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Chronic Stress, Depressive Symptoms, Anger, Hostility, and Risk of Stroke and Transient Ischemic Attack in the Multi-Ethnic Study of Atherosclerosis

Originally publishedhttps://doi.org/10.1161/STROKEAHA.114.004815Stroke. 2014;45:2318–2323

Abstract

Background and Purpose—

This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults.

Methods—

Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years.

Results—

One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend ≤0.02) but not for trait anger (P>0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16–2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11–2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29–3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor–adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables.

Conclusions—

Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.

Introduction

Stress and negative emotions, including depression, anger, and hostility, adversely affect cardiovascular disease morbidity and mortality.1 Less is known about their impact on stroke risk, and there are methodological limitations to previous work. Studies limited to men or whites suggest that psychological stress and reactions to stressful experiences may increase stroke risk.25 Two recent meta-analyses concluded that stroke risk is elevated in depressed individuals, especially women, although most evidence is from homogenous white populations.6,7 Single-item measures of psychosocial stress and depression were significant stroke risk factors in A Study of the Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World (INTERSTROKE), an international multicenter case–control study conducted in 22 predominantly low- and middle-income countries.8 A composite of depressive symptoms, perceived stress, neuroticism, and dissatisfaction with life was related to stroke mortality and incident stroke in community-dwelling blacks and whites.9 Anger, a negative emotion related to hostile personality and aggressive behavior, has been related to excess stroke risk,10,11 but was protective in another study12; 2 of these studies included only white men and small numbers of strokes.10,12 Many of these previous studies did not use adjudicated stroke events, and most had limited risk factor data or limited assessments of psychosocial factors.

We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) to investigate the association of chronic stress and negative emotions with a combined end point of incident stroke and transient ischemic attacks (TIAs). MESA includes clinically adjudicated outcome data, repeat assessments of stress and negative emotions, and a broad array of risk factor data, allowing us to control for important confounding variables and examine potential underlying mechanisms.

Methods

Study Design and Participants

MESA is a longitudinal observational study of risk factors for subclinical and clinical cardiovascular disease, conducted at 6 field centers (Baltimore, MD; Chicago, IL; St. Paul, MN; Los Angeles, CA; New York City, NY; Forsyth County, NC)13 and adheres to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (http://www.strobe-statement.org/fileadmin/Strobe/uploads/checklists/STROBE_checklist_v4_combined.pdf). Between July 2000 and August 2002, 6814 participants (60% of eligible) aged 45 to 84 years and free of clinical cardiovascular disease were recruited and completed a baseline examination. The cohort is 53% women, 38.5% non-Hispanic white, 27.8% black, 11.8% Chinese, and 21.9% Hispanic. Four additional examinations have been completed (visit 2: September 2002 to February 2004; visit 3: March 2004 to September 2005; visit 4: September 2005 to May 2007; visit 5: April 2010 to February 2012). All visits follow similar study protocols. Institutional review boards at all participating institutions approved the study; each participant provided written informed consent. Persons with missing data on all psychosocial measures or on any demographic variables were excluded; 6749 participants were eligible for analyses of depressive symptoms, chronic stress burden, and anger, and 6089 were eligible for analysis of hostility.

Outcome

MESA uses a standard adjudication protocol to classify events, as previously reported.14 Stroke was defined as rapid onset of documented focal neurological deficits lasting 24 hours or until death and, if <24 hours, with imaging evidence (typically computed tomography or MRI) of a clinically relevant lesion. TIA was defined as a documented focal neurological deficit lasting 30 seconds to 24 hours and without imaging evidence of a clinically relevant lesion or without imaging completed. A combined outcome was used that included 147 strokes (82.3% ischemic; 14.3% hemorrhagic; 3.4% unspecified) and 48 TIA ascertained through February 22, 2012. Previous studies of psychosocial factors and stroke often included TIA as part of the stroke outcome (eg, defining stroke by International Classification of Diseases, Ninth Revision, codes 430–438) but rarely distinguished TIA from incident stroke events. Detailed outcome data in MESA allow us to make this distinction.

