ABSTRACTBackground: Poststroke depression is common in stroke survivors. Evidence suggests that caregivers of stroke survivors also experience depression, at rates similar to survivors (30–40%). Wh...

Women in mid-life experience unique stressors, including transitions within their family roles, informal caregiving, job stress, and perceived discrimination. The impact of these stressors on cardiovascular health in women during mid-life is of growing interest in both the popular and scientific literature. The objective of this review is to summarize the recent literature on stress and cardiovascular health in mid-life women. We focus on stressors that are relevant to mid-life women, including social stress and discrimination, and long-term risk of CVD events and subclinical CVD measures. We systematically reviewed the literature published between January 2012 and April 2018 for studies examining stress in mid-life and either CVD endpoints or subclinical CVD outcomes. Eligible studies included at least one psychosocial stress exposure, a CVD or subclinical CVD outcome, and either included only female participants, reported sex-stratified analyses or tested for a sex*stress interaction. We identified 37 studies published since 2012 that met our criteria and included women between the ages of 40 and 65, including 3 case-control studies, 15 cross-sectional studies, and 19 prospective cohort studies. Because clinical CVD events typically occur after age 65 in women, only 22 studies were available that evaluated stress and hard CVD events in samples with mid-life women. Results from these studies suggested an increased and significant risk of CVD due to stress. Of the 15 studies that included subclinical CVD outcomes, the majority showed that mid-life women experiencing greater levels of stress had more subclinical CVD, as indicated by carotid intima-media thickness, flow-mediated dilation and arterial stiffness; however, several studies reported null associations. General life stress, including perceived stress and life events, in mid-life was significantly related to later-life CVD risk and mid-life subclinical CVD in the majority of studies published in the past six years. Job stress was inconsistently related to CVD risk in women, and fewer studies examined characteristics of other social roles, such as marriage, motherhood or caregiving. Perceived discrimination also was associated with CVD events and subclinical CVD in some samples of mid-life women. Further investigation into specific stressors relevant to women in mid-life, including caregiving and marital stress, are needed to understand the full extent to which life stress impacts CVD risk in mid-life women.

Small clinical studies suggest depression is associated with alterations in adiponectin and leptin, adipocyte-derived secretory proteins involved in metabolic regulation; however, longitudinal data on these association are lacking. This study examined cross-sectional and longitudinal associations of depressive symptoms and major depressive disorder (MDD) with adiponectin and leptin in healthy middle-aged women (mean (SD) age, 45.6 (2.5) years). Cross-sectional analyses included 575 women with baseline adipokine data; longitudinal analyses included 262 women with 2-4 adipokine measurements over 5 years. The 20-item Center for Epidemiologic Studies Depression scale (CES-D) was used to assess depressive symptoms; history of MDD was determined by the Structured Clinical Interview for DSM-IV. Adipokines were assayed from stored serum specimens; values were log-transformed for analyses. Linear and repeated measure random effects regression models evaluated associations of baseline CES-D scores with baseline adipokine concentrations and changes over time, respectively. Secondary analyses evaluated the relation of MDD history with adipokine concentrations. Mean (SD) baseline concentrations of adiponectin and leptin were 9.90 (4.92) μg/mL and 27.02 (20.06) ng/mL; both increased over time (p < .0001). CES-D scores were associated with lower adiponectin at baseline (per 1-SD: estimate=-0.04, SE=.02, p=.03) and over time (per 1-SD: estimate=-0.055, SE = .024, p=.02). Associations were unchanged in risk factor-adjusted models. Women with elevated CES-D scores (≥16) had 6.9% (95% CI: -1.1%, 14.3%; p = .089) lower median adiponectin at baseline and 11.5% (95% CI: 1.5%, 20.4%, p = .025) lower median adiponectin over time in adjusted models, compared to women with CES-D<16. Rate of change in adipokines did not vary by baseline depressive symptoms or MDD history. Depressive symptoms and MDD history were unrelated to leptin. In women at midlife, depressive symptoms are associated with lower adiponectin, a critical anti-inflammatory biomarker involved in metabolic and cardiovascular conditions.

