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1.  Changes in Alcohol Intake and their Relation to Health Status over a 24 Year Follow-up Period in Community-Dwelling Older Adults 
Journal of the American Geriatrics Society  2013;61(8):10.1111/jgs.12366.
To determine whether alcohol use changes over time in older adults, and whether alcohol intake is associated with common chronic diseases.
Longitudinal study spanning 24 years.
Southern California community
1076 members of the Rancho Bernardo cohort, aged 50–89 years at baseline.
Participants completed two to six research visits at approximate four year intervals between 1984 and 2009. At each visit, participants completed standard questionnaires on alcohol use, chronic diseases, and behaviors. Mixed-effects linear models were used to examine changes in average weekly alcohol intake over time and in relation to health status.
Prevalence and frequency of alcohol use was high throughout the study with more than 60% of participants reporting weekly alcohol intake. The average amount consumed declined over time with advancing age, irrespective of the presence of any of the eight most common chronic diseases. Prevalence of drinking in excess of age and sex-specific low risk guidelines was high across all visits and did not vary by disease burden. At the final visit, 29% of participants drank in excess of low risk drinking guidelines; including 28% of those with hypertension and 31% of those with diabetes.
Prevalence and frequency of alcohol intake remained stable over a 24 year follow-up in this cohort of White, educated middle class older adults, although average amount consumed decreased over time with advanced age. Despite this decrease, a high proportion of older adults, including those with common chronic health conditions, drank in excess of current guidelines. Clinicians should provide more education on the importance of moderating alcohol intake in older patients.
PMCID: PMC3819601  PMID: 23865905
aging; alcohol trajectories; drinking; hypertension; diabetes
2.  Sex-Specific Association of Fetuin-A With Type 2 Diabetes in Older Community-Dwelling Adults 
Diabetes Care  2013;36(7):1994-2000.
This study evaluated the sex-specific association of plasma fetuin-A levels with prevalent and incident type 2 diabetes in community-dwelling older adults.
Participants were 684 men and 1,058 women (median age, 71 years) whose fetuin-A levels, diabetes prevalence, and diabetes risk factors were evaluated in 1992–1996. The participants were followed for incident diabetes through 2010 (median follow-up, 9 years).
Women with impaired glucose tolerance had elevated fetuin-A levels compared with women with normal glucose tolerance (P = 0.019), but fetuin-A levels were not elevated in women with impaired fasting glucose. Fetuin-A did not vary by glucose tolerance status in men. There were significant interactions of fetuin-A by sex for prevalent (P = 0.007) and incident (P = 0.020) diabetes. For women, each SD (0.10 g/L) higher fetuin-A level was associated with a higher odds of prevalent diabetes (odds ratio [OR] 1.79, 95% CI 1.47–2.17) and greater risk of incident diabetes (hazard ratio [HR] 1.66, 95% CI 1.18–2.34), adjusting for age and estrogen therapy. These associations were not materially altered by adjustment for diabetes risk factors but were attenuated by adjusting for postchallenge glucose levels. Among men, although positive associations with prevalent (OR 1.15 [0.94–1.41]) and incident (HR 1.24 [0.93–1.65]) diabetes were suggested in age-adjusted models, risk estimates attenuated to one after multivariable adjustment.
Higher fetuin-A concentrations were independently associated with an increased risk of developing type 2 diabetes in older women but were not related to diabetes risk in older men. Fetuin-A may provide novel insights into mechanisms underlying sex differences in glucose homeostasis and diabetes risk in old age.
PMCID: PMC3687317  PMID: 23315604
3.  Reductions in glucose among postmenopausal women who use and do not use estrogen therapy 
Menopause (New York, N.Y.)  2013;20(4):393-400.
Among postmenopausal women who do not use estrogen hormone therapy (HT) we have previously reported that intensive lifestyle intervention (ILS) leads to increases in sex hormone binding globulin (SHBG), and such increases were associated with reductions in fasting plasma glucose (FPG) and 2-hour post-challenge glucose (2HG). Oral HT decreases FPG and increases 2HG, while increasing both SHBG and estradiol (E2). It is unknown if ILS reduces glucose among HT users, if changes in SHBG and E2 might mediate any glucose decreases in HT users, and if these patterns differ from non-HT users.
