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1.  Circulating and Dietary Trans Fatty Acids and Incident Type 2 Diabetes in Older Adults: The Cardiovascular Health Study 
Diabetes Care  2015;38(6):1099-1107.
To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.
In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 ± 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.
In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95% CI 1.04–2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20–3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03–1.86], P-trend = 0.02), t-18:1 (1.32 [1.00–1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05–1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.
Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.
PMCID: PMC4439533  PMID: 25784660
2.  Urinary uromodulin, kidney function and cardiovascular disease in elderly adults 
Kidney international  2015;88(5):1126-1134.
Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end stage renal disease (ESRD), and in a random sub-cohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/mL. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each standard deviation higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77, (95% CI 0.62, 0.96)) and a 10% lower risk of mortality (hazard ratio 0.90, (95% CI 0.83, 0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.
PMCID: PMC4653069  PMID: 26154925
uromodulin; tamm-horsfall protein; chronic kidney disease; cardiovascular disease; urinary biomarkers
3.  Potassium and Glucose Measures in Older Adults: The Cardiovascular Health Study 
We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.
Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.
Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of −0.18 (−0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of −0.61 (−0.94, −0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.
Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.
PMCID: PMC4366599  PMID: 24895271
Potassium; Glucose metabolism; Older adults.
4.  Testosterone and Dihydrotestosterone and Incident Ischemic Stroke in Men in the Cardiovascular Health Study 
Clinical endocrinology  2014;81(5):746-753.
Ischemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine if testosterone (T) or dihydrotestosterone (DHT) were associated with incident ischemic stroke in elderly men.
Cohort study
Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease, or prostate cancer as of 1994 and were followed until December 2010.
Adjudicated ischemic stroke
Among 1032 men (mean age 76, range 66-97), followed for a median of 10 years, 114 had an incident ischemic stroke. Total T and free T were not significantly associated with stroke risk while DHT had a nonlinear association with incident stroke (p=.006) in analyses adjusted for stroke risk factors. The lowest risk for stroke was at DHT levels of 50-75 ng/dL, with greater risk for stroke at DHT levels above 75 ng/dl or below 50ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischemic stroke with HR 0.77 (95% CI, 0.61, 0.98) per standard deviation in analyses adjusted for stroke risk factors.
DHT had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify if there is an optimal androgen range associated with the least risk for adverse outcomes in elderly men.
PMCID: PMC4169352  PMID: 24645738
androgens; testosterone; dihydrotestosterone; stroke; cohort
5.  Plasma Free Fatty Acids and Risk of Stroke in the Cardiovascular Health Study 
While free fatty acids (FFA) have been positively associated with risk factors for stroke, the role of plasma FFA in the development of stroke has not been elucidated in older adults.
We sought to examine the association between plasma FFA and incident stroke.
Prospective cohort of 4,369 men and women ≥65 years of age in the Cardiovascular Health Study. Plasma levels of FFA were measured at the 1992–93 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with FFA concentrations.
The average age among participants was 75 ± 5.2 years. During a median follow-up of 11.4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14.5, 14.9, and 17.6 per 1,000 person-years across increasing tertiles of plasma FFA. The adjusted hazard ratio (95% CI) for incident stroke was 1.05 (0.97–1.14) per standard deviation (SD) increase in plasma FFA. Restriction to ischemic stroke did not alter the results [hazard ratio (95% CI): 1.04 (0.96–1.14) per SD higher FFA] and there was no effect modification by adiposity (p interaction = 0.18) or by diabetes (p interaction = 0.15).
Our data did not show an association of plasma FFA with incident stroke among community dwelling older adults.
PMCID: PMC4105335  PMID: 24447493
6.  Plasma Free Fatty Acids, Fatty Acid-binding Protein 4, and Mortality in Older Adults (From the Cardiovascular Health Study) 
The American journal of cardiology  2014;114(6):843-848.
Plasma free fatty acids (FFA) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992–1993 as part of the Cardiovascular Health Study, an observational cohort of community dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio (HR) per standard deviation (SD): 1.14, 95% confidence interval (CI) 1.09–1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98–1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death due to cardiovascular disease, dementia, infection, and respiratory causes, but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p=0.45), but FABP4 appeared to be associated with total mortality differentially among men and women (HR 1.17 (1.08–1.26) for men, HR 1.02 (0.96–1.07) for women, interaction p-value <0.001). In conclusion, in a cohort of community-dwelling older individuals, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and non-cardiovascular mortality.
PMCID: PMC4162821  PMID: 25073566
Fatty acids; Mortality; Epidemiology
7.  Fibrosis-Related Biomarkers and Incident Cardiovascular Disease in Older Adults: The Cardiovascular Health Study 
Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.