PURPOSE Reduced access to care and barriers have been shown in rural populations and in publicly insured populations. Barriers limiting health care access in publicly insured populations living in rural areas are not understood. This study investigates rural-urban differences in system-, provider-, and individual-level barriers and access to preventive care among adults and children enrolled in a public insurance program in Minnesota. METHODS This was a secondary analysis of a 2008 statewide, cross-sectional survey of publicly insured adults and children (n = 4,388) investigating barriers associated with low utilization of preventive care. Sampling was stratified with oversampling of racial/ethnic minorities. RESULTS Rural enrollees were more likely to report no past year preventive care compared to urban enrollees. However, this difference was no longer statistically significant after controlling for demographic and socioeconomic factors (OR: 1.37, 95% CI: 1.00-1.88). Provider- and system-level barriers associated with low use of preventive care among rural enrollees included discrimination based on public insurance status (OR: 2.26, 95% CI: 1.34-2.38), cost of care concerns (OR: 1.72, 95% CI: 1.03-2.89) and uncertainty about care being covered by insurance (OR: 1.70, 95% CI: 1.01-2.85). These and additional provider-level barriers were also identified among urban enrollees. CONCLUSIONS Discrimination, cost of care, and uncertainty about insurance coverage inhibit access in both the rural and urban samples. These barriers are worthy targets of interventions for publicly insured populations regardless of residence. Future studies should investigate additional factors associated with access disparities based on rural-urban residence.

Cardiovascular disease risk increases in women after the menopausal transition; why this inflection point occurs remains uncertain. We aimed to characterize the influence of menopause on vascular aging by prospective assessment of change in indexes of subclinical atherosclerosis across the menopausal transition. We evaluated 411 healthy women from SWAN Heart, an ancillary study of SWAN (Study of Women's Health Across the Nation), for subclinical atherosclerosis at baseline and again after an average of 2.3 years. Carotid intima-media thickness and aortic pulse wave velocity were measured by ultrasound. Coronary artery calcium scores were obtained by computed tomography. Women were grouped by menopausal status as premenopausal, postmenopausal, or having undergone the transition during follow-up. Analyses of changes were adjusted for age at baseline and time between scans. Mean age at baseline was 51 ± 3 years; 93 (23%) subjects transitioned to menopause (Pre-Post), 147 (36%) remained premenopausal (Pre-Pre), while 171 (41%) were postmenopausal at baseline (Post-Post). Blood pressure readings did not differ between groups with similar increase noted in carotid intima-media thickness and log coronary artery calcium + 1 from baseline to follow-up. Change in aortic pulse wave velocity from baseline to follow-up was higher in Pre-Post (121 ± 23 cm/s) compared with Pre-Pre (38 ± 250 cm/s, p = 0.029) and Post-Post (41 ± 228 cm/s, p = 0.045). In conclusion, changes in aortic stiffness were more sensitive measures of perimenopausal vascular aging than morphologic indexes of subclinical atherosclerosis in women undergoing the menopausal transition. Serial assessment of such changes could potentially elucidate mechanisms of disease and identify women to target for aggressive lifestyle risk factor modification.

Background We examined associations of three markers of subclinical cardiovascular disease (intimal-medial thickening, coronary artery calcification , and ankle-brachial index) with changes in self-reported walking over time. Methods Data were from 6,490 Multi-Ethnic Study of Atherosclerosis participants (aged 45-84 years), free of clinical cardiovascular disease at baseline. Outcomes, assessed four times over 11 years, included self-reported walking pace (none to striding pace; score, 0-4) and total walking time (minutes/week). Linear generalized estimating equation models estimated associations of baseline intimal-medial thickening (z-scored), coronary artery calcification (Agatston units), and ankle-brachial index (ratio of ankle-to-arm systolic blood pressure) with walking pace and walking time modeled continuously in separate analyses. Results Median follow-up was 9.2 years (maximum, 11.4). Walking pace (estimate, -0.042 points [95% CI; -0.048, -0.036], p < 0.0001) and walking time (estimate, -4.71 minutes [95% CI: -8.54, -0.88], p = 0.016) decreased yearly. Greater baseline intimal-medial thickening related to faster decline in walking pace in multivariable analyses: walking pace score decreased 0.004 points (95% CI: -0.008, -0.001) more per year for each 1-SD higher intimal-medial thickening z-score, equivalent to an additional 10% slower yearly walking. Greater coronary artery calcification was associated with slower walking but inconsistently related to decline in walking pace. Higher ankle-brachial index was associated with faster baseline walking pace (estimate, 0.043 points [95% CI: 0.027, 0.059] per 1-SD) but unrelated to changes in walking pace. Cardiovascular disease measures were unrelated to total walking time. Conclusions Greater subclinical cardiovascular disease is associated with prevalent slower self-reported walking pace in middle-aged and older adults but has limited impact on changes in walking over time.

