@article {713, title = {In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {22}, year = {2002}, month = {2002 Dec 01}, pages = {2066-71}, abstract = {

OBJECTIVE: Interleukin (IL)-6-mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the -174G>C genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study.

METHODS AND RESULTS: Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The -174C allele was associated with higher C-reactive protein (11\% higher, P=0.02), fibrinogen (3\% higher, P=0.02), and IL-6 (5\% higher; P=0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the -174C allele was associated with risk of MRI infarcts (odds ratio 1.5).

CONCLUSIONS: IL-6 levels differentiated those with subclinical CVD from those without. Although the -174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.

}, keywords = {Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Cytosine, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Guanine, Health Surveys, Humans, Inflammation, Interleukin-6, Linear Models, Male, Polymorphism, Genetic, Predictive Value of Tests, Promoter Regions, Genetic}, issn = {1524-4636}, doi = {10.1161/01.atv.0000040224.49362.60}, author = {Jenny, Nancy S and Tracy, Russell P and Ogg, Malcolm S and Luong, Le Ahn and Kuller, Lewis H and Arnold, Alice M and Sharrett, A Richey and Humphries, Steve E} } @article {717, title = {Multiple imputation of baseline data in the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {157}, year = {2003}, month = {2003 Jan 01}, pages = {74-84}, abstract = {

Most epidemiologic studies will encounter missing covariate data. Software packages typically used for analyzing data delete any cases with a missing covariate to perform a complete case analysis. The deletion of cases complicates variable selection when different variables are missing on different cases, reduces power, and creates the potential for bias in the resulting estimates. Recently, software has become available for producing multiple imputations of missing data that account for the between-imputation variability. The implementation of the software to impute missing baseline data in the setting of the Cardiovascular Health Study, a large, observational study, is described. Results of exploratory analyses using the imputed data were largely consistent with results using only complete cases, even in a situation where one third of the cases were excluded from the complete case analysis. There were few differences in the exploratory results across three imputations, and the combined results from the multiple imputations were very similar to results from a single imputation. An increase in power was evident and variable selection simplified when using the imputed data sets.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Cause of Death, Cohort Studies, Data Collection, Data Interpretation, Statistical, Epidemiologic Studies, Female, Humans, Linear Models, Male, Mathematical Computing, Models, Statistical, Predictive Value of Tests, Proportional Hazards Models, Risk Factors, Software, Survival Analysis, United States, Ventricular Remodeling}, issn = {0002-9262}, doi = {10.1093/aje/kwf156}, author = {Arnold, Alice M and Kronmal, Richard A} } @article {757, title = {"Successful aging": effect of subclinical cardiovascular disease.}, journal = {Arch Intern Med}, volume = {163}, year = {2003}, month = {2003 Oct 27}, pages = {2315-22}, abstract = {

BACKGROUND: Cardiovascular diseases are the primary cause of death in older adults. Among those without clinical disease, high levels of subclinical disease are associated with poor survival. The effect of the extent of subclinical cardiovascular disease on the quality of the remaining years has not been defined.

METHODS: In a longitudinal cohort study, 2932 men and women aged 65 years and older were followed up for 8 years to determine the likelihood of maintaining intact health and functioning. Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and with intact physical and cognitive functioning.

RESULTS: Younger age at study entry and a lower extent of subclinical cardiovascular disease were independently associated with the likelihood of maintaining successful aging. In age-stratified summaries, those with subclinical disease had a trajectory of decline similar to subjects 5 years older without subclinical vascular disease. Regression analyses showed that the decline associated with subclinical disease was equivalent to 6.5 (95\% confidence interval, 6.4-6.6) years of aging for women and 5.6 (95\% confidence interval, 5.4-5.8) years of aging for men. Individual measures of the extent of cardiovascular disease, diabetes mellitus, smoking, and higher C-reactive protein level were also independently predictive of fewer years of successful aging, but none of these factors substantially attenuated the effect of age itself.

CONCLUSIONS: There is a graded relationship between the extent of vascular disease measured noninvasively and the likelihood of maintaining intact health and function. Prevention of subclinical vascular disease may increase the quality and the quantity of years in late life.

}, keywords = {Aged, Aged, 80 and over, Aging, C-Reactive Protein, Cardiovascular Diseases, Female, Health Status, Humans, Longitudinal Studies, Male, Quality of Life, Regression Analysis, Risk Factors}, issn = {0003-9926}, doi = {10.1001/archinte.163.19.2315}, author = {Newman, Anne B and Arnold, Alice M and Naydeck, Barbara L and Fried, Linda P and Burke, Gregory L and Enright, Paul and Gottdiener, John and Hirsch, Calvin and O{\textquoteright}Leary, Daniel and Tracy, Russell} } @article {764, title = {Prevalence of specific variant carotid geometric patterns and incidence of cardiovascular events in older persons. The Cardiovascular Health Study (CHS E-131).}, journal = {J Am Coll Cardiol}, volume = {43}, year = {2004}, month = {2004 Jan 21}, pages = {187-93}, abstract = {

OBJECTIVES: We hypothesized that variant geometric patterns of the common carotid artery (CCA) predict the incidence of cardiovascular disease (CVD), after accounting for CCA intima-medial thickness (IMT).

BACKGROUND: Common carotid artery intima-media thickness has been associated with the incidence of cardiovascular disease.

METHOD: Noninvasive measurements of IMT were made with high-resolution ultrasonography in 5,640 subjects 65 years of age or older participating in the Cardiovascular Health Study. New coronary and/or cerebrovascular events served as outcome variables over a median 10.2-year follow-up. To characterize different carotid structural geometric patterns (CGP), vascular mass (VM) was combined with the wall-to-lumen ratio (W/L). Normal values for W/L and VM were defined as age-adjusted, gender-specific 75th percentiles of the 1,899 normotensive subjects free of CVD at baseline. Four CGPs were defined: CGP1 = normal W/L ratio and VM; CGP2 = arterial remodeling (i.e., increased W/L ratio with normal VM); CGP3 = arterial hypertrophy (i.e., increased W/L ratio with increased VM); and CGP4 = arterial hypertrophy with dilation (i.e., normal W/L ratio and increased VM).

