (74.6%) | 73 (67.0%) | 0.189 |
| Use of blood pressure medication | 79 (15.0%) | 22 (7.7%) | 30 (22.4%) † | 27 (24.8%) † | <.001 |
| Statin § use | 23 (4.4%) | 14 (4.9%) | 6 (4.5%) | 3 (2.8%) | 0.373 |
| Use of anti-depressant medication | 52 (9.9%) | 26 (9.1%) | 12 (9.0%) | 14 (12.8%) | 0.328 |
| BMI (kg/m 2 , mean [SD]) | 29.0 (6.1) | 25.8 (3.8) | 31.6 (4.9) † | 33.9 (7.5) † ‡ | <.001 |
| SBP (mmHg, mean [SD]) | 119.0 (15.6) | 114.9 (14.3) | 122.1 (14.6) † | 125.7 (18.4) † | <.001 |
| DBP (mmHg, mean [SD]) | 75.8 (9.9) | 73.6 (9.4) | 78.1 (9.5) † | 78.9 (10.3) † | <.001 |
| HDL cholesterol (mg/dL, mean [SD]) | 57.9 (14.5) | 60.8 (14.8) | 55.2 (13.5) † | 53.8 (13.6) † | <.001 |
| LDL cholesterol (mg/dL, mean [SD]) | 118.1 (31.3) | 113.8 (29.3) | 120.9 (33.5) | 125.8 (32.0) † | 0.001 |
| Total cholesterol (mg/dL, mean [SD]) | 199.3 (36.4) | 195.2 (33.6) | 200.6 (38.5) | 208.6 (39.0) † | 0.004 |
| Triglycerides (mg/dL, mean [SD]) | 114.7 (64.8) | 102.2 (51.0) | 120.5 (63.4) † | 140.5 (86.8) † | <.001 |
| Depressive Episodes | |||||
| 0 | 322 (61.0%) | 178 (62.5%) | 83 (61.9%) | 61 (56.0%) | 0.083 |
| 1 | 102 (19.3%) | 53 (18.6%) | 29 (21.6%) | 20 (18.3%) | |
| 2 | 47 (8.9%) | 29 (10.1%) | 10 (7.5%) | 8 (7.3%) | |
| ≥3 | 57 (10.8%) | 25 (8.8%) | 12 (9.0%) | 20 (18.4%) | |
∗ The Cochran-Armitage trend test was used for dichotomous characteristics, the Cochran-Mantel-Haenszel test was used for categorical characteristics with more than 2 categories (i.e., education), and an ANOVA F-test was used for continuous characteristics.
† p <0.05 compared with 0 Agatston units adjusted per Bonferroni.
‡ p <0.05 compared with >0, <10 Agatston units adjusted per Bonferroni.
CAC was measured by electron-beam computed tomography in 2 passes. The first provided landmarks and the second provided the coronary artery images. Thirty to forty contiguous 3-mm-thick transverse images from the level of the aortic root to the apex of the heart were obtained during maximal breath holding. Electrocardiogram triggering was used so that each 100-ms exposure was obtained during the same phase of the cardiac cycle (60% of the RR interval). Calcification, using the method established by Agatston, was present if at least 3 contiguous pixels showed >130 Hounsfield units. The calcium score was the sum of scores for each of the 4 major epicardial coronary arteries categorized as 0 (none), 1 to 10 (minimal), or >10 (moderate).
Covariates were chosen from the literature based on the association with CAC. Age, highest educational degree, marital status, smoking status, medication usage, and hormone therapy were assessed by questionnaire. Menopausal status was assessed by self-reported bleeding criteria as pre-/peri-menopausal or postmenopausal (no menses for at least 12 months). Economic hardship was assessed with 1 question about how difficult it is to pay for “basics” (i.e., food, housing, medical care) and analyzed as “somewhat or very hard” versus “not hard at all.” Resting blood pressure was measured with a mercury sphygmomanometer, using an appropriately sized cuff and a standard protocol with at least a 5-minute rest and participants seated. Two sequential blood pressure readings were obtained, 2 minutes apart, and averaged. Total cholesterol and high-density lipoprotein cholesterol were analyzed on ethylenediaminetetraacetic acid–treated plasma using standard methods. Low-density lipoprotein cholesterol was calculated using the Friedewald equation.
