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1.  Low Ankle Brachial Index and the Development of Rapid Estimated GFR Decline and CKD 
Background
Low ankle brachial index (ABI) is associated with increases in serum creatinine. Whether low ABI is associated with the development of rapid estimated glomerular filtration rate (eGFR) decline, stage 3 chronic kidney disease (CKD), or microalbuminuria is uncertain.
Study Design
Prospective cohort study.
Setting & Participants
Framingham Offspring cohort participants who attended the sixth (1995-98) and eighth (2005-08) exams.
Predictor
ABI, categorized as normal (>1.1 to <1.4), low-normal (>0.9 to 1.1), and low (≤0.9).
Outcomes
Rapid eGFR decline (eGFR decline ≥3mL/min/1.73m2 per year), incident stage 3 CKD (eGFR<60mL/min/1.73m2), incident microalbuminuria.
Measurements
GFR was estimated using the serum creatinine-based CKD-EPI (CKD Epidemiology Collaboration) equation. Urinary albumin-creatinine ratio (UACR) was determined based on spot urine samples.
Results
Over 9.5 years, 9.0% (232 of 2592) experienced rapid eGFR decline and 11.1% (270 of 2426) developed stage 3 CKD. Compared to a normal ABI, low ABI was associated with a 5.73-fold increased odds of rapid eGFR decline (95% CI, 2.77-11.85; p<0.001) after age, sex, and baseline eGFR adjustment; this persisted after multivariable adjustment for standard CKD risk factors (OR, 3.60; 95% CI, 1.65-7.87; p=0.001). After adjustment for age, sex, and baseline eGFR, low ABI was associated with a 2.51-fold increased odds of stage 3 CKD (OR, 2.51; 95% CI, 1.16-5.44; p=0.02), although this was attenuated after multivariable adjustment (OR, 1.68; 95% CI, 0.75-3.76; p=0.2). Among 1902 free of baseline microalbuminuria, low ABI was associated with an increased odds of microalbuminuria after adjustment for age, sex, and baseline UACR (OR, 2.81; 95% CI, 1.07-7.37; p=0.04), with attenuation upon further adjustment (OR, 1.88; p=0.1).
Limitations
Limited number of events with a low ABI. Outcomes based on single serum creatinine and UACR measurements at each exam.
Conclusions
Low ABI is associated with an increased risk of rapid eGFR decline, suggesting that systemic atherosclerosis predicts decline in kidney function.
doi:10.1053/j.ajkd.2012.07.009
PMCID: PMC3517695  PMID: 22901770
2.  Sarcopenia Definitions Considering Body Size and Fat Mass Are Associated With Mobility Limitations: The Framingham Study 
Background.
Sarcopenia defined by lean mass has been inconsistently associated with disability in elders. Studies suggest that definitions should consider body size and additional influences of high fat mass (FM; sarcopenic-obesity). We examined sarcopenia accounting for body size, and sarcopenic-obesity, in relation to mobility limitations among 767 elderly men and women (mean age 79 years) from the Framingham Study.
Methods.
Whole-body dual-energy x-ray absorptiometry measured appendicular lean mass (ALM) and total FM in 1992–1995. Sarcopenia was defined in two ways: ALM/height squared (ALM/ht2) and ALM adjusted for height and FM (residuals). Sarcopenic-obesity categories (referent, obese, sarcopenic, and sarcopenic-obese) were defined by cross-classifying ALM/ht2 and obesity (% body fat: more than 30 for men and more than 40 for women). Mobility limitation was defined as self-reported inability to walk one-half mile, climb stairs, or perform heavy housework. Sex-specific logistic regression calculated odds ratios (OR) and 95% confidence intervals (CI) for mobility limitation, adjusting for covariates.
Results.
Sixteen percent of men and 30% of women had mobility limitation. Among men, both ALM/ht2 (OR = 6.3, 95% CI = 2.5–16.1) and residuals (OR = 4.6, 95% CI = 2.0–10.5) sarcopenia were associated with increased limitation. For sarcopenic-obesity, odds of limitation was higher in sarcopenic (OR = 6.1, 95% CI = 2.2–16.9) and sarcopenic-obese categories (OR = 3.5, 95% CI = 1.0–12.7) but suggested no synergistic effect. In women, only residuals sarcopenia was associated with higher odds of limitation (OR = 1.8, 95% CI = 1.2–2.9).
Conclusions.
Low lean mass is associated with mobility limitations after accounting for body size and fat, and lean and FM have independent effects on mobility in elders. These findings support previous reports that sarcopenia definitions should consider body size and fat.
doi:10.1093/gerona/gls109
PMCID: PMC3598358  PMID: 22503991
Sarcopenia; Lean mass; Disability
3.  Depressive symptoms are associated with visceral adiposity in a community-based sample of middle-aged women and men 
Obesity (Silver Spring, Md.)  2013;21(8):1713-1719.