Methods and Results
We determined the associations of two biomarkers of fibrosis, transforming growth factor- β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction (MI), and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1,371) and PIIINP (n=2,568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β’s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein (CRP) in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per standard deviation [SD]=1.07, 95% confidence interval [CI]: 1.01-1.14) and heart failure (HR per SD=1.08, CI: 1.01-1.16), but not MI or stroke. TGF-β was not associated with any CVD outcomes in the full cohort, but was associated with total CVD (HR per SD=1.16, CI: 1.02-1.31), heart failure (HR per SD=1.16, CI: 1.01-1.34), and stroke (HR per SD=1.20, CI: 1.01-1.42) among individuals with CRP above the median, 2.3 mg/L (P-interaction < 0.05).
Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.
PMCID: PMC4140969  PMID: 24963008
collagen; cardiovascular disease; heart failure; epidemiology
8.  Fibrosis-Related Biomarkers and Risk of Total and Cause-Specific Mortality 
American Journal of Epidemiology  2014;179(11):1331-1339.
Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996–2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.
PMCID: PMC4036218  PMID: 24771724
biomarkers; fibrosis; inflammation; mortality
9.  The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults 
It is unknown whether sex differences in the association of diabetes with cardiovascular outcomes vary by race. We examined sex differences in the associations of diabetes with incident congestive heart failure (CHF) and coronary heart disease (CHD) between older black and white adults.
We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort study of community-dwelling individuals aged ≥65 from four U.S. counties. We included 4817 participants (476 black women, 279 black men, 2447 white women and 1625 white men). We estimated event rates and multivariate-adjusted hazard ratios for incident CHF, CHD, and all-cause mortality by Cox regression and competing risk analyses.
Over a median follow-up of 12.5 years, diabetes was more strongly associated with CHF among black women (HR, 2.42 [95%CI, 1.70-3.40]) than black men (1.39 [0.83-2.34]); this finding did not reach statistical significance (P for interaction 0.08). Female sex conferred a higher risk for a composite outcome of CHF and CHD among black participants (2.44[1.82-3.26]) vs. (1.44[0.97-2.12]), P for interaction 0.03). There were no significant sex differences in the HRs associated with diabetes for CHF among whites, or for CHD or all-cause mortality among blacks or whites. The three-way interaction between sex, race, and diabetes on risk of cardiovascular outcomes was not significant (P = 0.07).
Overall, sex did not modify the cardiovascular risk associated with diabetes among older black or white adults. However, our results suggest that a possible sex interaction among older blacks merits further study.
PMCID: PMC4004690  PMID: 24461547
diabetes mellitus; sex-specific; ethnicity; African-American; epidemiology
10.  Common FABP4 Genetic Variants and Plasma Levels of Fatty Acid Binding Protein 4 in Older Adults 
Lipids  2013;48(11):10.1007/s11745-013-3838-7.
We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3′untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.
PMCID: PMC3883501  PMID: 24043587
Fatty acid binding proteins; Metabolism; Genetics
11.  Circulating 25-hydroxyvitamin D and insulin resistance in older adults: The Cardiovascular Health Study 
Metabolism: clinical and experimental  2013;62(12):1788-1794.
Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.
To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.
Methods and Results
Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992–1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996–1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95%CI (−0.17, −0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.
Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.
PMCID: PMC4159161  PMID: 23987236
Vitamin D; 25(OH)D; insulin resistance
12.  Adiposity and Cognitive Decline in the Cardiovascular Health Study 
Neuroepidemiology  2013;40(4):274-281.
Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis (BIA), body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.
Cognitive performance was assessed with the modified Mini Mental State Examination (3MS), the Digit Symbol Substitution Test (DSST), and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.
The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.
Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by pre-existing conditions.
PMCID: PMC4044822  PMID: 23445925
adiposity; fat mass; bioelectrical impedance; body mass index; waist circumference; cognition
13.  Ginkgo biloba and risk of cancer: Secondary Analysis of the Ginkgo Evaluation of Memory (GEM) Study 
Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.
A total of 3,069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.
During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.87–1.36; p=0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95% CI, 0.97–4.80; p=0.06) and colorectal (HR, 1.62; 95% CI, 0.92–2.87; p=0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95% CI, 0.43–1.17; p=0.18).
Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.
PMCID: PMC2917376  PMID: 20582906
Ginkgo biloba; randomized controlled trial; breast cancer; prostate cancer; complimentary and alternative medicine
14.  Association Between Adiposity in Midlife and Older Age and Risk of Diabetes in Older Adults 
Adiposity is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, but the relationship between body composition and type 2 diabetes is not well described among older adults.