Depressive symptoms were assessed using the Center for Epidemiological Studies Depression Scale (CES-D). 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 of or all the time). Item responses are summed for a total score (range 0 to 60); greater scores indicate more depressive symptomatology. A score of ≥16 is typically used to identify potential clinical depression. This instrument has been validated with good test–retest reliability in racially diverse samples and has been used widely in epidemiologic studies. Over the course of 5 study visits before the assessment of CAC, a visit where a participant exhibited high depressive symptoms (CES-D ≥16) was classified as a depressive episode. The number of depressive episodes was summed over the 5 visits and the covariate of interest defined as a 4-level categorical variable: 0, 1, 2, or ≥3 episodes. Self-reported antidepressant medication used was verified by a clinical psychiatrist. Subscales of the CES-D were defined as in other published studies on subscales of the CES-D and CAC ; depressed affect (e.g., sadness and loneliness), somatic symptoms (e.g., poor appetite and sleep disturbance), interpersonal distress (e.g., feeling disliked), and lack of positive affect (e.g., happiness and life satisfaction). As there are no accepted cutpoints for the subscales, the average score over 5 years up to CAC assessment was calculated to yield a measure of chronicity of these symptoms.
Participant characteristics were summarized using mean and SD for continuous measurements and n (%) for categorical measurements. To detect overall trends across the 3 CAC categories, the Cochran–Armitage trend test was used for dichotomous characteristics and the Cochran-Mantel-Haenszel test was used for categorical characteristics with >2 groups. For continuous characteristics, overall differences between the 3 CAC categories were examined with the analysis of variance (ANOVA) F test, with contrasts used to detect trends. For all characteristics, 3 pairwise comparisons were conducted, comparing the middle CAC category to the lowest, the highest to the middle, and the highest to the lowest. These were performed using the ANOVA contrast or the chi-square test, depending on the nature of the characteristic. All pairwise comparisons were adjusted using the Bonferroni correction, with p <0.017 indicating a statistically significant result.
CAC is known to follow a highly right-skewed distribution with many 0s in healthy populations. In the present study, 54% had a score of 0 Agatston units. Consequently, the relation between CAC and covariates was assessed through a trichotomous dependent variable (0, >0 but <10, and ≥10 Agatston units) using cumulative logit models. Because the proportional odds assumption was not satisfied, partial proportional odds models were used, allowing the effect of the covariates on the log odds of being in the upper 2 outcome categories to be different from the log odds of being in the highest outcome category. A backward stepwise procedure was used to determine which covariates had a significantly different effect on the pair of log odds. Continuous covariates were standardized to facilitate model interpretation. Models were rerun with each of the 4 component scores separately.
About 13% of participants had ≥1 visits with missing depressive symptoms. However, 96% of the sample had complete data on depressive symptoms for ≥4 years. Sensitivity analyses used multiple imputation. All statistical analyses were performed with SAS 9.2 (SAS version 9.2, SAS Institute, Inc, Cary, North Carolina) and STATA 12 (StataCorp. 2011, Stata Statistical Software: Release 12 , College Station, Texas: StataCorp LP). p Values <0.05 were considered statistically significant. The authors had full access to the data and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Results
Table 1 provides the cohort characteristics overall and grouped by CAC level. On average, women were healthy but heavy (mean body mass index [BMI] = 29) with blood pressure and lipids in the normal range. Economic hardship, marital status, smoking, hormone therapy, family history of CVD, cholesterol-lowering medication use, and use of antidepressant medication were not associated with CAC levels. There was a significant upward trend in the proportion of black women across the categories, mostly due to the substantial difference between the upper 2 categories relative to the 0 Agatston units category (p = 0.013, p = 0.014). There was an upward trend in the proportion of postmenopausal women across the CAC categories driven by a significant difference between the middle and highest CAC category (p = 0.014). The rate of blood pressure medication utilization increased across the categories, most notably between the upper 2 relative to the 0 Agatston units category (both p <0.001). Participant age, BMI, systolic blood pressure, diastolic blood pressure (SBP), low-density lipoprotein cholesterol, total cholesterol, and triglycerides all exhibited a positive trend across the CAC categories. The number of depressive episodes was marginally related to higher CAC levels in this overall test.
