Karen A. Matthews’s research while affiliated with University of Pittsburgh and other places

Objective: HDL cholesterol efflux capacity (CEC) is a key metric of the cardioprotective HDL functionality. CEC generally rises as women traverse the menopause but it is unclear whether this rise reduces future CVD risk. We tested whether the association between CEC and subclinical CVD burden, measured using a composite subclinical CVD score based on carotid-intima media thickness (c-IMT), carotid-femoral pulse wave velocity (cf-PWV) and presence of coronary artery calcium (CAC score ≥10), varies by time relative to the final menstrual period (FMP). Design: We included 279 women (at baseline: age 51±2.8 years; 68.5% White; 31.5% Black; 60.6% Pre-/perimenopausal) who had HDL metrics and subclinical CVD outcome measures measured once (N=115 [41.2%]) or twice (N=164 [58.8%]). The composite subclinical CVD score was computed using a factor analysis for mixed data approach (FactoMineR R package), which combines principal component analysis for continuous (c-IMT, cf-PWV) and multiple correspondence analysis for categorical data (CAC≥10). A linear mixed effects model was used to model the composite score of subclinical CVD and estimates were back transformed to the individual observed components. We tested the interaction between CEC and time relative to FMP in this model. Results: Higher CEC was associated with a lower composite subclinical CVD score at FMP in unadjusted analyses (Illustration). This association was negligible after adjustment for confounders. In all models, association of CEC varied by time relative to FMP such that the pre-FMP protective association of CEC diminishes after the FMP. This pattern was consistent across all components of the composite score (Illustration). Conclusions: In women, higher CEC is associated with a lower risk of subclinical CVD burden before but not after menopause. High CEC is not a consistent indicator of CVD protection in women traversing menopause.

Inflammation is a mechanistic pillar of aging contributing to the pathogenesis of several common medical conditions. Numerous in-vitro and animal experiments support a link between estrogen decline over the menopause transition (MT) and inflammation. Whether the MT per-se is associated with increased inflammatory load is not obvious. Using longitudinal data from 1,459 (11,373 observations) women (at baseline: 42-52 years old; underweight/normal 39.6%, overweight 28%, obese 32.4%; White 44.5%, Black 27.8%, Chinese 10.7%, Japanese 12.1%, Hispanic 4.9%) with a known final-menstrual-period (FMP) date and at least 3-measures of high sensitivity C-reactive protein (hs-CRP) spanning between 10 years before to 14 years after FMP, we characterized trajectories of hs-CRP and their associations with premenopausal obesity and race/ethnicity. Observations indicating acute inflammation were deleted and data were censored at first use of hormone therapy. Group-based trajectory modeling adjusted for time-varying smoking-status and steroids/statin use was utilized to identify trajectories. LOESS plots and piecewise linear mixed-effects models were used to determine if trajectories were linear or had inflection points around FMP. Three distinct hs-CRP trajectories were identified: low-rise (low-level significantly increased 2.5Yrs after FMP; 26.6%), medium-stable (remained stable across MT; 41.7%), and high-decline (high-level significantly declined at FMP; 31.7%). White women were more likely to show the medium-stable trajectory, Black and Hispanic the high-decline, and Chinese and Japanese the low-rise trajectory. Premenopausal obesity predicted the high-decline trajectory, underweight/normal predicted the low-rise, while overweight predicted the medium-stable trajectory. Heterogeneous patterns of hs-CRP over the MT exist and are related to women’s race/ethnicity and premenopausal obesity.