To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.
doi:10.1002/oby.20130
PMCID: PMC3748158  PMID: 23666906
4.  Clinical correlates of sex steroids and gonadotropins in men over the late adulthood : the Framingham Heart Study 
Background
Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over the late adulthood are less clearly understood.
Methods
We analyzed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2,520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations.
Results
Age, body mass index, and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations.
Conclusion
Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.
doi:10.1111/j.1365-2605.2012.01285.x
PMCID: PMC3434249  PMID: 22640232
sex steroids; gonadotropins; testosterone; aging male; Framingham Heart Study
5.  Temporal Trends in Self-reported Functional Limitations and Physical Disability Among Community-dwelling Elders: The Framingham Heart Study 
American journal of public health  2008;98(7):1256-1262.
Objective
To determine change in the prevalence of functional limitations and physical disability in community-dwelling elders across three decades.
Methods
We studied original participants of the Framingham Study, aged 79 to 88 years, at exam 15 (1977–1979, 177 women, 103 men), exam 20 (1988–1990, 159 women, 98 men) and exam 25 (1997 to 1999, 174 women, 119 men). Self-reported 1) functional limitation defined using the Nagi scale and 2) physical disability defined using the Rosow-Breslau and Katz scales.
Results
Functional limitations declined across examinations from 74.6% to 60.5% to 37.9% (p< 0.001) in women and 54.2%, 37.8%, and 27.8% (p<0.001) in men. Physical disability declined from 74.5% to 48.5% to 34.6% (p< 0.001) in women and 42.3% to 33.3% to 22.8% (p=0.009) in men. Women had a greater decline in disability than men (p=0.03). In women, improvements in functional limitations (p=0.05) were greater from exam 20 to 25 whereas for physical disability (p=0.02) improvements were greater from exam 15 to 20. Improvements in function were constant across the three examinations in men.
Conclusions
Among community-dwelling elders the prevalence of functional limitations and physical disability declined significantly from the 1970s to the 1990s.
doi:10.2105/AJPH.2007.128132
PMCID: PMC2424084  PMID: 18511716
functional limitations; physical disability; trends; elders
6.  The Search for Longevity and Healthy Aging Genes: Insights From Epidemiological Studies and Samples of Long-Lived Individuals 
Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span.
doi:10.1093/gerona/gls089
PMCID: PMC3326242  PMID: 22499766
Longevity; Genetics; Epidemiological studies
7.  Age of Natural Menopause and Atrial Fibrillation: the Framingham Heart Study 
American Heart Journal  2012;163(4):729-734.
Background
Early menopausal age is associated with risk of cardiovascular events including myocardial infraction, stroke, and increased mortality. Relations between menopausal age and atrial fibrillation (AF) have not been investigated. We examined the association between menopausal age and AF.
Methods
Framingham Heart Study women ≥60 years without prevalent AF and natural menopause were followed for 10 years or until incident AF. Menopausal age was modeled as a continuous variable and by categories (<45, 45–53, and >53 years). We used Cox proportional hazards regression to determine associations between menopausal age and AF risk.
Results
In 1,809 Framingham women (2,662 person-examinations, mean baseline age 71.4±7.6 years, menopausal age 49.8±3.6 years) there were 273 unique participants with incident AF. We did not identify a significant association between the standard deviation (SD) of menopausal age (3.6 years) and AF (hazard ratio [HR] per SD, 0.94; 95% CI, 0.83 to 1.06; P=0.29). In a multivariable model with established risk factors for AF, menopausal age was not associated with incident AF (HR per SD, 0.97; 95% CI, 0.86 to 1.09; P=0.60). Examining categorical menopausal age, earlier menopausal age (<45 years) was not significantly associated with increased AF risk compared to older menopausal age>53 (HR, 1.20; 95% CI, 0.74 to 1.94; P=0.52) or menopausal age 45–53 years (HR, 1.38; 95% CI, 0.93 to 2.04; P=0.11).
Conclusion
In our moderate sized, community-based sample, we did not identify menopausal age as significantly increasing AF risk. However, future larger studies will need to examine whether there is a small effect of menopausal age on AF risk.
doi:10.1016/j.ahj.2012.01.010
PMCID: PMC3334861  PMID: 22520541
epidemiology; atrial fibrillation; risk factors; menopause; women
8.  Parental Intermittent Claudication as a Risk Factor for Claudication in Adults 
The American Journal of Cardiology  2011;109(5):736-741.
