Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia.

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

Association Between Depressive Symptoms and Incident Cardiovascular Diseases.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs). Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. Design, Setting, and Participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline. Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder). Main Outcomes and Measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. Conclusions and Relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

Physical Activity and Trajectories of Cognitive Change in Community-Dwelling Older Adults: The Rancho Bernardo Study.

BACKGROUND: Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain. OBJECTIVE: To determine whether physical activity in youth and older age are associated with age-related cognitive change. METHODS: Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988- 1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive. RESULTS: Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002). CONCLUSION: Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

Effects of APOE on cognitive aging in community-dwelling older adults.

OBJECTIVE: The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). METHOD: A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. RESULTS: ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. CONCLUSIONS: These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes.

Background: This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis. Methods: Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomly assigned to metformin vs placebo and to a weight loss intervention vs control (ie, usual care). The 2 × 2 factorial design allows a single randomized trial to investigate the effect of two factors and interactions between them. Outcomes were changes in fasting insulin, glucose, C-reactive protein (CRP), estradiol, testosterone, and sex-hormone binding globulin (SHBG). The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control. All tests of statistical significance were two-sided. Results: A total of 313 women (94.0%) completed the six-month trial. High prescription adherence (ie, ≥80% of pills taken) ranged from 65.9% of participants in the metformin group to 81.3% of those in the placebo group (P < .002). Mean percent weight loss was statistically significantly higher in the weight loss group (-5.5%, 95% confidence interval [CI] = -6.3% to -4.8%) compared with the control group (-2.7%, 95% CI = -3.5% to -1.9%). Statistically significant group differences (ie, percent change in metformin group minus placebo group) were -7.9% (95% CI = -15.0% to -0.8%) for insulin, -10.0% (95% CI = -18.5% to -1.5%) for estradiol, -9.5% (95% CI = -15.2% to -3.8%) for testosterone, and 7.5% (95% CI = 2.4% to 12.6%) for SHBG. Statistically significant group differences (ie, percent change in weight loss group minus placebo group) were -12.5% (95% CI = -19.6% to -5.3%) for insulin and 5.3% (95% CI = 0.2% to 10.4%) for SHBG. Conclusions: As adjuvant therapy, weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality.

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.

Adipokines and severity and progression of coronary artery calcium: Findings from the Rancho Bernardo Study.

BACKGROUND AND AIMS: Adipokines are known to predict cardiovascular events, yet their association with coronary artery calcium (CAC), a surrogate marker of coronary atherosclerosis and risk factor for cardiovascular disease (CVD), is unclear. We aimed at assessing the association between adipokines and the severity and progression of CAC in healthy older adults, and at exploring potential modification by gender. METHODS: 409 men and women from the Rancho Bernardo Study with no known CVD underwent a chest computed tomography scan to determine baseline CAC severity; 329 returned 4.5 years later for a repeat scan to evaluate CAC progression. Adipokines (IL-6, adiponectin, leptin, and TNF-α) were measured from baseline blood samples. Ordinal linear and logistic regression models were used to determine the association of each adipokine with baseline severity and future progression of CAC. RESULTS: Adjusting for age and sex, IL-6 and leptin were associated with greater odds of increasing CAC severity (OR = 1.63, 95% CI 1.22-2.19; OR = 1.19, 95% CI 0.99-1.43, respectively, per SD). The association with IL-6 remained significant in models further adjusted for lifestyle, body size, CVD risk factors, and body fat distribution. Adiponectin was associated with CAC progression (OR = 0.68, 95% CI 0.51-0.92 in fully adjusted models). This was modified by sex, with protective effects seen for men (OR = 0.57, 95% CI 0.38-0.85), but not for women (OR = 0.93, 95% CI 0.67-1.32; p-for-interaction = 0.04). CONCLUSIONS: IL-6 and leptin predicted greater CAC severity while adiponectin predicted lower odds of CAC progression. More research is needed to explore biological mechanisms, including differences by sex.

