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Background/objectivesHigher volumes of ectopic cardiovascular fat (ECF) are associated with greater risk of coronary heart disease (CHD). Identifying factors that are associated with ECF volumes may lead to new preventive efforts to reduce risk of CHD. Significant racial/ethnic differences exist for overall and central adiposity measures, which are known to be associated with ECF volumes. Whether racial/ethnic differences also exist for ECF volumes and their associations with these adiposity measures remain unclear.Subjects/methodsBody mass index (BMI), computerized tomography-measured ECF volumes (epicardial, pericardial and their summation) and visceral adipose tissue (VAT) were examined in a community-based sample of 1199 middle-aged men (24.2% Caucasians, 7.0% African-Americans, 23.6% Japanese-Americans, 22.0% Japanese, 23.2% Koreans).ResultsSignificant racial/ethnic differences existed in ECF volumes and their relationships with BMI and VAT. ECF volumes were the highest among Japanese-Americans and the lowest among African-Americans. The associations of BMI and VAT with ECF differed by racial/ethnic groups. Compared with Caucasians, for each 1-unit increase in BMI, African-Americans had lower, whereas Koreans had higher increases in ECF volumes (P-values

Objectives: Determine if clinical parameters of resuscitated patients predict coronary angiography (CATH) performance and if receiving CATH after cardiac arrest is associated with outcome. Introduction: CATH is associated with survival in patients suffering out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation or ventricular tachycardia(VF/VT). Its effect on outcome in other cohorts is unknown. Methods: Chart review of resuscitated cardiac arrest patients between 2005 and 2007. Exclusion criteria: immediate withdrawal of care, hemodynamic collapse, or neurologic exam under sedation. Clinical parameters included Glasgow Coma Scale (GCS) arrest location, presenting rhythm, age, and acute ischemic ECG changes (new left bundle branch block or ST-elevation myocardial infarction-STEMI). Logistic regression identified clinical parameters predicting CATH. The association between CATH and good outcome (discharge home or to acute rehabilitation facility) was determined using logistic regression adjusting for likelihood of receiving CATH via propensity score. Result: Of the 241 patients, 96 (40%) received CATH. Significant disease (>/=70% stenosis) of >/=1 coronary arteries was identified in 69% of patients including 57% of patients without acute ischemic ECG changes. Unadjusted predictors of CATH were sex, method of arrival, OHCA, presenting rhythm, acute ischemic ECG changes, and GCS. Propensity adjusted logistic regression demonstrated an association between CATH and good outcome (OR 2.16; 95% CI 1.12, 4.19; P < 0.02). Conclusion: CATH is more likely to be performed in certain patients and identifies a significant number of high-grade stenoses in this population. Receiving CATH was independently associated with good outcome. [ABSTRACT FROM AUTHOR]

Context: Limited data provides evidence-based insights on the association between comprehensive metrics of high-density lipoproteins (HDL) and cognitive performance, especially in midlife women for whom benefit might be the greatest., Objective: To assess the associations of serum HDL metrics including HDL lipid content [HDL cholesterol, phospholipid (HDL-PL), triglyceride], proteins/subclasses [apolipoprotein A-1 (apoA-1); small, medium, large, total HDL particle (HDL-P); and HDL size], and cholesterol efflux capacity with cognitive performance in midlife women., Methods: This prospective cohort study was conducted among 503 midlife women (1234 observations) from the Study of Women's Health Across the Nation HDL ancillary study. Joint models were applied to examine associations of HDL metrics assessed at midlife (50.2 ± 2.9 years, baseline of the current study) and their changes over midlife (6.1 ± 3.9 years of duration) with subsequent cognitive performance [working memory (Digit Span Backward Test), processing speed (Symbol Digit Modalities Test), and episodic memory immediate and delayed recall (East Boston memory test)] assessed repeatedly (maximum 5 times) 1.5 ± 1 years later over 7.72 ± 4.10 years of follow up., Results: Higher total HDL-P and smaller HDL size at midlife were associated with a better subsequent immediate recall, delayed recall and/or processing speed. Greater increase in HDL-PL, apoA-1, medium HDL-P, and total HDL-P and less increase in HDL size over midlife were associated with a better subsequent immediate and/or delayed recall., Conclusions: Enhancing specific serum HDL metrics during midlife could be promising in cognitive restoration, particularly memory, the initial and predominant symptom of Alzheimer's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Fibroids are non-cancerous uterine tumors potentially associated with cardiovascular risk factors. We examined prospectively associations of glucose, insulin, sex hormone binding globulin (SHBG), and diabetes with incidence of fibroid diagnoses in midlife., Methods: Participants in the Study of Women's Health Across the Nation (SWAN) cohort (n=2570) reported fibroid diagnoses at enrollment (1996-1997) and 13 follow-up visits (1996-2013). At all visits, we measured glucose, insulin, and SHBG in fasting blood samples and calculated homeostatic model assessment for insulin resistance (HOMA-IR). Diabetes was defined using glucose levels, self-reported diabetes, or diabetes medication use. We used discrete-time survival models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of time-varying biomarkers and diabetes with incident fibroid diagnoses, adjusted for demographics and healthcare utilization. We also evaluated effect modification by menopausal status., Results: At baseline, 2.7% of participants (n=70) were using diabetes medication. Time-varying glucose, insulin, HOMA-IR, and SHBG were not associated with fibroid diagnosis. However, diabetes was associated with a 28% lower incidence of fibroid diagnosis (adjusted HR: 0.72, 95% CI: 0.44, 1.17), driven by participants using metformin (adjusted HR: 0.49, 95% CI: 0.21, 1.12), though precision was limited. After stratification by menopausal status, higher HOMA-IR and insulin were associated with greater incidence of fibroid diagnosis during premenopause but not perimenopause, while the inverse association between diabetes and fibroids was strongest during perimenopause., Conclusion: The effect of diabetes and biomarkers on fibroids may vary by menopausal status. Fibroid risk may increase with insulin resistance and decrease with diabetes treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: The clinical utility of high-density lipoprotein cholesterol (HDL-C) in risk classification is limited, especially in midlife women. Novel metrics of HDL may better reflect this risk. We clustered a comprehensive profile of HDL metrics into favorable and unfavorable clusters and assessed how these two clusters are related to future subclinical atherosclerosis (carotid intima media thickness [cIMT], interadventitial diameter [IAD], and carotid plaque presence) in midlife women., Methods: Four hundred sixty-one women (baseline age: 50.4 [2.7] years; 272 White, 137 Black, 52 Chinese) from the Study of Women's Health Across the Nation HDL ancillary study who had baseline measures of HDL cholesterol efflux capacity (HDL-CEC), lipid contents (HDL-phospholipids [HDL-PL] and HDL triglycerides [HDL-Tg]), and HDL particle (HDL-P) distribution and size, followed by carotid ultrasound (average 12.9 [SD: 2.6] years later), were included. Using latent cluster analysis, women were clustered into a favorable (high HDL-CEC, HDL-PL, large and medium HDL-P, less HDL-Tg and small HDL-P, larger size) or an unfavorable HDL cluster (low HDL-CEC, HDL-PL, large and medium HDL-P, more HDL-Tg, and small HDL-P, smaller size) and then linked to future subclinical atherosclerosis using linear or logistic regression., Results: The favorable HDL cluster was associated with lower cIMT, IAD, and odds of carotid plaque presence. These associations were attenuated by body mass index, except in Chinese women where the association with cIMT persisted (0.72 [0.63, 0.83])., Conclusions: The association between favorable HDL clusters and a better postmenopausal subclinical atherosclerosis profile is largely explained by body mass index; however, racial/ethnic differences may exist., Competing Interests: Financial disclosure/conflicts of interest: Maria M. Brooks is a Data and Safety Monitoring Board member for Cerus Corporation. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Objective: High-density lipoprotein cholesterol (HDL-C) is one of 5 components [high blood pressure, glucose, triglycerides, waist circumference, low HDL-C], 3 of which, needed to diagnose metabolic syndrome (MetS). Evolving research shows that higher HDL-C is not necessarily cardioprotective in midlife women, supporting a need to re-evaluate HDL-C's contribution to risks related to MetS. We tested whether risk of future diabetes and higher carotid intima-media thickness (cIMT) differ by HDL-C status in midlife women diagnosed with MetS based on the other 4 components., Methods Midlife Women Were Classified Into 3 Groups: 1) no MetS, 2) MetS with HDL-C ≥ 50 mg/dL (MetS hiHDL), and 3) MetS with HDL-C < 50 mg/dL (MetS loHDL). cIMT was measured 13.8 ± 0.6 years post baseline. Incident diabetes was assessed yearly., Results: Among 2773 women (1350 (48 %) of them had cIMT), 2383 (86 %) had no MetS, 117 (4 %) had MetS hiHDL, 273 (10 %) had MetS loHDL. Compared with no MetS, both MetS- hiHDL and loHDL groups had higher cIMT and diabetes risk. Risk of having high cIMT did not differ between MetS loHDL vs. hiHDL groups. Adjusting for levels of MetS criteria other than HDL-C at baseline explained the associations of each of the two MetS groups with cIMT. Conversely, after adjustment, associations of MetS hiHDL and MetS loHDL with incident diabetes persisted., Conclusions: In midlife women, HDL-C status matters for predicting risk of incident diabetes but not higher cIMT beyond other MetS components., Competing Interests: We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. Dr. Rebecca Thurston is a consultant and advisor for Astellas Pharma, consultant and received travel support from Bayer, and on the medical advisory board for Hello Therapeutics. All other coauthors have nothing to disclose., (© 2024 The Author(s).)

