Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer.

BACKGROUND: Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. PATIENTS AND METHODS: In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. RESULTS: Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). CONCLUSIONS: Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

The adipokine profile of metabolically benign obese and at-risk normal weight postmenopausal women: the Women's Health Initiative Observational Study.

OBJECTIVE: Nearly, a third of obese individuals, termed metabolically benign obese, have a low burden of adiposity-related cardiometabolic abnormalities, whereas a substantial proportion of normal-weight individuals possess risk factors. METHODS: In cross-sectional analyses of 699 normal weight and 1,294 overweight/obese postmenopausal women enrolled in a nested case-control stroke study ancillary to the Women's Health Initiative Observational Study, we compared levels of adiponectin, leptin, and resistin among metabolically benign normal weight, at-risk normal weight, metabolically benign obese, and at-risk obese women using components of the ATP III definition of the metabolic syndrome (metabolically benign: ≤1 of the four components; at-risk phenotype: ≥2 components or diabetes). RESULTS: Overall, 382/699 normal-weight women (54.6%) and 328/1,194 overweight/obese women (27.5%) were metabolically benign. Among normal-weight women, at-risk women had higher leptin and lower adiponectin levels compared to metabolically benign women; multivariate-adjusted odds ratios were significant for having leptin (OR: 2.51; 95% CI: 1.28-5.01) and resistin (1.46; 1.03-2.07) in the top tertile and adiponectin in the bottom tertile (2.64; 1.81-3.84). Compared to metabolically benign overweight/obese women, at-risk obese women had higher odds of having leptin in the top tertile (1.62; 1.24-2.12) and adiponectin in the bottom tertile (2.78; 2.04-3.77). CONCLUSIONS: Overall, metabolically benign overweight/obese women had an intermediate adipokine profile (between at-risk obese and metabolically benign normal-weight women), whereas at-risk normal-weight women had a less favorable profile compared to metabolically benign normal-weight women. As adiponectin was the only adipokine independent of BMI, it may be most likely to have a role in the etiological pathway of these phenotypes.

Liver fat and SHBG affect insulin resistance in midlife women: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women's Health Across the Nation (SWAN). DESIGN AND METHODS: A subset of midlife African American and Caucasian women from SWAN (n = 208; 50.9 ± 0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers. RESULTS: The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r = -0.25, P < 0.001 and r = -0.18, P = 0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction P = 0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (P = 0.023 and 0.001 respectively). CONCLUSION: These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG's influence on insulin levels.

Ectopic fat and adipokines in metabolically benign overweight/obese women: the Kronos Early Estrogen Prevention Study.

OBJECTIVE: It is unclear why despite a comparable cardiometabolic risk profile, "metabolically benign" overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals. DESIGN AND METHODS: In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined "metabolically benign" with ≤ 1, and "at-risk" with ≥2 components of the metabolic syndrome. RESULTS: Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62-5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94). CONCLUSIONS: Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state.

Associations of testosterone and sex hormone binding globulin with adipose tissue hormones in midlife women.

OBJECTIVE: Regulators of adipose tissue hormones remain incompletely understood, but may include sex hormones. As adipose tissue hormones have been shown to contribute to numerous metabolic and cardiovascular disorders, understanding their regulation in midlife women is of clinical importance. Therefore, we assessed the associations between testosterone (T) and sex hormone binding globulin (SHBG) with leptin, high molecular weight (HMW) adiponectin, and the soluble form of the leptin receptor (sOB-R) in healthy midlife women. DESIGN AND METHODS: Cross-sectional analyses were performed using data from 1,881 midlife women (average age 52.6 (±2.7) years) attending the sixth Annual follow-up visit of the multiethnic Study of Women's Health Across the Nation. RESULTS: T was weakly negatively associated with both HMW adiponectin and sOB-R (r = -0.12 and r = -0.10, respectively; P < 0.001 for both), and positively associated with leptin (r = 0.17; P < 0.001). SHBG was more strongly and positively associated with both HMW adiponectin and sOB-R (r = 0.29 and r = 0.24, respectively; P < 0.001 for both), and more strongly and negatively associated with leptin (r = -0.27; P < 0.001). Adjustment for fat mass, insulin resistance, or waist circumference only partially diminished associations with HMW adiponectin and sOB-R, but attenuated associations with leptin. In conclusion, in these midlife women, lower SHBG values, and to a lesser extent, higher T levels, were associated with lower, or less favorable, levels of adiponectin and sOB-R, independent of fat mass. CONCLUSIONS: These data suggest that variation in these adipose hormones resulting from lower SHBG levels, and possibly, though less likely, greater androgenicity, may contribute to susceptibility for metabolic and cardiovascular outcomes during midlife in women.