The Association of the C-Reactive Protein Inflammatory Biomarker with Breast Cancer Incidence and Mortality in the Women's Health Initiative.

Purpose: To examine associations of prediagnosis high-sensitivity C-reactive protein (hsCRP) with breast cancer incidence and postdiagnosis survival and to assess whether associations are modified by body mass index (BMI).Methods: A prospective analysis of the Women's Health Initiative was conducted among 17,841 cancer-free postmenopausal women with baseline hsCRP measurements. Cox proportional hazards models were used to examine associations between hsCRP concentrations and (i) breast cancer risk (n cases = 1,114) and (ii) all-cause mortality after breast cancer diagnosis. HRs are per 1 SD in log hsCRP.Results: hsCRP was not associated with breast cancer risk overall [HR = 1.05; 95% confidence interval (CI), 0.98-1.12]; however, an interaction between BMI and hsCRP was observed (Pinteraction = 0.02). A 1 SD increase in log hsCRP was associated with 17% increased breast cancer risk (HR = 1.17; 95% CI, 1.03-1.33) among lean women (BMI < 25), whereas no association was observed among overweight/obese (BMI ≥ 25) women. Prediagnosis hsCRP was not associated with overall mortality (HR, 1.04; 95% CI, 0.88-1.21) after breast cancer diagnosis; however, an increased mortality risk was apparent among leaner women with higher hsCRP levels (HR, 1.39, 95% CI, 1.03-1.88).Conclusions: Prediagnosis hsCRP levels are not associated with postmenopausal breast cancer incidence or survival overall; however, increased risks are suggested among leaner women. The observed effect modification is in the opposite direction of a previous case-control study finding and warrants further investigation.Impact: Associations of higher CRP levels with incident breast cancer and survival after breast cancer may depend on BMI. Cancer Epidemiol Biomarkers Prev; 26(7); 1100-6. ©2017 AACR.

Low Testosterone, but Not Estradiol, Is Associated With Incident Falls in Older Men: The International MrOS Study.

Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged ≥65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow-up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86-0.91) and BioT (OR = 0.86, 95% CI 0.83-0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91-0.96; BioT: OR = 0.91, 95% CI 0.89-0.94). E2, BioE2, and sex hormone-binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men. © 2017 American Society for Bone and Mineral Research.

The Limited Clinical Utility of Testosterone, Estradiol, and Sex Hormone Binding Globulin Measurements in the Prediction of Fracture Risk and Bone Loss in Older Men.

Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG (>59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men. © 2016 American Society for Bone and Mineral Research.

Relation of Depressive Symptoms With Coronary Artery Calcium Determined by Electron-Beam Computed Tomography (from the Rancho Bernardo Study).

Studies linking depressive symptoms and coronary artery calcium (CAC), a measure of subclinical atherosclerosis, have yielded mixed results. No longitudinal studies of depressive symptoms and CAC have included older adults of both genders. This study examined the association of depressive symptoms with CAC and CAC progression in older men and women. Participants were 417 community-dwelling older adults (mean age = 67 ± 7) with no history of heart disease who attended a 1997 to 1999 research clinic visit when depressive symptoms were assessed using the Beck Depression Inventory (BDI). CAC was measured using electron-beam computed tomography in 2000 to 2002 and again in 2005 to 2007. Median BDI was 3, range = 0 to 37; 39% of men and 10% of women had severe CAC (Agatston score ≥ 400) in 2000 to 2002. Ordinal logistic regression analyses examining the odds of greater compared with lesser CAC severity by BDI quartiles showed an unexpected negative association whereby women with the lowest depressive symptoms had 2.4 times the odds of increasing CAC severity compared with women in the second BDI quartile (95% CI 1.1 to 5.4). A nonlinear, U-shaped association was observed in men with those in the first and fourth BDI quartiles having 2.6 and 3.0 times higher odds of increasing CAC severity than subjects in the second quartile (95% CI 1.2 to 5.6 and 1.3 to 6.9, respectively) after adjustment for coronary heart disease risk factors. No significant associations were observed for CAC progression although similar nonlinear patterns were observed in men. In conclusion, our results suggest that depressive symptoms have a gender-specific, cross-sectional association with CAC but no statistically significant associations with CAC progression.