Objective: To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes., Research Design and Methods: We followed 2,952 participants in the Study of Women's Health Across the Nation (SWAN) who were premenopausal or early perimenopausal and diabetes-free at baseline. SHBG,T, and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years). We used complementary log-log-based discrete-time survival models anchored at baseline., Results: Diabetes developed in 376 women. A 5-unit increase in time-varying SHBG was associated with a 10% reduced risk of diabetes (hazard ratio [HR] 0.91, 95% CI 0.87-0.95), adjusting for covariates, and baseline SHBG,T, and E2 levels. Time-varying T was not associated with diabetes risk. Compared with the lowest quartile for annual rate of change of SHBG since baseline (quartile 1 [Q1] -92.3 to -1.5 nmol/L), all other quartiles were associated with a decreased risk of diabetes adjusting for covariates and baseline SHBG; associations persisted after adjusting for rate of change of T and E2 (Q2 [> -1.5 to -0.2 nmol/L] HR 0.33, 95% CI 0.23-0.48; Q3 [> -0.2 to 1.3 nmol/L] HR 0.37, 95% CI 0.25-0.55; Q4 [>1.3 to 82.0 nmol/L] HR 0.43, 95% CI 0.30-0.63)., Conclusions: Increasing levels of SHBG over the menopause transition were associated with a decreased risk of incident diabetes. Stable to increasing rates of change in SHBG were also independently associated with a decreased risk of diabetes compared with decreasing rates of change, suggesting SHBG may affect glucose through a mechanism beyond androgenicity., (© 2024 by the American Diabetes Association.)

Importance: Fibroids are benign neoplasms associated with severe gynecologic morbidity. There are no strategies to prevent fibroid development., Objective: To examine associations of hypertension, antihypertensive treatment, anthropometry, and blood biomarkers with incidence of reported fibroid diagnosis in midlife., Design, Setting, and Participants: The Study of Women's Health Across the Nation is a prospective, multisite cohort study in the US. Participants were followed-up from enrollment (1996-1997) through 13 semiannual visits (1998-2013). Participants had a menstrual period in the last 3 months, were not pregnant or lactating, were aged 42 to 52 years, were not using hormones, and had a uterus and at least 1 ovary. Participants with prior fibroid diagnoses were excluded. Data analysis was performed from November 2022 to February 2024., Exposures: Blood pressure, anthropometry, biomarkers (cholesterol, triglycerides, and C-reactive protein), and self-reported antihypertensive treatment at baseline and follow-up visits were measured. Hypertension status (new-onset, preexisting, or never [reference]) and hypertension treatment (untreated, treated, or no hypertension [reference]) were categorized., Main Outcomes and Measures: Participants reported fibroid diagnosis at each visit. Discrete-time survival models estimated hazard ratios (HRs) and 95% CIs for associations of time-varying hypertension status, antihypertensive treatment, anthropometry, and biomarkers with incident reported fibroid diagnoses., Results: Among 2570 participants without a history of diagnosed fibroids (median [IQR] age at screening, 45 [43-48] years; 1079 [42.1%] college educated), 526 (20%) reported a new fibroid diagnosis during follow-up. Risk varied by category of hypertension treatment: compared with those with no hypertension, participants with untreated hypertension had a 19% greater risk of newly diagnosed fibroids (HR, 1.19; 95% CI, 0.91-1.57), whereas those with treated hypertension had a 20% lower risk (HR, 0.80; 95% CI, 0.56-1.15). Among eligible participants with hypertension, those taking antihypertensive treatment had a 37% lower risk of newly diagnosed fibroids (HR, 0.63; 95% CI, 0.38-1.05). Risk also varied by hypertension status: compared with never-hypertensive participants, participants with new-onset hypertension had 45% greater risk of newly diagnosed fibroids (HR, 1.45; 95% CI, 0.96-2.20). Anthropometric factors and blood biomarkers were not associated with fibroid risk., Conclusions and Relevance: Participants with untreated and new-onset hypertension had increased risk of newly diagnosed fibroids, whereas those taking antihypertensive treatment had lower risk, suggesting that blood pressure control may provide new strategies for fibroid prevention.