Little is known about the familial aggregation of intermittent claudication (IC). Our objective was to examine whether parental IC increased adult offspring risk of IC independent of established cardiovascular risk factors. We evaluated Offspring cohort participants of the Framingham Heart Study (FHS) who were 30 years or older, cardiovascular disease (CVD) free, and had both parents enrolled in the FHS (n= 2970 unique participants, 53% women). Pooled proportional hazards regression was used to examine whether the 12 year risk for incident IC in offspring participants was associated with parental IC adjusting for age, sex, diabetes, smoking, systolic blood pressure, total cholesterol, high density lipoprotein (HDL) cholesterol, anti-hypertensive and lipid treatment. Among 909 person-exams in the parental IC history group and 5397 person-exams in the no parental IC history group there were 101 incident IC events (29 with parental IC history, 72 without parental IC history) during follow-up. Age and sex adjusted 12-year cumulative incidence rates per 1000 person-years were 5.08 (95% CI: 2.74; 7.33) and 2.34 (95% CI: 1.46; 3.19) in participants with and without parental IC history. Parental history of IC significantly increased the risk of incident IC in offspring (multivariable adjusted hazard ratio of 1.81, 95% CI 1.14, 2.88). The hazard ratio was unchanged with adjustment for occurrence of CVD (1.83, 95% CI 1.15, 2.91). In conclusion, IC in parents increases risk for IC in adult offspring independent of established risk factors. These data suggest a genetic component of peripheral artery disease and support future research into genetic causes.
doi:10.1016/j.amjcard.2011.10.032
PMCID: PMC3288128  PMID: 22154319
claudication; peripheral artery disease; risk factors; family history
9.  Relation of Socioeconomic Position With Ankle–Brachial Index 
The American journal of cardiology  2011;108(11):1651-1657.
Potential upstream determinants of coronary heart disease (CHD) include life-course socioeconomic position (e.g., childhood socioeconomic circumstances, own education and occupation); however, several plausible biological mechanisms by which socioeconomic position (SEP) may influence CHD are poorly understood. Several CHD risk factors appear to be more strongly associated with SEP in women than in men; little is known as to whether any CHD risk factors may be more strongly associated with SEP in men. Objectives were to evaluate whether cumulative life-course SEP is associated with a measurement of subclinical atherosclerosis, the ankle–brachial index (ABI), in men and women. This study was a prospective analysis of 1,454 participants from the Framingham Heart Study Offspring Cohort (mean age 57 years, 53.8% women). Cumulative SEP was calculated by summing tertile scores for father’s education, own education, and own occupation. ABI was dichotomized as low (≤ 1.1) and normal (> 1.1 to 1.4). After adjustment for age and CHD risk factors cumulative life-course SEP was associated with low ABI in men (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.22 to 3.42, for low vs high cumulative SEP score) but not in women (OR 0.86, 95% CI 0.56 to 1.33). Associations with low ABI in men were substantially driven by their own education (OR 4.13, 95% CI 1.86 to 9.16, for lower vs higher than high school education). In conclusion, cumulative life-course SEP was associated with low ABI in men but not in women.
doi:10.1016/j.amjcard.2011.07.030
PMCID: PMC3575172  PMID: 21907950
10.  Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies 
Murabito, Joanne M. | White, Charles C. | Kavousi, Maryam | Sun, Yan V. | Feitosa, Mary F. | Nambi, Vijay | Lamina, Claudia | Schillert, Arne | Coassin, Stefan | Bis, Joshua C. | Broer, Linda | Crawford, Dana C. | Franceschini, Nora | Frikke-Schmidt, Ruth | Haun, Margot | Holewijn, Suzanne | Huffman, Jennifer E. | Hwang, Shih-Jen | Kiechl, Stefan | Kollerits, Barbara | Montasser, May E. | Nolte, Ilja M. | Rudock, Megan E. | Senft, Andrea | Teumer, Alexander | van der Harst, Pim | Vitart, Veronique | Waite, Lindsay L. | Wood, Andrew R. | Wassel, Christina L. | Absher, Devin M. | Allison, Matthew A. | Amin, Najaf | Arnold, Alice | Asselbergs, Folkert W. | Aulchenko, Yurii | Bandinelli, Stefania | Barbalic, Maja | Boban, Mladen | Brown-Gentry, Kristin | Couper, David J. | Criqui, Michael H. | Dehghan, Abbas | Heijer, Martin den | Dieplinger, Benjamin | Ding, Jingzhong | Dörr, Marcus | Espinola-Klein, Christine | Felix, Stephan B. | Ferrucci, Luigi | Folsom, Aaron R. | Fraedrich, Gustav | Gibson, Quince | Goodloe, Robert | Gunjaca, Grgo | Haltmayer, Meinhard | Heiss, Gerardo | Hofman, Albert | Kieback, Arne | Kiemeney, Lambertus A. | Kolcic, Ivana | Kullo, Iftikhar J. | Kritchevsky, Stephen B. | Lackner, Karl J. | Li, Xiaohui | Lieb, Wolfgang | Lohman, Kurt | Meisinger, Christa | Melzer, David | Mohler, Emile R | Mudnic, Ivana | Mueller, Thomas | Navis, Gerjan | Oberhollenzer, Friedrich | Olin, Jeffrey W. | O’Connell, Jeff | O’Donnell, Christopher J. | Palmas, Walter | Penninx, Brenda W. | Petersmann, Astrid | Polasek, Ozren | Psaty, Bruce M. | Rantner, Barbara | Rice, Ken | Rivadeneira, Fernando | Rotter, Jerome I. | Seldenrijk, Adrie | Stadler, Marietta | Summerer, Monika | Tanaka, Toshiko | Tybjaerg-Hansen, Anne | Uitterlinden, Andre G. | van Gilst, Wiek H. | Vermeulen, Sita H. | Wild, Sarah H. | Wild, Philipp S. | Willeit, Johann | Zeller, Tanja | Zemunik, Tatijana | Zgaga, Lina | Assimes, Themistocles L. | Blankenberg, Stefan | Boerwinkle, Eric | Campbell, Harry | Cooke, John P. | de Graaf, Jacqueline | Herrington, David | Kardia, Sharon L. R. | Mitchell, Braxton D. | Murray, Anna | Münzel, Thomas | Newman, Anne | Oostra, Ben A. | Rudan, Igor | Shuldiner, Alan R. | Snieder, Harold | van Duijn, Cornelia M. | Völker, Uwe | Wright, Alan F. | Wichmann, H.-Erich | Wilson, James F. | Witteman, Jacqueline C.M. | Liu, Yongmei | Hayward, Caroline | Borecki, Ingrid B. | Ziegler, Andreas | North, Kari E. | Cupples, L. Adrienne | Kronenberg, Florian
Background
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
Conclusions
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
doi:10.1161/CIRCGENETICS.111.961292
PMCID: PMC3303225  PMID: 22199011
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
11.  Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study 
Background
Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT.
Methods and Results
Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005).
Conclusions
Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.
doi:10.1161/JAHA.112.004200
PMCID: PMC3540666  PMID: 23316328
body fat distribution; obesity; perivascular adipose tissue; risk factors; visceral adipose tissue
12.  Influence of Sex and Hormone Status on Circulating Natriuretic Peptides 
Objectives
To assess the relationship between sex hormones and natriuretic peptide levels in community-based adults
Background
Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion.
Methods
We measured plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone binding globulin (SHBG) in 4,056 men and women (mean age 40±9 years) from the Framingham Heart Study Third Generation cohort. Sex/hormone status was grouped as: 1) men, 2) postmenopausal women not receiving hormone replacement therapy, 3) premenopausal women not receiving hormonal contraceptives, 4) postmenopausal women receiving hormone replacement therapy and 5) premenopausal women receiving hormonal contraceptives.
Results
Circulating NT-proBNP was associated with sex/hormone status (overall P<0.0001). Men had lower NT-proBNP than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP than women who were not receiving hormone therapy (all P<0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, FT decreased and SHBG increased in tandem with increasing NT-proBNP. In sex-specific analyses, NT-proBNP decreased across increasing quartiles of free testosterone in men (P for trend<0.01) and in women (P for trend<0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations.
Conclusions
These findings suggest that lower circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women.
doi:10.1016/j.jacc.2011.03.042
PMCID: PMC3170816  PMID: 21798425
natriuretic peptides; sex; hormones
13.  Minimal Social Networks Effects Evident in Cancer Screening Behavior 
Cancer  2011;117(13):3045-3052.
Background
Social networks may influence screening behaviors. We assessed whether screening for breast, prostate, or colorectal cancer is influenced by the actual screening behaviors of siblings, friends, spouse, and coworkers.
Methods
Observational study using Framingham Heart Study data to assess screening for eligible individuals during the late 1990s. We used logistic regression to assess if the probability of screening for breast, prostate, or colorectal cancer was influenced by the proportion of siblings, friends, and coworkers who had the same screening, as well as spouse’s screening for colorectal cancer, adjusting for other factors that might influence screening rates.
Results
Among 1660 women aged 41–70, 71.7% reported mammography in the past year; among 1217 men aged 51–70, 43.3% reported prostate specific antigen testing in the past year; and among 1426 men and women aged 51–80, 46.9% reported stool blood testing and/or sigmoidoscopy in the past year. An increasing proportion of sisters who had mammography in the past year was associated with mammography screening in the ego (odds ratio [OR]=1.034, 95% confidence interval [CI]=1.000–1.065 for each 10% increase). A spouse with recent screening was associated with more colorectal cancer screening (OR 1.65, 95% CI=1.39–1.98 vs. unmarried). Otherwise, screening behaviors of siblings, friends, and coworkers were not associated with screening in the ego.