RESULTS: Coronary or cerebrovascular events (adjusted for age, gender, traditional risk factors, and IMT) were associated with CGP in subjects free of CVD at baseline. Specifically, the hazard ratio (Cox proportional-hazards analyses) for CGP3 (arterial hypertrophy) was 1.25 (95\% confidence interval [CI] 1.03 to 1.53), and for CGP4 (arterial hypertrophy with dilation) was 1.43 (95\% CI 1.16 to 1.75) compared with CGP1 (normal).

CONCLUSIONS: Arterial hypertrophy defined by variant CGP patterns is associated with the development of new CVD, independent of age, traditional risk factors, and CCA IMT.

}, keywords = {Aged, Cardiovascular Diseases, Carotid Arteries, Female, Humans, Hypertrophy, Incidence, Male, Predictive Value of Tests, Prevalence, Prospective Studies, Ultrasonography}, issn = {0735-1097}, doi = {10.1016/j.jacc.2003.08.035}, author = {Scuteri, Angelo and Manolio, Teri A and Marino, Emily K and Arnold, Alice M and Lakatta, Edward G} } @article {788, title = {White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke.}, journal = {Stroke}, volume = {35}, year = {2004}, month = {2004 Aug}, pages = {1821-5}, abstract = {

BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors.

METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8\% per year for participants with high WMG (grades > or =5), compared with only 0.6\% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

}, keywords = {Aged, Brain, Female, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Radiography, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000132193.35955.69}, author = {Kuller, Lewis H and Longstreth, W T and Arnold, Alice M and Bernick, Charles and Bryan, R Nick and Beauchamp, Norman J} } @article {845, title = {C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study.}, journal = {Circulation}, volume = {112}, year = {2005}, month = {2005 Jul 05}, pages = {25-31}, abstract = {

BACKGROUND: High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available.

METHODS AND RESULTS: Baseline CRP was measured in 3971 men and women > or =65 years of age without prior vascular diseases; 26\% had elevated concentrations (>3 mg/L). With 10 years of follow-up, 547 participants developed coronary heart disease (CHD; defined as myocardial infarction or coronary death). With elevated CRP, the 10-year cumulative CHD incidences were 33\% in men and 17\% in women. The age-, ethnicity-, and sex-adjusted relative risk of CHD for CRP >3 mg/L compared with <1 mg/L was 1.82 (95\% CI, 1.46 to 2.28). Adjusting for conventional risk factors reduced the relative risk to 1.45 (95\% CI, 1.14 to 1.86). The population-attributable risk of CHD for elevated CRP was 11\%. Risk relationships did not differ in subgroups defined by baseline risk factors. We assessed whether CRP improved prediction by the Framingham Risk Score. Among men with a 10-year Framingham-predicted risk of 10\% to 20\%, the observed CHD incidence was 32\% for elevated CRP. Among women, CRP discriminated best among those with a 10-year predicted risk >20\%; the incidences were 31\% and 10\% for elevated and normal CRP levels, respectively.

CONCLUSIONS: In older men and women, elevated CRP was associated with increased 10-year risk of CHD, regardless of the presence or absence of cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high-Framingham-risk women.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Coronary Disease, Female, Humans, Incidence, Inflammation, Male, Myocardial Infarction, Predictive Value of Tests, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.104.504159}, author = {Cushman, Mary and Arnold, Alice M and Psaty, Bruce M and Manolio, Teri A and Kuller, Lewis H and Burke, Gregory L and Polak, Joseph F and Tracy, Russell P} } @article {812, title = {Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Jan}, pages = {56-61}, abstract = {

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) scans in the elderly commonly show white matter findings that may raise concerns. We sought to document incidence, manifestations, and predictors of worsening white matter grade on serial imaging.

METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people aged 65 years and older, of whom 1919 have had extensive initial and follow-up evaluations, including 2 MRI scans separated by 5 years. Scans were read without clinical information in standard side-by-side fashion to determine worsening white matter grade.

RESULTS: Worsening was evident in 538 participants (28\%), mostly (85\%) by 1 grade. Although similar at initial scan, participants with worsening white matter grade, compared with those without, experienced greater decline on modified Mini-Mental State examination and Digit-Symbol Substitution test (both P< or =0.001) after controlling for potential confounding factors, including occurrence of transient ischemic attack or stroke between scans. Independent predictors of worsening white matter grade included cigarette smoking before initial scan and infarct on initial scan. Otherwise, predictors differed according to white matter grade on initial scan. For low initial grade, increased age, increased diastolic blood pressure, increased high-density lipoprotein cholesterol, and decreased low-density lipoprotein cholesterol were associated with increased risk of worsening. For high initial grade, any cardiovascular disease and low ankle-arm index were associated with decreased risk of worsening, whereas use of diuretics and statins were associated with increased risk.

CONCLUSIONS: Worsening white matter grade on serial MRI scans in elderly is common, is associated with cognitive decline, and has complex relations with cardiovascular risk factors.

}, keywords = {Aged, Brain, Cardiovascular Diseases, Cognition Disorders, Female, Humans, Incidence, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000149625.99732.69}, author = {Longstreth, W T and Arnold, Alice M and Beauchamp, Norman J and Manolio, Teri A and Lefkowitz, David and Jungreis, Charles and Hirsch, Calvin H and O{\textquoteright}Leary, Daniel H and Furberg, Curt D} } @article {820, title = {Incidence of cardiovascular disease in older Americans: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Feb}, pages = {211-8}, abstract = {

OBJECTIVES: To estimate incidence rates of major cardiovascular disease (CVD) in older Americans.

DESIGN: Longitudinal cohort study using prospectively collected data on cardiovascular events.

SETTING: Four U.S. communities in the Cardiovascular Health Study (CHS).

PARTICIPANTS: Five thousand eight hundred eighty-eight participants in CHS, aged 65 or older at enrollment, including 3,393 women (581 African American) and 2,495 men (343 African American).

MEASUREMENTS: At semiannual contacts, participants reported any occurrence of clinical CVD. Medical records were obtained and adjudicated to confirm diagnosis of CVD.