Psychosocial Factors

Standard questionnaires were administered in the respondent’s language of choice (English, Spanish, and Chinese). Chronic stress was measured at visits 1 and 3 with the Chronic Burden Scale,15 which assesses the presence and severity of ongoing stress in 5 domains: one’s own health problems, health problems of close others, job or ability to work, relationships, finances. Participants were coded as experiencing stress for each domain in which they indicated an ongoing problem as moderately or very stressful. The chronic stress score was the number of domains for which a participant had ongoing difficulties (range, 0–5); 3 stress groups were created based on scores of 0, 1, and ≥2. The 20-item Center for Epidemiologic Studies Depression Scale (CES-D)16 was administered at visits 1, 3, and 4; higher scores indicate more depressive symptoms (range, 0–60). Five CES-D groups were created based on the score distribution in approximate quartiles, with the top quartile split into 2 such that the top group represented the 12.9% of persons with a score ≥16, a value commonly used to identify clinically relevant symptoms. The Spielberger Trait Anger scale,17 a 10-item scale that assesses the extent and frequency of experiencing anger (range, 10–40), was administered at visits 1 and 3. Hostility was measured only at visit 2 using 8 true/false items previously derived from the Cook–Medley Hostility Scale18 that measures individuals’ hostile attitudes and cynical expectations regarding others’ motives.19 All true responses were summed to create a hostility score (range, 0–8). For both anger and hostility, 4 groups were created based on approximate quartiles. MESA examination forms are available at http://www.mesa-nhlbi.org/ex1forms.aspx.

Covariates

Sociodemographic variables included age, race/ethnicity, sex, and education. Stroke risk factors included resting systolic blood pressure obtained via standard protocol, self-reported smoking and alcohol use, physical activity assessed via the MESA Typical Week Physical Activity Survey,20 body mass index and height (cm), high-density lipoprotein cholesterol and triglycerides measured from fasting blood specimens using standard assays, use of antihypertensive medications, and diabetes mellitus status defined by fasting glucose and American Diabetes Association criteria.21 Additional covariates were visit 1 carotid artery intima medial thickness assessed by a standard protocol,22 high-sensitivity C-reactive protein, fibrinogen, and interleukin 6 measured from fasting blood specimens using standard assays. Antidepressant use was coded as a yes/no variable based on self-reported current use of tricyclic antidepressants, monoamine oxidase inhibitors, and other nontricyclic antidepressants at visit 1.

Data Analysis

Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of each psychosocial measure with the composite outcome of incident stroke/TIA, and secondarily, with the outcome limited to incident strokes. There was no violation of the proportional hazards assumptions in any model. Person-years accrued from the participant’s visit 1 date (visit 2 for hostility) to the date of the participant’s first stroke or TIA event, loss to follow-up, death, or February 22, 2012, whichever occurred first. With the outcome limited to incident strokes, follow-up time accrued until the participant’s first stroke, loss to follow-up, death, or February 22, 2012.

Initial models adjusted for race, sex, age, education, and MESA field center site. Subsequent models adjusted for systolic blood pressure, alcohol use, smoking status, physical activity, body mass index, height, antihypertensive medication use, diabetes mellitus, high-density lipoprotein cholesterol, and triglycerides. Similar models were run with the psychosocial measures modeled continuously and then categorically according to the groupings described. Interactions between psychosocial measures and age, sex, and race/ethnicity were evaluated by including cross-product terms in each model. Additional Cox models adjusted for intima medial thickness and inflammatory markers (C-reactive protein, fibrinogen, and interleukin 6), or antidepressant use (CES-D models only).

Primary analyses estimated the association of the psychosocial measures with the outcome ascertained during follow-up and included covariates from visit 1 (visit 2 for hostility except alcohol use, assessed at visit 1 only). The psychosocial measures were evaluated in separate models. Secondary analyses were conducted with psychosocial measures modeled simultaneously, with CES-D, chronic stress, and anger, obtained at visit 1, in 1 model, together with baseline covariates and risk factors, and hostility from visit 2 added in a second model.

Additional analyses used repeat assessments of psychosocial factors and stroke risk factors through visit 4. Initial time-dependent models updated just the covariates across study visits to determine if changes in behaviors and risk factors accounted for any observed associations; subsequent models updated data on both psychosocial measures and covariates to determine whether more recent experiences of these psychosocial characteristics were more strongly related to the outcome than previous assessments.

Results

Table 1 presents baseline characteristics of all participants and by the primary outcome. Persons who experienced an incident event had more vascular risk factors than those who did not. Correlations among psychosocial measures ranged from r=0.05 (stress and hostility) to r=0.39 (CES-D and stress). Median follow-up was 8.5 years (range, 0.02–10.9 years).

