Sex hormones are thought to play an important role in the pathophysiology of depressive disorders in women. This study assessed the associations of total testosterone (T), bioavailable T, estradiol (E2), dehydroepiandrosterone (DHEA) and sex hormone binding globulin (SHBG) with depressive symptoms stratified on postmenopausal stage to determine whether associations were strongest for early postmenopausal women.
Women (N=1824) free of depressive symptoms at baseline (2000–2002) in the Multi-Ethnic Study of Atherosclerosis were categorized into tertiles of years postmenopause: T1, 0–10 years; T2, 11–20 years; and T3, 21–58 years. Multivariable-adjusted relative risks (RR) and 95% confidence intervals were computed for the incidence of depressive symptoms, as defined by a score of 16 or higher on the Center for Epidemiologic Studies Depression scale at examination 3 (2004–2005).
In analysis including all sex hormones, the RRs for incident depressive symptoms associated with 1 unit higher log(total T) was 0.57 (p=0.13), log(E2) was 0.78 (p=0.04), log(SHBG) was 1.84 (p=0.003) and log(DHEA) was 1.45 (p=0.08) in T1. Without adjustment for SHBG, the RR for log(bioavailable T) was 0.16 (p=0.04). However, in T2 and T3, there were no meaningful associations of hormone or SHBG levels with incident depressive symptoms. When stratified by HT use, results were consistent for HT users but attenuated for HT non-users.
In women early postmenopause, sex hormones were associated with incident depressive symptoms.
sex hormones; CES-D; depression; testosterone; estradiol; SHBG
Age is one of the strongest predictors of cardiovascular disease (CVD) risk. Treatment with statins can significantly reduce CVD events and mortality in both primary and secondary prevention. Yet despite the high CVD risk among the elderly, there is underutilization of statins in this population (ie, the treatment-risk paradox). Few studies have investigated the use of statins in the elderly, particularly for primary prevention and, as a result, guidelines for treating the elderly are limited. This is likely due to: uncertainties of risk assessment in older individuals where the predictive value of individual risk factors is decreased; the need to balance the benefits of primary prevention with the risks of polypharmacy, health care costs, and adverse medication effects in a population with decreased life expectancy; the complexity of treating patients with many other comorbidities; and increasingly difficult social and economic concerns. As life expectancy increases and the total elderly population grows, these issues become increasingly important. JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) is the largest primary prevention statin trial to date and enrolled a substantial number of elderly adults. Among the 5695 JUPITER participants ≥70 years of age, the absolute CVD risk reduction associated with rosuvastatin was actually greater than for younger participants. The implications of this JUPITER subanalysis and the broader role of statins among older adults is the subject of this review.
JUPITER; rosuvastatin; elderly; risk
Deficient 25-hydroxyvitamin D [25(OH)D] levels are associated with cardiovascular disease (CVD) events and mortality. Both 25(OH)D deficiency and stroke are more prevalent among blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared to whites.
Research Methods and Procedures
The Third National Health and Nutrition Examination Survey, a probability sample of US civilians, measured 25(OH)D levels and CVD risk factors between 1988–1994. Vital status through December 2006 was obtained via linkage with the National Death Index. Among white and black adults without CVD reported at baseline (n=7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race.
During a median of 14.1 years, there were 116 and 60 fatal strokes among whites and blacks respectively. The risk of fatal stroke was greater in blacks compared to whites in models adjusted for socio-economic status and CVD risk factors, [HR 1.60 (95% CI 1.01–2.53)]. Mean baseline 25(OH)D levels were significantly lower in blacks compared to whites (19.4 vs 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels <15 ng/mL were associated with fatal stroke among whites [HR 2.13 (1.01–4.50)] but not blacks [HR 0.93 (0.49–1.80)].
Vitamin D deficiency was associated with increased risk of stroke death in whites but not blacks. Although blacks had a higher rate of fatal stroke compared to whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence and therefore 25(OH)D levels did not explain this excess risk.
vitamin D; stroke; racial differences
Statins have emerged at the forefront of preventive cardiology and have significantly reduced cardiovascular events and mortality. Nonetheless, cardiovascular disease remains the leading cause of death in the United States and in other developed countries, as well as the etiology of significant morbidity and health-care expenditure. In an attempt to reduce potentially missed opportunities for instituting preventive therapy, the JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and the AURORA study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) examined the effect of statins in two specific patient populations who currently do not meet the guidelines for statin treatment, but nonetheless, are at high cardiovascular risk. This review outlines the JUPITER and AURORA trials, interprets the data and significance of the results, analyses the drawbacks and impact of both trials and delineates the potential for further clinical trials.