RESULTS: During 10 years of follow-up, incidence of coronary heart disease (CHD) per 1,000 person-years was 39.6 (95\% confidence interval (CI)=36.4-43.1) in men and 22.3 (95\% CI=20.4-24.2) in women. Cumulative event rates for CHD and myocardial infarction for women aged 75 and older at baseline were similar to those for men aged 65 to 74. The overall incidence of stroke was similar for men and women (14.7 (95\% CI=13.0-16.6) and 13.7 (95\% CI=12.4-15.1) per 1,000 person-years, respectively), but the risk of stroke increased with age more rapidly in women, resulting in a greater cumulative event rate for stroke in women than in men aged 75 and older. The incidence of congestive heart failure increased 9\% with each year of age over 65 and was greater than 6\% per year in Caucasian men and women aged 85 and older at baseline. Rates were similar in African Americans and Caucasians.

CONCLUSION: The occurrence of new CVD in older Americans is high, indicating that preventive efforts need to be maintained into older ages.

}, keywords = {African Americans, Age Distribution, Aged, Aged, 80 and over, Cardiovascular Diseases, European Continental Ancestry Group, Female, Geriatric Assessment, Humans, Incidence, Longitudinal Studies, Male, Sex Distribution, Survival Rate, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53105.x}, author = {Arnold, Alice M and Psaty, Bruce M and Kuller, Lewis H and Burke, Gregory L and Manolio, Teri A and Fried, Linda P and Robbins, John A and Kronmal, Richard A} } @article {830, title = {Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Apr}, pages = {649-54}, abstract = {

OBJECTIVES: To determine whether severity of subclinical brain magnetic resonance imaging (MRI) abnormalities predicts incident self-reported physical impairment or rate of decline in motor performance.

DESIGN: Longitudinal analysis, average follow-up time: 4.0 years.

SETTING: Cardiovascular Health Study (CHS).

PARTICIPANTS: CHS participants with modified Mini-Mental State Examination (3MS) score of 80 or greater, no self-reported disability, no history of stroke, and at least one assessment of mobility (n=2,450, mean age=74.4).

MEASUREMENTS: Brain MRI abnormalities (ventricular enlargement, white matter hyperintensities, subcortical and basal ganglia small brain infarcts), self-reported physical impairment (difficulty walking half a mile or with one or more activities of daily living), and motor performance (gait speed, timed chair stand).

RESULTS: After adjusting for demographics, cardiovascular risk factors, and diseases, risk of incident self-reported physical impairment was 35\% greater for those with severe ventricular enlargement than for those with minimal ventricular enlargement, 22\% greater for those with moderate white matter hyperintensities than for those with minimal white matter hyperintensities, and 26\% greater for participants with at least one brain infarct than for those with no infarcts. Those with moderate to severe brain abnormalities experienced faster gait speed decline (0.02 m/s per year) than those with no MRI abnormalities (0.01 m/s per year). Further adjustment for incident stroke, incident dementia, and 3MS score did not substantially attenuate hazard ratios for incident self-reported physical impairment or coefficients for decline in gait speed.

CONCLUSION: Subclinical structural brain abnormalities in high-functioning older adults can increase the risk of developing physical disabilities and declining in motor performance.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Brain, Female, Follow-Up Studies, Gait, Humans, Incidence, Magnetic Resonance Imaging, Male, Proportional Hazards Models, Psychomotor Disorders, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53214.x}, author = {Rosano, Caterina and Kuller, Lewis H and Chung, Hyoju and Arnold, Alice M and Longstreth, William T and Newman, Anne B} } @article {878, title = {10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {166}, year = {2006}, month = {2006 Jan 09}, pages = {71-8}, abstract = {

BACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older.

METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61\% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study.

RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals.

CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95\% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.

}, keywords = {African Continental Ancestry Group, Aged, Blood Chemical Analysis, Cardiovascular Diseases, Comorbidity, Coronary Disease, Echocardiography, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Incidence, Male, Multivariate Analysis, Prevalence, Proportional Hazards Models, Regression Analysis, Risk Factors, Sex Distribution, United States}, issn = {0003-9926}, doi = {10.1001/archinte.166.1.71}, author = {Kuller, Lewis H and Arnold, Alice M and Psaty, Bruce M and Robbins, John A and O{\textquoteright}Leary, Daniel H and Tracy, Russell P and Burke, Gregory L and Manolio, Teri A and Chaves, Paolo H M} } @article {875, title = {Left atrial volume, geometry, and function in systolic and diastolic heart failure of persons > or =65 years of age (the cardiovascular health study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 Jan 01}, pages = {83-9}, abstract = {

The left atrium enlarges in association with many factors, including aging, atrial fibrillation, hypertension, diastolic dysfunction, and heart failure (HF) with low ejection fraction. However, left atrial (LA) volume, geometry, and emptying have not been compared between diastolic and systolic HF, nor has the association of LA volume for new HF been determined in older subjects, many of whom have normal ejection fraction. We used echocardiography to measure the LA volume, geometry, and emptying in 851 community-dwelling subjects > or =65 years of age, including 180 with HF at baseline and 255 participants who subsequently developed HF. The LA volume, area, and linear dimensions were higher in the prevalent and incident HF groups than in controls and did not differ between those with systolic versus diastolic HF, independent of co-morbidities and Doppler measures of diastolic function. The fractional area change was associated with prevalent, but not incident, HF. In conclusion, in population-based older subjects, the LA size is increased and LA emptying decreased in patients with either systolic or diastolic HF. LA size is associated with the new development of HF. These findings highlight the important role of the left atrium in HF, with or without a decreased ejection fraction.

}, keywords = {Aged, Atrial Function, Left, Case-Control Studies, Diastole, Echocardiography, Female, Heart Atria, Heart Failure, Humans, Male, Multivariate Analysis, Systole}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.07.126}, author = {Gottdiener, John S and Kitzman, Dalane W and Aurigemma, Gerard P and Arnold, Alice M and Manolio, Teri A} } @article {890, title = {Thyroid status, cardiovascular risk, and mortality in older adults.}, journal = {JAMA}, volume = {295}, year = {2006}, month = {2006 Mar 01}, pages = {1033-41}, abstract = {

CONTEXT: Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system.

OBJECTIVE: To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study.

MAIN OUTCOME MEASURES: Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism.

RESULTS: Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15\% (n = 496) had subclinical hypothyroidism, 1.6\% (n = 51) had overt hypothyroidism, and 1.5\% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95\% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95\% confidence interval, 0.90-1.28) for incident coronary heart disease.

CONCLUSION: Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.