To examine the relationship between adiposity, changes in adiposity, and risk of incident type 2 diabetes in adults 65 years of age and older.
Design, Setting, and Participants
Prospective cohort study (1989-2007) of 4193 men and women 65 years of age and older in the Cardiovascular Health Study. Measures of adiposity were derived from anthropometry and bioelectrical impedance data at baseline and anthropometry repeated 3 years later.
Main Outcome Measure
Incident diabetes was ascertained based on use of antidiabetic medication or a fasting glucose level of 126 mg/dL or greater.
Over median follow-up of 12.4 years (range, 0.9-17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person-years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9-6.5) for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), 3.0 (95% CI, 2.0-4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8-6.4) for weight, 4.0 (95% CI, 2.6-6.0) for fat mass, 4.2 (95% CI, 2.8-6.2) for waist circumference, 2.4 (95% CI, 1.6-3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6-5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (±2 kg), those who gained the most weight from 50 years of age to baseline (≥9 kg), and from baseline to the third follow-up visit (≥6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9-4.3) and 2.0 (95% CI, 1.1-3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1-2.8) compared with those who gained or lost 2 cm or less.
Among older adults, overall and central adiposity, and weight gain during middle age and after the age of 65 years are associated with risk of diabetes.
PMCID: PMC3047456  PMID: 20571017
15.  Insulin Resistance and Risk of Incident Heart Failure: Cardiovascular Health Study 
Circulation. Heart failure  2013;6(3):364-370.
Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
PMCID: PMC3888807  PMID: 23575256
heart failure; insulin; epidemiology
16.  Plasma Fatty Acid Binding Protein 4 and Risk of Sudden Cardiac Death in Older Adults 
Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95% CI: 0.95–1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95% CI: 1.07–1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95% CI: 0.62–1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.
PMCID: PMC3888692  PMID: 24455402
17.  Serum Organochlorine Pesticide Residues and Risk of Testicular Germ Cell Carcinoma: A Population-Based Case-Control Study 
Testicular germ cell carcinoma (TGCC) is the most common malignancy among men aged 20–34. Although the pathogenesis of TGCC is poorly understood, sub-optimal androgen levels or impaired androgen signaling may play a role. Some persistent organochlorine pesticides commonly found in human tissue possess anti-androgenic properties. We examined whether the risk of TGCC is associated with serum levels of 11 organochlorine pesticides, including p,p’-DDE, and whether the p,p-DDE-TGCC association is modified by CAG or GGN repeat polymorphisms in the androgen receptor (AR) gene. We conducted a population-based case-control study among 18–44 year-old male residents of three Washington State counties. Cases (n=246) were diagnosed during 1999–2003 with a first, primary TGCC. Controls (n=630) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors. A blood specimen provided serum for gas chromatography-high resolution mass spectrometry analysis of organochlorine pesticide residues, and DNA for genotyping. We observed no clear patterns between TGCC risk and concentrations of any of the organochlorines measured, nor did we observe that the risk associated with p,p’-DDE was modified by AR CAG (<23 vs.23+ repeats) or GGN (<17 vs.17+ repeats) genotype. This study does not provide support for the hypothesis that adult exposure to organochlorine pesticides is associated with risk of TGCC. Due to uncertainty regarding how well organochlorine levels measured in adulthood reflect exposures during early life, further research is needed using exposure measurements collected in utero or during infancy.
PMCID: PMC2766345  PMID: 18708392
testicular cancer; organochlorines; DDE; pesticides; androgen receptor
18.  Omega-3 Fatty Acids and incident Type 2 Diabetes: A Systematic Review and Meta-Analysis 
The British journal of nutrition  2012;107(0 2):S214-S227.
The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant (alpha-linolenic acid, ALA) sources and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95% CIs. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n=13 studies; RR per 100g/d=1.12, 95% CI=0.94, 1.34); nor were consumption of EPA+DHA (n=16 cohorts; RR per 250mg/d=1.04, 95% CI=0.97, 1.10) or circulating levels of EPA+DHA biomarkers (n=5 cohorts; RR per 3% of total fatty acids=0.94, 95% CI=0.75, 1.17). Both dietary ALA (n=7 studies; RR per 0.5g/d=0.93, 95% CI=0.83, 1.04) and circulating ALA biomarker levels (n=6 studies; RR per 0.1% of total fatty acid=0.90, 95% CI=0.80, 1.00, P=0.06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I2~80%) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity (<55%) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-Interaction ≤ 0.02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.