A growing literature links discrimination to key markers of biobehavioral health. While racial or ethnic differences in pain are seen in experimental and clinical studies, the authors were interested in how chronic discrimination contributes to pain within multiple racial or ethnic groups over time. Participants were 3056 African American, Caucasian, Chinese, Hispanic, and Japanese women from the Study of Women's Health Across the Nation. The Everyday Discrimination Scale was assessed from baseline through 13 follow-up examinations. The bodily pain subscale of the MOS 36-Item Short-Form Health Survey (SF-36) was assessed annually. There were large racial or ethnic differences in reports of discrimination and pain. Discrimination attributions also varied by race or ethnicity. In linear mixed model analyses, initially adjusted for age, education, and pain medications, chronic everyday discrimination was associated with more bodily pain in all ethnic groups (beta = -5.84; P < 0.002 for Japanese; beta = -6.17; P < 0.001 for African American; beta = -8.74; P < 0.001 for Chinese; beta = -10.54; P < 0.001 for Caucasians; beta = -12.82; P < 0.001 for Hispanic). Associations remained significant in all ethnic groups after adjusting for additional covariates in subsequent models until adding depressive symptoms as covariate; in the final fully-adjusted models, discrimination remained a significant predictor of pain for African American (beta = -4.50; P < 0.001), Chinese (beta = -6.62; P < 0.001), and Caucasian (beta = -7.86; P < 0.001) women. In this longitudinal study, experiences of everyday discrimination were strongly linked to reports of bodily pain for the majority of women. Further research is needed to determine if addressing psychosocial stressors, such as discrimination, with patients can enhance clinical management of pain symptoms.

Experiences of discrimination are associated with increased risk of adverse health outcomes; however, it is unknown whether discrimination is related to incident type 2 diabetes mellitus (diabetes). We investigated the associations of major experiences of discrimination (unfair treatment in 6 situations) and everyday discrimination (frequency of day-to-day experiences of unfair treatment) with incident diabetes among 5,310 participants from the Multi-Ethnic Study of Atherosclerosis, enrolled in 2000-2002. Using Cox proportional hazards models, we estimated hazard ratios and confidence intervals, adjusting for demographic factors, depressive symptoms, stress, smoking, alcohol, physical activity, diet, waist circumference, and body mass index. Over a median follow-up of 9.4 years, 654 diabetes cases were accrued. Major experiences of discrimination were associated with greater risk of incident diabetes when modeled continuously (for each additional experience of discrimination, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17) or categorically (for ≥2 experiences vs. 0, hazard ratio = 1.34, 95% confidence interval: 1.08, 1.66). Similar patterns were observed when evaluating discrimination attributed to race/ethnicity or to a combination of other sources. Everyday discrimination was not associated with incident diabetes. In conclusion, major experiences of discrimination were associated with increased risk of incident diabetes, independent of obesity or behavioral and psychosocial factors. Future research is needed to explore the mechanisms of the discrimination-diabetes relationship.