We conducted a secondary analysis of postmenopausal women in the Diabetes Prevention Program who used HT at baseline and 1 year follow-up (n=324) and who did not use HT at either time point (n=382). Participants were randomized to ILS, metformin, or placebo administered 850 mg twice a day.
HT users were younger, more often white, and more likely to have had bilateral oophorectomy than non-HT users. Among HT 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 to placebo. Associations between SHBG and total E2 with FPG and 2HG were not significant among women randomized to ILS or to metformin. These patterns differed from those observed among women who did not use HT.
We conclude that among glucose intolerant HT users, interventions to reduce glucose are effective but possibly mediated through different pathways than among women who did not use HT.
PMCID: PMC3582709  PMID: 23168523
menopause; estrogen; progestogen; hormone therapy; glucose
4.  Associations of pericardial and intra-thoracic fat with coronary calcium presence and progression in a multi-ethnic study 
Obesity (Silver Spring, Md.)  2013;21(8):1704-1712.
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, we examined the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC). 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 four years apart from which CAC presence, severity and progression, as well as pericardial and intra-thoracic 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. 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 intra-thoracic fat were associated with CAC progression. Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. We did, however, demonstrate a significant association between intra-thoracic fat and both the presence and severity of CAC. Studies measuring fat in the thoracic cavity may consider defining intra-thoracic fat as a separate entity from pericardial fat.
PMCID: PMC3748173  PMID: 23666866
5.  Kidney Function and Progression of Coronary Artery Calcium in Community-Dwelling Older Adults (From the Rancho Bernardo Study) 
The American journal of cardiology  2012;110(10):1425-1433.
Longitudinal studies of the association of estimated glomerular filtration rate (eGFR) and albuminuria with coronary artery calcium, a measure of cardiovascular disease (CVD) burden, are few and contradictory. In this study, 421 community-dwelling men and women (mean age 67 years) without known heart disease had eGFR estimated by the Modification of Diet in Renal Disease equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) between 1997–1999. Mean eGFR was 78 mL/min/1.73m2, median ACR was 10 mg/g. Coronary artery calcium (CAC) was measured by electron beam computed tomography between 2000–2001 when median total Agatston CAC score was 77; 4.5 years later 338 participants still without heart disease had a repeat scan (median CAC score 112); 46% of participants showed CAC progression, defined as an increase ≥2.5 mm3 in square-root transformed CAC volume score. Cross-sectional and longitudinal logistic regression analyses showed no separate or joint association between eGFR or ACR with 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 CVD with initial or sequential scanning for CAC. In the elderly, kidney function and CAC may not progress together.
PMCID: PMC3483450  PMID: 22883164
albuminuria; chronic kidney disease; coronary artery calcium; coronary heart disease; elderly; glomerular filtration rate
6.  Relationships Between Serum and Urine Phosphorus with All-Cause and Cardiovascular Mortality: the Osteoporotic Fractures in Men (MrOS) Study 
Serum phosphorus is associated with cardiovascular disease (CVD) in the general population but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus/creatinine ratio (UPi/UCr, a marker of intestinal absorption) or urine fractional excretion of phosphorus (FePi, a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain.
Study Design
Prospective observational study.
Setting and Participants
1,325 community-dwelling men aged ≥65 years.
Serum phosphorus, UPi/UCr, and FePi.
All-cause and CVD death.
Mean age was 74±6 years, eGFR was 75±16 ml/min/1.73m2, and serum phosphorus was 3.2±0.4 mg/dL. During 9.3 years median follow-up, there were 364 deaths (120 CVD deaths). After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), UPi/UCr, and FePi were 1.63 (95% CI 1.23-2.17), 1.22 (95% CI 0.90-1.65), and 0.88 (95% CI 0.64-1.23), respectively. Results were similar for CVD death. Results were also similar irrespective of eGFR above or below 60 ml/min/1.73m2.
Older, all male cohort. Few had advanced CKD. Specimens were collected in the morning after an overnight fast.
In community-living older men, higher serum phosphorus is associated with all-cause and CVD death. In contrast, UPi/UCr and FePi were not. These findings do not support using UPi/UCr or FePi as adjuvant measures to predict risk of mortality or CVD in the general population.