}, keywords = {Aged, Atrial Fibrillation, Cardiovascular Diseases, Female, Humans, Hyperthyroidism, Hypothyroidism, Male, Proportional Hazards Models, Risk Factors, Thyroid Gland, Thyrotropin}, issn = {1538-3598}, doi = {10.1001/jama.295.9.1033}, author = {Cappola, Anne R and Fried, Linda P and Arnold, Alice M and Danese, Mark D and Kuller, Lewis H and Burke, Gregory L and Tracy, Russell P and Ladenson, Paul W} } @article {886, title = {Usefulness of aortic root dimension in persons > or = 65 years of age in predicting heart failure, stroke, cardiovascular mortality, all-cause mortality and acute myocardial infarction (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 Jan 15}, pages = {270-5}, abstract = {

Echocardiographic measures of left ventricular (LV) function and structure as well as left atrial size have been reported to predict adverse cardiovascular disease (CVD) outcomes. Although anatomic changes of the aortic root are likely to reflect effects of hypertension and atherosclerosis, few data are available on the predictive value of aortic root dimension (ARD) for outcome in free-living populations. The purpose of this investigation was to determine whether in a cohort of patients aged > or = 65 years ARD was associated with traditional coronary heart disease (CHD) risk factors and with 10-year incident CVD outcomes. In the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Health Study, 3,933 free-living black and white men and women > or = 65 years of age without prevalent CVD had 2-dimensional directed M-mode echocardiographic measurements of ARD as part of a comprehensive evaluation. ARD was associated with age and gender (greater in men) but not race. ARD was also positively associated with diastolic blood pressure, LV hypertrophy, major electrocardiographic abnormalities, and other echocardiographic measures, including LV mass, ventricular septal and posterior wall thickness, and LV dimension. After adjustment for other known risk factors, high ARD was associated with an increased risk for incident congestive heart failure (CHF) in men (hazard ratio for upper compared with all other quintiles 1.47, p = 0.014), stroke in men and women (hazard ratio 1.39 per cm, p = 0.015), CVD mortality in men and women (hazard ratio 1.48 per cm, p = 0.007), and total mortality in men and women taking antihypertensive medications (hazard ratio 1.46 per cm, p = 0.007), but not with incident myocardial infarction (MI) (hazard ratio 0.89, p = 0.39). In conclusion, in a cohort of patients aged > or = 65 years without clinical CVD at baseline, ARD was associated with several CHD risk factors and measures of subclinical disease and was predictive of incident CHF, stroke, CVD mortality, and all-cause mortality, but not of incident MI.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aorta, Cardiovascular Diseases, Echocardiography, Doppler, Female, Heart Failure, Humans, Hypertrophy, Left Ventricular, Male, Multicenter Studies as Topic, Myocardial Infarction, Predictive Value of Tests, Risk Factors, Sex Factors, Stroke}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.08.039}, author = {Gardin, Julius M and Arnold, Alice M and Polak, Joseph and Jackson, Sharon and Smith, Vivienne and Gottdiener, John} } @article {967, title = {Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {116}, year = {2007}, month = {2007 Jul 03}, pages = {32-8}, abstract = {

BACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction.

METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72\% (95\% CI, 1.46 to 2.01) increased risk for CVD death and a 52\% (95\% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54\% for CVD death and 79\% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic.

CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.

}, keywords = {African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Carotid Artery Diseases, Cohort Studies, Comorbidity, Diabetes Mellitus, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Hyperlipidemias, Hypertension, Incidence, Inflammation, Kaplan-Meier Estimate, Male, Mass Screening, Mortality, Myocardial Infarction, Obesity, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, ROC Curve, Smoking, Stroke, Survival Analysis, Tunica Intima, Tunica Media, Ultrasonography, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.106.645606}, author = {Cao, Jie J and Arnold, Alice M and Manolio, Teri A and Polak, Joseph F and Psaty, Bruce M and Hirsch, Calvin H and Kuller, Lewis H and Cushman, Mary} } @article {930, title = {Serum amyloid P and cardiovascular disease in older men and women: results from the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {27}, year = {2007}, month = {2007 Feb}, pages = {352-8}, abstract = {

OBJECTIVE: Serum amyloid P (SAP), a pentraxin like C-reactive protein (CRP), functions in innate immunity. However, associations of SAP with cardiovascular disease (CVD) are unknown.

METHODS AND RESULTS: We examined these associations in the Cardiovascular Health Study using a case-cohort design. Nonexclusive case groups were incident angina (n=523), myocardial infarction (MI; n=308), stroke (n=323), and CVD death (n=288). 786 participants had no events. SAP was correlated with CRP, CVD risk factors (obesity, blood pressure, lipids), common and internal carotid wall thickness, and ankle-brachial index (all P<0.02). In Cox regression models adjusted for age, sex, and ethnicity, a standard deviation increase in SAP (9.8 mg/L) was associated with angina (hazard ratio; 95\% confidence interval 1.3; 1.2 to 1.5) and MI (1.3; 1.1 to 1.5), but not stroke (1.1; 0.9 to 1.3) or CVD death (1.1; 0.9 to 1.3). Adding CRP to the models had no significant effect on associations. Adjusting for CVD risk factors slightly attenuated SAP associations with CVD events; however, associations with angina and MI remained significant.

CONCLUSIONS: Although both are pentraxins, SAP and CRP may represent different facets of inflammation. The association of SAP with CVD in these older adults further supports the role of innate immunity in atherosclerosis.

}, keywords = {Aged, Aged, 80 and over, Aging, Angina, Unstable, Atherosclerosis, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Humans, Hypertension, Immunity, Innate, Male, Myocardial Infarction, Obesity, Prevalence, Proportional Hazards Models, Risk Factors, Serum Amyloid P-Component}, issn = {1524-4636}, doi = {10.1161/01.ATV.0000254150.97741.fe}, author = {Jenny, Nancy Swords and Arnold, Alice M and Kuller, Lewis H and Tracy, Russell P and Psaty, Bruce M} } @article {907, title = {White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Sep}, pages = {1307-15}, abstract = {

High white matter grade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (n=3245) mean age 75 years, 50\% black and 40\% men, we evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting for numerous determinants of longevity over an approximate 10-12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Biomarkers, Brain, Cardiovascular Diseases, Cerebral Ventricles, European Continental Ancestry Group, Female, Geriatric Assessment, Health Status, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Retrospective Studies, Risk Factors, Sex Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.06.010}, author = {Kuller, Lewis H and Arnold, Alice M and Longstreth, W T and Manolio, Teri A and O{\textquoteright}Leary, Daniel H and Burke, Gregory L and Fried, Linda P and Newman, Anne B} } @article {1017, title = {Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study.}, journal = {Circulation}, volume = {117}, year = {2008}, month = {2008 Feb 26}, pages = {1010-7}, abstract = {

BACKGROUND: Long-term data describing small abdominal aortic aneurysms (AAAs) and increasing infrarenal aortic diameters and their relationship to future surgical repair, total mortality, and incident cardiovascular disease (CVD) events, particularly among women, are sparse.