PMCID: PMC3744862  PMID: 22591895
19.  Plasma Fatty Acid–Binding Protein 4, Nonesterified Fatty Acids, and Incident Diabetes in Older Adults 
Diabetes Care  2012;35(8):1701-1707.
To examine the relation of fatty acid–binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.
We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992–2007) based on the use of hypoglycemic medications, fasting glucose ≥126 mg/dL, or nonfasting glucose ≥200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.
Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95% CI 1.10–1.65) for women and 1.45 (1.13–1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m2 (HR per SD: 1.78 [95% CI 1.13–2.81]). There was a modest and nonsignificant association of NEFA with diabetes (Ptrend = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95% CI 1.12–2.53), and 1.63 (1.07–2.50) across consecutive tertiles of NEFA (Ptrend = 0.03).
Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.
PMCID: PMC3402261  PMID: 22584136
20.  Association of Fetuin-A with Incident Diabetes in Community-Living Older Adults: The Cardiovascular Health Study 
Circulation  2012;125(19):2316-2322.
The liver secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes in older persons, and to determine if the association differs by age, sex, and race, and among persons with CVD.
Methods and Results
Among 3,710 community-living individuals aged ≥ 65 years without diabetes at baseline, serum fetuin-A was measured in serum collected in 1992–93. Participants were followed for 10.6 years (median) for incident diabetes. Cox regression models evaluated the association of fetuin-A with incident diabetes. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75years, 60% were female, 15% were black, and 16% had CVD. Mean fetuin-A concentrations were 0.47 ± 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10g/L (SD) greater fetuin-A was associated with 19% higher risk of diabetes (HR 1.19; 95%CI 1.06–1.33) after adjusting for demographics, life-style factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and CRP) moderately attenuated the association (HR 1.13; 95% CI 1.00–1.28). Results were similar by sex, race, and CVD status, but were stronger in persons <75 years old (P-interaction 0.01).
Higher fetuin-A is associated with incident diabetes in older persons, irrespective of sex, race, or prevalent CVD status. The association may be attenuated in those aged ≥ 75 years.
PMCID: PMC3390925  PMID: 22511752
cardiovascular disease; cardiovascular diseases; diabetes mellitus; fetuin-A; risk factors
21.  Serum 25-Hydroxyvitamin D Concentration and Risk for Major Clinical Disease Events in a Community-Based Population of Older Adults 
Annals of internal medicine  2012;156(9):627-634.
Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration.
To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D.
Cohort study.
The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis.
1621 white older adults.
Serum 25-(OH)D concentration (using a high-performance liquid chromatography–tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death.
Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of −0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.
The observational study was restricted to white participants.
Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25-(OH)D concentration may be more appropriate than static targets when evaluating health risk.
Primary Funding Source
National Institutes of Health.
PMCID: PMC3632351  PMID: 22547472
22.  Non-esterified Fatty Acids and Risk of Sudden Cardiac Death in Older Adults 
While non-esterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.
Methods and Results
Using a prospective design, we studied 4,657 older men and women (mean age 75 y) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95% CI) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first five years of follow up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.
Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.
PMCID: PMC3329563  PMID: 22281952
epidemiology; sudden death; fatty acid binding protein 4; risk factors
23.  Insulin Resistance and Incident Peripheral Artery Disease in the Cardiovascular Health Study 
Type 2 diabetes is a risk factor for PAD, and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by 2 methods. PAD was first defined as the development of an abnormal ankle brachial index (ABI) (dichotomous outcome) after six years of follow-up. PAD was alternatively defined as the development of clinical PAD (time to event analysis). The study samples included adults over the age of 65 who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, BMI, smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n=2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (Odds Ratio=1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.20-2.71). In the clinical PAD analysis (n=4208), we found a similar relation (Hazard ratio=2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval 1.15-4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.
PMCID: PMC3563259  PMID: 22402937
Peripheral artery disease; Diabetes; Insulin Resistance; Epidemiology
24.  Markers of Inflammation in Prevalent and Incident Parkinson’s Disease in the Cardiovascular Health Study 
Parkinsonism & related disorders  2011;18(3):274-278.
Studies demonstrate existence of inflammation in prevalent Parkinson’s disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.
Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor–α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.
Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR] = 1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).
Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.
PMCID: PMC3288759  PMID: 22119505
albumins; C-reactive protein; inflammation; interleukin-6; odds ratio; Parkinson’s disease; tumor necrosis factor-α
25.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually by an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.
PMCID: PMC3577072  PMID: 21841254
Caffeine; coffee; cognition; tea

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