PMCID: PMC3815620  PMID: 23261120
Phosphorus; urine phosphorus; mortality; cardiovascular disease; kidney disease; geriatrics
7.  Sex Hormones and Serum Phosphorus in Older Men: The Osteoporotic Fractures in Men (MrOs) Study 
Kidney international  2010;78(4):415-422.
Older women have higher phosphorus levels than men. Estradiol causes phosphaturia in rodents. Whether sex hormones associate with phosphorus levels in humans is unknown. In 1,346 community-living older men, we evaluate the cross-sectional association of sex hormones with serum phosphorus, using linear regression with serum phosphorus levels as the dependent variable. Mean age was 76 years, phosphorus was 3.2±0.4mg/dl, and 18% had moderate kidney disease. Each 10pg/ml higher total estradiol associated with 0.05mg/dL lower serum phosphorus levels (95 % CI −0.09 to −0.02; P < 0.01) in a model adjusted for age, race, testosterone, sex hormone binding globulin, calcium, eGFR, intact PTH, 25(OH) vitamin D, body mineral density, and alkaline phosphatase. Results were similar in individuals with or without CKD. Serum testosterone levels were also associated with lower serum phosphorus levels (β per 200ng/dL greater total testosterone = −0.08; 95% CI −0.13 to −0.04; P < 0.001). Results were confirmed in an independent sample of 2,555 older men, and associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Estradiol may induce phosphaturia in humans. Future studies are required to elucidate potential effects of testosterone on phosphorus homeostasis.
PMCID: PMC3787687  PMID: 20531458
Phosphorus; estradiol; testosterone; menopause; sex hormones; kidney disease; cardiovascular disease
8.  Extremes of an Aromatase Index Predict Increased 25-year Risk of Cardiovascular Mortality in Older Women 
Clinical endocrinology  2012;77(3):391-398.
Peripheral conversion of androgens to estrogens via aromatase is the primary source of estrogen in postmenopausal women and may play a role in cardiovascular health.
Participants, Measurements
The association of an index of aromatase activity (AROM), the serum estrone to androstenedione ratio, with 25 year cardiovascular (CVD) mortality was examined in 819 postmenopausal non-estrogen using women (mean age at baseline=72).
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 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 to 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=.001) such that high AROM was associated with a 63% reduction in risk of CVD death for women with low BMI (<22 kg/m2), but with 2.1 to 2.5-fold increased risk in women with mid-range (22–<25 kg/m2) and high (≥25 kg/m2) BMI. Estradiol did not influence AROM associations and was not independently related to CVD death.
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.
PMCID: PMC3298636  PMID: 22066939
cardiovascular mortality; aromatase; women; epidemiology; aging
9.  Metabolic Syndrome and 16-year Cognitive Decline in Community-Dwelling Older Adults 
Annals of Epidemiology  2012;22(5):310-317.
To determine whether metabolic syndrome is associated with accelerated cognitive decline in community-dwelling older adults.
Longitudinal study of 993 adults (mean 66.8 ± 8.7 years) from the Rancho Bernardo Study. Metabolic syndrome components, defined by 2001 NCEP-ATP III criteria, were measured in 1984–87. Cognitive function was first assessed in 1988–92. Cognitive assessments were repeated approximately every four years, for a maximum 16-year follow-up. Mixed-effects models examined longitudinal rate of cognitive decline by metabolic syndrome status, controlling for factors plausibly associated with cognitive function (diabetes, inflammation).
Metabolic syndrome was more common in men than women (14% vs. 9%, p=0.01). In women, metabolic syndrome was associated with greater executive function and long term memory decline. These associations did not differ by inflammatory biomarker levels. Diabetes did not alter the association of metabolic syndrome with long-term recall but modified the association with executive function: metabolic syndrome was associated with accelerated executive function decline in diabetic women only. Metabolic syndrome was not related to rate of decline on any cognitive measure in men.
Metabolic syndrome was a risk factor for accelerated cognitive decline, but only in women. Prevention of metabolic syndrome may aid in maintenance of cognitive function with age.