Progression rates of carotid intima-media thickness and adventitial diameter during the menopausal transition.

OBJECTIVE: The aim of this study is to assess whether the levels and progression rates of carotid intima-media thickness (IMT) and adventitial diameter (AD) vary by menopausal stage. METHODS: Two hundred forty-nine women (aged 42-57 y; 49% premenopausal and 46% early perimenopausal) from the Study of Women's Health Across the Nation were included in the current analysis. Participants were followed up for up to 9 years (median, 3.7 y) and underwent up to five carotid scans. Linear mixed-effect models were used for the analysis. RESULTS: The overall rate of change in IMT was 0.007 mm/year. Independent of age and race, the progression rate of IMT increased substantially in the late perimenopausal stage (0.017 mm/y) compared with both the premenopausal stage (0.007 mm/y) and the early perimenopausal stage (0.005 mm/y; P ≤ 0.05). For AD, although the overall rate of change was negative (-0.009 mm/y), significant positive increases in the rate of change were observed in the late perimenopausal stage (0.024 mm/y) and the postmenopausal stage (0.018 mm/y) compared with the premenopausal stage (-0.032 mm/y; P < 0.05). In the final models, the postmenopausal stage was independently associated with higher levels of IMT and AD (P < 0.05) compared with the premenopausal stage. CONCLUSIONS: During the menopausal transition, the carotid artery undergoes adaptation that is reflected in adverse changes in IMT and AD. These changes may have an impact on the vulnerability of the vessel to disease in older women.

The role of metal components in the cardiovascular effects of PM2.5.

Exposure to ambient fine particulate matter (PM2.5) increases risks for cardiovascular disorders (CVD). However, the mechanisms and components responsible for the effects are poorly understood. Based on our previous murine exposure studies, a translational pilot study was conducted in female residents of Jinchang and Zhangye, China, to test the hypothesis that specific chemical component of PM2.5 is responsible for PM2.5 associated CVD. Daily ambient and personal exposures to PM2.5 and 35 elements were measured in the two cities. A total of 60 healthy nonsmoking adult women residents were recruited for measurements of inflammation biomarkers. In addition, circulating endothelial progenitor cells (CEPCs) were also measured in 20 subjects. The ambient levels of PM2.5 were comparable between Jinchang and Zhangye (47.4 and 54.5 µg/m(3), respectively). However, the levels of nickel, copper, arsenic, and selenium in Jinchang were 82, 26, 12, and 6 fold higher than Zhangye, respectively. The levels of C-reactive protein (3.44 ± 3.46 vs. 1.55 ± 1.13), interleukin-6 (1.65 ± 1.17 vs. 1.09 ± 0.60), and vascular endothelial growth factor (117.6 ± 217.0 vs. 22.7 ± 21.3) were significantly higher in Jinchang. Furthermore, all phenotypes of CEPCs were significantly lower in subjects recruited from Jinchang than those from Zhangye. These results suggest that specific metals may be important components responsible for PM2.5-induced cardiovascular effects and that the reduced capacity of endothelial repair may play a critical role.

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.

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.

Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study.