METHODS AND RESULTS: In 1992 to 1993, 4734 Cardiovascular Health Study participants > or = 65 years old had an abdominal aortic ultrasound evaluation. Of those screened, 416 had an AAA (infrarenal aortic diameter > or = 3.0 cm or an infrarenal/suprarenal ratio > or = 1.2). By 2002, there were 56 surgical AAA repairs and 10 AAA-related deaths. A single ultrasound screening demonstrated that aneurysm dilation > or = 3 cm identified 68\% of all AAA repairs over the next 10 years and 6 of the 10 AAA-related deaths in 4\% of the total population and that a > or = 2.5-cm dilation identified 91\% of all AAA repairs and 9 of the 10 deaths in 10\% of the total population. With adjusted Cox proportional hazard models, AAAs were associated with a higher risk of total mortality (hazard ratio 1.44, 95\% confidence interval 1.25 to 1.66) and incident CVD events (hazard ratio 1.52, 95\% confidence interval 1.25 to 1.85). Compared with diameters < 2.0 cm, infrarenal aortic diameters 2.0 to < 3.0 cm were associated with increased risk of incident CVD events in women and total mortality in men.

CONCLUSIONS: This study suggests that a 1-time screening of the abdominal aorta can acceptably identify individuals with a clinically significant AAA. Infrarenal aortic diameters > 2.0 cm are associated with a significantly increased risk of future CVD events and total mortality.

}, keywords = {Aged, Aged, 80 and over, Aorta, Abdominal, Aortic Aneurysm, Abdominal, Cause of Death, Female, Follow-Up Studies, Humans, Incidence, Intermittent Claudication, Kidney, Male, Prospective Studies, Risk Factors, Sex Distribution, Ultrasonography}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.107.720219}, author = {Freiberg, Matthew S and Arnold, Alice M and Newman, Anne B and Edwards, Matthew S and Kraemer, Kevin L and Kuller, Lewis H} } @article {1066, title = {Prevalence, prognosis, and implications of isolated minor nonspecific ST-segment and T-wave abnormalities in older adults: Cardiovascular Health Study.}, journal = {Circulation}, volume = {118}, year = {2008}, month = {2008 Dec 16}, pages = {2790-6}, abstract = {

BACKGROUND: The prevalence and prognostic significance of isolated minor nonspecific ST-segment and T-wave abnormalities (NSSTTAs) in older adults are poorly understood.

METHODS AND RESULTS: Cardiovascular Health Study participants free of both clinical cardiovascular disease and major ECG abnormalities were included. We examined the prospective association of isolated minor NSSTTAs (defined by Minnesota Codes 4-3, 4-4, 5-3, and 5-4) with total, cardiovascular, and coronary mortality and incident nonfatal myocardial infarction. Among 3224 participants (61.9\% women; mean age, 72 years), 233 (7.2\%) had isolated NSSTTAs at baseline. Covariates associated with isolated NSSTTAs included older age, nonwhite race (20.5\% of blacks versus 4.8\% of whites; P<0.001), diabetes, and higher blood pressure and body mass index but not the presence of subclinical cardiovascular disease. After 39 518 person-years of follow-up, the presence of isolated NSSTTAs was associated with significantly increased risk for coronary heart disease mortality (multivariable-adjusted hazards ratio, 1.76; 95\% CI, 1.18 to 2.61) but not with incident nonfatal myocardial infarction (multivariable-adjusted hazards ratio, 0.71; 95\% CI, 0.43 to 1.17). The association of isolated NSSTTAs with coronary death was independent of subclinical atherosclerosis and left ventricular mass measures. In secondary analyses, among those with cardiac death, there was a significantly higher rate of primary arrhythmic death (32.3\% versus 15.4\%; P=0.02) in participants with isolated NSSTTAs versus those without NSSTTAs.

CONCLUSIONS: Isolated NSSTTAs are common in older Americans and are associated with significantly increased risk for coronary death. However, isolated NSSTTAs are not associated with incident nonfatal myocardial infarction, suggesting that they are associated particularly with increased risk for primary arrhythmic death.

}, keywords = {Age Factors, Aged, Arrhythmias, Cardiac, Cardiovascular Diseases, Cohort Studies, Electrocardiography, Female, Health Status, Humans, Male, Middle Aged, Prevalence, Prognosis, Prospective Studies}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.108.772541}, author = {Kumar, Anita and Prineas, Ronald J and Arnold, Alice M and Psaty, Bruce M and Furberg, Curt D and Robbins, John and Lloyd-Jones, Donald M} } @article {1072, title = {Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {29}, year = {2009}, month = {2009 Apr}, pages = {594-9}, abstract = {

OBJECTIVE: We examined associations of pentraxin 3 (PTX3), a vascular inflammation marker, with incident cardiovascular disease (CVD) and all-cause death.

METHODS AND RESULTS: 1583 Cardiovascular Health Study participants free of prevalent CVD were included. Nonexclusive case groups were angina (n=476), myocardial infarction (MI; n=237), stroke (n=310), CVD death (n=282), and all-cause death (n=772). 535 participants had no events. PTX3 levels were higher in those with subclinical CVD (1.90+/-1.89 ng/mL) than those without (1.71+/-1.88 ng/mL; P=0.001). Using Cox regression adjusted for age, sex, and ethnicity, a standard deviation increase in PTX3 (1.89 ng/mL) was associated with CVD death (hazard ratio 1.11; 95\% confidence interval 1.02 to 1.21) and all-cause death (1.08; 1.02 to 1.15). PTX3 was not associated with angina (1.09; 0.98 to 1.20), MI (0.96; 0.81 to 1.12), or stroke (1.06; 0.95 to 1.18). Adding C-reactive protein (CRP) or CVD risk factors to the models had no significant effects on associations.