Objective Perimenopausal women experience a steep increase in low-density lipoprotein cholesterol (LDL-C) that is related to a higher risk of carotid plaque later in life. Low-density lipoprotein subclasses have been linked to cardiovascular diseases beyond LDL-C, promising a better risk stratification. We aim to characterize changes in LDL subclasses and assess their associations with presence of coronary artery calcium (CAC score ≥10) and carotid intima-media thickness (cIMT) over the menopausal transition (MT) and by menopause stage. Methods Nuclear magnetic resonance spectroscopy LDL subclasses were measured for a maximum of five time points. Coronary artery calcification and cIMT were measured for a maximum of two time points. LOESS (locally weighted regression with scatter smoothing) plots, linear mixed-effects models, and generalized estimating equations were used for analyses. Results The study included 471 women (baseline: age, 50.2 ± 2.7 years; 79.0% premenopausal/early perimenopausal), of whom 221 had data on CAC or cIMT. Low-density lipoprotein subclasses increased over the MT, whereas intermediate density-lipoprotein particles declined. In adjusted models, higher total LDL particles (LDL-P) and apolipoprotein B were associated with greater CAC prevalence and greater cIMT. Although none of the associations were modified by menopause stage, higher LDL-C, apolipoprotein B, and total LDL-P were associated with greater cIMT during the perimenopause or postmenopause stages, whereas higher LDL-C and small LDL-P were associated with greater CAC prevalence, mainly during perimenopause. Conclusions During the MT, women experience significant increases in LDL subclasses found to be related to greater cIMT levels and CAC prevalence. Whether these changes could better predict future risk of hard cardiovascular disease events beyond LDL-C remains a research question to address.

Cardiovascular disease (CVD) is the number one cause of death for women, and major life events across midlife may contribute to CVD risk. The present study aimed to test whether greater exposure to major life events across nearly two decades of longitudinal follow-up would be associated with higher risk of clinical cardiovascular disease events. 3,222 middle-aged women from the multi-ethnic Study of Women’s Health Across the Nation reported and provided up to 15 years of major life events, non-fatal incident CVD events, traditional biobehavioral and sociodemographic factors, and death certificates. Cox proportional hazards models were used to test the association between average annual life events and incident fatal and nonfatal CVD events. Each additional major life event was associated with a 1.16-fold (95% CI: 1.08-1.23) increase in CVD events. CVD risk will be discussed considering evidence of racial/ethnic disparities in exposure to major life events.

Older adults, particularly those with trauma histories, may be vulnerable to adverse psychosocial outcomes during the COVID‐19 pandemic. We tested associations between prepandemic childhood abuse or intimate partner violence (IPV) and elevated depressive, anxiety, conflict, and sleep symptoms during the pandemic among aging women. Women (N = 582, age: 65–77 years) from three U.S. sites (Pittsburgh, Boston, Newark) of the longitudinal Study of Women's Health Across the Nation (SWAN) reported pandemic‐related psychosocial impacts from June 2020–March 2021. Prepandemic childhood abuse; physical/emotional IPV; social functioning; physical comorbidities; and depressive, anxiety, and sleep symptoms were drawn from SWAN assessments between 2009 and 2017. There were no measures of prepandemic conflict. In total, 47.7% and 35.3% of women, respectively, reported childhood abuse or IPV. Using logistic regression models adjusted for age; race/ethnicity; education; site; prepandemic social functioning and physical comorbidities; and, in respective models, prepandemic depressive, anxiety, or sleep symptoms, childhood abuse predicted elevated anxiety symptoms, OR = 1.67, 95% CI [1.10, 2.54]; household conflict, OR = 2.19, 95% CI [1.32, 3.61]; and nonhousehold family conflict, OR = 2.14, 95% CI [1.29, 3.55]. IPV predicted elevated sleep problems, OR = 1.63, 95% CI [1.07, 2.46], and household conflict, OR = 1.96, 95% CI [1.20, 3.21]. No associations emerged for depressive symptoms after adjusting for prepandemic depression. Aging women with interpersonal trauma histories reported worse anxiety, sleep, and conflict during the COVID‐19 pandemic than those without. Women's trauma histories and prepandemic symptoms are critical to understanding the psychosocial impacts of the pandemic.

