Relation of Persistent Depressive Symptoms to Coronary Artery Calcification in Women Aged 46 to 59 Years.

Depressive disorders have been associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis has not been well described, particularly in women and minorities. The relation between repeated episodes of high depressive symptoms and coronary calcium (CAC) is unknown in women at midlife when depression is common. Participants in the Study of Women's Health Across the Nation Heart study were assessed annually for depressive symptoms (Center for Epidemiological Studies Depression Scale [CES-D scale]) over 5 years before CAC assessment and classified as high (CES-D ≥16) or not. CAC, measured by computed tomography, was analyzed as a categorical variable using cumulative logit partial proportional odds models. In these middle-aged women free of CVD and diabetes (194 black, 334 white), high depressive symptoms over 5 years were common; 19% had 1, 9% had 2, and 11% experienced ≥3 episodes. CAC was low; 54% had no CAC, 25% had scores from 0 to 10, and 21% had CAC ≥10 Agatston score. After adjusting for CVD risk factors, women with ≥3 episodes were twice as likely to have significant CAC (≥10 Agatston units) than women with no depressive episodes (odds ratio 2.20, 95% confidence interval 1.13 to 4.28, p = 0.020) with no difference by race. Women with 1 or 2 episodes did not differ from women with no episodes. In conclusion, in healthy women aged 46 to 59 years without clinical CVD or diabetes, persistent depressive symptoms were significantly associated with elevated CAC scores, suggesting that they are more likely to have pathophysiological and behavioral effects on the development of subclinical CVD than does a single episode of elevated depressive symptoms.

Calcified carotid artery plaques predict cardiovascular outcomes in the elderly.

BACKGROUND: Identifying plaque composition using ultrasound may aid in stratifying patients at high risk for cardiovascular disease (CVD). Calcification is an integral part of plaque progression and may contribute to plaque vulnerability. We investigated the ability of calcified carotid plaques identified using carotid ultrasound to predict cardiovascular outcomes in older adults. METHODS: Participants included 187 hypertensive and 187 normotensive adults undergoing a duplex scan to identify the presence of calcified carotid plaques. Hypertensive participants received either blood pressure treatment or placebo, and all participants were followed for incident cardiovascular events and death for a maximum of 11 years. RESULTS: The untreated hypertensive group was significantly associated with a higher time-to-any CVD event [relative risk (RR) 2.97, 95% confidence interval (CI) 2.03-4.35, P < 0.0001] and mortality (RR 3.11, 95% CI 1.92-5.04, P < 0.0001) when compared to the normotensive group. Participants with calcified carotid plaques had higher cardiovascular event rates (RR 6.22, 95% CI 1.97-19.6, P = 0.0018) and mortality (RR 6.30, 95% CI 1.55-25.7, P = 0.010) when compared to those without plaque. After controlling for age, male sex, blood pressure status, glucose, and IMT, the presence of calcified carotid plaques remained predictive of CVD events (RR 2.35, 95% CI 1.5-3.8, P = 0.0005) and mortality (RR 2.72, 95% CI 1.4-5.2, P = 0.0021). CONCLUSION: Calcified carotid plaques may predict mortality and cardiovascular outcomes independent of traditional CVD risk factors and may serve as an additional CVD risk assessment in the elderly.

Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis.

INTRODUCTION: Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes' expression is related to atherosclerosis in SLE. METHODS: Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined. RESULTS: Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors. CONCLUSIONS: Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.

Complement protein C3 and coronary artery calcium in middle-aged women with polycystic ovary syndrome and controls.

Circulating complement protein C3 (C3) levels have been associated with coronary artery calcification (CAC) in women with systemic lupus erythematosus, but have yet to be evaluated in women with polycystic ovary syndrome (PCOS). We aimed to determine whether C3 levels were elevated in women with PCOS compared to controls and to quantify the association of C3 with cardiovascular disease (CVD) risk factors and CAC and if PCOS modified this association. This cross-sectional analysis included 132 women with PCOS and 155 controls, 35-62 years old, from the third visit of a case-control study. CAC was measured during the study visit, and circulating C3 was measured in stored sera. The presence of CAC and CAC categories (Agatston score 0, 1-9.9 and ≥ 10) were used for logistic and ordinal regression analysis, respectively. C3 levels were not significantly different between women with PCOS and controls. Among all women, C3 was associated with the presence of CAC and increasing CAC groups after adjusting for age, PCOS status and insulin or body mass index (BMI), all p<0.05. In addition, C3 was associated with the presence of CAC after adjusting for age, PCOS status, BMI, insulin and African American race, p=0.049. PCOS status did not modify these associations. In conclusion, circulating C3 levels may prove beneficial in identifying women at risk of CVD in women with PCOS and the general population.

Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study.

BACKGROUND: Both carotid-femoral (cf) pulse wave velocity (PWV) and brachial-ankle (ba) PWV employ arterial sites that are not consistent with the path of blood flow. Few previous studies have reported the differential characteristics between cfPWV and baPWV by simultaneously comparing these with measures of pure central (aorta) and peripheral (leg) arterial stiffness, i.e., heart-femoral (hf) PWV and femoral-ankle (fa) PWV in healthy populations. We aimed to identify the degree to which these commonly used measures of cfPWV and baPWV correlate with hfPWV and faPWV, respectively, and to evaluate whether both cfPWV and baPWV are consistent with either hfPWV or faPWV in their associations with cardiovascular (CV) risk factors. METHODS: A population-based sample of healthy 784 men aged 40-49 (202 white Americans, 68 African Americans, 202 Japanese-Americans, and 282 Koreans) was examined in this cross-sectional study. Four regional PWVs were simultaneously measured by an automated tonometry/plethysmography system. RESULTS: cfPWV correlated strongly with hfPWV (r = .81, P < .001), but weakly with faPWV (r = .12, P = .001). baPWV correlated moderately with both hfPWV (r = .47, P < .001) and faPWV (r = .62, P < .001). After stepwise regression analyses with adjustments for race, cfPWV shared common significant correlates with both hfPWV and faPWV: systolic blood pressure (BP) and body mass index (BMI). However, BMI was positively associated with hfPWV and cfPWV, and negatively associated with faPWV. baPWV shared common significant correlates with hfPWV: age and systolic BP. baPWV also shared the following correlates with faPWV: systolic BP, triglycerides, and current smoking. CONCLUSIONS: Among healthy men aged 40 - 49, cfPWV correlated strongly with central PWV, and baPWV correlated with both central and peripheral PWVs. Of the CV risk factors, systolic BP was uniformly associated with all the regional PWVs. In the associations with factors other than systolic BP, cfPWV was consistent with central PWV, while baPWV was consistent with both central and peripheral PWVs.

Do differences in risk factors explain the lower rates of coronary heart disease in Japanese versus U.S. women?

BACKGROUND: Mortality from coronary heart disease (CHD) in women in Japan is one of the lowest in developed countries. In an attempt to shed some light on possible reasons of lower CHD in women in Japan compared with the United States, we extensively reviewed and analyzed existing national data and recent literature. METHODS: We searched recent epidemiological studies that reported incidence of acute myocardial infarction (AMI) and examined risk factors for CHD in women in Japan. Then, we compared trends in risk factors between women currently aged 50-69 years in Japan and the United States, using national statistics and other available resources. RESULTS: Recent epidemiological studies have clearly shown that AMI incidence in women in Japan is lower than that reported from other countries, and that lipids, blood pressure (BP), diabetes, smoking, and early menopause are independent risk factors. Comparing trends in risk factors between women in Japan and the United States, current levels of serum total cholesterol are higher in women in Japan and levels have been similar at least since 1990. Levels of BP have been higher in in Japan for the past 3 decades. Prevalence of type 2 diabetes has been similar in Japanese and white women currently aged 60-69 for the past 2 decades. In contrast, rates of cigarette smoking, although low in women in both countries, have been lower in women in Japan. CONCLUSIONS: Differences in risk factors and their trends are unlikely to explain the difference in CHD rates in women in Japan and the United States. Determining the currently unknown factors responsible for low CHD mortality in women in Japan may lead to new strategy for CHD prevention.

Prior preterm birth and maternal subclinical cardiovascular disease 4 to 12 years after pregnancy.