Conclusion
Aside from a slight increase in breast cancer screening among women whose sisters were screened and colorectal cancer screening if spouses were screened, the screening behavior of siblings, friends, or coworkers did not influence cancer screening behaviors.
doi:10.1002/cncr.25849
PMCID: PMC3119780  PMID: 21264828
cancer screening; mammography; prostate specific antigen; social networks
14.  Relationship Between Central and Peripheral Atherosclerosis and Left Ventricular Dysfunction in a Community Population 
We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and PAD in a community cohort. 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65±9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional LV systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at Examination 7. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p<0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p<0.001) and volume of aortic plaque were associated with decreased ABI (p<0.001). After multivariable adjustment, ABI≤0.9 or prior revascularization was associated with a three-fold odds of aortic plaque (p=0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p<0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment suggesting shared mechanisms beyond those captured by traditional risk factors.
doi:10.1177/1358863X11408640
PMCID: PMC3249244  PMID: 21708875
Aortic atherosclerosis; peripheral arterial disease; left ventricular wall motion abnormality; epidemiology; MRI
15.  Peri-Aortic Fat Deposition Is Associated with Peripheral Arterial Disease: The Framingham Heart Study 
Background
Central obesity is associated with peripheral arterial disease (PAD), suggesting that ectopic fat depots may be associated with localized diseases of the aorta and lower extremity arteries. We hypothesized that individuals with greater amounts of peri-aortic fat are more likely to have clinical peripheral arterial disease (PAD) and a low ankle-brachial index (ABI).
Methods and Results
We quantified peri-aortic fat surrounding the thoracic aorta using a novel volumetric quantitative approach in 1205 individuals from the Framingham Heart Study Offspring cohort (mean age 65.9 years, 54% women); visceral abdominal fat (VAT) was also measured. Clinical PAD was defined as a history of intermittent claudication and ABI was dichotomized as low ABI≤0.9 or lower extremity revascularization vs normal ABI >0.9 to < 1.4. Regression models were created to examine the association between peri-aortic fat and intermittent claudication or low ABI (n=66 participants). In multivariable logistic regression, per 1 standard deviation increase in peri-aortic fat, the odds ratio (OR) for the combined end-point was 1.52 (p-value=0.004); these results were strengthened with additional adjustment for BMI (OR 1.69, p=0.002) or visceral abdominal fat (OR 1.67, p=0.009) whereas no association was observed for VAT (p=0.16). Similarly, per standard deviation increase in BMI or waist circumference, no association was observed after accounting for VAT (p=0.35 [BMI]; p=0.49 [waist circumference]).
Conclusions
Peri-aortic fat is associated with low ABI and intermittent claudication.
doi:10.1161/CIRCIMAGING.110.958884
PMCID: PMC3060043  PMID: 20639302
obesity; atherosclerosis; peripheral arterial disease
16.  Health Insurance and Cardiovascular Disease Risk Factors 
The American journal of medicine  2010;123(8):741-747.
Background
Compared to those with health insurance, the uninsured receive less care for chronic conditions such as hypertension and diabetes and they experience higher mortality.
Methods
We investigated the relations of health insurance status to prevalence, treatment, and control of major cardiovascular disease risk factors, hypertension and elevated low-density lipoprotein (LDL) cholesterol, among Framingham Heart Study (FHS) participants in sex-specific age-adjusted analyses. Participants who attended either the seventh Offspring cohort examination cycle (1998–2001) or the first Third Generation cohort examination cycle (2002–2005) were studied.
Results
Among 6098 participants, 3.8% were uninsured at the time of the FHS clinic examination and participants’ ages ranged from 19 to 64 years. The prevalence of hypertension and elevated LDL cholesterol was similar for the insured and uninsured, however the proportion of those who obtained treatment and achieved control of these risk factors was lower among the uninsured. Uninsured men and women were less likely to be treated for hypertension with odds ratios for treatment of 0.19 (95% CI 0.07–0.56) for men and 0.31 (95% CI 0.12–0.79) for women. Among men, the uninsured were less likely to receive treatment or achieve control of elevated LDL cholesterol than the insured, with odds ratios of 0.12 (95% CI 0.04–0.38) for treatment and 0.17 (95% CI 0.05–0.56) for control.
Conclusions
The treatment and control of hypertension and hypercholesterolemia are lower among uninsured adults. Increasing the proportion of insured individuals may be a means to improve the treatment and control of cardiovascular disease risk factors and reduce health disparities.
doi:10.1016/j.amjmed.2010.02.013
PMCID: PMC2913281  PMID: 20670729
health insurance; cardiovascular risk factors; hypertension; health disparities
17.  “LIFE COURSE SOCIOECONOMIC POSITION IS ASSOCIATED WITH INFLAMMATORY MARKERS: THE FRAMINGHAM OFFSPRING STUDY” 
Social science & medicine (1982)  2010;71(1):187-195.