BACKGROUND: The published literature regarding the relationships between retinol-binding protein 4 (RBP4) and cardiometabolic risk factors and subclinical atherosclerosis is conflicting, likely due, in part, to limitations of frequently used RBP4 assays. Prior large studies have not utilized the gold-standard western blot analysis of RBP4 levels. METHODS: Full-length serum RBP4 levels were measured by western blot in 709 postmenopausal women screened for the Kronos Early Estrogen Prevention Study. Cross-sectional analyses related RBP4 levels to cardiometabolic risk factors, carotid artery intima-media thickness (CIMT), and coronary artery calcification (CAC). RESULTS: The mean age of women was 52.9 (± 2.6) years, and the median RBP4 level was 49.0 (interquartile range 36.9-61.5) µg/mL. Higher RBP4 levels were weakly associated with higher triglycerides (age, race, and smoking-adjusted partial Spearman correlation coefficient = 0.10; P = 0.01), but were unrelated to blood pressure, cholesterol, C-reactive protein, glucose, insulin, and CIMT levels (all partial Spearman correlation coefficients ≤0.06, P > 0.05). Results suggested a curvilinear association between RBP4 levels and CAC, with women in the bottom and upper quartiles of RBP4 having higher odds of CAC (odds ratio [95% confidence interval] 2.10 [1.07-4.09], 2.00 [1.02-3.92], 1.64 [0.82-3.27] for the 1st, 3rd, and 4th RBP4 quartiles vs. the 2nd quartile). However, a squared RBP4 term in regression modeling was non-significant (P = 0.10). CONCLUSIONS: In these healthy, recently postmenopausal women, higher RBP4 levels were weakly associated with elevations in triglycerides and with CAC, but not with other risk factors or CIMT. These data using the gold standard of RBP4 methodology only weakly support the possibility that perturbations in RBP4 homeostasis may be an additional risk factor for subclinical coronary atherosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00154180.

Race-ethnic differences in adipokine levels: the Study of Women's Health Across the Nation (SWAN).

Differences in adipose tissue secretory profile, as measured by adipokine levels, may play a role in race-ethnic disparities in cardiovascular disease (CVD). We examined race-ethnic differences in adipokine levels in a group of mid-life Caucasian, African American (AA), Chinese and Japanese women, after accounting for adiposity. Data on 1876 women from the Study of Women's Health Across the Nation were analyzed. In multivariable adjustment, including total fat mass, differences in total and high molecular weight (HMW) adiponectin, leptin and soluble leptin receptor (sOB-R) levels were examined. Despite intermediate levels of adiposity, Caucasian women had higher levels of both total and HMW adiponectin, when compared to both AA and Chinese and Japanese women. After multivariable adjustment, compared to Caucasian women, AA women had significantly lower total (ß: -3.40; 95% CI: -4.29, -2.52; P<.001) and HMW adiponectin (ß: -0.53; 95% CI: -0.64, -0.43; P<.001) levels, higher leptin levels (ß: 3.26; 95% CI: 1.36, 5.16; P<.001) and lower sOB-R levels (ß: -0.07; 95% CI: -0.11, -0.03; P<.001). Compared to Caucasian women, both Chinese and Japanese women had lower total (Chinese: ß: -5.50; 95% CI: -7.07, -3.93; P<.001; Japanese: ß: -5.48; 95% CI: -6.95, -4.02; P<.001) and HMW adiponectin (Chinese: ß: -0.57; 95% CI: -0.75, -0.38; P<.001; Japanese: ß: -0.61; 95% CI: -0.78, -0.44; P<.001) levels and lower sOB-R levels (Chinese: ß: -0.13; 95% CI: -0.20, -0.06; P<.001; Japanese: ß: -0.09; 95% CI: -0.15, -0.02; P=.008). Significant race-ethnic differences exist in circulating adipokines, even after accounting for adiposity. Further research is needed to explicitly determine if such differences contribute to known racial differences in CVD risk.

Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS).

OBJECTIVE: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women. METHODS: Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n=650). RESULTS: Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r=0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides=-0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; p for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat. CONCLUSION: While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.

Incident cardiovascular disease events in metabolically benign obese individuals.