CONCLUSIONS: In these older adults, PTX3 was associated with CVD and all-cause death independent of CRP and CVD risk factors. PTX3 likely reflects different aspects of inflammation than CRP and may provide insight into vascular health in aging and chronic diseases of aging that lead to death.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Health Surveys, Humans, Inflammation Mediators, Linear Models, Male, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Serum Amyloid P-Component, Time Factors, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.108.178947}, author = {Jenny, Nancy Swords and Arnold, Alice M and Kuller, Lewis H and Tracy, Russell P and Psaty, Bruce M} } @article {1067, title = {High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over.}, journal = {J Clin Endocrinol Metab}, volume = {94}, year = {2009}, month = {2009 Apr}, pages = {1342-5}, abstract = {

CONTEXT: Thyroid hormone use is common in older populations, but the frequency of over- or under-replacement is debated.

OBJECTIVE: We sought to describe the frequency of and factors associated with thyroid hormone over- or under-replacement in a population of older men and women.

DESIGN: Participants were 3678 U.S. community dwelling individuals aged 65 yr or older enrolled in the Cardiovascular Health Study who had thyroid function tests in 1989-1990. Thyroid hormone users (n = 339) were identified and classified into low TSH (<0.45 mU/liter), euthyroid (0.45-4.5 mU/liter), and high TSH (>4.5 mU/liter).

RESULTS: Of the 339 thyroid hormone users, 41\% had a low TSH, 16\% had a high TSH, and 43\% were in the euthyroid range. In multivariable analyses, lower weight (P < 0.001) was independently associated with low TSH status. For every 10 kg lower weight, the likelihood of having low TSH increased by 65\% [odd ratio (OR) 1.65; 95\% confidence interval (CI) 1.31-2.07]. Those with renal insufficiency were less likely to have low TSH levels (P = 0.02). The presence of diabetes was independently associated with having low (OR 3.35; 95\% CI 1.46-7.65) and high TSH levels (OR 2.66; 95\% CI 1.14-6.21).

CONCLUSIONS: There is a very high prevalence of thyroid function testing abnormalities in older people taking thyroid hormone preparations, particularly in those of low weight or with diabetes. Because of potential adverse cardiovascular and skeletal effects from over-replacement, older people represent a key population for increased TSH monitoring on therapy.

}, keywords = {Aged, Body Mass Index, Body Weight, Diabetes Mellitus, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Hormone Replacement Therapy, Humans, Male, Multivariate Analysis, Renal Insufficiency, Risk Factors, Thyroid Diseases, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1945-7197}, doi = {10.1210/jc.2008-1696}, author = {Somwaru, Lily L and Arnold, Alice M and Joshi, Neha and Fried, Linda P and Cappola, Anne R} } @article {1136, title = {Left atrial volume and geometry in healthy aging: the Cardiovascular Health Study.}, journal = {Circ Cardiovasc Imaging}, volume = {2}, year = {2009}, month = {2009 Jul}, pages = {282-9}, abstract = {

BACKGROUND: The left atrium is a validated marker of clinical and subclinical cardiovascular disease. Left atrial enlargement is often seen among older individuals; however, there are few population-based data regarding normal left atrial size among older persons, especially from those who are healthy, and from women. Furthermore, because the left atrium is a 3D structure, the commonly used parasternal long-axis diastolic diameter often underdiagnoses left atrial enlargement.

METHODS AND RESULTS: We evaluated left atrial size in 230 healthy participants (mean age, 76+/-5 years) free of prevalent cardiac disease, rhythm abnormality, hypertension, and diabetes selected from the Cardiovascular Health Study, a prospective community-based study of risk factors for cardiovascular disease in 5888 elderly participants. In addition to the standard long-axis measurement, we obtained left atrial superoinferior and lateral diameters and used these dimensions to estimate left atrial volume. These measurements were used to generate reference ranges for determining left atrial enlargement in older men and women, based on the 95\% percentiles of the left atrial dimensions in healthy participants, both unadjusted, and after adjustment for age, height, and weight. In healthy elderly subjects, indices of left atrial size do not correlate with age or height but with weight and other measures of body build.

CONCLUSIONS: These data provide normative reference values for left atrial size in healthy older women and men. The results should be useful for refining diagnostic criteria for left atrial dilation in the older population and may be relevant for cardiovascular risk stratification.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Atrial Function, Left, Body Size, Body Surface Area, Echocardiography, Three-Dimensional, Female, Heart Atria, Humans, Linear Models, Male, Models, Biological, Organ Size, Population Surveillance, Prospective Studies, Reference Values, Sex Factors, United States}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.108.826602}, author = {Aurigemma, Gerard P and Gottdiener, John S and Arnold, Alice M and Chinali, Marcello and Hill, Jeffrey C and Kitzman, Dalane} } @article {1075, title = {Long-term function in an older cohort--the cardiovascular health study all stars study.}, journal = {J Am Geriatr Soc}, volume = {57}, year = {2009}, month = {2009 Mar}, pages = {432-40}, abstract = {

OBJECTIVES: To evaluate shared and unique risk factors for maintaining physical and cognitive function into the ninth decade and beyond.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: One thousand six hundred seventy-seven participants in the Cardiovascular Health Study All Stars Study, assessed in 2005/06. Median age was 85 (range 77-102), 66.5\% were women, and 16.6\% were black.

MEASUREMENTS: Intact function was defined as no difficulty with any activities of daily living and a score of 80 or higher on the Modified Mini-Mental State Examination. Baseline characteristics assessed in 1992/93 included demographics, behavioral health factors, chronic disease history, subclinical disease markers, cardiovascular risk factors, and inflammatory markers. Multinomial logistic regression was used to compare risk for physical disability, cognitive impairment,and combined impairments with no functional impairment.

RESULTS: Of the 1,677 participants evaluated in both domains, 891 (53\%) were functionally intact. Continuous measures of function, including the Digit Symbol Substitution Test and gait speed, showed that all groups, including the most functional, had declined over time. The functional group had less decline but also tended to have higher starting values. Functional individuals had a higher baseline health profile than those with either or cognitive impairment or both impairments combined. Women and individuals with greater weight had higher rates of physical impairment but not cognitive impairment. Risk factors common to both types of impairment included cardiovascular disease and hypertension.