Associations between life course socioeconomic position (SEP) and novel biological risk markers for coronary heart disease such as inflammatory markers are not well understood. Most studies demonstrate inverse associations of life course SEP with C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen, however little is known about associations between life course SEP and other inflammatory markers including intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor II (TNFR2), lipoprotein phospholipase A2 (Lp-PLA2) activity, monocytechemoattractant protein-1 (MCP-1) or P-selectin. The objectives of this analysis were to determine whether three life course SEP frameworks (“accumulation of risk”, “social mobility” and “sensitive periods”) are associated with the aforementioned inflammatory markers. We examined 1413 Framingham Offspring Study participants (mean age 61.2±8.6 years, 54% women), using multivariable regression analyses. In age- and sex-adjusted regression analyses, cumulative SEP (“accumulation of risk” SEP framework), for low vs. high SEP, was inversely associated with CRP, IL-6, ICAM-1, TNFR2, Lp-PLA2 activity, MCP-1 and fibrinogen. We found that there were few consistent trends between social mobility trajectories and most inflammatory markers. Own educational attainment was inversely associated with 7 of 8 studied inflammatory markers, while father’s education, father’s occupation and own occupation were inversely associated with 4, 5 and 4 inflammatory markers, respectively, in age- and sex-adjusted analyses. The strengths of association between SEP and inflammatory markers were typically substantially accounted for by CHD risk markers (smoking, body mass index, systolic blood pressure, total:HDL cholesterol ratio, fasting glucose, medications, depressive symptomatology) suggesting these may be important mechanisms that explain associations between SEP and the studied inflammatory markers.
doi:10.1016/j.socscimed.2010.03.012
PMCID: PMC2895737  PMID: 20430502
USA; socioeconomic position; inflammatory markers; life course; social mobility; heart disease
18.  Consent for Genetic Research in the Framingham Heart Study 
Extensive efforts have been aimed at understanding the genetic underpinnings of complex diseases that affect humans. Numerous genome-wide association studies have assessed the association of genes with human disease; including the Framingham Heart Study (FHS), which genotyped 550,000 SNPs in 9,000 participants. The success of such efforts requires high rates of consent by participants, which is dependent on ethical oversight, communications, and trust between research participants and investigators. To study this we calculated percentages of participants who consented to collection of DNA and to various uses of their genetic information in two FHS cohorts between 2002 and 2009. The data included rates of consent for providing a DNA sample, creating an immortalized cell line, conducting research on various genetic conditions including those that might be considered sensitive, and for notifying participants of clinically significant genetic findings were above 95%. Only with regard to granting permission to share DNA or genetic findings with for-profit companies was the consent rate below 95%. We concluded that the FHS has maintained high rates of retention and consent for genetic research that has provided the scientific freedom to establish collaborations and address a broad range of research questions. We speculate that our high rates of consent have been achieved by establishing frequent and open communications with participants that highlight extensive oversight procedures. Our approach to maintaining high consent rates via ethical oversight of genetic research and communication with study participants is summarized in this report and should be of help to other studies engaged in similar types of research.
doi:10.1002/ajmg.a.33377
PMCID: PMC2923558  PMID: 20425830
epidemiology; genetics; genome-wide association; medical ethics; population study
19.  Breastfeeding in Infancy and Adult Cardiovascular Disease Risk Factors 
The American journal of medicine  2009;122(7):656-63.e1.
Background
Public health recommendations advocate breastfeeding in infancy as a means to reduce later-life obesity. Several prior studies relating breastfeeding to cardiovascular risk factors have been limited by lack of adjustment for maternal and participant confounding factors.
Methods
We ascertained breastfeeding history via questionnaire from mothers enrolled in the Framingham Offspring Study. In their young to middle-aged adult children enrolled in the Framingham Third Generation, we examined the relations between maternal breastfeeding history (yes, no) to cardiovascular risk factors, including: body mass index (BMI), HDL cholesterol, total cholesterol, triglycerides, fasting blood glucose, systolic and diastolic blood pressure. We applied Generalized estimating equations (GEE) to account for sibling correlations and adjusted for maternal and participant lifestyle, education and cardiovascular risk factors.