The association between abdominal muscle and type II diabetes across weight categories in diverse post-menopausal women.

CONTEXT: Despite the key role of muscle in glucose regulation, little is known about the association between muscle area and prevalence of metabolic disorders, or the role low muscle may play in normal weight metabolic obesity. OBJECTIVE: The objective was to assess the independent associations between both abdominal muscle and fat depositions (measured by computed tomography) and the prevalence of type II diabetes, and to explore the modifying role of weight category. DESIGN: We conducted a cross-sectional analysis of the 2001-2002 visit for the Rancho Bernardo Study, Filipino Women's Health Study, and Health Assessment Study of African American Women. SETTING AND PARTICIPANTS: Participants were 392 community-dwelling older women (mean age = 64) free of clinical cardiovascular disease. MAIN OUTCOME MEASURE: The main outcome was prevalence of type II diabetes, defined as use of anti-diabetes medication, fasting plasma glucose ≥ 126 mg/dL, and/or OGTT ≥ 200 mg/dL. RESULTS: Adjusting for demographics, hypertension, estrogen use, lipids, smoking, physical activity, visceral fat area, and height, a greater muscle-to-total abdominal area ratio (MAR) was associated with lower odds of diabetes [OR = 0.63 per standard deviation, 95% CI (0.43-0.92), p = .02]. Higher visceral fat was associated with greater odds of diabetes in fully adjusted models including total muscle area [OR = 1.48, 95% CI (1.09, 2.01), p = .01]. Associations between MAR and diabetes were stronger for normal weight (BMI 18.5-24.9; OR = 0.32) than overweight/obese women (BMI ≥ 25, OR = 0.71, p-for-interaction = 0.046). Associations with visceral fat did not differ by BMI (p-for-interaction = 0.71). CONCLUSIONS: In older women, abdominal muscle area is inversely associated with type II diabetes independent of visceral adiposity, particularly for normal weight women.

Relation of serum uric acid to severity and progression of coronary artery calcium in postmenopausal White and Filipino women (from the Rancho Bernardo study).

Elevated serum uric acid (UA) is associated with cardiovascular disease (CVD) but its association with coronary artery calcium (CAC) is inconsistent. This study examined ethnic differences in the association of UA levels with CAC severity and progression. Participants included 202 white and 166 Filipino postmenopausal women without known CVD. White women originated from the Rancho Bernardo cohort study, whereas Filipino women were convenience sampled from comparable localities. Baseline UA levels and CVD risk factors were measured in 1995 to 1999. CAC was assessed by electron beam computed tomography (EBCT) in 2000 to 2002 (EBCT1) and repeated in 2005 to 2007 (EBCT2). EBCT1 CAC density scores were categorized by severity: minimal 0 to 10, mild 11 to 100, moderate 101 to 399, and severe ≥400. Progression was defined as CAC volume score increases of ≥2.5 mm3 between scans. White women were older at baseline than Filipinas (64.6 vs 59.3 years, p<0.001). Filipinas had increased UA levels (235.8 vs 294.2 µmol/L, p<0.001), diabetes (35.5% vs 5.2%, p<0.001), hypertension (69.6% vs 45.2%, p<0.001), and statin use (32.8% vs 18.7%, p=0.002). CAC severity did not vary by ethnicity (p=0.502), but Filipinas experienced more CAC progression than whites (53.0% vs 39.1%, p=0.016). Adjustment for CVD risk factors identified a positive association between UA levels and increasing CAC severity at EBCT1 in Filipinas (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.05 to 1.71) but not whites (OR 0.94, 95% CI 0.71 to 1.25). Higher UA levels predicted CAC progression in both cohorts (OR 1.26, 95% CI 1.02 to 1.56). In conclusion, these results support use of UA as an ethnicity-specific marker of CAC severity and as a marker of CAC progression among postmenopausal women.