Background Dysregulation in physiological responses to stress may provide a mechanism through which low socioeconomic status (SES) in childhood negatively impacts health. Evidence linking early life SES to physiological stress responses is inconsistent. Exposure to childhood trauma may be an important source of heterogeneity accounting for mixed findings. Guided by the adaptive calibration model, we examined whether childhood SES and childhood trauma jointly predict ambulatory measures of cardiovascular responses to daily life stressors.MethodA sample of 377 healthy, middle-aged adults (62% female, 80% White, 64% college-educated, Mage = 52.59 ± 7.16) completed a 4-day ecological momentary assessment protocol that measured task strain, social conflict, and ambulatory systolic and diastolic blood pressure (SBP and DBP, respectively) at hourly intervals throughout the day. Average ambulatory blood pressure responses to stress were calculated by regressing momentary SBP and DBP on momentary measures of stress within the multilevel models. Early life SES and childhood trauma were measured retrospectively by self-report questionnaire.ResultsMultilevel models controlling for momentary influences on blood pressure and age, sex, and race showed no main effects of early life SES or childhood trauma on ambulatory measures of cardiovascular responses to daily life stress. An interaction emerged for DBP responses to social conflict, where individuals raised in middle SES families who experienced trauma showed a blunted response relative to those who did not (${\gamma }_{14}=$−0.93, 95% CI: [−1.62, −0.24], p = .008). There was no significant SES-trauma interaction in predicting SBP responses to social conflict or blood pressure responses to task strain.Conclusion Results do not provide support for our predictions that were derived from the adaptive calibration model, but do suggest that the impacts of early childhood experiences on cardiovascular responses may vary by type of daily stress experience.

Background The menopause transition (MT) is linked to adverse changes in lipids/lipoproteins. However, the related contributions of Anti-Müllerian hormone (AMH) and estradiol (E2) are not clear. Objective To evaluate the independent associations of premenopausal AMH and E2 levels and their changes with lipids/lipoproteins levels [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-1 (apoA-1)] over the MT. Methods SWAN participants who transitioned to menopause without exogenous hormone use, hysterectomy, or bilateral oophorectomy with data available on both exposure and outcomes when they were premenopausal until the 1st visit postmenopausal were studied. Results The study included 1,440 women (baseline-age:mean±SD=47.4±2.6) with data available from up to 9 visits (1997-2013). Lower premenopausal levels and greater declines in AMH were independently associated with greater TC and HDL-C, whereas lower premenopausal levels and greater declines in E2 were independently associated with greater TG and apo B and lower HDL-C. Greater declines in AMH were independently associated with greater apoA-1, and greater declines in E2 were independently associated with greater TC and LDL-C. Conclusions AMH and E2 and their changes over the MT relate differently to lipids/lipoproteins profile in women during midlife. Lower premenopausal and/or greater declines in E2 over the MT were associated with an atherogenic lipid/lipoprotein profile. On the other hand, lower premenopausal AMH and/or greater declines in AMH over the MT were linked to higher apo A-1 and HDL-C; the later found previously to be related to a greater atherosclerotic risk after menopause.

Background Utility of high‐density lipoprotein cholesterol (HDL‐C) in assessing the antiatherogenic properties of HDL may be limited in midlife women. Novel metrics of HDL function, lipid contents, and subclasses may better reflect the atheroprotective capacities of HDL, supporting the need to evaluate how cardiovascular health affects these metrics in women. We assessed the relationship of early midlife Life's Simple 7 (LS7) score and its health behavior components with future HDL function (HDL–cholesterol efflux capacity), HDL‐phospholipid, HDL‐triglyceride, HDL particles (HDL‐P) and size, and the relationship between LS7 score and changes in HDL metrics over time. Methods and Results We analyzed 529 women (baseline age: 46.4 [2.6] years, 57% White) from the SWAN HDL (Study of Women's Health Across the Nation HDL) study who had baseline LS7 followed by future repeated HDL metrics. Multivariable linear mixed models were used. Higher LS7 score was associated with favorable future HDL profile (higher HDL‐phospholipid, total HDL‐P and large HDL‐P, lower HDL‐triglyceride, and larger overall HDL size). Ideal body mass index was associated with higher HDL–cholesterol efflux capacity, HDL‐phospholipid, and large HDL‐P, lower HDL‐triglyceride and small HDL‐P, and larger overall HDL size. Ideal physical activity was associated with higher HDL‐phospholipid, and total, large, and medium HDL‐P. Ideal smoking was associated with less HDL‐triglycerides. Diet was not related to HDL metrics. Higher LS7 score and ideal body mass index were associated with slower progression of HDL size over time. Conclusions Novel HDL metrics may better reflect the clinical utility of HDL. Improving lifestyle at midlife, particularly maintaining ideal body mass index, is associated with better future HDL phenotype.