PMCID: PMC3338905  PMID: 22285865
Aging; cognition; inflammation; diabetes; memory; executive function
10.  Plasma NGAL is Independently Associated with Cardiovascular Disease and Mortality in Community-Dwelling Older Adults: The Rancho Bernardo Study 
To determine the association between neutrophil gelatinase-associated lipocalin (NGAL) levels and cardiovascular and all-cause mortality in community-dwelling older adults.
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.
We measured plasma NGAL levels in 1393 Rancho Bernardo Study participants without CVD, mean age 70. Participants were followed for a mean of 11 years.
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 (HR per SD log increase: 1.33, 95% CI[1.12–1.57]), all-cause mortality (HR 1.19[1.07–1.32]), and a combined cardiovascular endpoint(HR 1.26[1.10–1.45]). After further adjusting for NT-proBNP and 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 (NRI>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 vs. those with only NT-proBNP elevated (HR 1.43[1.12–1.82]).
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.
PMCID: PMC3312791  PMID: 22421304
Cardiovascular disease; biomarkers; elderly; natriuretic peptides; risk factors
11.  The Associations of Fetuin-A with Subclinical Cardiovascular Disease in Community-Dwelling Persons: the Rancho Bernardo Study 
To determine the association of fetuin-A with subclinical CVD in community-living individuals.
Fetuin-A is a hepatic secretory protein that inhibits arterial calcium deposition in vitro. Lower fetuin-A levels are associated with arterial calcification and death in end-stage renal disease populations. The association of fetuin-A with subclinical cardiovascular disease (CVD) in the general population is unknown.
Among 1,375 community-living individuals without prevalent clinical CVD, we measured plasma fetuin-A concentrations measured by ELISA. Peripheral arterial disease (PAD) was defined by ankle brachial index (ABI) < 0.90, coronary artery calcification (CAC) was measured by computed tomography, and common and internal intima media thickness (cIMT) were measured by carotid ultrasound. PAD was measured concurrent with fetuin-A, and CAC and cIMT was measured 4.6 years (mean) later.
Mean age was 70 ± 11 years and 64% were female. Fetuin-A levels were inversely associated with CAC severity. When evaluated as CAC categories (0, 1–100, 101–300, > 300) using ordinal logistic regression, each standard deviation higher fetuin-A was associated with a 31% lower odds of CAC severity (proportional odds ratio [POR] 0.69; 95% confidence interval [CI] 0.46, 0.92; p=0.008) in models adjusted for demographics, lifestyle factors, traditional CVD risk factors and kidney function. In contrast, no association of fetuin-A was observed with PAD or high common or internal cIMT in adjusted models.
Lower fetuin-A levels are independently associated with greater CAC severity, but not PAD or cIMT. If confirmed, fetuin-A may mark calcium deposition within the vasculature, but not atherosclerosis per se.
PMCID: PMC3224791  PMID: 22115642
Fetuin-A; Cardiovascular Disease; Coronary Artery Calcification
12.  Relation of Sex and Estrogen Therapy to Serum Fibroblast Growth Factor 23, Serum Phosphorus, and Urine Phosphorus: The Heart and Soul Study 
M[ND1]enopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown.
Study Design & Setting
Cross-sectional study among ambulatory individuals with prevalent cardiovascular disease.
Sex, and among women, use or non-use of estrogen.
Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to GFR (TMP/GFR), and plasma FGF-23 concentrations.
Among 987 participants, the mean age was 67 ± 11 years, 182 (18%) were female; 46 (25%) were taking estrogen. The mean eGFR was 71 ± 23 (SD) ml/min/1.73m2. Compared to women who were not taking estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 in RU/ml were 68.7 (95% CI, 59.7–79.0) in non estrogen using women, 43.8 (95% CI, 41.2–46.5) in men, and 45.1 (95% CI, 35.2–57.4) in women using estrogen in adjusted analysis (P< 0.001).
The majority of participants were men. Estrogen therapy was not randomly assigned.
Older women who are not taking estrogen have higher FGF-23 levels than either men or women taking estrogen. In the context of prior literature, these data suggest that post-menopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause.
PMCID: PMC3199317  PMID: 21855188
Menopause; fibroblast growth factor-23; phosphorus; estradiol; sex hormones
13.  Sex Differences in the Association of Framingham Cardiac Risk Score with Cognitive Decline in Community-Dwelling Elders without Clinical Heart Disease 
Psychosomatic medicine  2011;73(8):683-689.