Background: Up to 50% of women report sleep problems in midlife, and cardiovascular disease (CVD) is the leading cause of death in women. How chronic poor sleep exposure over decades of midlife is related to CVD risk in women is poorly understood. We tested whether trajectories of insomnia symptoms or sleep duration over midlife were related to subsequent CVD events among SWAN (Study of Women's Health Across the Nation) participants, whose sleep was assessed up to 16 times over 22 years., Methods: At baseline, SWAN participants (n=2964) were 42 to 52 years of age, premenopausal or early perimenopausal, not using hormone therapy, and free of CVD. They completed up to 16 visits, including questionnaires assessing insomnia symptoms (trouble falling asleep, waking up several times a night, or waking earlier than planned ≥3 times/week classified as insomnia), typical daily sleep duration, vasomotor symptoms, and depressive symptoms; anthropometric measurements; phlebotomy; and CVD event ascertainment (ie, fatal or nonfatal myocardial infarction, stroke, heart failure, revascularization). Sleep trajectories (ie, insomnia, sleep duration) were determined by means of group-based trajectory modeling. Sleep trajectories were tested in relation to CVD in Cox proportional hazards models (multivariable models: site, age, race and ethnicity, education, CVD risk factors averaged over visits; additional covariates: vasomotor symptoms, snoring, depression)., Results: Four trajectories of insomnia symptoms emerged: low insomnia symptoms (n=1142 [39% of women]), moderate insomnia symptoms decreasing over time (n=564 [19%]), low insomnia symptoms increasing over time (n=590 [20%]), and high insomnia symptoms that persisted (n=668 [23%]). Women with persistently high insomnia symptoms had higher CVD risk (hazard ratio, 1.71 [95% CI, 1.19, 2.46], P =0.004, versus low insomnia; multivariable). Three trajectories of sleep duration emerged: persistently short (~5 hours: n=363 [14%]), moderate (~6 hours: n=1394 [55%]), and moderate to long (~8 hours: n=760 [30%]). Women with persistent short sleep had marginally higher CVD risk (hazard ratio, 1.51 [95% CI, 0.98, 2.33], P =0.06, versus moderate; multivariable). Women who had both persistent high insomnia and short sleep had significantly elevated CVD risk (hazard ratio, 1.75 [95% CI, 1.03, 2.98], P =0.04, versus low insomnia and moderate or moderate to long sleep duration; multivariable). Relations of insomnia to CVD persisted when adjusting for vasomotor symptoms, snoring, or depression., Conclusions: Insomnia symptoms, when persistent over midlife or occurring with short sleep, are associated with higher CVD risk among women., Competing Interests: Disclosures Dr Thurston is a consultant and advisor for Astellas Pharma, a consultant for Bayer, and on the medical advisory board for Hello Therapeutics. The other authors have no conflicts to disclose.

Objective: Carotid artery intima media thickness (cIMT) and adventitial diameter (AD) are subclinical atherosclerosis indicators. Metabolic syndrome (MetS) and obesity are risk factors for atherosclerosis, but their combined impact on atherosclerosis risk is unknown. This study sought to examine the effect of the co-occurrence of MetS with obesity on cIMT and AD., Methods: The Study of Women's Health Across the Nation (SWAN) is a multi-center, multi-ethnic study. Carotid ultrasound assessments and concurrent physiologic measurements were undertaken between 2009 and 2013. This cross-sectional analysis included 1,433 women with body mass index ≥18.5 kg/m 2 and free of prevalent clinical cardiovascular disease. Multivariable linear regression models were used to relate maximum cIMT and AD (dependent variables) with obesity, MetS and their interaction., Results: The average age was 60.1 years (standard deviation [SD], 2.7 y). The prevalence of obesity and MetS was 44% and 35%, respectively. Women with obesity had a 0.051 mm larger mean cIMT and women with MetS had a 0.057 mm larger cIMT versus women without the respective conditions (both P < 0.001). There was a statistically significant interaction between obesity and MetS ( P = 0.011); women with both had a model-adjusted predicted mean cIMT of 0.955 mm (95% confidence interval [CI], 0.897-1.013), higher than those with MetS alone (0.946 mm; 95% CI, 0.887-1.005), obesity alone (0.930 mm; 95% CI, 0.873-0.988), or neither condition (0.878 mm; 95% CI, 0.821-0.935). AD results were similar., Conclusions: Early detection and treatment of atherosclerotic changes may prevent significant disease. This study suggests there is a minimal impact of obesity on carotid artery thickness beyond MetS alone. All individuals with metabolic dysfunction, regardless of obesity status, should be considered at increased risk for atherosclerotic changes., Competing Interests: Financial disclosure/conflicts of interest: E.A.J. receives ongoing institutional funding from the National Institute of Health, Agency for Healthcare Research and Quality, and the VA health system. E.A.J. is a member of the American Heart Association editorial board, a consultant for American College of Cardiology and Optum Health, an expert witness for DeBlase, Brown, and Eyerly LLP, and received past institutional funding from Amgen Research. C.A.K.-G. received payment from the University of Jyväskylä Finland for services as expert reviewer of a dissertation. The other authors have nothing to disclose., (Copyright © 2023 by The Menopause Society.)

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., Competing Interests: Financial disclosure/conflicts of interest: M.M.B. serves as a Data and Safety Monitoring Board member for Cerus Corporation. S.C. received a payment for statistical consulting from the University of Pittsburgh. The other authors report no conflicts., (Copyright © 2023 by The Menopause Society.)

Introduction: Cardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes., Methods: The associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women., Results: Higher thoracic PVAT volume was associated with a higher future episodic memory (β[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (β[SE] = -0.06 [0.03], P = 0.045) and working (β[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT., Discussion: Mid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation., Highlights: Higher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition., (© 2023 the Alzheimer's Association.)