Nearly one-third of obese individuals are classified as metabolically benign; however whether this subgroup is at a lower risk of cardiovascular disease (CVD) is unclear. Using pooled data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies, we assessed incident CVD (coronary heart disease and stroke) using three definitions of the metabolically benign phenotype: (i) the ATP-III metabolic syndrome definition (≤2 of the ATP-III components, excluding abdominal obesity (ii) the expanded ATP-III definition (≤1 of: any ATP-III components, insulin resistance (IR), or systemic inflammation), and (iii) the IR-based definition (sex-specific lowest quartile of the HOMA(IR) distribution). The sample included 6,106 normal weight, 7,115 overweight, and 4,323 obese participants. Among obese, 27.0%, 18.1%, and 20.4% were metabolically benign by the three definitions, respectively. The CVD incidence rates (mean follow-up 11.8 years) were 7.1, 5.8, and 8.4 per 1,000 person-years in metabolically benign obese via the three definitions, respectively, compared to 14.3, 13.8, and 13.3 in at-risk obese, and 7.5, 6.7, and 8.2 in metabolically benign normal weight participants. Multivariable-adjusted hazard ratios of incident CVD in metabolically benign obese compared to their at-risk obese counterparts were 0.59 (95% CI 0.47-0.73), 0.52 (0.39-0.68), and 0.71 (0.57-0.90), respectively; and 1.24 (0.99-1.57), 1.16 (0.86-1.56), and 1.28 (1.01-1.62) compared to metabolically benign normal weight individuals. Only 28.7% of obese participants classified as metabolically benign by at least one definition were "metabolically benign" by all three definitions. Despite similar CVD risk estimates, the three definitions identified different subgroups of the obese population, perhaps suggesting distinct etiologies.

Adiposity and the menopausal transition.

This review summarizes the published literature on the potentially circular relationship between adiposity and the menopause. Although data are limited, current information suggests there are substantial effects of obesity and adiposity on the magnitude of hormone changes experienced during the transition, as well as on the risks of chronic disease resulting from the menopause transition. However, evidence regarding the reverse, namely, effects of the menopause transition and its associated hormone changes on weight gain and redistribution of body fat, are inconclusive.

Projected impact of polypill use among US adults: Medication use, cardiovascular risk reduction, and side effects.

BACKGROUND: Polypills, which include multiple medications for reducing cardiovascular disease (CVD) risk in a single pill, have been proposed for population-wide use. The number of US adults eligible for polypills and potential benefits are unknown. METHODS: The National Health and Nutrition Examination Survey 2003-2004 and 2007-2008 were analyzed to estimate treatment rates for medications proposed for inclusion in polypills (aspirin, statin, an angiotensin-converting enzyme [ACE] inhibitor, and a thiazide-type diuretic for those without and a ß-blocker for those with a history of myocardial infarction) among US adults. The number of coronary heart disease (CHD) and stroke events potentially prevented through polypill use was projected by published meta-analyses and 3 large population-based cohort studies. Two polypill eligibility criteria were analyzed: (1) US adults ≥55 years and (2) US adults with a history of CVD. RESULTS: There are 67.6 million US adults ≥55 years and 15.4 million US adults with a history of CVD and, thus, eligible for polypills using the 2 outlined criteria. In 2007 to 2008, 37.3% of US adults ≥55 years and 57.0% of those with a history of CVD were taking statins. Use of other polypill medications was also low. Polypill use by US adults aged ≥55 years is projected to potentially prevent 3.2 million CHD events and 1.7 million strokes over 10 years. Among those with a history of CVD, the potential to prevent of 0.9 million CHD events and 0.5 million strokes is projected. CONCLUSIONS: Polypills have the potential to lower CVD incidence substantially among US adults.

Effect modification of obesity on associations between endogenous steroid sex hormones and arterial calcification in women at midlife.