Table 1. Participant Characteristics, Visit 1: Multi-Ethnic Study of Atherosclerosis, 2000 to 2002

All Participants (n=6749)Incident Stroke or TIAP Value*
Yes (n=195)No (n=6554)
n (%)
 Men3181 (47.1)96 (49.2)3085 (47.1)0.55
 Women3568 (52.9)99 (50.8)3469 (52.9)
 Race
  Non-Hispanic white2602 (38.6)79 (40.5)2523 (38.5)0.02
  Black1863 (27.6)58 (29.7)1805 (27.5)
  Hispanic1485 (22.0)49 (25.1)1436 (21.9)
  Chinese799 (11.8)9 (4.6)790 (12.0)
 Education
  Less than high school diploma1214 (18.0)43 (22.0)1171 (17.9)0.03
  High school diploma or some college3150 (46.7)100 (51.3)3050 (46.5)
  College degree or higher2385 (35.3)52 (26.7)2333 (35.6)
 Smoking status
  Never3395 (50.3)96 (49.2)3299 (50.3)0.36
  Former2472 (36.6)67 (34.4)2405 (36.7)
  Current882 (13.1)32 (16.4)850 (13.0)
 Alcohol use
  Nondrinker3217 (48.1)91 (47.4)3126 (48.1)0.69
  Light drinker (1–7 drinks/wk)2440 (36.5)67 (34.9)2373 (36.5)
  Moderate drinker (8–14 drinks/wk)574 (8.6)21 (10.9)553 (8.5)
  Heavy drinker (>14 drinks/wk)458 (6.8)13 (6.8)445 (6.8)
 Use of antihypertensives2514 (37.3)104 (53.3)2410 (36.8)<0.0001
 Fasting glucose/diabetes mellitus status
  Normal4949 (73.6)121 (62.4)4828 (73.9)<0.0001
  Impaired fasting glucose928 (13.8)26 (13.4)902 (13.8)
  Untreated diabetes mellitus179 (2.7)7 (3.6)172 (2.6)
  Treated diabetes mellitus669 (9.9)40 (20.6)629 (9.6)
 Antidepressant use496 (7.3)17 (8.7)479 (7.3)0.46
Mean (SD)
 Age, y62.1 (10.2)68.3 (9.4)62.0 (10.2)<0.0001
 SBP, mm Hg126.6 (21.5)140.7 (23.4)126.2 (21.3)<0.0001
 BMI, kg/m228.3 (5.5)28.6 (4.9)28.3 (5.5)0.40
 Height, cm166.3 (10.0)165.3 (9.9)166.4 (10.0)0.13
 Moderate/vigorous physical activity (MET-min/wk)5753 (5896)4948 (5116)5777 (5917)0.03
 HDL cholesterol, mg/dL51.0 (14.8)47.6 (12.0)51.1 (14.9)0.0001
 Triglycerides, mg/dL131.7 (88.9)144.4 (78.0)131.3 (89.2)0.02
 Psychosocial measures
  CES-D (range, 0–60)7.6 (7.6)8.6 (8.2)7.5 (7.6)0.06
  Chronic stress (range, 1–5)1.22 (1.21)1.27 (1.21)1.22 (1.21)0.31
  Trait anger (range, 10–40)14.8 (3.7)14.5 (3.4)14.8 (3.7)0.43
  Hostility (range, 0–8)2.7 (2.3)3.0 (2.3)2.7 (2.3)0.08

BMI indicates body mass index; CES-D, Center for Epidemiologic Studies Depression Scale; HDL, high-density lipoprotein; MET, metabolic equivalent of task; SBP, systolic blood pressure; and TIA, transient ischemic attack.

*P values from χ2 tests or t tests, as appropriate, are for comparisons of those who did or did not experience a stroke or TIA during follow-up.

Hostility was measured at visit 2 only (n=6089; 137 with and 5952 without an event).

Controlling for race, sex, age, education, and site, each 1 point higher score for CES-D (HR, 1.03; 95% CI, 1.01–1.04), chronic stress (HR, 1.19; 95% CI, 1.05–1.34), and hostility (HR, 1.10; 95% CI, 1.01–1.19) was related to increased risk of stroke/TIA in separate models. Associations remained significant with further risk factor adjustment (CES-D: HR, 1.02; 95% CI, 1.01–1.04; chronic stress: HR, 1.16; 95% CI, 1.02–1.31; hostility: HR, 1.08; 95% CI, 1.00–1.17). Anger was not significantly related to risk of stroke or TIA (P>0.10). As shown in Table 2, with the psychosocial measures modeled categorically, statistically significant gradients of increasing risk were observed for depressive symptoms, chronic stress, and hostility; the trend for anger was nonsignificant but associations were in the expected direction. Persons in the top groups (those with the highest scores) for CES-D, chronic stress, and hostility were at 1.5 to >2-fold increased risk of stroke/TIA during follow-up, relative to the lowest scoring group on each measure (model 1). HRs were diminished but remained significant with further risk factor adjustment (model 2). Adjusting for antidepressant use had no effect on observed associations (not shown).