Objectives: To determine whether physical function (PF) before menopause is related to cardiovascular disease (CVD) risk., Methods: Participants were N = 2950 pre-/early peri-menopausal women (median age 46, (25th-75th percentile: 43-48 years). Physical function was assessed at baseline using the Physical Function subscale of the SF-36 and scores were trichotomized (no, some, or substantial limitations). Clinical CVD events were ascertained at annual/biennial clinical assessments through the 15th follow-up visit. Risk of CVD was determined with Cox proportional hazards models. Results: Women were followed for a median of 19.1 years, during which 220 women had a CVD event. In fully adjusted models, women with substantial limitations at baseline had higher CVD risk compared to women with no limitations (hazards ratio [HR] = 1.55, 95% confidence interval [CI]: 1.12-2.33). Discussion: Substantial PF limitations in pre- and early peri-menopausal women are associated with higher risk of clinical CVD events, consistent with literature in older adults.

The menopause transition is a critical period for cardiovascular health. During this stage, women experience adverse changes in multiple components that are key for optimal cardiovascular health. Additionally, women struggle to maintain ideal health behaviors, which if adopted collectively, have been shown in observational studies to prevent more than 70% of coronary heart disease cases. Significant efforts should be directed toward increasing awareness among women and healthcare professionals about the menopause transition as a stage of cardiovascular disease risk acceleration that is amenable to reduction with positive lifestyle measures., (Copyright © 2023 by The North American Menopause Society.)

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., Competing Interests: Declaration of Competing Interest Samar R. El Khoudary: None, Xirun Chen: None, Meiyuzhen Qi: None, Carol Derby: None, Maria M. Brooks: DSMB member: Cerus Corporation, Rebecca C. Thurston: Consulting/Advisory Board: Astellas, Bayer, Happify Health, Vira Health, Imke Janssen: None, Sybil Crawford: None, Jennifer S. Lee: None, Elizabeth A. Jackson: research funding from NIH, and Amgen; editorial board membership: Circulation: Cardiovascular Quality and Outcomes; consulting: American College of Cardiology and McKesson, Inc.; Expert witness for DeBlase Brown Everly LLP.; and royalties from UpToDate, Claudia Chae: None, Dan McConnell: None, Karen A. Matthews: None, (Copyright © 2022. Published by Elsevier Inc.)

In this JCL Roundtable, we bring together three experts to discuss women's cardiovascular health throughout the lifespan, viewed from the standpoint of clinical lipidology. Overall, heart disease leads to one out of every 3 deaths of American women, but unfortunately patient awareness of cardiovascular risk actually has declined since 2009. Younger women are not exempt, since their risk can be increased by smoking, birth control, adverse lifestyle and diet, and genetic disorders. Age at menarche can influence lifetime risk. Polycystic ovary syndrome, noted in 5-13% of women of reproductive age, has been linked to increased cardiovascular risk, partly through atherogenic dyslipidemia. Oral contraception has improved greatly since its introduction, but remains a risk for venous thromboembolism and stroke, particularly in smokers. Fetal nutritional and metabolic requirements in pregnancy impose high vascular demand on the placenta and lead to escalating maternal triglycerides and cholesterol especially in the 3rd trimester. Triglycerides may require special management. Adverse pregnancy outcomes associated with placental dysfunction signal subsequent increased risk for maternal atherosclerotic disease. Early menopause has long been recognized as a risk enhancing factor for atherosclerosis with pathophysiology remaining unclear. The menopause transition represents a period when cardiovascular risk for women increases rapidly and approaches that of men. Current studies are evaluating hormonal changes and even clonal hematopoiesis as potential causes. At the same time, lifestyle habits and routine chronic conditions such as hypertension and obesity/diabetes/metabolic syndrome play a large role and need attention., (Copyright © 2019. Published by Elsevier Inc.)

It is known that the menopause transition (MT) is a complex period during a woman's life, but there has been ongoing debate on whether the increase in cardiovascular disease (CVD) during midlife is due to chronological aging or ovarian aging. The purpose of this review is to summarize the recent findings on the role of ovarian aging versus chronological aging on cardiovascular disease (CVD) outcomes and its risk factors in women. Recent data from longitudinal studies have shown that menopause-related factors, such as earlier age at menopause and surgical menopause are associated with higher CVD outcomes. The MT is also associated with detrimental changes in vascular health as well as cardiometabolic risk factors including body composition, visceral fat accumulation, lipids/lipoproteins, blood pressure and the metabolic syndrome. The robust evidence from recent research indicating increases in CVD risk over the MT beyond aging call for immediate efforts to rise awareness among women and their health care providers of CVD risk acceleration accompanying the MT. Efforts should also be directed toward developing and testing novel preventive approaches that target women during this time period to counteract the expected increase in CVD risk., Competing Interests: Declaration of Interest: None Declaration of Interest: Dr. El Khoudary: Supported by funds from NIA and NHLBI Dr. Nasr: Graduate Student Researcher on The Study Of women’s Health Across the Nation (SWAN) HDL

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.

Background: Atrial fibrillation (AF) is a highly morbid condition which requires long-term adherence to oral anticoagulation and may be associated with adverse quality of life and health care utilization. We developed a relational agent-an interactive smartphone-based intervention accessible regardless of digital or health literacy-to assist individuals residing in rural, Western Pennsylvania, with AF with chronic disease self-management., Methods: The "Mobile health intervention for rural atrial fibrillation" is a single center, parallel-arm randomized clinical trial for adults with AF funded by the National Institute of Health's National Heart, Lung, and Blood Institute to enroll 264 participants. All participants receive a smartphone with data plan: The intervention is a 4 month relational agent coupled with the AliveCor Kardia for heart rate and rhythm monitoring provided by smartphone, and the control a pre-installed, smartphone-based application for health-related information (WebMD). The study uses remote recruitment and engagement to enroll individuals who would otherwise be unlikely to participate in clinical research due to rurality. The primary outcome of the trial is adherence to oral anticoagulation, determined by proportion of days covered, as measured at 12 months. The secondary outcomes are quality of life, both AF-specific and general, and health care utilization. The study entails a baseline visit, a 4 month intervention phase, and 8 and 12 month follow-up visits., Conclusions: This mobile health trial tests the effectiveness of a smartphone-based relational agent to improve clinical and patient-reported outcomes in rural-dwelling individuals., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Aortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC., Methods: We used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784)., Results: After adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups., Conclusions: In a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC.

