Low-density lipoprotein subclasses over the menopausal transition and risk of coronary calcification and carotid atherosclerosis: the SWAN Heart and HDL ancillary studies.

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.

The independent associations of anti-Müllerian hormone and estradiol levels over the menopause transition with lipids/lipoproteins: The Study of Women's health Across the Nation.

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.

Associations of HDL subclasses and lipid content with complement proteins over the menopause transition: The SWAN HDL ancillary study: HDL and complement proteins in women.

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.

Lipoprotein subfractions and subclinical vascular health in middle aged women: does menopause status matter?

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.

Design and rationale of the mobile health intervention for rural atrial fibrillation.

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.

Patterns of menstrual cycle length over the menopause transition are associated with subclinical atherosclerosis after menopause.

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 ±â€Š0.42 and 15.25 ±â€Š0.70 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.

Age at Menopause in Relationship to Lipid Changes and Subclinical Carotid Disease Across 20 Years: Study of Women's Health Across the Nation.

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.

Rurality and atrial fibrillation: a pathway to virtual engagement and clinical trial recruitment in response to COVID-19.

Study Objective: To summarize trial adaptation from in-clinic to virtual design in response to the SARS-2 coronavirus-2 (COVID-19). Design: A clinical trial of a mobile health intervention to improve chronic disease self-management for rural individuals with atrial fibrillation (AF). The trial has a 4-month intervention - accessible regardless of health or digital literacy - to enhance AF medication adherence and patient experience with 8- and 12-month assessments of sustainability. Setting: Rural, western Pennsylvania. Participants: Rural individuals with AF receiving oral anticoagulation for stroke prevention. Interventions: Enrolled participants underwent a telephone-based orientation, provided verbal consent, and were randomized using a digital platform. They received a smartphone with intervention or control applications and a curriculum on usage tailored for study arm. Participants received study assessments by mail with telephone-based administration and contact for the 12-month trial. Main Outcome Measures: Successful adaptation to virtual engagement and recruitment. Results: The study enrolled 18 participants during in-clinic recruitment (January-March 2020). From 5/1/2020 to 5/6/2021 the study team enrolled 130 individuals (median age 72.4 years, range 40.8-92.2; 49.2% women, 63.1% without college degree, and 45.4% with limited health literacy. Retention of participants enrolled using virtual methods during the 4-month intervention phase is 92%. Conclusions: We report a virtual trial of a mobile health intervention for rural individuals with AF. Our successful implementation suggests promise for engaging geographically isolated rural individuals, potential to enhance digital health access, and advance rural health equity.

Greater Periaortic Fat Volume at Midlife Is Associated with Slower Gait Speed Later in Life in Women: The SWAN Cardiovascular Fat Ancillary Study.

BACKGROUND: Higher perivascular adipose tissue (PVAT) contributes to adverse physiologic alterations in the vascular wall, and thus could potentially limit normal physical function later in life. We hypothesize that higher PVAT volume at midlife is prospectively associated with slower gait speed later in life, independent of overall adiposity and other risk factors. METHODS: Participants from the Study of Women's Health Across the Nation (SWAN) cardiovascular fat ancillary study were included. PVAT volume around the descending aorta was quantified using existing computed tomography scans at midlife, while gait speed was measured after an average of 10.4 ± 0.7 years. RESULTS: Two hundred and seventy-six women (aged 51.3 ± 2.8 years at PVAT assessment) were included. Mean gait speed was 0.96 ± 0.21 m/s. Adjusting for study site, race, education level, menopausal status, and length of descending aorta at PVAT assessment, and age, body mass index, difficulty paying for basics, overall health and smoking status at gait speed assessment, a higher midlife PVAT volume was associated with a slower gait speed later in life (p = .03). With further adjustment for presence of any comorbid conditions by the time of gait speed assessment, the association persisted; every 1SD increase in log-PVAT was associated with 3.3% slower gait speed (95% confidence interval: 0.3-6.3%; p = .03). CONCLUSION: Greater PVAT in midlife women may contribute to poorer physical function in older age supporting a potential role of midlife PVAT in multiple domains of healthy aging. Additional research is needed to fully elucidate the physiologic changes associated with PVAT that may underlie the observed associations.