JUPITER; AURORA; rosuvastatin; cardiovascular disease
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
coronary calcium; Framingham risk score; risk factors; progression
In 2002 the United States Preventive Services Task Force and the American Heart Association recommended aspirin for the primary prevention of Coronary Heart Disease (CHD) in individuals with a Framingham risk score ≥ 6% or ≥ 10%, respectively. The regular use of aspirin (≥ 3 days per week) was examined in a cohort of 6452 White, Black, Hispanic, and Chinese individuals without cardiovascular disease in 2000-2002 and 5181 individuals from the same cohort in 2005-2007. Framingham risk scores were stratified into low (< 6%), increased (6% to 9.9%), and high risk (≥ 10%). In 2000-2002 the prevalence of aspirin use was 18% and 27% for those at increased and high risk, respectively. Whites (25%) used aspirin more than Blacks (14%), Hispanics (12%), or Chinese (14%) (P < 0.001) in the increased risk group. Corresponding prevalences for the high risk group were 38%, 25%, 17%, and 21%, respectively (P < 0.001). In 2005-2007 the prevalence of aspirin use was 31% and 44% for those at increased and high risk, respectively. Whites (41%) used aspirin more than Blacks (27%), Hispanics (24%), or Chinese (15%) in the increased risk group (P < 0.001). Corresponding prevalences for the high risk group were 53%, 43%, 38%, and 28%, respectively (P < 0.001). Racial/ethnic differences persisted after adjustment for age, gender, diabetes, income, and education. In conclusion, regular aspirin use in adults at increased and high risk for CHD remains suboptimal. Important racial/ethnic disparities exist for unclear reasons.
Framingham risk score; aspirin; coronary heart disease; race and ethnicity
A prediction model, developed in the Framingham Heart Study (FHS), has been proposed for use in estimating a given individual’s risk of hypertension. We compared this model with systolic blood pressure (SBP) alone and age-specific diastolic blood pressure (DBP) categories for the prediction of hypertension. Participants in the Multi-Ethnic Study of Atherosclerosis, without hypertension or diabetes (n=3013), were followed for the incidence of hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg and/or the initiation of antihypertensive medication). The predicted probability of developing hypertension between four adjacent study examinations, with a median of 1.6 years between examinations, was determined. The mean (standard deviation) age of participants was 58.5 (9.7) years and 53% were women. During follow-up, 849 incident cases of hypertension occurred. The c-statistic for the FHS model was 0.788 (95% CI: 0.773, 0.804) compared with 0.768 (95% CI: 0.751, 0.785; p=0.096 compared to the FHS model) for SBP alone and 0.699 (95% CI: 0.681, 0.717; p<0.001 compared to the FHS model) for age-specific DBP categories. The relative integrated discrimination improvement index for the FHS model versus SBP alone was 10.0% (95% CI: −1.7%, 22.7%) and versus age-specific DBP categories was 146% (95% CI: 116%, 181%). Using the FHS model, there were significant differences between observed and predicted hypertension risk (Hosmer-Lemeshow goodness of fit p<0.001); re-calibrated and best-fit models produced a better model fit (p=0.064 and 0.245, respectively). In this multi-ethnic cohort of U.S. adults, the FHS model was not substantially better than SBP alone for predicting hypertension.
hypertension; epidemiology; systolic blood pressure; diastolic blood pressure; risk prediction
Evidence suggests low vitamin D and elevated parathyroid hormone (PTH) concentrations may increase risk for cardiovascular disease. However, little is known about the association between vitamin D or PTH and subclinical atherosclerosis. This cross-sectional study included 654 community-dwelling older adults aged 55–96 years (mean age, 75.5 years) without a history of coronary heart disease, revascularization, or stroke enrolled in the Rancho Bernardo Study who completed a clinic examination in 1997–1999 and provided a blood sample for determination of serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH concentrations. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of atherosclerosis at two sites with B-mode ultrasound. After adjusting for age, sex, smoking, alcohol intake, waist-to-hip ratio, exercise, season of blood draw, diabetes, and hypertension, geometric mean internal carotid IMT (ptrend 0.022), but not common carotid IMT (ptrend 0.834) decreased in a dose-dependent fashion with increasing concentration of 25(OH)D. There was no association of 1,25(OH)2D or PTH with either measure of carotid IMT. In subgroup analyses, 1,25(OH)2D was inversely associated with internal carotid IMT among those with hypertension (p for interaction 0.036). These findings from a population-based cohort of older adults suggest a potential role for vitamin D in the development of subclinical atherosclerosis. Additional research is needed to determine whether vitamin D may influence the progression of atherosclerosis, including the effects of supplementation on the atherosclerotic process.