Background: The menopause transition (MT) could trigger low-grade chronic inflammation which may modify high-density lipoproteins (HDL) and lead to additional inflammatory responses contributing to atherosclerosis development., Objective: To test whether complement proteins C3 and C4 increase around the final menstrual period (FMP), and whether changes in HDL subclasses and lipid content associate with C3 and C4 levels over time in midlife women., Methods: The study included 471 women (at baseline: age 50.2(2.7) years; 87.3% pre or peri-menopausal) who had nuclear magnetic resonance spectroscopy HDL subclasses, lipid content, and C3 and C4 measured up to 5 times over the MT., Results: Adjusted annual changes in C3 and C4 varied by time segments relative to FMP with significant increases, steeper for C3, only observed within 1 year before to 2 years after the FMP. Greater decreases in large HDL particles (HDL-P), HDL size, and HDL-phospholipids, and greater increases in small HDL-P and HDL-Triglycerides were associated with higher C3 and C4 over time, although associations with C4 were weaker than those with C3., Conclusion: Complement proteins C3 and C4 significantly rise around menopause with C3 showing the steepest rise. Changes in HDL subclasses, overall size, and lipid content, over the MT may play a role in modulating inflammation responses known to be related to atherosclerosis. These results raise the possibility that novel therapeutic agents focusing on HDL might contribute to CVD protection by modulating inflammation., Competing Interests: Declaration of Competing Interest Samar R El Khoudary: None. Xirun Chen: None. Dan McConnell: None. Maria M Brooks: None. Jeff Billheimer: None. Trevor Orchard: None., (Copyright © 2022. Published by Elsevier Inc.)

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., Competing Interests: Financial disclosure/conflicts of interest: R.M.K. receives money (paid to the institution) from Quest Diagnostics and receives royalties for a patent on ion mobility methodology. M.M.B. receives funding from Cerus Corporation. S.L.C. receives funding from the University of Pittsburgh. The other authors have nothing to disclose., (Copyright © 2022 by The North American Menopause Society.)

Background: Long-term change in CRP is not well characterized in the context of RYGB., Objective: To report C-reactive protein (CRP) after Roux-en-Y gastric bypass surgery (RYGB)., Setting: Between 2006 and 2009 1770 adults enrolled in a prospective cohort study underwent Roux-en-Y gastric bypass (RYGB) at 1 of 10 U.S. hospitals., Methods: Research assessments were conducted before surgery and annually postoperatively for up to 7 years. This study included those with high-sensitivity CRP assessed before surgery and 1 or more follow-up assessments (n = 1180)., Results: Before surgery, participants' median age was 46 years, and the median body mass index (BMI) was 46 kg/m 2 ; 80% were female. Before surgery, mean (95% confidence interval [CI]) CRP was the highest of all time points (1.01 [.95-1.08] mg/L); it then decreased to a nadir of .18 (.15-.22) mg/L at 2 years postoperatively (P < .001). CRP was higher at 7 years (.26 [.22, .29] mg/L) than at 2 years postoperatively (P < .001) but remained lower at 7 years than preoperatively (P < .001). Additionally, only 3.2% (95% CI: 1.6%-4.8%) of participants had elevated CRP (>1 mg/dL) 7 years postoperatively versus 32.9% (95% CI: 30.2%-35.3%) preoperatively (P < .001). Several preoperative factors were associated with following a less favorable CRP trajectory over time, including higher preoperative CRP level, higher BMI, current smoking, and diabetes., Conclusion: The vast majority of adults who underwent RYGB experienced a sustained improvement in CRP throughout 7 years of follow-up with nonelevated values. However, those with higher preoperative CRP and BMI levels and diabetes and who smoke may benefit from additional testing and monitoring to ensure nonelevated inflammation after surgery., (Copyright © 2022 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes., Design: Individual participant pooled analysis of eight prospective cohort studies., Setting: Cohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012., Participants: 618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke., Main Outcome and Measures: Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data., Results: The median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes., Conclusion: A history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the Australian National Health and Medical Research Council Centres of Research Excellence for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Excessive gestational weight gain (GWG) is consistently linked with maternal risk of obesity. However, the literature on its long-term cardiovascular risk is minimal and conflicting. We evaluated whether excessive GWG is associated with a high-risk cardiovascular profile among parous women in midlife. Materials and Methods: Participants were women in the multiethnic cohort Study of Women's Health Across the Nation with a history of live birth(s). Excessive GWG was defined according to Institute of Medicine guidelines and collected by self-recall. Outcomes were the atherosclerotic cardiovascular disease (ASCVD) risk score and C-reactive protein (CRP), measured at the study baseline when mean age was 47 years, and at 10 follow-up visits (1996-2017). We estimated the association of excessive GWG with outcomes through linear mixed model regression. Results: The analytic sample included 1318 women with 3049 singleton births. Over 40% (536) reported one or more pregnancies with excessive GWG. Longitudinal models estimated that at a mean age of 67, women with a history of excessive GWG had a 9.8% (9.2, 10.5) 10-year ASCVD risk, compared to 9.5% (8.9, 10.1) for those without, and mean CRP of 2.20 mg/L (1.89, 2.57) versus 1.85 mg/L (1.61, 2.14), respectively, adjusted for participant characteristics. Conclusions: In this multiethnic cohort of parous women, a history of excessive GWG was associated with a small, but statistically significant difference in ASCVD risk, and a moderate, statistically significant difference in CRP across midlife. More research is necessary to understand the mechanistic pathway between excessive GWG and long-term maternal cardiovascular health.