Table 2 provides characteristics of the cohort by the number of depressive episodes. Economic hardship, being unmarried, smoking, and use of antidepressant medication were all positively associated, and high-density lipoprotein cholesterol was negatively associated with frequency of depressive episodes. No other covariates were significantly related to the frequency of depressive episodes.
| Variable | Depressive Episodes | p-value † | |||
|---|---|---|---|---|---|
| 0 (n=322) | 1 (n=102) | 2 (n=47) | 3 or more (n=57) | ||
| Age (years, mean [SD]) | 50.9 (3.0) | 50.8 (2.6) | 50.7 (2.6) | 51.0 (2.9) | |
| Black | 114 (35.4%) | 35 (34.3%) | 20 (42.6%) | 25 (43.9%) | |
| Economic hardship | 72 (22.4%) | 39 (38.2%) | 23 (48.9%) | 28 (49.1%) | *** |
| Unmarried | 87 (27.0%) | 25 (24.5%) | 17 (36.2%) | 25 (43.9%) | ** |
| Education | |||||
| ≤ High School | 52 (16.2%) | 19 (18.6%) | 7 (14.9%) | 13 (22.8%) | |
| Some College | 83 (25.8%) | 32 (31.4%) | 19 (40.4%) | 20 (35.1%) | |
| College Degree | 187 (58.1%) | 51 (50.0%) | 21 (44.7%) | 24 (42.1%) | |
| Smoker | 48 (14.9%) | 11 (10.9%) | 9 (19.2%) | 21 (36.8%) | *** |
| Post-menopausal | 88 (27.3%) | 24 (23.5%) | 12 (25.5%) | 19 (33.3%) | |
| Hormone Therapy use | 12 (3.7%) | 3 (2.9%) | 6 (12.8%) | 4 (7.0%) | |
| Family history of CVD | 219 (68.0%) | 71 (69.6%) | 26 (55.3%) | 36 (63.2%) | |
| Use of blood pressure medication | 48 (14.9%) | 12 (11.8%) | 8 (17.0%) | 11 (19.3%) | |
| Statin ‡ use | 14 (4.3%) | 4 (3.9%) | 4 (8.5%) | 1 (1.8%) | |
| Use of anti-depressant medication | 13 (4.0%) | 13 (12.8%) | 12 (25.5%) | 14 (24.6%) | *** |
| BMI (kg/m 2 , mean [SD]) | 28.9 (6.2) | 29.5 (5.8) | 28.4 (5.4) | 29.0 (6.8) | |
| SBP (mmHg, mean [SD]) | 119.3 (15.4) | 118.7 (15.7) | 116.9 (18.3) | 119.2 (17.8) | |
| DBP (mmHg, mean [SD]) | 75.9 (9.9) | 76.3 (9.8) | 74.0 (9.9) | 76.0 (10.2) | |
| HDL cholesterol (mg/dL, mean [SD]) | 59.3 (15.0) | 56.7 (13.1) | 55.6 (13.2) | 54.5 (14.6) | * |
| LDL cholesterol (mg/dL, mean [SD]) | 117.2 (30.3) | 116.9 (31.7) | 126.3 (33.4) | 118.4 (33.9) | |
| Total cholesterol (mg/dL, mean [SD]) | 199.3 (36.5) | 196.6 (32.9) | 204.8 (38.5) | 199.5 (40.0) | |
| Triglycerides (mg/dL, mean [SD]) | 112.8 (65.3) | 113.6 (60.5) | 111.5 (49.5) | 130.2 (78.4) | |
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