Associations of physical activity and sedentary behavior with regional fat deposition.

INTRODUCTION: Increased sedentary behavior predicts greater cardiovascular morbidity and mortality and does so independently of physical activity (PA). This association is only partially explained by body mass index (BMI) and overall body fat, suggesting mechanisms besides general increased adiposity. The purpose of this study was to explore associations of self-reported leisure PA and sitting time with regional fat depositions and abdominal muscle among community-dwelling older adults. METHODS: Participants were 539 diverse adults (mean age = 65 yr) who completed a study visit in 2001-2002. Areas of pericardial, intrathoracic, subcutaneous, visceral, and intermuscular fat, as well as abdominal muscle, were measured using computed tomography. Leisure PA and sitting hours were entered simultaneously into multivariate regression models to determine associations with muscle and fat areas. RESULTS: After adjusting for demographics, smoking, diabetes, hypertension, triglycerides, and cholesterol, greater PA was associated with less intrathoracic, visceral, subcutaneous, and intermuscular fat (for all P < 0.05), while greater sedentary time was associated with greater pericardial and intrathoracic fat (for both P < 0.05). After further adjusting for BMI, each hour of weekly PA was associated with 1.85 cm less visceral fat (P < 0.01) but was not associated with other fat depositions. Conversely, each hour of daily sitting was associated with 2.39 cm more pericardial fat (P < 0.05) but was not associated with any other fat depositions. There were no associations with abdominal muscle area. Adjusting for common inflammatory markers had little effect. Associations between fat and PA were stronger for men. CONCLUSIONS: Sitting and PA have distinct associations with regional fat deposition in older adults. The association between sitting and pericardial fat could partially explain the link between sitting and coronary heart disease.

Associations of pericardial and intrathoracic fat with coronary calcium presence and progression in a multiethnic study.

OBJECTIVE: Body mass index (BMI) may not accurately or adequately reflect body composition or its role in the development of cardiovascular disease (CVD). Ectopic adipose depots may provide a more refined representation of the role of adiposity in CVD. Thus, the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC) was examined. DESIGN AND METHODS: Nearly 600 white men and women, as well as Filipina women and African-American women, all without known CVD, had abdominal and chest computed tomography (CT) scans at two time points about 4 years apart from which CAC presence, severity and progression, as well as pericardial and intrathoracic fat volumes were obtained. Logistic and linear regression models with staged adjustment were used to assess associations of pericardial and intra-thoracic fat with CAC presence, severity, and progression. RESULTS: After adjustment for age, BMI, sex/ethnic group, ever smoking, and lipids, each standard deviation higher increment of intra-thoracic fat, but not pericardial fat, was significantly associated with 3.84-fold higher odds of prevalent CAC (95% CI (1.54, 9.58), P = 0.004) and a 38.4% higher CAC score (95% CI (3.5%, 90.0%), P = 0.03). Neither pericardial nor intrathoracic fat were associated with CAC progression. CONCLUSIONS: Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. However, a significant association between intrathoracic fat and both the presence and severity of CAC was demonstrated. Studies measuring fat in the thoracic cavity may consider defining intrathoracic fat as a separate entity from pericardial fat.

Reductions in glucose among postmenopausal women who use and do not use estrogen therapy.