BACKGROUND: We considered that women with prior preterm birth (PTB) would have evidence of subclinical atherosclerosis, endothelial dysfunction, and arterial stiffness. METHODS: Four to 12 years after pregnancy, blood pressure and fasting lipids were analyzed, and women underwent evaluation, following standardized protocols, of carotid intima-media thickness (IMT), brachial flow-mediated dilation (FMD), and pulse wave velocity (PWV). Women with prior preterm (<37 weeks, n=181) or term births (>= 37 weeks, n=306) were compared. Those with preeclampsia or term small-for-gestational-age (SGA) births were excluded. RESULTS: Women with a prior preterm vs. term birth had higher blood pressure, on average, and a more atherogenic lipid profile. They also had marginally higher IMT (0.579 standard error [SE] 0.005-vs. 0.567 [0.004] mm, p=0.06), adjusted for body size, demographics, and smoking. IMT differences were greater among those with non-preeclamptic-indicated PTB (0.034 mm, p=0.05) and PTB<34 weeks (0.024 mm, p=0.04) compared to those with term births. These differences appeared to be explained in part by the atherogenic lipid elevations in women with preterm birth. Women with prior PTB<34 weeks tended to have lower FMD, but results were not statistically significant. PWV did not differ according to PTB. CONCLUSIONS: In the decade following pregnancy, women with non-preeclamptic-indicated PTB or PTB delivered before 34 weeks had higher blood pressure, atherogenic lipids, and IMT compared to women with term births. There may be subgroups of women with a prior PTB with excess cardiovascular risk that is detectable before overt clinical disease.

Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.

Physical activity intensity and cardiovascular risk by ankle-brachial index.

A low ankle-brachial index (ABI) is associated with increased risk for cardiovascular events and mortality. Physical inactivity in individuals with a low ABI may further increase their risk for cardiovascular events. The purpose of this paper is to examine the relationship between the intensity of free-living physical activity and cardiovascular disease (CVD) risk by ABI status. During 2003-2004, the National Health and Nutrition Examination Survey included an accelerometer module and collected ABI data. Individuals were classified as having a normal (1-1.4) or low (< 1) ABI. The Framingham risk score (FRS) was used to determine CVD risk. Multiple linear regression was used to determine the association of total accelerometer counts and time spent at various physical activity intensity levels with FRS by ABI groups. Individuals with a low ABI spent less time engaging in moderate-to-vigorous intensity physical activity (MVPA) (9.1 min/day vs 13.2 min/day; p = 0.06) when compared to those with a normal ABI. There were no differences in light intensity physical activity (LPA) or sedentary behavior between ABI groups. Total accelerometer counts were inversely related to FRS. MVPA, but not LPA, was inversely related to FRS in both normal and low ABI groups (p < 0.001 and p = 0.001, respectively). In conclusion, these findings suggest that even modestly higher levels of physical activity may be beneficial for secondary risk prevention in this high-risk group.

Evidence for a genetic link between bone and vascular measures in African ancestry families.

Bone mineral density (BMD) has been inversely associated with subclinical and clinical cardiovascular disease (CVD) in population studies, but the potential mechanisms underlying this relationship are unclear. To test if there is a genetic basis underlying this association, we determined the phenotypic and genetic correlations between BMD and carotid artery ultrasound measures in families. Dual-energy X-ray absorptiometry and peripheral quantitative computed tomography were used to measure BMD in 461 individuals with African ancestry belonging to seven large, multigenerational families (mean family size 66; 3414 total relative pairs). Carotid artery ultrasound was used to measure adventitial diameter (AD) and intima-media thickness (IMT). Phenotypic and genetic correlations between BMD and carotid measures were determined using pedigree-based maximum likelihood methods. We adjusted for potential confounding factors, including age, sex, body weight, height, menopausal status, smoking, alcohol intake, walking for exercise, diabetes, hypertension, serum lipid and lipoprotein levels, inflammation markers, and kidney function. We found statistically significant phenotypic (ρ = -0.19) and genetic (ρG = -0.70) correlations (p < 0.05 for both) between lumbar spine BMD and AD in fully adjusted models. There was also a significant genetic correlation between trabecular BMD at the radius and IMT in fully adjusted models (ρG = -0.398; p < 0.05). Our findings indicate that the previously observed association between osteoporosis and CVD in population-based studies may be partly mediated by genetic factors and that the pleiotropic effects of these genes may operate independently of traditional risk pathways.