BACKGROUND Volumes of paracardial adipose tissue (PAT) and epicardial adipose tissue (EAT) are greater after menopause. Interestingly, PAT but not EAT is associated with estradiol decline, suggesting a potential role of menopause in PAT accumulation. We assessed whether volumes of heart fat depot (EAT and PAT) were associated with coronary artery calcification (CAC) in women at midlife and whether these associations were modified by menopausal status and estradiol levels. METHODS AND RESULTS EAT and PAT volumes and CAC were measured using electron beam computed tomography scans. CAC was evaluated as (1) the presence of CAC (CAC Agatston score ≥10) and (2) the extent of any CAC (log CAC Agatston score >0). The study included 478 women aged 50.9 years (58% pre- or early perimenopausal, 10% late perimenopausal, and 32% postmenopausal). EAT was significantly associated with CAC measures, and these associations were not modified by menopausal status or estradiol. In contrast, associations between PAT and CAC measures were modified by menopausal status (interaction-P≤0.01). Independent of study covariates including other adiposity measures, each 1-SD unit increase in log PAT was associated with 102% higher risk of CAC presence (P=0.04) and an 80% increase in CAC extent (P=0.008) in postmenopausal women compared with pre- or early perimenopausal women. Additional adjustment for estradiol and hormone therapy attenuated these differences. Moreover, the association between PAT and CAC extent was stronger in women with lower estradiol levels (interaction P=0.004). CONCLUSIONS The findings suggest that PAT is a potential menopause-specific coronary artery disease risk marker, supporting the need to monitor and target this fat depot for intervention in women at midlife.

There is a critical need for objective data to guide effective health promotion and care for homeless populations. However, many investigators exclude homeless populations from clinical trials due to practical concerns about conducting research with this population. This report is based on our experience and lessons learned while conducting two large NIH-funded randomized controlled trials targeting smoking cessation among persons who are homeless. The current report also addresses challenges when conducting clinical trials among homeless populations and offers potential solutions. Homeless individuals face several challenges including the need to negotiate daily access to food, clothing, and shelter. Some of the critical issues investigators encounter include recruitment and retention obstacles; cognitive impairment, mental health and substance abuse disorders; transportation and scheduling challenges; issues pertaining to adequate study compensation; the need for safety protocols for study staff; and issues related to protecting the wellbeing of these potentially vulnerable adults. Anticipating realistic conditions in which to conduct studies with participants who are homeless will help investigators to design efficient protocols and may improve the feasibility of conducting clinical trials involving homeless populations and the quality of the data collected by the researchers. TRIAL REGISTRATION ClinicalTrials.gov, ID: NCT00786149 . Registered on 5 November 2008; ClinicalTrials.gov, ID: NCT01932996 . Registered on 20 November 2014.

OBJECTIVES The present cross-sectional study aimed to a) examine associations between measures of psychological well-being, specifically life satisfaction and life engagement, and intima media thickness, a subclinical marker of atherosclerosis; b) investigate if the interaction of psychological well-being and life events correlated with intima media thickness; and c) explore these relationships across race. METHODS A sample of 485 women (38% African American and 62% white; mean [standard deviation] age = 50.2 [2.9] years) underwent ultrasonography to assess carotid artery intima media thickness (IMT). The women completed self-report measures of life satisfaction, life engagement, and life events. RESULTS Average (standard deviation) IMT was 0.666 (0.10) mm. Life satisfaction showed a significant, independent, inverse relationship with IMT, after controlling for demographic, behavioral, psychological, and cardiovascular covariates (β = -0.105, p = .039), such that each 1-point higher life satisfaction score was correlated with a significant 0.008-mm lower level of mean IMT. No significant association was seen between life events and IMT (r = 0.05, p = .32), and life satisfaction did not interact with life events on IMT (β = -0.036, p = .46). No significant interaction between life satisfaction and race on IMT was observed (β = 0.068, p = .37). In contrast to life satisfaction, life engagement was not a significant correlate of IMT (r = -0.07, p = .12). CONCLUSIONS Life satisfaction, a measure of psychological well-being, is an important independent correlate of subclinical atherosclerosis in middle-aged women.