OBJECTIVE: Among postmenopausal women who do not use estrogen therapy (ET), we have previously reported that intensive lifestyle modification (ILS) leads to increases in sex hormone-binding globulin (SHBG) and that such increases are associated with reductions in fasting plasma glucose (FPG) and 2-hour postchallenge glucose (2HG). Oral ET decreases FPG and increases 2HG while increasing both SHBG and estradiol (E2). It is unknown if ILS reduces glucose among ET users, if changes in SHBG and E2 might mediate any glucose decreases in ET users, and if these patterns differ from those in non-ET users. METHODS: We conducted a secondary analysis of postmenopausal women in the Diabetes Prevention Program who used ET at baseline and 1-year follow-up (n = 324) and who did not use ET at either time point (n = 382). Participants were randomized to ILS, metformin, or placebo administered at 850 mg BID. RESULTS: ET users were younger, more often white, and more likely to have had bilateral oophorectomy than non-ET users. Among ET users, ILS reduced FPG (P < 0.01) and 2HG (P < 0.01), and metformin reduced FPG (P < 0.01) but not 2HG (P = 0.56), compared with placebo. Associations between SHBG and total E2 with FPG and 2HG were not significant among women randomized to ILS or metformin. These patterns differed from those observed among women who did not use ET. CONCLUSIONS: We conclude that among glucose-intolerant ET users, interventions to reduce glucose are effective but possibly mediated through different pathways than among women who do not use ET.

Kidney function and progression of coronary artery calcium in community-dwelling older adults (from the Rancho Bernardo Study).

Longitudinal studies of the association of estimated glomerular filtration rate (eGFR) and albuminuria with coronary artery calcium (CAC), a measure of cardiovascular disease burden, are few and contradictory. In this study, 421 community-dwelling men and women (mean age 67 years) without known heart disease had eGFRs assessed using the Modification of Diet in Renal Disease (MDRD) equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) from 1997 to 1999. The mean eGFR was 78 ml/min/1.73 m(2), and the median ACR was 10 mg/g. CAC was measured using electron-beam computed tomography from 2000 to 2001, when the median total Agatston CAC score was 77; 4.5 years later, 338 participants still without heart disease underwent repeat scans (median CAC score 112); 46% of participants showed CAC progression, defined as an increase ≥2.5 mm(3) in square root-transformed CAC volume score. Cross-sectional and longitudinal logistic regression analyses showed no separate or joint association between eGFR or ACR and CAC severity or progression. In conclusion, this study does not support the use of eGFR or ACR to identify asymptomatic older adults who should be screened for subclinical cardiovascular disease with initial or sequential scanning for CAC. In the elderly, kidney function and CAC may not progress together.

Racial/ethnic differences in sex hormone levels among postmenopausal women in the diabetes prevention program.

CONTEXT: Sex hormones may differ by race/ethnicity in postmenopausal women. Whether racial/ethnic differences also exist among those who are overweight and glucose intolerant is not clear. OBJECTIVES: The objective of the study was to compare sex hormones by race/ethnicity [non-Hispanic white (NHW), Hispanic, African-American (AA)] in overweight, glucose-intolerant, postmenopausal women. DESIGN: This was a secondary analysis of a randomized controlled trial. PARTICIPANTS: Participants included postmenopausal glucose-intolerant women participating in the Diabetes Prevention Program. INTERVENTIONS: Interventions included intensive lifestyle modification (consisting of diet and physical activity) or metformin 850 mg twice a day vs. placebo. MAIN OUTCOME MEASURES: Baseline levels and 1-yr intervention-related changes in SHBG, total and bioavailable estradiol (E2), total and bioavailable testosterone, and dehydroepiandrosterone were measured. RESULTS: At baseline, among women not using estrogen (n = 370), NHW had higher total and bioavailable E2 and testosterone levels than Hispanics independent of age, type of menopause, waist circumference, alcohol intake, and current smoking. NHW also had higher levels of bioavailable E2 and lower levels of SHBG than AA. At baseline, among estrogen users (n = 310), NHW had higher total and bioavailable E2 than Hispanics and higher levels of SHBG than AA after adjustment. At 1 yr, among women not using estrogen, NHW had larger declines in total E2 and bioavailable E2 levels than AA after adjustment for the above covariates, changes in waist circumference, and randomization arm. At 1 yr, among estrogen users, sex hormone changes did not differ by race/ethnicity. CONCLUSIONS: Among postmenopausal women, there were significant race/ethnicity differences in baseline sex hormones and changes in sex hormones.