Table 2. Categorical Psychosocial Measures and Risk of Stroke or Transient Ischemic Attack: MESA 2000 to 2012

Group 1Group 2Group 3Group 4Group 5P Value for Trend
CES-D score0–23–56–1011–15≥16
 Model 1; events/nReferent; 46/18211.14 (0.75–1.73); 42/15391.17 (0.78–1.77); 48/16991.31 (0.80–2.15); 25/8101.86 (1.16–2.96); 33/8690.02
 Model 2; events/nReferent; 46/18051.09 (0.71–1.67); 40/15151.15 (0.76–1.74); 47/16741.26 (0.77–2.08); 25/7961.73 (1.08–2.77); 32/8530.03
Chronic stress score01≥2
 Model 1; events/nReferent; 57/22921.22 (0.85–1.74); 64/20981.59 (1.11–2.27); 72/23240.01
 Model 2; events/nReferent; 57/22631.13 (0.79–1.63); 62/20731.48 (1.03–2.13); 70/22830.03
Hostility score01–23–4≥5
 Model 1; events/nReferent; 24/14261.47 (0.88–2.46); 39/17231.49 (0.86–2.57); 31/15222.22 (1.29–3.81); 43/14180.006
 Model 2; events/nReferent; 24/14121.36 (0.81–2.28); 38/17061.37 (0.79–2.38); 31/15112.00 (1.15–3.47); 42/14000.02
Trait anger score10–1213–1415–16≥17
 Model 1; events/nReferent; 60/19911.23 (0.85–1.79); 52/16971.17 (0.76–1.78); 34/13081.45 (0.98–2.14); 48/17460.09
 Model 2; events/nReferent; 59/19651.27 (0.87–1.87); 51/16781.21 (0.78–1.89); 32/12821.41 (0.95–2.10); 48/17210.11

Numbers (n) varied based on availability of data on psychosocial measures and covariates. Numbers for hostility analyses are lower because they were assessed at MESA visit 2; all other psychosocial measures were assessed at visit 1. Psychosocial measures were analyzed in separate models. Model 1 adjusted for age, race, sex, education, and study site. Model 2 further adjusted for systolic blood pressure, alcohol use, smoking status, moderate and vigorous physical activity, body mass index, height, use of antihypertensives, diabetes mellitus/fasting blood glucose status, high-density lipoprotein cholesterol, and triglycerides. Values shown are hazard ratio (95% confidence interval) unless otherwise noted. CES-D indicates Center for Epidemiologic Studies Depression Scale; and MESA, Multi-Ethnic Study of Atherosclerosis.

With CES-D scores, chronic stress, and anger modeled simultaneously with visit 1 covariates, each measure showed a nonsignificant gradient of increasing risk across categories (all P for trend>0.10). HR and 95% CI for the highest relative to the lowest scoring category were 1.41 (0.84–2.35) for the CES-D, 1.35 (0.92–1.98) for chronic stress, and 1.27 (0.84–1.92) for anger. This analysis included 188 events among 6607 participants. With hostility included there were 133 events among 5962 participants. The HR (95% CI) for the most versus least hostile group was 1.74 (0.99–3.06), but the risk gradient across groups was nonsignificant (P for trend=0.08).

No interactions between psychosocial measures and age, sex, or race/ethnicity were observed (all P>0.10; not shown), but power to detect differences by race/ethnicity in particular was limited by small numbers. Adjusted models that also included intima medial thickness, C-reactive protein, or interleukin 6 were unchanged from those shown in Table 2 (model 2; not shown).

Patterns of association with the outcome limited to total incident strokes or incident ischemic strokes were similar to analyses with the combined end point (Table I in the online-only Data Supplement). Analyses with time-varying variables also showed results similar to the primary analyses (Table II in the online-only Data Supplement), with the highest-scoring groups for depressive symptoms and chronic stress having slightly larger HR when those measures were time-varying rather than baseline measures. Further controlling for marital status as a proxy for social support did not alter results (Table III in the online-only Data Supplement).

Discussion

This study found that higher levels of depressive symptoms, greater chronic stress, and higher levels of hostility predicted increased risk of stroke and TIA. There was a similar albeit nonsignficant trend for trait anger. Associations were relatively unchanged after adjusting for known stroke risk factors in our primary analyses using risk factors assessed at baseline and in the time-dependent models with time-varying covariates. Results were similar when limiting analyses to incident strokes. Findings highlight the importance of considering nontraditional factors when assessing risk of stroke/TIA.