To investigate a possible link between cardiovascular risk factors and age-related cognitive decline, the association of the 1998 Framingham Cardiac Risk Score (FCRS) with the trajectory of cognitive function test (CFT) performance over 18 years was examined in adults 50 years and older without clinical heart disease at baseline.
Participants were 985 men and women who had assessments of cognitive function at three to four year intervals. The association of FCRS category with CFT score trajectory was examined using mixed effect models stratified by sex and controlling for age, education, and number of repeat cognitive assessments.
At baseline, median FCRS corresponded to a 14% risk of a CHD event within 10 years for men and a 8% risk for women; 31% of men and 6% of women were at high (>20%) risk. In longitudinal analyses, women with FCRS risk >7% had a higher rate of decline on tests of verbal fluency (p’s <.05) and long term recall (p’s <.01) compared to low risk women; modest, but significant (p’s <.05), differences in the trajectory of MMSE and Trails B scores were also apparent. FCRS category was not related to the rate of decline in CFT performance in men.
For older women, very low levels of CHD risk were associated with preservation of cognitive function over 10 years, suggesting that maintenance of cardiovascular health may slow cognitive decline. The minimal association in men, who were at higher baseline risk, may be due to selective attrition of men with greater cognitive decline.
PMCID: PMC3188670  PMID: 21949428
aging; cardiovascular; cognitive function; prospective
14.  Elevated NT-proBNP Levels are Associated with Poor Cognitive Function in Community-Dwelling Older Adults: Results from the Rancho Bernardo Study 
The American journal of medicine  2011;124(7):670.e1-670.e8.
Natriuretic peptides (NP’s) have prognostic value across a wide spectrum of cardiovascular diseases and may predict cognitive dysfunction in patients with cardiovascular disease even in the absence of prior stroke. Little is known about the association of NP’s with cognitive function in community-dwelling adults. We assessed the association between NT-proBNP levels and cognitive function in community-dwelling ambulatory older adults in the Rancho Bernardo Study.
We studied 950 men and women, aged 60 years and older, who attended a research clinic visit where a medical history and examination were performed, and blood for cardiovascular disease risk factors and NT-proBNP levels were obtained. Three cognitive function tests were administered: Mini Mental State Exam (MMSE), Trail-Making Test B (Trails B), and Category Fluency.
Participants with high NT-proBNP levels (≥450 pg/mL, n=198) were older and had a higher prevalence of coronary heart disease (12% vs. 30%), and stroke (5% vs. 11%) (both p’s≤0.001). In unadjusted analyses, all three cognitive function test scores were significantly associated with NT-proBNP levels (p<0.001). After adjusting for age, sex, education, hypertension, body mass index, exercise, alcohol use, smoking, low density lipoprotein cholesterol, creatinine clearance, and prior cardiovascular disease, elevated NT-proBNP levels remained independently associated with poor cognitive performance on MMSE (odds ratio [95% confidence interval] 2.0 [1.1–3.6], p=0.02) and Trails B (1.7 [1.2–2.7], p=0.01), but not Category Fluency (1.4 [0.9–2.2], p=0.19). Results were unchanged after excluding the 6% of participants with a history of stroke.
NT-proBNP levels were strongly and independently associated with poor cognitive function in community-dwelling older adults.
PMCID: PMC3173742  PMID: 21683832
natriuretic peptides; cerebrovascular disorders; cardiovascular diseases; community; elderly; cognitive function
15.  Growth-Differentiation Factor-15 is a Robust, Independent Predictor of 11-Year Mortality Risk in Community-Dwelling Older Adults: The Rancho Bernardo Study 
Circulation  2011;123(19):2101-2110.
Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic marker in patients with cardiovascular disease (CVD), but its prognostic value in community-dwelling adults has not been reported. We hypothesized that GDF-15 would add incremental power for prediction of mortality in a population of community-dwelling older adults without known heart disease.