Plasma neutrophil gelatinase-associated lipocalin is independently associated with cardiovascular disease and mortality in community-dwelling older adults: The Rancho Bernardo Study.

OBJECTIVES: The purpose of this study was to determine the association between neutrophil gelatinase-associated lipocalin (NGAL) levels and cardiovascular and all-cause mortality in community-dwelling older adults. BACKGROUND: NGAL is a novel marker best known for its role in rapidly identifying acute kidney injury. Although expressed in atherosclerosis, its association with cardiovascular disease (CVD) in the community has not been reported. METHODS: We measured plasma NGAL levels in 1,393 Rancho Bernardo Study participants without CVD, mean age 70 years. Participants were followed for a mean time period of 11 years. RESULTS: During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and creatinine clearance, NGAL was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase: 1.33, 95% confidence interval [CI]: 1.12 to 1.57), all-cause mortality (HR: 1.19, 95% CI: 1.07 to 1.32), and a combined cardiovascular endpoint (HR: 1.26, 95% CI: 1.10 to 1.45). After further adjusting for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), NGAL remained an independent predictor of each outcome. NGAL improved the C-statistic (0.835 to 0.842) for prediction of CVD death (p = 0.001). Net reclassification improvement (>0) with the addition of NGAL was 18% (p = 0.02); the integrated discrimination index was also significant (p = 0.01). Participants with NGAL and NT-proBNP above the median had increased risk of CVD death versus those with only NT-proBNP elevated (HR: 1.43, 95% CI: 1.12 to 1.82). CONCLUSIONS: Plasma NGAL is a significant predictor of mortality and CVD in community-dwelling older adults, independent of traditional risk factors and kidney function, and adds incremental value to NT-proBNP and CRP. The potential impact of these results includes providing insight into new mechanisms of CVD and the possibility of improving screening, intervention, and prevention.

Extremes of an aromatase index predict increased 25-year risk of cardiovascular mortality in older women.

BACKGROUND: Peripheral conversion of androgens to oestrogens via aromatase is the primary source of oestrogen in postmenopausal women and may play a role in cardiovascular health. DESIGN: Prospective. PARTICIPANTS, MEASUREMENTS: The association of an index of aromatase activity (AROM), the serum oestrone-to-androstenedione ratio, with 25-year cardiovascular disease (CVD) mortality was examined in 819 postmenopausal non-oestrogen using women (mean age at baseline = 72). RESULTS: Overall, 247 deaths were attributed to CVD. The median AROM value was 60 (95% range 17-129). AROM was positively correlated with age (r = 0·28) and body mass index (BMI) (r = 0·22) (P < 0·001). The age-adjusted risk for CVD mortality was significantly elevated for women in the lowest (HR = 2·01, 95% CI 1·31-3·12) and highest (HR = 1·51, 95%CI 1·02-2·22) quintiles of AROM, compared with the middle quintile. This U-shaped association persisted after additional adjustment for BMI, waist-to-hip ratio, exercise, smoking, alcohol use and traditional CVD risk factor covariates. There was a significant interaction of AROM and BMI (P = 0·001), such that high AROM was associated with a 63% reduction in risk of CVD death for women with low BMI (<22 kg/m(2) ), but with 2·1- to 2·5-fold increased risk in women with mid-range (22-<25 kg/m(2) ) and high (≥25 kg/m(2) ) BMI. Oestradiol did not influence AROM associations and was not independently related to CVD death. CONCLUSIONS: These results suggest that aromatase is a novel endocrine factor predictive of CVD mortality among postmenopausal women. If confirmed, additional studies are needed to determine whether extremes of aromatase reflect genetic influences or underlying disease processes.