Assuming a causal association, the pathways by which stress and negative emotions contribute to increased risk of stroke and TIA need to be elucidated. Common biological mechanisms may link these individual psychosocial characteristics with adverse cardiovascular outcomes, including stroke. Stress and negative emotions activate the hypothalamic–pituitary–adrenal axis, leading to changes in glucocorticoids and increases in circulating catecholamines; influence endothelial dysfunction and platelet activation; and have documented metabolic, neuroendocrine, and immunologic effects.23,24 Therefore, persons who experience higher levels of stress, depressive symptoms, or hostility could experience autonomic or neuroendocrine changes that exacerbate risk for stroke and TIA. However, the present study did not evaluate specific mechanisms related to such pathways. Inflammatory pathways also are plausible; the psychosocial factors measured here are associated with increased C-reactive protein, fibrinogen, and interleukin 6,25,26 which are related to stroke risk.27,28 Yet, adjusting for these variables did not alter observed relationships. We only had baseline measures of these inflammatory markers, but this study provides little evidence for an inflammatory pathway. Including baseline intima medial thickness as a covariate did not alter observed associations, suggesting that nonatherosclerotic mechanisms could be involved.

Persons experiencing stress and negative emotions typically have more adverse behavioral risk profiles and experience difficulty in maintaining healthy lifestyles and adhering to treatment recommendations. When controlling for baseline measures of smoking, physical activity, alcohol consumption, body mass index and blood pressure, or allowing these risk factors to vary across time, the effects of stress, depressive symptoms, and hostility on risk for stroke/TIA remained robust. Our data suggest that these lifestyle factors are not a primary pathway through which stress and negative emotions contribute to subsequent stroke.

Several study limitations should be noted. We had relatively small numbers of events; only 195 participants experienced either a stroke or TIA during follow-up, which is unsurprising given the initial age of MESA participants (mean age, 62.1 years). This limitation impacted our ability to examine potential racial/ethnic differences in the observed associations. Also, psychosocial factors are challenging to measure. We used standard self-report questionnaires with good reliability and validity, yet measurement error may be present if participants did not feel comfortable endorsing certain statements or chose not to respond in a forthright manner. Such error would be expected to weaken associations. The robustness and consistency of our findings across analytic models suggest that measurement error did not unduly influence our results. Only selected psychosocial characteristics were included in this study; other important psychosocial constructs not evaluated here could either exacerbate or protect against stroke risk. We did not evaluate coping strategies, which could mitigate adverse effects of stress and negative emotions. Finally, we cannot rule out the possibility that covert vascular disease such as white matter changes or brain infarcts (defined by imaging) could be present in our participants and influencing their levels of depressive symptoms, stress, hostility, and anger.

These limitations are offset by several strengths. MESA uses clinically adjudicated outcomes for event data, including incident stroke and TIA, which distinguishes this study from many previous reports. Our findings are consistent with previous studies that have linked measures of stress and depression with stroke outcomes, ascertained by self-report, administrative databases, or registry data,2,3,9,10,29 and add to the literature by showing that higher levels of hostility increase risk for stroke and TIA. We had assessments of stress, depressive symptoms, and anger from >1 study visit. The consistency of findings across models suggests that these psychosocial characteristics may be relatively stable attributes. With a broad array of risk factor data, we were able to evaluate the impact of many important stroke risk factors on our observed associations. Finally, MESA is a population-based study conducted at 6 US sites and includes participants from 4 racial/ethnic groups, thereby enhancing generalizability of the findings.

Conclusions

Our study demonstrates associations between excess stroke/TIA risk and depressive symptoms, chronic stress, and hostility, which were not explained by traditional stroke risk factors, inflammatory markers, or subclinical atherosclerosis. Better understanding of important, potentially modifiable stroke risk factors, including stress and negative emotions, is needed given the aging population and increasing burden of stroke.

Acknowledgments

Dr Everson-Rose and N.S. Roetker had full access to all data and take responsibility for the integrity and accuracy of the data and analyses. We thank investigators, staff, and participants of the Multi-Ethnic Study of Atherosclerosis (MESA) study for their valuable contributions. A full list of participating MESA investigators and institutions is at http://www.mesa-nhlbi.org.

Footnotes

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.004815/-/DC1.

Correspondence to Susan Everson-Rose, PhD, MPH, University of Minnesota, 717 Delaware St SE, Suite 166, Minneapolis, MN 55414. E-mail

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