Results
In Third Generation participants (n=962, mean age=41 years, 54% women), 26% of their mothers reported breastfeeding. Compared to non-breastfed individuals, breastfed adult participants had lower multivariable-adjusted BMI [26.1 kg/m2 vs. 26.9 kg/m2, p=0.04] and higher HDL cholesterol levels [HDL 56.6 mg/dL vs. 53.7 mg/dL, p=0.01]. Upon additional adjustment for BMI the association between breastfeeding and HDL cholesterol was attenuated (p=0.09). Breastfeeding was not associated with total cholesterol, triglycerides, fasting blood glucose, systolic blood pressure or diastolic blood pressure.
Conclusions
Breastfeeding in infancy is inversely associated with adult BMI and positively associated with HDL cholesterol. Associations between breastfeeding and BMI may mediate the association between breastfeeding and HDL cholesterol.
doi:10.1016/j.amjmed.2008.11.034
PMCID: PMC2704490  PMID: 19559168
Breastfeeding; lactation; risk factors; early nutrition; infancy; body mass index; HDL cholesterol
20.  Life-Course Socioeconomic Position and Incidence of Coronary Heart Disease 
American Journal of Epidemiology  2009;169(7):829-836.
Cumulative exposure to socioeconomic disadvantage across the life course may be inversely associated with coronary heart disease (CHD); the mechanisms are not fully clear. An objective of this study was to determine whether cumulative life-course socioeconomic position (SEP) is associated with CHD incidence in a well-characterized US cohort that had directly assessed childhood and adulthood measures of SEP and prospectively measured CHD incidence. Furthermore, analyses aimed to evaluate whether adjustment for CHD risk factors reduces the association between cumulative life-course SEP and CHD. The authors examined 1,835 subjects who participated in the Framingham Heart Study Offspring Cohort from 1971 through 2003 (mean age, 35.0 years; 52.4% women). Childhood SEP was measured as father's education; adulthood SEP was assessed as own education and occupation. CHD incidence included myocardial infarction, coronary insufficiency, and coronary death. Cox proportional hazards analyses indicated that cumulative SEP was associated with incident CHD after adjustment for age and sex (hazard ratio = 1.82, 95% confidence interval: 1.17, 2.85 for low vs. high cumulative SEP score). Adjustment for CHD risk factors reduced that magnitude of association (hazard ratio = 1.29, 95% confidence interval: 0.78, 2.13). These findings underscore the potential importance of CHD prevention and treatment efforts for those whose backgrounds include low SEP throughout life.
doi:10.1093/aje/kwn403
PMCID: PMC2727217  PMID: 19179358
cohort studies; coronary disease; myocardial ischemia; social class; socioeconomic factors
21.  Cross-sectional Relations of Multiple Inflammatory Biomarkers to Peripheral Arterial Disease: The Framingham Offspring Study 
Atherosclerosis  2008;203(2):509-514.
Background
Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers.
Methods
In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n=2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using 1) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and 2) stepwise multivariable logistic regression with forward selection of markers with separate models for 1) ankle-brachial index (ABI) category (<0.9, 0.9 to 1.0, >1.0) and 2) presence of clinical PAD (intermittent claudication or lower extremity revascularization).
Results
The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p= 0.01 and p= 0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p=0.005) and 1.19 (p=0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD.
Conclusion
Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway.
doi:10.1016/j.atherosclerosis.2008.06.031
PMCID: PMC2690511  PMID: 18701106
peripheral arterial disease; ankle-brachial index; interleukin-6; tumor necrosis factor receptor 2
22.  Age at Natural Menopause and Risk of Ischemic Stroke: The Framingham Heart Study 
Background
Women have increased lifetime stroke risk and more disabling strokes compared with men. Insights into the association between menopause and stroke could lead to new prevention strategies for women. The objective of this study was to examine the association of age at natural menopause with ischemic stroke risk in the Framingham Heart Study.
Methods
Participants included women who survived stroke-free until age 60, experienced natural menopause, did not use estrogen prior to menopause, and who had complete data (n=1,430). Participants were followed until first ischemic stroke, death, or end of follow-up (2006). Age at natural menopause was self-reported. Cox proportional hazards models were used to examine the association between age at natural menopause (<42, 42-54, ≥55) and ischemic stroke risk adjusted for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease and estrogen use.
Results
There were 234 ischemic strokes identified. Average age at menopause was 49 years (sd=4). Women with menopause at ages 42-54 (HR=0.50; 95% CI:0.29-0.89) and at ages ≥55 (HR=0.31; 95% CI:0.13-0.76) had lower stroke risk compared with those with menopause <42 years adjusted for covariates. Women with menopause before age 42 had twice the stroke risk compared to all other women (HR=2.03; 95% CI: 1.16-3.56).
Conclusion
In this prospective study, age at natural menopause before age 42 was associated with increased ischemic stroke risk. Future stroke studies with measures of endogenous hormones are needed to inform the underlying mechanisms so that novel prevention strategies for mid-life women can be considered.
doi:10.1161/STROKEAHA.108.542993
PMCID: PMC2682709  PMID: 19233935
Stroke; cerebrovascular disease; women; menopause; bone mineral density
23.  Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study 
European Heart Journal  2009;30(7):850-856.