OBJECTIVE: The aim of this study was to examine whether obesity modifies the effects of endogenous steroid sex hormones on arterial calcification in women at midlife. METHODS: Associations between estradiol, testosterone, sex hormone-binding globulin, and free androgen index and the presence and extent of coronary and aortic calcification were evaluated in 187 obese (body mass index, ≥30 kg/m) and 281 nonobese (body mass index, <30 kg/m) women from the Study of Women's Health Across the Nation. Logistic and linear regressions were used as appropriate. RESULTS: Prevalence rates of coronary and aortic calcification were significantly higher among obese compared with nonobese women (P < 0.001, for both). In multivariable analyses, steroid sex hormones were not associated with the presence of coronary calcification. However, for the extent of coronary calcification, significant interactions were found between obesity and both sex hormone-binding globulin (P < 0.0001) and free androgen index (P = 0.008). In nonobese women, higher sex hormone-binding globulin (P = 0.0006) and lower free androgen index (P = 0.01) were associated with a greater extent of coronary calcification, whereas lower sex hormone-binding globulin was associated with greater extent of coronary calcification in obese women (P = 0.05). For aortic calcification outcomes, higher sex hormone-binding globulin was associated with the presence of aortic calcification among nonobese women (odds ratio, 1.64; 95% CI, 1.16-2.32, for each 1-SD greater sex hormone-binding globulin). CONCLUSIONS: Associations between endogenous steroid sex hormones and arterial calcification vary by obesity status among perimenopausal women. Further research is needed to better understand the possible mechanisms of these associations.

Clustering of metabolic abnormalities among obese patients and mortality after percutaneous coronary intervention.

Although current literature demonstrates metabolic abnormalities are associated with mortality, obese patients who tend to have more metabolic abnormalities paradoxically have lower overall mortality rates compared to their normal-weight counterparts. In this study, we examined the prevalence of metabolic abnormality clustering and its relation to mortality in obese and normal-weight patients after percutaneous coronary intervention (PCI). Patients (n = 9,673) undergoing elective PCI from October 2003 through December 2006 at a single urban hospital were categorized by body mass index (BMI) levels of 18.5 to 24.9, 25.0 to 29.9, 30.0 to 34.9, and ≥35 kg/m(2) and by number of metabolic abnormalities possessed (hypertension, impaired fasting glucose/diabetes, triglycerides ≥150 mg/dl, high-density lipoprotein cholesterol < 40 mg/dl, and C-reactive protein ≥2.0 mg/L). All-cause mortality was assessed through June 30, 2007. Mean age of patients was 65.9 years and 66% were men. Prevalences of 4 or 5 metabolic abnormalities were 12%, 18%, 24%, and 31% in patients with BMI levels of 18.5 to 24.9, 25.0 to 29.9, 30 to 34.9, and ≥35 kg/m(2), respectively. In patients with BMI of 30.0 to 34.9 kg/m(2), hazard ratios (95% confidence intervals) for mortality associated with 2, 3, and 4 to 5 metabolic abnormalities versus 0 to 1 metabolic abnormality were 1.31 (0.79 to 2.17), 1.42 (0.83 to 2.43), and 2.39 (1.24 to 4.59), respectively. Analogous hazard ratios for patients with BMI ≥35 kg/m(2) were 1.94 (0.90 to 4.20), 1.44 (0.63 to 3.28), and 2.17 (0.91 to 5.18). All-cause mortality rates per 1,000 person-years were 55.5, 33.7, 28.3, and 33.8 in patients with BMI levels of 18.5 to 24.9, 25 to 29.9, 30 to 34.9, and ≥35 kg/m(2), respectively. In conclusion, BMI levels of 25.0 to 29.9 and 30 to 34.9 kg/m(2) were associated with lower all-cause mortality after PCI. However, an increased number of metabolic abnormalities translated into increased all-cause mortality.

Burden of subclinical cardiovascular disease in "metabolically benign" and "at-risk" overweight and obese women: the Study of Women's Health Across the Nation (SWAN).