CONCLUSION: Intact function was found in only approximately half of these older adults in the ninth decade and beyond. High baseline function and low vascular disease risk characterized functional aging.

}, keywords = {Activities of Daily Living, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Attention, Cardiovascular Diseases, Chronic Disease, Cohort Studies, Comorbidity, Cross-Sectional Studies, Female, Follow-Up Studies, Gait, Geriatric Assessment, Hand Strength, Health Surveys, Humans, Male, Memory, Short-Term, Mental Status Schedule, Proportional Hazards Models, Psychometrics, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.02152.x}, author = {Newman, Anne B and Arnold, Alice M and Sachs, Michael C and Ives, Diane G and Cushman, Mary and Strotmeyer, Elsa S and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Fried, Linda P and Robbins, John} } @article {1107, title = {NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {5}, year = {2009}, month = {2009 Jun}, pages = {e1000539}, abstract = {

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95\% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

}, keywords = {Aged, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Obesity, Polymorphism, Single Nucleotide, Waist Circumference}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1000539}, author = {Heard-Costa, Nancy L and Zillikens, M Carola and Monda, Keri L and Johansson, Asa and Harris, Tamara B and Fu, Mao and Haritunians, Talin and Feitosa, Mary F and Aspelund, Thor and Eiriksdottir, Gudny and Garcia, Melissa and Launer, Lenore J and Smith, Albert V and Mitchell, Braxton D and McArdle, Patrick F and Shuldiner, Alan R and Bielinski, Suzette J and Boerwinkle, Eric and Brancati, Fred and Demerath, Ellen W and Pankow, James S and Arnold, Alice M and Chen, Yii-Der Ida and Glazer, Nicole L and McKnight, Barbara and Psaty, Bruce M and Rotter, Jerome I and Amin, Najaf and Campbell, Harry and Gyllensten, Ulf and Pattaro, Cristian and Pramstaller, Peter P and Rudan, Igor and Struchalin, Maksim and Vitart, Veronique and Gao, Xiaoyi and Kraja, Aldi and Province, Michael A and Zhang, Qunyuan and Atwood, Larry D and Dupuis, Jos{\'e}e and Hirschhorn, Joel N and Jaquish, Cashell E and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and White, Charles C and Aulchenko, Yurii S and Estrada, Karol and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Oostra, Ben A and Kaplan, Robert C and Gudnason, Vilmundur and O{\textquoteright}Connell, Jeffrey R and Borecki, Ingrid B and van Duijn, Cornelia M and Cupples, L Adrienne and Fox, Caroline S and North, Kari E} } @article {1090, title = {Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {103}, year = {2009}, month = {2009 Apr 15}, pages = {1120-7}, abstract = {

In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15\% to 20\% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Cohort Studies, Continental Population Groups, European Continental Ancestry Group, Female, Heart Failure, Humans, Incidence, Male, Proportional Hazards Models, Sex Factors, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2008.12.043}, author = {Parashar, Susmita and Katz, Ronit and Smith, Nicholas L and Arnold, Alice M and Vaccarino, Viola and Wenger, Nanette K and Gottdiener, John S} } @article {1124, title = {Total and cause-specific mortality in the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1251-61}, abstract = {

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cause of Death, Chronic Disease, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Kaplan-Meier Estimate, Male, Probability, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp127}, author = {Newman, Anne B and Sachs, Michael C and Arnold, Alice M and Fried, Linda P and Kronmal, Richard and Cushman, Mary and Psaty, Bruce M and Harris, Tamara B and Robbins, John A and Burke, Gregory L and Kuller, Lewis H and Lumley, Thomas} } @article {1097, title = {Using telephone and informant assessments to estimate missing Modified Mini-Mental State Exam scores and rates of cognitive decline. The cardiovascular health study.}, journal = {Neuroepidemiology}, volume = {33}, year = {2009}, month = {2009}, pages = {55-65}, abstract = {

AIM: To estimate an equivalent to the Modified Mini-Mental State Exam (3MSE), and to compare changes in the 3MSE with and without the estimated scores.

METHODS: Comparability study on a subset of 405 participants, aged >or=70 years, from the Cardiovascular Health Study (CHS), a longitudinal study in 4 United States communities. The 3MSE, the Telephone Interview for Cognitive Status (TICS) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were administered within 30 days of one another. Regression models were developed to predict the 3MSE score from the TICS and/or IQCODE, and the predicted values were used to estimate missing 3MSE scores in longitudinal follow-up of 4,274 CHS participants.

RESULTS: The TICS explained 67\% of the variability in 3MSE scores, with a correlation of 0.82 between predicted and observed scores. The IQCODE alone was not a good estimate of 3MSE score, but improved the model fit when added to the TICS model. Using estimated 3MSE scores classified more participants with low cognition, and rates of decline were greater than when only the observed 3MSE scores were considered.

CONCLUSIONS: 3MSE scores can be reliably estimated from the TICS, with or without the IQCODE. Incorporating these estimates captured more cognitive decline in older adults.

}, keywords = {Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cognition Disorders, Female, Humans, Interviews as Topic, Longitudinal Studies, Male, Predictive Value of Tests, Psychiatric Status Rating Scales, Regression Analysis, Risk Factors, ROC Curve, United States}, issn = {1423-0208}, doi = {10.1159/000215830}, author = {Arnold, Alice M and Newman, Anne B and Dermond, Norma and Haan, Mary and Fitzpatrick, Annette} } @article {1237, title = {Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {937-48}, abstract = {

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and \~{} 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 {\texttimes} 10$^{-}$$^{8}$), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