Aims
The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD).
Methods and results
Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11–1.57; P = 0.002] and VAT (OR 1.35, 95% CI 1.11–1.57; P = 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93–1.39; P = 0.22), were significantly associated with prevalent CVD in age–sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P > 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03–1.82; P = 0.03).
Conclusion
Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis.
doi:10.1093/eurheartj/ehn573
PMCID: PMC3693564  PMID: 19136488
Pericardial fat; Visceral abdominal fat; Cardiovascular disease; Framingham Heart Study; Epidemiology
24.  Long-Term Trends in Myocardial Infarction Incidence and Case-Fatality in the National Heart, Lung, and Blood Institute’s Framingham Heart Study 
Circulation  2009;119(9):1203-1210.
Background
Whereas prevalence of coronary heart disease (CHD) risk factors has declined over past decades in the United States, acute myocardial infarction (AMI) rates were steady. We hypothesized that this paradox is partly due to the advent of increasingly sensitive biomarkers for AMI diagnosis.
Methods and Results
In Framingham Heart Study participants over four decades, we compared incidence/survival rates of initial AMI diagnosis by electrocardiogram (AMI-ECG) irrespective of biomarkers, to those exclusively based on infarction biomarkers (AMI-marker). We employed Poisson regression to calculate annual incidence rates of first AMI over four decades (1960–69, 1970–79, 1980–89 and 1990–99), and compared rates of AMI-ECG with rates of AMI-marker. Cox proportional hazards was used to compare AMI case-fatality over four decades. In 9,824 persons (54% women; follow-up of 212,539 persons-years, aged 40–89 years) there were 941 AMIs including 639 AMI-ECG and 302 AMI-marker. From 1960 to 1999, rates of AMI-ECG declined by about fifty percent and rates of AMI-marker increased approximately two-fold. Crude 30-day, 1-year and five-year case fatality rates in 1960–69 and 1990–99, respectively, were 0.20 and 0.14; 0.24 and 0.21; and 0.45 and 0.41. Age- and sex-adjusted 30-day, 1-year and 5-year AMI case-fatality declined by 60% 1960 to 1999 (p-trend <0.001), with parallel declines noted following AMI-ECG and AMI-marker.
Conclusions
Over the past forty years, rates of AMI-ECG, have declined by fifty percent whereas rates of AMI diagnosed by biomarker have doubled. Our findings offer an explanation for apparent steady national AMI rates in the face of improvements in primary prevention.
doi:10.1161/CIRCULATIONAHA.108.825364
PMCID: PMC2725400  PMID: 19237656
Myocardial infarction; temporal trends; biomarkers; electrocardiogram; diagnostic drift
25.  Long-Term Trends in the Incidence of Heart Failure after Myocardial Infarction 
Circulation  2008;118(20):2057-2062.
Background
Although mortality after myocardial infarction (MI) declined in the United States in recent decades, there are few community-based investigations of the long-term trends in incidence of heart failure post-MI and their results appear to be conflicting.
Methods and Results
We evaluated 676 Framingham Heart Study participants between ages 45-85 years (mean age 67 years, 34% women) who developed a first MI between 1970 and 1999. We assessed the incidence rates of heart failure and death without heart failure in each of three decades (1970-79, 1980-89, 1990-99). We estimated the multivariable-adjusted risk of events in the latter two decades, with the period 1970-79 serving as referent. The 30-day incidence of heart failure post-MI rose from 10% in 1970-79 to 23.1% in 1990-99 (p for trend 0.003), whereas 30-day mortality post-MI declined from 12.2% (1970-79) to 4.1% (1990-99). The 5-year incidence of heart failure post-MI rose from 27.6% in 1970-79 to 31.8% in 1990-99 (p for trend 0.02), whereas 5-year mortality post-MI declined from 41.1 (1970-79) to 17.3% (1990-99). In multivariable analyses, compared to the period 1970-79, we observed higher 30-day (risk ratio [RR] 2.05, 95% confidence interval [CI] 1.25-3.36) and 5-year risks of heart failure (RR 1.74, 95% CI 1.07-2.84) in the decade 1990-1999. These trends were accompanied by lower 30-day (RR 0.21, 95% CI 0.09-0.47) and 5-year mortality (risk ratio 0.31, 95% CI 0.18-0.54) in 1990-99.
Conclusions
In our community-based sample, we observed an increase in incidence of heart failure in recent decades paralleling decrease in mortality post-MI.
doi:10.1161/CIRCULATIONAHA.108.784215
PMCID: PMC2729712  PMID: 18955667
Heart failure; myocardial infarction; trends

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