Methods and Results
We measured plasma GDF-15, NT-proBNP, and CRP levels in 1391 Rancho Bernardo Study participants, mean age 70, with no history of CVD, and followed them for a mean of 11 years. In models adjusted for traditional CVD risk factors, GDF-15 was a robust predictor of all-cause, cardiovascular, and non-cardiovascular mortality. GDF-15 was a stronger predictor of all-cause mortality than either NT-proBNP or C-reactive protein (hazard ratio [HR] [95% confidence interval] per standard deviation log10 units 1.5 [1.3–1.8], p<0.0001 for GDF-15, versus 1.3 [1.2–1.5], p<0.0001 for NT-proBNP; CRP was not a significant predictor). Among biomarkers considered, only GDF-15 predicted non-cardiovascular death (HR 1.6 [1.4–2.0], p<0.0001). Growth differentiation factor-15 improved discrimination and modestly but significantly improved reclassification for all-cause, and noncardiovascular mortality with borderline improvement for cardiovascular mortality; NT-proBNP significantly improved reclassification for all-cause and for cardiovascular mortality; C-reactive protein did not improve reclassification for any end point tested. Participants in the highest quartile of both GDF-15 and NT-proBNP had an increased risk of death compared to participants with only NT-proBNP elevated (HR 1.5 [1.1–2.0], p=0.01).
GDF-15 is a strong predictor of all-cause, cardiovascular, and non-cardiovascular mortality in community-dwelling older individuals, adding incremental value to traditional risk factors and to NT-proBNP and CRP levels.
PMCID: PMC3107013  PMID: 21536998
Biomarker; elderly; GDF-15; cardiovascular disease; natriuretic peptides
16.  Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes 
We examined if the reduced risk of breast cancer events seen among women without baseline hot flash symptoms in the Women’s Healthy Eating and Living (WHEL) dietary intervention trial was related to changes in sex hormone concentrations.
Baseline and year one concentrations of total and bioavailable estradiol and testosterone and sex hormone binding globulin (SHBG) were compared by intervention arm among 447 postmenopausal women without hot flashes. Cox proportional hazard models tested interaction terms between study arm and baseline hormone concentrations adjusted for study site, anti-estrogen use, positive nodes, tumor size, oophorectomy status, and hormone replacement therapy use.
Sex hormone concentrations did not differ by study arm at baseline nor at year one. Twenty-two (9.8%) events occurred in the intervention arm vs. 42 (18.9%) in the comparison arm (p=0.009). Baseline bioavailable testosterone was significantly, positively associated with additional events (HR 1.69, 95% CI: 1.00-2.84; p=0.049). There were significant interactions between the intervention and total (p=0.015) and bioavailable (p=0.050) testosterone: the intervention was more protective among participants with higher baseline total (HR 0.3, 95% CI: 0.2-0.7) or bioavailable (HR 0.4, 95%CI: 0.2-0.7) testosterone than for participants with lower baseline total (HR 0.8, 95% CI: 0.4-1.5) or bioavailable (HR 0.8, 95%CI: 0.4-1.5) testosterone. No significant effects were seen for estradiol or SHBG.
The WHEL dietary intervention may have modified other risk factors of recurrence correlated with testosterone.
Sex hormones should be considered as part of a larger biological system related to the risk of breast cancer recurrence.
PMCID: PMC3089679  PMID: 21415358
Postmenopausal; hot flashes; sex hormones; breast cancer
17.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
18.  Abdominal Aortic Diameter and Vascular Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population.
Cross-sectional cohort
A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation.
In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized β=0.97), male sex (β=1.88), body surface area (standardized β=0.92), current smoking (β=0.42), D-dimer levels (β=0.19) and hypertension (β=0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (β=-0.70) (P<.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (β's= -0.59, -0.49, and -0.52, respectively, all P<.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (β=0.11 to 0.19), associated with larger AD.
Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.
PMCID: PMC3070051  PMID: 21236707
aorta; aneurysm; atherosclerosis; ethnicity; epidemiology
19.  Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2010;29(1):54-60.
Self-reported diabetes has been associated with poor breast cancer outcomes. Research is needed to investigate the relationship between biologically determined glycemic control and breast cancer prognosis.