Context: The menopause transition is accompanied by declines in the atheroprotective features of high-density lipoprotein (HDL), which are linked to deleterious cardiovascular (CV) outcomes., Objective: This work aimed to assess the relationship between abdominal and CV visceral adipose tissues (VAT) with future HDL metrics in midlife women, and the role of insulin resistance (IR) on these associations., Methods: Temporal associations compared abdominal and CV fat with later measures of HDL metrics. This community-based cohort comprised 299 women, baseline mean age 51.1 years (SD: 2.8 years), 67% White, 33% Black, from the Study of Women's Health Across the Nation (SWAN) HDL ancillary study. Exposures included volumes of abdominal VAT, epicardial AT (EAT), paracardial AT (PAT), or perivascular AT (PVAT). Main outcomes included HDL cholesterol efflux capacity (HDL-CEC); HDL phospholipids (HDL-PL), triglycerides (HDL-Tgs), and cholesterol (HDL-C); apolipoprotein A-I (ApoA-I), and HDL particles (HDL-P) and size., Results: In multivariable models, higher abdominal VAT was associated with lower HDL-CEC, HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher PAT was associated with lower HDL-PL, HDL-C, and large HDL-P and smaller HDL size. Higher EAT was associated with higher small HDL-P. Higher PVAT volume was associated with lower HDL-CEC. The Homeostatic Model Assessment of Insulin Resistance partially mediated the associations between abdominal AT depots with HDL-CEC, HDL-C, large HDL-P, and HDL size; between PVAT with HDL-CEC; and PAT with HDL-C, large HDL-P, and HDL size., Conclusion: In midlife women, higher VAT volumes predict HDL metrics 2 years later in life, possibly linking them to future CV disease. Managing IR may preclude the unfavorable effect of visceral fat on HDL metrics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Charting the Path to Health in Midlife and Beyond: The Biology and Practice of Wellness was a Translational Science Symposium held on Tuesday, September 21, 2021. Foundational psychosocial and behavioral approaches to promote healthy aging and strategies to disseminate this information were discussed. The following synopsis documents the conversation, describes the state of the science, and outlines a path forward for clinical practice. Wellness, in its broadest sense, prioritizes an orientation toward health, and an embrace of behaviors that will promote it. It involves a journey to improve and maintain physical and mental health and overall well-being to fully engage and live one's best life. It is more about recognizing and optimizing what one can do than what one cannot do and emphasizes the individual's agency over changing what they are able to change. Wellness is therefore not a passive state but rather an active goal to be sought continually. When viewed in this fashion, wellness is accessible to all. The conference addressed multiple aspects of wellness and embraced this philosophy throughout., Competing Interests: Financial disclosures/conflicts of interest: N.F.S. reports receiving advisory fees from Astellas and Que-Oncology, research support from Menogenix, Inc (paid to the University of Colorado), and consultant fees from Ansh Labs. H.J. reports receiving grant support Merck, Pfizer, Que-Oncology, and NeRRe/KaNDy and consultant and advisory fees from Eisai, Jazz, and Bayer. H.J. also reports her spouse is an employee of Arsenal Biosciences and has an equity stake in Merck Research Labs and Tango Therapeutics., (Copyright © 2022 by The North American Menopause Society.)

Background Traumatic experiences have been linked to risk for cardiovascular disease (CVD). Interpersonal violence is a trauma that is prevalent in women. Among midlife women followed up for 2 decades, we examined whether interpersonal violence (childhood abuse, adulthood abuse, or intimate partner violence [IPV]) was related to increased risk of subsequent clinical CVD events. Methods and Results A total of 2201 women, aged 42 to 52 years at baseline, underwent up to 16 in-person visits over 22 years. Measures included questionnaires (including of childhood physical/sexual abuse, adult physical/sexual abuse, and IPV), physical measures, phlebotomy, and reported CVD events (myocardial infarction, stroke, heart failure, and revascularization). Death certificates were collected. Relationships between childhood abuse, adult abuse, and IPV with incident fatal/nonfatal CVD were tested in Cox proportional hazards models. Women with a childhood abuse history had increased risk for incident CVD (versus no abuse; hazard ratio [HR] [95% CI], 1.65 [1.12-2.44]; P =0.01; adjusted for demographics and CVD risk factors); associations were strongest for childhood sexual abuse. Adult abuse was not significantly associated with CVD. Women with IPV had a doubling of risk for incident CVD in demographic-adjusted models (versus no IPV; IPV: HR [95% CI], 2.06 [1.01-4.23]; P =0.04; no partner: HR [95% CI], 1.79 [0.91-3.53]; P =0.09); systolic blood pressure partially mediated relationships between IPV and CVD. Conclusions Childhood abuse, particularly sexual abuse, was associated with increased risk of CVD in women. IPV was associated with risk for CVD, with the higher systolic blood pressure among IPV-exposed women important in these associations. Interpersonal violence prevention may contribute to CVD risk reduction in women.

Background Prevention of cardiovascular disease (CVD) is a public health priority. The combination of physical activity, a healthy diet, and abstaining from tobacco plays an important role in prevention whereas aspects of psychosocial well-being have largely been examined separately with conflicting results. This study evaluated whether the combination of indices of psychosocial well-being was associated with less progression of coronary artery calcium (CAC). Methods and Results Participants were 312 women (mean age 50.8) from the SWAN (Study of Women's Health Across the Nation) ancillary Heart Study, free of clinical CVD at baseline. A composite psychosocial well-being score was created from 6 validated psychosocial questionnaires assessing optimism, vitality, life engagement, life satisfaction, rewarding multiple roles, and positive affect. Subclinical CAC progression was defined as an increase of ≥10 Agatston units over 2.3 years measured using electron beam tomography. Relative risk (RR) regression models examined the effect of well-being on CAC progression, progressively adjusting for sociodemographic factors, depression, healthy lifestyle behaviors, and standard CVD risk factors. At baseline, 42.9% had a CAC score >0, and progression was observed in 17.6%. Well-being was associated with less progression (RR, 0.909; 95% CI, 0.843-0.979; P =0.012), which remained significant with adjustment for potential confounders, depression, and health behaviors. Further adjustment for standard CVD risk factors weakened the association for the total sample (RR, 0.943; 95% CI, 0.871-1.020; P =0.142) but remained significant for the 134 women with baseline CAC>0 (RR, 0.921; 95% CI, 0.852-0.995; P =0.037). Conclusions Optimum early prevention of CVD in women may result from including the mind side of the mind-heart-body continuum.

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman's reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

Background: Whether changes in blood pressure (BP) over women's midlife are more driven by chronological aging or the menopause transition has been debated. We sought to determine whether women can be classified into distinct trajectory groups based on pattern and level of systolic BP (SBP), diastolic BP, pulse pressure (PP), and mean arterial pressure (MAP) over the menopause transition, and to assess whether menopause-related factors predict the group and level of BP measures., Methods: Participants were from the SWAN (Study of Women's Health Across the Nation). Group-based trajectory modeling was used to identify women who shared distinct BP trajectories over time relative to menopause onset and to assess associations of menopause-related factors with trajectory group and level of BP measures. An accelerated rise relative to menopause onset suggests a menopause contribution., Results: The study included 3302 multiracial and multiethnic women with BP measures over 17 follow-up visits (baseline age [SD]: 46.3 [2.7]). Women were classified into either low, medium, or high trajectory group in each BP measure. The low SBP, PP, and MAP trajectories (in 35%, 53%, and 28% of the cohort, respectively) were rising slowly before menopause but showed a significant accelerated rise 1 year after menopause, indicating a menopause contribution. The remaining BP trajectories were rising up until menopause and either continued with the same rise or declined after menopause. A younger menopause age predicted the low SBP, PP, and MAP trajectories. A greater follicle-stimulating hormone level predicted lower SBP and PP levels, while vasomotor symptoms occurrence predicted higher SBP, PP, and MAP levels over time. Estradiol did not predict trajectory or level of any BP measure., Conclusions: Distinct BP trajectories over the menopause transition exist that revealed a group of women whose SBP, PP, and MAP trajectories are consistent with a menopause contribution. Our findings support frequent monitoring of BP during the menopause transition.