Atherosclerosis; Vitamin D; Parathyroid Hormone; Cardiovascular Diseases
Coronary artery calcium (CAC), carotid intimal medial thickness (cIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. We identified factors associated with low levels of subclinical vascular disease in 1824 participants ≥70 years in the Multi-Ethnic Study of Atherosclerosis. 452 had low CAC (<25th percentile), 441 had low cIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all three parameters. This combination index was independently associated with younger age [OR=2.5 per 1 SD (95%CI 1.8–3.6)], female gender [OR=3.0(1.9–4.8)], lower BMI [OR=1.6 per 1 SD (1.2–2.0)], absence of hypertension [OR=1.8(1.2–2.6)], absence of dyslipidemia [OR=1.6 (1.04–2.4)], and never smoking [OR=1.7(1.1–2.6)]. No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging.
The relationship between vitamin D metabolites and subclinical vascular disease is controversial. Because low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with many cardiovascular disease (CVD) risk factors, we hypothesized that serum 25(OH)D levels would be inversely associated with inflammation as measured by C-reactive protein (CRP) and with subclinical vascular disease as measured by carotid intimal medial thickness (cIMT) and coronary artery calcification (CAC).
We measured 25(OH)D levels in 650 Amish participants. CAC was measured by computed tomography, and cIMT by ultrasound. The associations of 25(OH)D levels with natural log(CAC+1), cIMT, and natural log(CRP) levels were estimated following adjustment for age, sex, family structure, and season of examination. Additional analyses were carried out adjusting for body mass index (BMI) and other CVD risk factors.
25(OH)D deficiency (<20 ng/ml) and insufficiency (21-30 ng/ml) were common among the Amish (38.2% and 47.7%, respectively). 25(OH)D levels were associated with season, age, BMI, and parathyroid hormone levels. In neither the minimally or fully adjusted analyses were significant correlations observed between 25(OH)D levels and CAC, cIMT, or CRP (R2 < 0.01 for all).
Contrary to our hypothesis, this study failed to detect a cross-sectional association between serum 25(OH)D levels and CAC, cIMT, or CRP. Either there is no causal relationship between 25(OH)D and CVD risk, or, if there is, it may be mediated through mechanisms other than subclinical vascular disease severity.
We determined associations between diet soda consumption and risk of incident metabolic syndrome, its components, and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis.
RESEARCH DESIGN AND METHODS
Diet soda consumption was assessed by food frequency questionnaire at baseline (2000–2002). Incident type 2 diabetes was identified at three follow-up examinations (2002–2003, 2004–2005, and 2005–2007) as fasting glucose >126 mg/dl, self-reported type 2 diabetes, or use of diabetes medication. Metabolic syndrome (and components) was defined by National Cholesterol Education Program Adult Treatment Panel III criteria. Hazard ratios (HRs) with 95% CI for type 2 diabetes, metabolic syndrome, and metabolic syndrome components were estimated, adjusting for demographic, lifestyle, and dietary confounders.
At least daily consumption of diet soda was associated with a 36% greater relative risk of incident metabolic syndrome and a 67% greater relative risk of incident type 2 diabetes compared with nonconsumption (HR 1.36 [95% CI 1.11–1.66] for metabolic syndrome and 1.67 [1.27–2.20] for type 2 diabetes). Of metabolic syndrome components, only high waist circumference (men ≥102 cm and women ≥88 cm) and high fasting glucose (≥100 mg/dl) were prospectively associated with diet soda consumption. Associations between diet soda consumption and type 2 diabetes were independent of baseline measures of adiposity or changes in these measures, whereas associations between diet soda and metabolic syndrome were not independent of these factors.
Although these observational data cannot establish causality, consumption of diet soda at least daily was associated with significantly greater risks of select incident metabolic syndrome components and type 2 diabetes.
Conflicting findings exist regarding the associations of sex hormones with subclinical atherosclerosis.
This is a substudy from MESA of 881 postmenopausal women and 978 men who had both abdominal aortic calcification (AAC) quantified by computed tomography and sex hormone levels assessed [Testosterone (T), estradiol (E2), dehydroepiandrosterone (DHEA), and sex hormone binding globulin (SHBG)]. We examined the association of sex hormones with presence and extent of AAC.
For women, SHBG was inversely associated with both AAC presence [OR=0.62, 95% CI 0.42 to 0.91 for 1 unit greater log(SHBG) level] and extent [0.29 lower log(AAC) for 1 unit greater log(SHBG) level, β= −0.29 (95% CI −0.57 to −0.006)] adjusting for age, race, hypertension, smoking, diabetes, BMI, physical activity, and other sex hormones. After further adjustment for total and HDL-cholesterol, SHBG was not associated with ACC presence or extent. In men, there was no association between SHBG and AAC. In both men and women, neither T, E2, nor DHEA was associated with AAC presence or extent.