Archived baseline blood samples from the Women's Healthy Eating and Living Study were used to measure hemoglobin A1C (HbA1C) among 3,003 survivors of early-stage breast cancer (age of diagnosis, 28 to 70 years) observed for a median of 7.3 years for additional breast cancer events and 10.3 years for all-cause mortality. HbA1C levels provide an accurate, precise measure of chronic glycemic levels. Cox regression analysis was performed to assess whether baseline HbA1C levels predicted disease-free and overall survival.
Only 5.8% of women had chronic hyperglycemia (defined as HbA1C levels ≥ 6.5%). Those with HbA1C ≥ 6.5% were older and more likely to be less educated, have nonwhite ethnicity, be obese, and have more advanced breast cancer at diagnosis. HbA1C was significantly associated with overall survival (Ptrend < .001). After adjusting for confounders, risk of all-cause mortality was twice as high in women with HbA1C ≥ 7.0% compared with women with HbA1C less than 6.5% (hazard ratio [HR], 2.35; 95% CI, 1.56 to 3.54). For disease-free survival, there was a nonsignificant 30% increase in risk for HbA1C levels ≥ 7.0% (HR, 1.26; 95% CI, 0.78 to 2.02). During study follow-up, previously diagnosed rather than undiagnosed diabetes seemed to account for the increased risk.
Chronic hyperglycemia is statistically significantly associated with reduced overall survival in survivors of early-stage breast cancer. Further study of diabetes and its relationship to breast cancer outcomes is warranted.
PMCID: PMC3055860  PMID: 21115861
20.  Medical Comorbidities Predict Mortality in Women with a History of Early Stage Breast Cancer 
This analysis was conducted to determine whether comorbid medical conditions predict additional breast cancer events and all-cause mortality in women with a history of early stage breast cancer.
Women (n=2542) participating in a randomized diet trial completed a selfadministered questionnaire regarding whether they were currently being treated for a wide variety of diseases (cardiovascular, diabetes, gallbladder, gastrointestinal, arthritis, and osteoporosis) and conditions (high blood pressure, elevated cholesterol level). Height and weight were measured at baseline. Participants were followed for a median of 7.3 years (range 0.8 to 15.0). Cox regression analysis was performed to assess whether comorbidities predicted disease-free and overall survival; hazard ratio (HR) was the measure of association.
Overall, there were 406 additional breast cancer events and 242 deaths. Participants with diabetes had over 2-fold the risk of additional breast cancer events (HR 2.1, 95% CI: 1.3, 3.4) and mortality (HR 2.5, 95% CI: 1.4, 4.4). The presence of multiple comorbidities did not statistically significantly predict additional breast cancer events. However, compared to no comorbidities, participants with 3 or more comorbidities had a HR of 2.1, 95% CI: 1.3, 3.3 for mortality.
Type 2 diabetes was associated with poor breast cancer prognosis. Given that 85 percent of deaths were caused by breast cancer, these findings suggest that multiple comorbidities may reduce the likelihood of surviving additional breast cancer events.
PMCID: PMC2895945  PMID: 20077000
comorbidities; breast cancer; mortality
21.  Lipoprotein-Associated Phospholipase A2 Is an Independent Predictor of Incident Coronary Heart Disease in an Apparently Healthy Older Population 
Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident coronary heart disease (CHD) in adults without known CHD, independent of heart disease risk factors. We examined whether the independent association was apparent in older adults.
Serum levels of Lp-PLA2, an enzyme that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles, have been associated with CHD and may help predict cardiovascular risk.
Participants were 1,077 community-dwelling men and women, median age 72 years, who had no known CHD at baseline (1984 to 1987) when blood samples and risk factor data were collected. Participants were followed for CHD events for a mean of 16 years, through 2002. Cox proportional hazards regression models were used to examine the association of serum Lp-PLA2 with incident CHD (myocardial infarction, angina, or coronary revascularization).
The Lp-PLA2 levels positively correlated with age (r = 0.09), body mass index (r = 0.11), low-density lipoprotein (r = 0.37), triglycerides (r = 0.25), and C-reactive protein (r = 0.10), and negatively correlated with high-density lipoprotein (r = −0.27) (all p < 0.05). During follow-up, 228 participants had incident CHD events. Lipoprotein-associated phospholipase A2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD compared with the lowest quartile (hazard ratios 1.66, 1.80, and 1.89, respectively; p < 0.05 for each). This association persisted after adjusting for C-reactive protein and other CHD risk factors.