Do reports of sleep disturbance relate to coronary and aortic calcification in healthy middle-aged women?: Study of women's health across the nation.

BACKGROUND: Poor sleep may be associated with the cardiovascular disease (CVD) morbidity and mortality. It is less clear if poor sleep is associated with subclinical CVD. We evaluated cross-sectional associations between self-reported sleep disturbance and duration and calcification in the coronary arteries (CAC) and aorta (AC) in healthy mid-life women. METHODS: 512 black and white women enrolled in the SWAN Heart Study, underwent a computed tomography protocol for measurement of CAC and AC and completed questionnaires about their sleep. Linear and partial proportional logit regression analyses adjusted for site, race, age, body mass index, and the Framingham risk score (model 1). Additional covariates of education, perceived health, hypnotic medication and alcohol use were evaluated (model 2), plus depressive symptoms (model 3). RESULTS: AC was related to higher levels of trouble falling asleep, waking earlier than planned, overall poor sleep quality, and cough/snoring and shorter sleep duration in linear regression analyses (model 1). Adjustments for additional covariates showed that poor sleep quality and waking earlier than planned remained associated with higher AC (models 2 and 3). CAC was unrelated to sleep characteristics. CONCLUSIONS: Poor sleep quality is related to AC in middle-aged women. Sleep quality should routinely be assessed in mid-life women.

Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-aged Japanese and Korean men.

BACKGROUND: Cigarette smoking is a risk factor of coronary heart disease. Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with coronary heart disease. The authors hypothesised that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence. METHODS: Random samples from populations of 313 Japanese and 302 Korean men aged 40-49 years were examined for calcification of the coronary artery and aorta using electron beam CT. CAC and AC were quantified using the Agatston score. The authors examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorised into two groups using median pack-years as a cut-off point in each of Japanese and Koreans. The never-smoker group was used as a reference for the multiple logistic regression analyses. RESULTS: The ORs of CAC (score ≥10) for smokers with higher pack-years were 2.9 in Japanese (p<0.05) and 1.3 in Koreans (non-significant) compared with never-smokers. The ORs of AC (score ≥100) for smokers with higher pack-years were 10.4 in Japanese (p<0.05) and 3.6 in Koreans (p<0.05). CONCLUSION: Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men.

The prevalence of aortic calcification in Japanese compared to white and Japanese-American middle-aged men is confounded by the amount of cigarette smoking.

BACKGROUND: The prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men. METHODS: We conducted a population-based study of 903 randomly-selected men aged 40-49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, US, and 292 Japanese men in Hawaii, US (2002-2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and ≥ 100. RESULTS: Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS ≥ 100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). The pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45). CONCLUSIONS: The prevalence of AC defined both >0 and ≥ 100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors.

Endogenous sex hormones impact the progression of subclinical atherosclerosis in women during the menopausal transition.

OBJECTIVE: To determine whether endogenous sex hormones (estradiol (E2), testosterone (T), sex hormone binding globulin (SHBG), and follicle stimulating hormone (FSH)) are longitudinally associated with progression of atherosclerosis among women at midlife. METHODS: 249 Pre- or early peri-menopausal women (42-57 years) from the Study of Women's Health Across the Nation (SWAN) were followed for up to 9 years (median = 3.7 years) and had up to 5 repeated measures of common carotid intima-media thickness (IMT) and adventitial diameter (AD). Linear mixed models were used for statistical analysis. Final models included age at baseline, time since baseline, cycle day of blood draw, race, income, SBP, BMI, insulin resistance index, lipids, C-reactive protein and co-morbidity. RESULTS: In final models for IMT, each one log unit decrease in SHBG was associated with a 0.005 mm/year increase in IMT progression (P = 0.003). E2, T, and FSH were not associated with level or progression of IMT. For AD, each one log unit decrease in E2 was associated with a 0.012 mm/year increase in AD progression (P = 0.04) and each one log unit increase in FSH was associated with a 0.016 mm/year increase in AD progression (P = 0.003). T and SHBG were not associated with progression or level of AD. CONCLUSIONS: Independent of SBP, BMI, lipids and other covariates, lower E2 and SHBG, and higher FSH were associated with increased subclinical atherosclerosis progression in women at midlife.