Objective: Vasomotor symptoms (VMS), the most frequently reported symptoms during the menopausal transition, have been associated with inflammation. Whether inflammation is a risk factor for or a consequence of VMS remains unclear. The objectives of these analyses were to determine if elevated proinflammatory marker levels were associated with increased incident VMS in women without VMS at baseline and whether these associations varied by menopause transition stage or race/ethnicity. Methods: We used longitudinal data on incident VMS, high-sensitivity C-reactive protein (hs-CRP; n = 1,922) and interleukin-6 (IL-6; n = 203) from 13 follow-up visits in the Study of Women's Health Across the Nation, which included five racial/ethnic groups of midlife women. We performed multivariable discrete-time survival analyses to determine adjusted hazard ratios (aHRs) for the association of these proinflammatory markers with incident VMS in women without VMS at baseline. Results: We found no significant associations of incident VMS with dichotomized hs-CRP (>3 vs ≤3 mg/L) at baseline, concurrent or prior visit (aHRs, 1.04-2.03) or IL-6 (>1.44 vs ≤1.44 pg/mL) at visit 1, concurrent or prior visit (aHRs, 0.67-1.62), or continuous hs-CRP or IL-6 values over 13 follow-up visits (with nonsignificant adjusted increased hazards ranging from 0% to 2%). Conclusions: Our results showed no significant association of the proinflammatory biomarkers, hs-CRP or IL-6, either concurrently or with subsequent incident VMS, indicating that inflammation was unlikely to be a risk factor for VMS. Thus, clinical treatments directed at reducing inflammation would be unlikely to reduce the occurrence of VMS.

Objective: During midlife, women experience changes in lipoprotein profiles and deterioration in vascular health measures. We analyzed the associations of groups of lipoprotein subfractions as determined by principal component analysis (PCA) with subclinical vascular health measures in midlife women and tested if these associations were modified by menopause status. Methods: PCA was used to generate principal components (PCs) from 12 lipoprotein subfractions quantified among 545 midlife women. The associations of the identified PCs and concurrent vascular health measures were assessed using linear or logistic regressions among participants with carotid intima-media thickness (cIMT; n = 259), coronary artery calcium (n = 249), or aortic calcium (n = 248) scores. Results: PCA generated four PCs representing groups of (1) small, medium, and large very low-density lipoproteins subclasses-very low-density lipoprotein PC; (2) very small, small, and medium low-density lipoprotein (LDL) subclasses-small-medium LDL-PC; (3) large and small high-density lipoproteins subclasses and midzone particles-high-density lipoprotein PC; and (4) large LDL and small intermediate-density lipoproteins-large LDL-PC. Small-medium LDL-PC was positively associated with cIMT, coronary artery calcium, and aortic calcium in unadjusted but not in adjusted models. Menopause status modified the positive association of the small-medium LDL-PC with cIMT (interaction P = 0.02) such that this association was stronger after versus before menopause (P = 0.01). Conclusions: Carotid intimal medial thickening is positively and independently associated with small- and medium-sized LDL particles after menopause. Monitoring levels of specific lipoprotein fractions may have value in identifying midlife women at risk for developing atherosclerotic vascular disease.