Background: Little is known about how adverse, midlife metabolic profiles affect future physical functioning. We hypothesized that a higher number of midlife metabolic syndrome (MetS) components are associated with poorer physical performance in early old age for multiethnic women., Methods: MetS status from 1996 to 2011 (8 visits) and objective physical performance in 2015/2016 (Short Physical Performance Battery [SPPB; 0-12], 40-foot walk [meter/second], 4-meter gait speed [meter/second], chair stands [seconds], stair climb [seconds]) were assessed in the Study of Women's Health Across the Nation (SWAN; n = 1722; age 65.4 ± 2.7 years; 26.9% African American, 10.1% Chinese, 9.8% Japanese, 5.5% Hispanic). Poisson latent class growth modeling identified MetS component trajectory groups: none (23.9%), 1 = low-MetS (28.7%), 2 = mid-MetS (30.9%), and ≥3 = high-MetS (16.5%). Adjusted linear regression related MetS groups to physical performance outcomes., Results: High-MetS versus none had higher body mass index, pain, financial strain, and lower physical activity and self-reported health (p < .0001). Compared with White, African American and Hispanic women were more likely to be in the high-MetS groups and had worse physical functioning along with Chinese women (SPPB, chair stand, stair climb, and gait speed-not Hispanic). After adjustments, high-MetS versus none demonstrated significantly worse 40-ft walk (β: -0.08; 95% CI: -0.13, -0.03), gait speed (β: -0.09; 95% CI: -0.15, -0.02), SPPB (β: -0.79; 95% CI: -1.15, -0.44), and chair stands (β: 0.69; 95% CI: 0.09, 1.28), but no difference in stair climb., Conclusions: Midlife MetS groups were related to poor physical performance in early old age multiethnic women. Midlife management of metabolic function may improve physical performance later in life., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND: For atrial fibrillation (AF) patients, oral anticoagulants (OACs) can reduce the risk of stroke by 60%; however, nearly 50% of patients recommended to receive OACs do not receive therapy. Integrated insurers that cover pharmacy and medical benefits may be incentivized to improve OAC use and adherence because they benefit from offsets in medical costs associated with prevented strokes. OBJECTIVE: To compare OAC use and adherence between AF patients enrolled in Medicare stand-alone prescription drug plans (PDPs), which only cover pharmacy benefits, and those enrolled in Medicare Advantage prescription drug (MAPD) plans, which cover medical and pharmacy benefits. METHODS: This was a retrospective cohort study, conducted using 2014-2016 Medicare claims data from the Centers for Medicare & Medicaid Services and a large regional health plan in Pennsylvania. Primary outcomes included OAC use and OAC adherence. OAC use was measured as filling at least 1 prescription for an OAC after AF diagnosis. OAC adherence was defined as having greater than or equal to 80% of days covered with an OAC. We constructed conditional logistic regression models in propensity score-matched samples to test the association between enrollment in PDPs or MAPD plans and outcomes. RESULTS: There were 2,551 AF patients enrolled in PDPs and 4,502 in MAPD plans before propensity score matching. The propensity score-matched sample included 2,537 patients in each group. OAC use was higher among MAPD beneficiaries (74%-76%) compared with PDP beneficiaries (70%; P < 0.001), and 41%-42% of MAPD beneficiaries were adherent to OACs, compared with 34% of PDP beneficiaries ( P < 0.001). In adjusted analyses among propensity score-matched samples, PDP enrollment was associated with lower odds of OAC use (OR = 0.67, 95% CI = 0.56-0.81) and adherence (OR = 0.68, 95% CI = 0.59-0.78) compared with MAPD enrollment. CONCLUSIONS: AF patients enrolled in MAPD plans were more likely to use and adhere to OACs compared with PDP enrollees. These results may reflect the financial incentives of MAPD plans to improve guideline-recommended OAC use, since MAPD insurers bear the risk of pharmacy and medical costs and thus may benefit from cost savings associated with averted stroke events. As efforts to improve use and adherence of OACs in AF patients increase, focus should be given to how insurance benefit designs can affect medication use. DISCLOSURES: No outside funding supported this study. Hernandez has received personal fees from BMS and Pfizer, unrelated to this study. The other authors have nothing to disclose.

Context: Novel metrics of high-density lipoprotein (HDL) (subclasses, lipid content, and function) may improve characterization of the anti-atherogenic features of HDL. In midlife women, changes in these metrics vary by time relative to the final menstrual period (FMP), supporting a contribution of estradiol (E2) and follicle-stimulating hormone (FSH)., Objective: We tested associations of endogenous E2 and FSH with novel HDL metrics and assessed whether these associations varied by time relative to FMP., Methods: This study was a longitudinal analysis from the Study of Women's Health Across the Nation (SWAN) HDL study, using a community-based cohort of 463 women, baseline mean age 50.2 (2.7) years. The main outcome measures were HDL cholesterol efflux capacity (HDL-CEC), HDL phospholipids (HDL-PL), HDL triglycerides (HDL-Tg), HDL particles (HDL-P), HDL size, and HDL cholesterol (HDL-C)., Results: In multivariable analyses, E2 was positively associated with HDL size, large HDL-P, HDL-CEC, and HDL-Tg, but negatively with medium HDL-P (P values < 0.05). The positive association between E2 and HDL-Tg was stronger 2 years post-FMP than before, (interaction P = 0.031). FSH was positively related to total and medium HDL-P, but negatively to HDL size, large HDL-P, and HDL-CEC per particle (P values < 0.05). Associations of higher FSH with greater total HDL-P and smaller HDL size were only evident at/after menopause (interaction P values < 0.05)., Conclusion: Some of the associations linking E2 and FSH with novel HDL metrics were vulnerable to time relative to menopause onset. Whether a late initiation of hormone therapy relative to menopause could have a detrimental effect on lipid content of HDL particles should be tested in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible., Study Design and Setting: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods., Results: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results., Conclusion: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Longer menstrual cycles have been associated with greater risk of cardiovascular disease, supporting a contribution of abnormal ovarian function. We aimed to characterize trajectories of menstrual cycle length over the menopause transition (MT) and test whether these trajectories are associated with postmenopausal markers of subclinical atherosclerosis., Methods: Women from the Study of Women's Health Across the Nation Daily Hormone Study were included if they had an observed date of the final menstrual period (FMP), recorded cycle lengths from ≥2 annual menstrual cycles (mean±SD: 4.22 ± 1.91 cycles), and had measurements of postmenopausal carotid intima-media thickness (cIMT) and/or brachial-ankle pulse wave velocity (baPWV). Trajectories of cycle length over the MT were identified using group-based trajectory modeling and linked with cIMT and baPWV using linear regression., Results: We studied 428 women who had 1,808 cycles over the MT (45.1 ± 2.3 y old at baseline visit), and of whom 263 had cIMT, and 213 had baPWV measured postmenopausally (after 13.88 ± 0.42 and 15.25 ± 0.70 y since baseline visit, respectively). Three distinct trajectories of cycle length were identified: stable (no changes in cycle length over the MT among 62.1% of women), late increase (a late increase 2 y before the FMP among 21.8%), and early-increase (an early increase 5 y before the FMP among 16.2%). Women with the late-increase pattern had significantly lower postmenopausal cIMT (0.72 mm) and baPWV (1392 cm/s) levels than the stable group (0.77 mm and 1508 cm/s, respectively) adjusting for race, concurrent age, socioeconomic status, physical activity level, and premenopausal cardiovascular risk profile., Conclusions: Patterns of cycle length over the MT seem to be a marker of future vascular health that may help identify groups at greater or lesser risk of atherosclerosis after menopause., Competing Interests: Financial Disclosures/Conflict of Interests: Thurston: Consultant/advisory board member for Astellas, Procter & Gamble, and Pfizer, Consultant fees from Virtue Health. Santoro: Consultant for Ansh labs, advisory board member for Astellas, and scientific advisory board and grant support to her institution: Menogenix, Inc. The other authors have nothing to disclose., (Copyright © 2021 by The North American Menopause Society.)