Vasomotor symptoms and insulin resistance in the study of women's health across the nation.

CONTEXT: Emerging research suggests links between menopausal hot flashes and cardiovascular disease risk. The mechanisms underlying these associations are unclear, due to the incomplete understanding of the physiology of hot flashes. OBJECTIVE AND MAIN OUTCOME MEASURES: We examined the associations between hot flashes/night sweats and glucose and insulin resistance over 8 yr, controlling for cardiovascular risk factors and reproductive hormones. DESIGN, SETTING, AND PARTICIPANTS: Participants in the Study of Women's Health Across the Nation (SWAN) (n=3075), a longitudinal cohort study, were ages 42-52 yr at entry. Women completed questionnaires (hot flashes, night sweats: none, 1-5 d, ≥6 d, past 2 wk), physical measures (blood pressure, height, weight), and a fasting blood draw [serum glucose, insulin, estradiol (E2), FSH] annually for 8 yr. Hot flashes/night sweats were examined in relation to glucose and the homeostasis model assessment (HOMA) in mixed models, adjusting for demographics, cardiovascular risk factors, medications, and E2/FSH. RESULTS: Compared to no flashes, hot flashes were associated with a higher HOMAlog index [vs. none; hot flashes, 1-5 d: % difference (95% confidence interval), 2.37 (0.36-4.43), P=0.02; and ≥6 d: 5.91 (3.17-8.72), P<0.0001] in multivariable models that included body mass index. Findings persisted adjusting for E2 or FSH, and were similar for night sweats. Findings were statistically significant, yet modest in magnitude, for the outcome glucose. CONCLUSIONS: Hot flashes were associated with a higher HOMA index, an estimate of insulin resistance, and to a lesser extent higher glucose. Metabolic factors may be relevant to understanding the link between hot flashes and cardiovascular disease risk.

The association of menopause status with physical function: the Study of Women's Health Across the Nation.

OBJECTIVE: The aim of this study was to determine whether postmenopause status is associated with self-reported limitations in physical function. METHODS: The Study of Women's Health Across the Nation is a multisite, multiethnic, longitudinal study of midlife women. Women aged 45 to 57 years (N = 2,566) completed the physical function scale of the Medical Outcomes Study Short-Form 36 on visit 4 (2000-2001). Scores created a three-category variable of physical function limitations: none (86-100), moderate (51-85), and substantial (0-50). In the Study of Women's Health Across the Nation, menopause status is a five-category list variable based on menstrual bleeding patterns and gynecological surgery. Premenopausal and perimenopausal women using hormones (n = 284) or missing physical function scores (n = 46) were excluded. Multinomial logistic regression was used to relate physical function and menopause status after adjustment for age, ethnicity, site, education, body mass index (BMI), and self-reported diabetes, hypertension, arthritis, depressive symptoms, smoking, and hormone use among postmenopausal women. RESULTS: Of 2,236 women, 8% were premenopausal, 51% were early perimenopausal, 12% were late perimenopausal, 24% were naturally postmenopausal, and 5% were surgically postmenopausal. In the full model, substantial limitations in physical function were higher in postmenopausal women, whether naturally postmenopausal (odds ratio, 3.82; 95% CI, 1.46-10.0) or surgically postmenopausal (odds ratio, 3.54; 95% CI, 1.15-10.84), than in premenopausal women. These associations were attenuated by higher BMI and depressive symptoms but remained significant. Moderate limitations in physical function were not significantly related to menopause status. CONCLUSIONS: Women experiencing surgical or naturally occurring postmenopause report greater limitations in physical function compared with premenopausal women, independent of age and only partly explained by higher BMI and depressive symptoms. This suggests that physiological changes in menopause could contribute directly to limitations in physical function.

Do changes in sex steroid hormones precede or follow increases in body weight during the menopause transition? Results from the Study of Women's Health Across the Nation.