After adjustment for non-lipid cardiovascular risk factors, SHBG levels are inversely associated with both the presence and severity of AAC in women but not in men, which may be accounted for by HDL.
sex hormone binding globulin; abdominal aortic calcification; sex hormones; subclinical atherosclerosis
In dialysis patients, activated vitamin D therapy is associated with reduced mortality. Observational data suggests that low 25-hydroxyl vitamin D levels are associated with diabetes mellitus, hypertension and cancers. However, whether low serum 25-hydroxyl vitamin D (25(OH)D) levels are associated with mortality in the general population is unknown.
We tested the association of low 25(OH)D levels with all-cause, cancer and cardiovascular disease (CVD) mortality in 13,331 nationally representative adults ≥20 years old from the Third National Health and Examination Survey (NHANES III) Linked Mortality Files. Participant vitamin D levels were collected in 1988-1994 and individuals were passively followed for mortality through 2000.
In cross-sectional multivariable analyses, increasing age, female sex, non-white race/ethnicity, diabetes, current smoking, and higher BMI were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D <17.8 ng/ml), while greater physical activity, vitamin D supplementation and non-winter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths including 777 from CVD. In multivariable models (adjusted for baseline demographics, season, traditional and novel CVD risk factors), compared to the highest quartile, 25(OH)D levels <17.8 ng/ml were associated with a 26% increased rate of all-cause mortality (1.26, 95% CI 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk which was not statistically significant.
The lowest quartile of 25(OH)D (<17.8 ng/ml) is independently associated with all-cause mortality in the general population.
To determine the association between 25-hydroxyvitamin D (25(OH)D) levels and the prevalence of peripheral arterial disease (PAD) in the general United States population.
Methods and Results
We analyzed data from 4,839 participants of the National Health and Nutrition Examination Survey 2001–2004 to evaluate the relationship between 25(OH)D and PAD (defined as an ankle-brachial index <0.9). Across quartiles of 25(OH)D, from lowest to highest, the prevalence of PAD was 8.1%, 5.4%, 4.9%, and 3.7% (p-trend<0.001). After multivariable adjustment for demographics, co-morbidities, physical activity level and laboratory measures, the prevalence ratio of PAD for the lowest, compared to the highest, 25(OH)D quartile (<17.8 and ≥29.2 ng/mL, respectively) was 1.80 (95% confidence interval: 1.19, 2.74). For each 10 ng/mL lower 25(OH)D level, the multivariable-adjusted prevalence ratio of PAD was 1.35 (95% confidence interval: 1.15, 1.59).
Low serum 25(OH)D levels are associated with a higher prevalence of PAD. Several mechanisms have been invoked in the literature to support a potential anti-atherosclerotic activity of vitamin D. Prospective cohort and mechanistic studies should be designed to confirm this association.
25-hydroxyvitamin D; peripheral arterial disease; phosphate; PTH; cardiovascular disease
While behavioral change is necessary to reverse the obesity epidemic, it can be difficult to achieve and sustain in unsupportive residential environments. This study hypothesized that environmental resources supporting walking and a healthy diet are associated with reduced obesity incidence. Data came from 4008 adults aged 45–84 at baseline who participated in a neighborhood ancillary study of the Multi-Ethnic Study of Atherosclerosis. Participants were enrolled at 6 study sites at baseline (2000–2002) and neighborhood scales were derived from a supplementary survey that asked community residents to rate availability of healthy foods and walking environments for a one-mile buffer area. Obesity was defined as body mass index (BMI) >=30 kg/m2. Associations between incident obesity and neighborhood exposure were examined using proportional hazards and generalized linear regression. Among 4008 non-obese participants, 406 new obesity cases occurred during 5 years of follow-up. Neighborhood healthy food environment was associated with 10% lower obesity incidence per standard deviation increase neighborhood score. The association persisted after adjustment for baseline BMI and individual level covariates (HR 0.88, 95% CI: 0.79, 0.97), and for correlated features of the walking environment but confidence intervals widened to include the null (HR 0.89, 95% CI: 0.77, 1.03). Associations between neighborhood walking environment and lower obesity were weaker and did not persist after adjustment for correlated neighborhood healthy eating amenities (HR 0.98, 95% CI 0.84, 1.15). Altering the residential environment so that healthier behaviors and lifestyles can be easily chosen may be a pre-condition for sustaining existing healthy behaviors and for adopting new healthy behaviors.
Adult; Health Behavior; Obesity/*epidemiology; Residence Characteristics; Longitudinal Studies; Geographic Information Systems; Environment Design; Public Health; Risk Factors