Elevated Lp-PLA2 levels predict CHD events in apparently healthy older adults, independent of CHD risk factors.
PMCID: PMC3096479  PMID: 18308160
22.  Higher Endogenous Estrogens Predict Four Year Decline in Verbal Fluency in Postmenopausal Women: The Rancho Bernardo Study 
Clinical endocrinology  2009;72(1):99-106.
Despite overwhelming biological plausibility, evidence for a protective effect of estrogen on cognitive function in postmenopausal women is inconsistent. This study examines the association between endogenous estrogen levels and subsequent four-year decline in cognitive function test performance in community-dwelling older women.
Longitudinal cohort study
343 postmenopausal women (median age 70 yrs)
Between 1984 and 1987, serum for measurement of sex hormones was obtained along with relevant covariates. Cognitive function was assessed in 1988–91 and again in 1992–96 using the Category Fluency test, the Mini-Mental Status Exam (MMSE) and Trail Making Test B (Trails B).
Women in the highest tertile of estrone and bioavailable estradiol had, respectively, 1.75 (95% CI 1.02, 3.07) and 1.79 (95% CI 1.04, 3.10) higher odds of 4 year decline in Category Fluency, a test of frontal lobe function, compared to those in the lowest tertile, independent of age and education. The 20% of women with highest tertile levels of both estrone and bioavailable estradiol had a two-fold higher odds of verbal fluency loss (OR=2.17; 95% CI 1.21, 3.89) Adjustment for testosterone levels or for obesity-related factors associated with high endogenous estrogens (higher BMI, waist girth, and triglycerides, and lower HDL cholesterol) did not alter results. Neither estrogen was associated with change in MMSE or Trails B scores.
Higher endogenous estrogen levels were associated with greater decline in verbal fluency in postmenopausal women. This association was not explained by elevated androgens or by obesity or obesity-related factors.
PMCID: PMC2805055  PMID: 19508596
estrogen; cognitive function; aging; postmenopausal women
24.  Dietary Pattern Influences Breast Cancer Prognosis in Women Without Hot Flashes: The Women's Healthy Eating and Living Trial 
Journal of Clinical Oncology  2009;27(3):352-359.
To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment.
Patients and Methods
A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines.
Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002).
A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.
PMCID: PMC2645853  PMID: 19075284
25.  Blood Pressure and Fasting Plasma Glucose Rather Than Metabolic Syndrome Predict Coronary Artery Calcium Progression 
Diabetes Care  2009;32(1):141-146.
OBJECTIVE—To examine the association of the metabolic syndrome, defined by World Health Organization (WHO) and Adult Treatment Panel III (ATP-III) criteria, and its components with coronary artery calcium (CAC) progression.
RESEARCH DESIGN AND METHODS—Participants were 338 older community-dwelling men and women without known heart disease who had measurements of heart disease risk factors and CAC at two clinic visits within an average interval of 4.5 years. Progression was defined as an increase in total CAC volume score ≥2.5 mm3.
RESULTS—At baseline, mean age was 67.6 years; metabolic syndrome was present in 15.1% by WHO criteria and in 11.8% by ATP-III criteria, and 5.3% met both criteria. Participants with WHO-defined metabolic syndrome had a greater change in total CAC volume score than those without (P = 0.001). There was no significant difference in CAC volume change by ATP-III–defined metabolic syndrome status (P = 0.69). Overall, 46.4% of participants were CAC progressors. In logistic regression analyses adjusted for age, sex, smoking status, and LDL cholesterol, neither WHO–nor ATP-III–defined metabolic syndrome predicted CAC progression. Among metabolic syndrome components, only hypertension was independently associated with CAC progression (odds ratio 2.11 [95% CI 1.33–3.3], P = 0.002). Fasting blood glucose (>100 mg/dl) was an independent predictor of CAC progression, but only for the 118 participants younger than age 65 years (2.3 [1.01–5.5], P = 0.04).
CONCLUSIONS—In older adults without known heart disease, blood pressure levels and fasting plasma glucose were better independent determinants of CAC progression than metabolic syndrome itself.
PMCID: PMC2606850  PMID: 18852333

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