Background Younger age at final menstrual period (FMP) is associated with increased risk for cardiovascular disease events. This paper evaluated whether older age at FMP is associated with more favorable patterns of lipid changes during the menopause transition and whether these changes are associated with less subclinical carotid disease in the postmenopausal years. Methods and Results Lipids and lipoproteins were measured repeatedly among 1554 premenopausal women who had a natural menopause during follow-up years (median=18.8 years); a subset of 890 women also had measures of carotid intima media thickness, adventitial diameter, and plaque. Women who had an older FMP age had less adverse changes in cholesterol from 1 to 3 years after FMP, and in triglycerides from FMP to 3 years after FMP, but they had more adverse changes in ApoB and Apo A1 from 3 years before to 1 year after the FMP. Increasing cholesterol and ApoB from 1 to 3 years after FMP were associated with greater intima media thickness and adventitial diameter, and the greater likelihood of a plaque score >2 the older the age at FMP. Conclusions Despite the epidemiological literature showing early age at FMP is associated with elevated risk for cardiovascular disease events, older age at FMP had inconsistent associations with less adverse lipid changes in midlife, which did not translate into less risk for subclinical carotid disease and in some cases more risk. These findings are restricted to women who experience FMP in the normative age range for the menopausal transition.

Background: Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive β-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the β-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling., Methods: Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15 N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy., Conclusion: This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension., Clinical Trial Registration: The trial protocol was registered at clinicaltrials.gov (NCT04713657)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Change in short-term (i.e., 10-year) and lifetime risk of cardiovascular disease (CVD) following Roux-en-Y gastric bypass (RYGB) has significant heterogeneity., Objective: To identify predictors of change in CVD risk and cardiovascular events following RYGB., Methods: Between 2006-2009, 1625 adults without a history of CVD enrolled in a prospective cohort study and underwent RYGB at 1 of 10 U.S. hospitals. Participants were followed annually for a maximum of 7 years. Associations between presurgery characteristics (anthropometric, sociodemographic, physical and mental health, alcohol/drug use, eating behaviors) and 1) pre to postsurgery change in 10 year and lifetime atherosclerotic CVD (ASCVD) risk scores, respectively, and 2) having a CVD event (nonfatal myocardial infarction, stroke, ischemic heart disease, congestive heart failure, angina, percutaneous coronary intervention, coronary artery bypass grafting, or CVD-attributed death) as repeated measures (yr 1-7) were evaluated., Setting: Observational cohort study at ten hospitals throughout the United States., Results: Presurgery factors independently associated with decreases in both 10-year and lifetime risk scores 1-7 years post-RYGB were higher CVD risk score, female sex, higher household income, and normal kidney function. Additionally, Black race and having diabetes were independently associated with decreases in 10-year risk, while not having diabetes and a higher (better) composite mental health score were independently related to decreases in lifetime risk. A lower (worse) presurgery composite physical health score was associated with a higher CVD event risk (RR = 1.68, per 10 points)., Conclusion: This study identified multiple presurgery factors that characterize patients who may have more cardiovascular benefit from RYGB, and patients who might require additional support to improve their cardiovascular health., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The menopausal transition is characterized by progressive changes in ovarian function and increasing circulating levels of gonadotropins, with some women having irregular menstrual cycles well before their final menstrual period. These observations indicate a progressive breakdown of the hypothalamic-pituitary-ovarian axis often associated with an increase in menopausal symptoms. Relationships between vasomotor symptoms (VMS) and depressed mood and sleep as well as a bidirectional association between VMS and depressed mood in mid-life women have been reported, but the endocrine foundations and hormone profiles associated with these symptoms have not been well described. Our objective was to determine the relationship between daily urinary hormone profiles and daily logs of affect and VMS during the early perimenopausal transition., Study Design: SWAN, the Study of Women's Health Across the Nation, is a large, mutli-ethnic, multisite cohort study of 3302 women aged 42-52 at baseline, designed to examine predictors of health and disease in women as they traversed the menopause. Inclusion criteria were: an intact uterus and at least one ovary present, at least one menstrual period in the previous three months, no use of sex steroid hormones in the previous three months, and not pregnant or lactating. A subset (n = 849) of women aged 43-53 years from all study sites in the first Daily Hormone Study collection were evaluated for this substudy., Outcome Measures: We measured daily VMS, and urinary hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), pregnanediol glucuronide (PdG) and estradiol (estrone conjugate, E1C)., Results: A variable pattern of LH and negative LH feedback were the hormone patterns most strongly associated with increased VMS. In contrast, no hormone pattern was significantly related to negative mood., Conclusion: Fluctuations of LH associated with low progesterone production were associated with VMS but not negative mood, suggesting different endocrine patterns may be related to increased negative mood than to the occurrence of VMS., (Copyright © 2021 Elsevier B.V. All rights reserved.)