CONTEXT: Whether menopause-related changes in sex steroids account for midlife weight gain in women or whether weight drives changes in sex steroids remains unanswered. OBJECTIVE: The objective of the study was to characterize the potential reciprocal nature of the associations between sex hormones and their binding protein with waist circumference in midlife women. DESIGN, SETTING, AND PARTICIPANTS: The study included 1528 women (mean age 46 yr) with 9 yr of follow-up across the menopause transition from the observational Study of Women's Health Across the Nation. MAIN OUTCOME MEASURES: Waist circumference, SHBG, testosterone, FSH, and estradiol were measured. RESULTS: Current waist circumference predicted future SHBG, testosterone, and FSH but not vice versa. For each SD higher current waist circumference, at the subsequent visit SHBG was lower by 0.04-0.15 SD, testosterone was higher by 0.08-0.13 SD, and log(2) FSH was lower by 0.15-0.26 SD. Estradiol results were distinct from those above, changing direction across the menopause transition. Estradiol and waist circumference were negatively associated in early menopausal transition stages and positively associated in later transition stages (for each SD higher current waist circumference, future estradiol was lower by 0.15 SD in pre- and early perimenopause and higher by 0.38 SD in late peri- and postmenopause; P for interaction <0.001). In addition, they appeared to be reciprocal, with current waist circumference associated with future estradiol and current estradiol associated with future waist circumference. However, associations in the direction of current waist circumference predicting future estradiol levels were of considerably larger magnitude than the reverse. CONCLUSIONS: These Study of Women's Health Across the Nation data suggest that the predominant temporal sequence is that weight gain leads to changes in sex steroids rather than vice versa.

Trajectory clustering of estradiol and follicle-stimulating hormone during the menopausal transition among women in the Study of Women's Health across the Nation (SWAN).

CONTEXT: Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. OBJECTIVE: The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. DESIGN: The Study of Women's Health Across the Nation is a longitudinal observational study of the menopausal transition. SETTING: Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. PARTICIPANTS: Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. MAIN OUTCOME MEASURES: Annual serum E2 and FSH levels anchored to final menstrual period were measured. RESULTS: Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. CONCLUSIONS: E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition.

Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults.

OBJECTIVE: Obesity increases cardiovascular disease risk and adversely affects vascular structure and function. Few studies have evaluated the vascular effects of non-surgical weight reduction in the severely obese. We hypothesized that weight loss and improvements in cardiometabolic factors would reduce common carotid artery intima-media thickness (CIMT) and inter-adventitial diameter (AD) in severely obese adults. METHODS: We performed carotid ultrasound and measured cardiometabolic factors in 90 severely obese participants (body mass index (BMI)≥35 kg/m(2), age 30-55) at baseline and 6 months in a randomized clinical trial of dietary intervention with (n=45) or without (n=45) physical activity. RESULTS: The achieved weight loss (mean=8%) did not differ significantly by intervention group (P=0.10) and resulted in a 0.07 mm mean decrease in AD (P=0.001). AD change was positively correlated with changes in BMI, waist circumference, abdominal visceral and subcutaneous fat, and body fat mass, and AD decreased more in men (P<0.05 for all). After multivariable adjustment, changes in BMI (P=0.03) and abdominal subcutaneous fat (P=0.04) were significant determinants of AD change. Although CIMT did not decrease significantly overall (-0.008 mm, P=0.16), individuals who lost at least 5% of their body weight experienced a significant mean reduction in CIMT of 0.02 mm (P=0.002). CIMT change was positively correlated with changes in BMI, waist circumference, fat-free mass, leptin, and insulin (P<0.05 for all). After multivariable adjustment, insulin reduction remained a significant determinant of CIMT decrease (P=0.03). CONCLUSION: A 6 month intensive behavioral intervention can significantly reverse metabolic and vascular abnormalities in severely obese adults.

Vasomotor symptoms and lipid profiles in women transitioning through menopause.

OBJECTIVE: To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle-stimulating hormone. METHODS: Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A-1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle-stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones. RESULTS: Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: ß [standard error]=1.48 [0.47], P<.01; 6 days or more: ß [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: ß [standard error]=0.30 [0.18]; 6 days or more: ß [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: ß [standard error]=0.92 [0.47], P<.10; 6 days or more: ß [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: ß [standard error]=1.41 [0.41], P<.001; 6 days or more: ß [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41-4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women. CONCLUSION: Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk. LEVEL OF EVIDENCE: II.