BACKGROUND Childhood maltreatment has been linked to adulthood cardiovascular disease (CVD). Little is known about the relationship between intimate partner violence (IPV) in late adolescence and young adulthood and CVD risk later in adulthood. PURPOSE To examine whether IPV perpetration and victimization experienced in late adolescence and young adulthood are associated with CVD risk among adults in the United States and whether this relationship differs by sex. METHODS Data include 9976 participants (50% female) in the National Longitudinal Study of Adolescent to Adult Health. Physical and sexual IPV were measured at wave 3 (2001/02) with items from the revised Conflict Tactics Scales. Participants'30-year risk of CVD was calculated at wave 4 (2008/09) using a Framingham prediction model. Linear regression models adjusted for confounders and IPV by sex interaction terms were tested to examine the relationship. RESULTS The mean CVD risk score was 13.18% (95% CI: 12.71, 13.64). Aone-standard deviation increase in the victimization score was associated with a 0.28% (95% CI: 0.03, 0.54) increase in CVD risk. Perpetration was similarly positively associated with CVD risk (beta: 0.33, 95% CI: 0.03, 0.62). When measured as a composite, all violence types were associated with increased CVD risk but only prior exposure to both victimization and perpetration reached statistical significance (0.62%, 95% CI: 0.01, 1.22). No differences by sex were detected. CONCLUSIONS Effect sizes are not large, but early detection of increased CVD risk in this relatively young population is notable and worthy of further study to inform the clinical response.

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.

BACKGROUND The apolipoprotein E (APOE) ε4 allele and stroke increase the risk of cognitive decline. However, the association of the APOE ε4 allele before and after stroke is not well understood. METHODS Using a prospective sample of 3444 (66% African Americans, 61% females, mean age=71.9 y) participants, we examined cognitive decline relative to stroke among those with and without the APOE ε4 allele. RESULTS In our sample, 505 (15%) had incident stroke. Among participants without stroke, the ε4 allele was associated with increased cognitive decline compared to noncarriers (0.080 vs. 0.036 units/year; P<0.0001). Among participants without the ε4 allele, cognitive decline increased significantly after stroke compared to before stroke (0.115 vs. 0.039 units/year; P<0.0001). Interestingly, cognitive decline before and after stroke was not significantly different among those with the ε4 allele (0.091 vs. 0.102 units/year; P=0.32). Poor cognitive function was associated with higher risk of stroke (hazard ratio=1.41, 95% confidence interval, 1.25-1.58), but the APOE ε4 allele was not (P=0.66). The APOE ε4 allele, cognitive function, and incident stroke were associated with mortality. CONCLUSIONS The association of stroke with cognitive decline appears to differ by the presence of the APOE ε4 allele, but no such interaction was observed for mortality.

BACKGROUND: Several individual-level stressors have been linked to incident coronary heart disease (CHD), but less attention has focused on the influence of neighbourhood-level sources of stress. In this study we examined prospective associations of individual-level and neighbourhood-level stressors with incident CHD. METHODS: Multi-Ethnic Study of Atherosclerosis participants aged 45-84 years at baseline (2000-2002) with complete data were included in the analyses (n=6678 for individual-level and n=6105 for neighbourhood-level stressors). CHD was defined as non-fatal myocardial infarction, resuscitated cardiac arrest or CHD death. Median follow-up was 10.2 years. Multivariable Cox proportional hazards models were fitted to estimate associations of individual-level and neighbourhood-level stressors (categorised into approximate tertiles) with incident CHD. RESULTS: Higher reported individual-level stressors were associated with higher incident CHD. Participants in the high individual-level stressor category had 65% higher risk of incident CHD (95% CI 1.23 to 2.22) than those in the low category after adjusting for sociodemographics (P for trend=0.002). This association weakened but remained significant with further adjustment for behavioural and biological risk factors. There was a non-linear relationship between neighbourhood-level stressors and incident CHD (P for quadratic term=0.01). Participants in the medium category had 49% higher CHD risk (95% CI 1.06 to 2.10) compared with those in the low category; those in the high category had only 27% higher CHD risk (95% CI 0.83 to 1.95). These associations persisted with adjustment for risk factors and individual-level stressors. CONCLUSIONS: Individual-level and neighbourhood-level stressors were independently associated with incident CHD, though the nature of the relationships differed.