BACKGROUND: Metabolically benign obese individuals have a 10-year cardiovascular disease (CVD) risk comparable to healthy normal weight individuals. However, the burden of subclinical CVD among metabolically benign obese is not well known. METHODS: In cross-sectional analyses of 475 mid-life women, we compared common carotid artery intima media thickness (CCA-IMT), aortic pulse wave velocity (aPWV) and coronary (CAC) and aortic calcification (AC) among three groups: healthy normal weight, metabolically benign overweight/obese (<3 metabolic syndrome components/elevated CRP), and at-risk overweight/obese (≥3 metabolic syndrome components/elevated CRP). RESULTS: The mean (SD) CCA-IMT and aPWV were lowest in the normal weight group (n=145), followed by the benign overweight/obese (n=260) and at-risk overweight/obese (n=70) groups [CCA-IMT: 0.64 (0.08) vs. 0.68 (0.09) vs. 0.73 (0.13) mm, p<0.001; aPWV: 731.0 (176.4) vs. 809.9 (182.3) vs. 875.7 (228.8) cm/s, p<0.001]. Similar results were found for the frequency (%) of women with increased CAC and AC [CAC: 13 (9%) vs. 53(20%) vs. 28(40%), p<0.001; AC: 47(32%) vs. 130 (50%) vs. 55(79%), p<0.001]. These differences remained significant after multivariable adjustment. Further adjustment for BMI attenuated the statistical significance of differences in aPWV and calcification between benign and at-risk overweight/obese women, but had little effect on the magnitude of these differences. CONCLUSIONS: Metabolically benign overweight/obese women have a significantly greater subclinical CVD burden than normal weight women, despite published data finding similar CVD event rates between the two groups. Prospective studies tracking the progression of subclinical atherosclerosis to clinical CVD in these women are needed.

Empirical derivation to improve the definition of the metabolic syndrome in the evaluation of cardiovascular disease risk.

OBJECTIVE: To examine whether a quantitatively derived metabolic syndrome definition predicts incident cardiovascular disease (CVD) events better than do existing definitions. RESEARCH DESIGN AND METHODS: Data were pooled from the Atherosclerosis Risk in Communities, Cardiovascular Health, and Framingham Offspring studies (n = 20,581). Incident coronary heart disease and stroke events were ascertained over 9 years. RESULTS: The sensitivity for incident CVD events was higher and the specificity lower for the empirically derived versus the Adult Treatment Panel (ATP) III, International Diabetes Federation (IDF), or Harmonized metabolic syndrome definitions (sensitivity/specificity 0.65/0.53 vs. 0.53/0.63, 0.51/0.66, and 0.64/0.56, respectively), resulting in no overall improvement in discrimination. Multivariable-adjusted hazard ratios for incident CVD events were similar across definitions and were 1.7 (95% CI 1.6-1.9) for ATP III, 1.8 (1.6-2.0) for IDF, 1.9 (1.7-2.0) for Harmonized, and 1.7 (1.6-1.9) for the empirically derived definition. CONCLUSIONS: Empirical derivation of the metabolic syndrome definition did not improve CVD discrimination or risk prediction.

Subcutaneous adipose tissue in relation to subclinical atherosclerosis and cardiometabolic risk factors in midlife women.

BACKGROUND: Limited data suggest that the effects of abdominal subcutaneous adipose tissue (SAT) on cardiovascular disease risk may depend on accompanying amounts of abdominal visceral adipose tissue (VAT). OBJECTIVE: The objective was to examine whether abdominal VAT area modifies the effects of abdominal SAT area on subclinical atherosclerosis and cardiometabolic risk factors in both whites and African Americans. DESIGN: Computed tomographic measures of abdominal SAT and VAT were examined in relation to carotid intima-media thickness (cIMT) and cardiometabolic risk factor levels in 500 African American and white women in midlife. A VAT × SAT interaction term was evaluated. RESULTS: The mean (±SD) age of the sample was 51.0 ± 2.9 y, and 37% were African American. Higher amounts of SAT and VAT were associated with higher cIMT, blood pressure, homeostasis model assessment insulin resistance index (HOMA-IR), and concentrations of glucose, triglycerides, and insulin and with lower concentrations of HDL cholesterol. However, in African Americans, but not in whites, higher amounts of VAT significantly attenuated associations between higher amounts of SAT and higher insulin concentrations (P for interaction = 0.032) and HOMA-IR (P for interaction = 0.011) and reversed associations with cIMT (P for interaction = 0.005) and glucose (P for interaction = 0.044). CONCLUSIONS: These results suggest that in midlife African American but not white women, adverse associations between abdominal SAT and cardiometabolic risk factors are attenuated and, in the case of subclinical atherosclerosis, are reversed as VAT amounts increase. Given that African American women suffer disproportionately from obesity and cardiovascular disease, further research into the role of this effect modification on obesity-associated vascular disease in African American women is warranted.