}, keywords = {Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.686}, author = {Speliotes, Elizabeth K and Willer, Cristen J and Berndt, Sonja I and Monda, Keri L and Thorleifsson, Gudmar and Jackson, Anne U and Lango Allen, Hana and Lindgren, Cecilia M and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Randall, Joshua C and Vedantam, Sailaja and Winkler, Thomas W and Qi, Lu and Workalemahu, Tsegaselassie and Heid, Iris M and Steinthorsdottir, Valgerdur and Stringham, Heather M and Weedon, Michael N and Wheeler, Eleanor and Wood, Andrew R and Ferreira, Teresa and Weyant, Robert J and Segr{\`e}, Ayellet V and Estrada, Karol and Liang, Liming and Nemesh, James and Park, Ju-Hyun and Gustafsson, Stefan and Kilpel{\"a}inen, Tuomas O and Yang, Jian and Bouatia-Naji, Nabila and Esko, T{\~o}nu and Feitosa, Mary F and Kutalik, Zolt{\'a}n and Mangino, Massimo and Raychaudhuri, Soumya and Scherag, Andre and Smith, Albert Vernon and Welch, Ryan and Zhao, Jing Hua and Aben, Katja K and Absher, Devin M and Amin, Najaf and Dixon, Anna L and Fisher, Eva and Glazer, Nicole L and Goddard, Michael E and Heard-Costa, Nancy L and Hoesel, Volker and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Ketkar, Shamika and Lamina, Claudia and Li, Shengxu and Moffatt, Miriam F and Myers, Richard H and Narisu, Narisu and Perry, John R B and Peters, Marjolein J and Preuss, Michael and Ripatti, Samuli and Rivadeneira, Fernando and Sandholt, Camilla and Scott, Laura J and Timpson, Nicholas J and Tyrer, Jonathan P and van Wingerden, Sophie and Watanabe, Richard M and White, Charles C and Wiklund, Fredrik and Barlassina, Christina and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Lawrence, Robert W and Pellikka, Niina and Prokopenko, Inga and Shi, Jianxin and Thiering, Elisabeth and Alavere, Helene and Alibrandi, Maria T S and Almgren, Peter and Arnold, Alice M and Aspelund, Thor and Atwood, Larry D and Balkau, Beverley and Balmforth, Anthony J and Bennett, Amanda J and Ben-Shlomo, Yoav and Bergman, Richard N and Bergmann, Sven and Biebermann, Heike and Blakemore, Alexandra I F and Boes, Tanja and Bonnycastle, Lori L and Bornstein, Stefan R and Brown, Morris J and Buchanan, Thomas A and Busonero, Fabio and Campbell, Harry and Cappuccio, Francesco P and Cavalcanti-Proen{\c c}a, Christine and Chen, Yii-Der Ida and Chen, Chih-Mei and Chines, Peter S and Clarke, Robert and Coin, Lachlan and Connell, John and Day, Ian N M and den Heijer, Martin and Duan, Jubao and Ebrahim, Shah and Elliott, Paul and Elosua, Roberto and Eiriksdottir, Gudny and Erdos, Michael R and Eriksson, Johan G and Facheris, Maurizio F and Felix, Stephan B and Fischer-Posovszky, Pamela and Folsom, Aaron R and Friedrich, Nele and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Gejman, Pablo V and Geus, Eco J C and Gieger, Christian and Gjesing, Anette P and Goel, Anuj and Goyette, Philippe and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Greenawalt, Danielle M and Groves, Christopher J and Gudnason, Vilmundur and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Hall, Alistair S and Havulinna, Aki S and Hayward, Caroline and Heath, Andrew C and Hengstenberg, Christian and Hicks, Andrew A and Hinney, Anke and Hofman, Albert and Homuth, Georg and Hui, Jennie and Igl, Wilmar and Iribarren, Carlos and Isomaa, Bo and Jacobs, Kevin B and Jarick, Ivonne and Jewell, Elizabeth and John, Ulrich and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Kaakinen, Marika and Kajantie, Eero and Kaplan, Lee M and Kathiresan, Sekar and Kettunen, Johannes and Kinnunen, Leena and Knowles, Joshua W and Kolcic, Ivana and K{\"o}nig, Inke R and Koskinen, Seppo and Kovacs, Peter and Kuusisto, Johanna and Kraft, Peter and Kval{\o}y, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lanzani, Chiara and Launer, Lenore J and Lecoeur, C{\'e}cile and Lehtim{\"a}ki, Terho and Lettre, Guillaume and Liu, Jianjun and Lokki, Marja-Liisa and Lorentzon, Mattias and Luben, Robert N and Ludwig, Barbara and Manunta, Paolo and Marek, Diana and Marre, Michel and Martin, Nicholas G and McArdle, Wendy L and McCarthy, Anne and McKnight, Barbara and Meitinger, Thomas and Melander, Olle and Meyre, David and Midthjell, Kristian and Montgomery, Grant W and Morken, Mario A and Morris, Andrew P and Mulic, Rosanda and Ngwa, Julius S and Nelis, Mari and Neville, Matt J and Nyholt, Dale R and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Ong, Ken K and Oostra, Ben and Par{\'e}, Guillaume and Parker, Alex N and Perola, Markus and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Polasek, Ozren and Pouta, Anneli and Rafelt, Suzanne and Raitakari, Olli and Rayner, Nigel W and Ridderstr{\r a}le, Martin and Rief, Winfried and Ruokonen, Aimo and Robertson, Neil R and Rzehak, Peter and Salomaa, Veikko and Sanders, Alan R and Sandhu, Manjinder S and Sanna, Serena and Saramies, Jouko and Savolainen, Markku J and Scherag, Susann and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Silander, Kaisa and Sinisalo, Juha and Siscovick, David S and Smit, Jan H and Soranzo, Nicole and Sovio, Ulla and Stephens, Jonathan and Surakka, Ida and Swift, Amy J and Tammesoo, Mari-Liis and Tardif, Jean-Claude and Teder-Laving, Maris and Teslovich, Tanya M and Thompson, John R and Thomson, Brian and T{\"o}njes, Anke and Tuomi, Tiinamaija and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Viikari, Jorma and Visvikis-Siest, Sophie and Vitart, Veronique and Vogel, Carla I G and Voight, Benjamin F and Waite, Lindsay L and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wiegand, Susanna and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Witteman, Jacqueline C and Xu, Jianfeng and Zhang, Qunyuan and Zgaga, Lina and Ziegler, Andreas and Zitting, Paavo and Beilby, John P and Farooqi, I Sadaf and Hebebrand, Johannes and Huikuri, Heikki V and James, Alan L and K{\"a}h{\"o}nen, Mika and Levinson, Douglas F and Macciardi, Fabio and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Ridker, Paul M and Stumvoll, Michael and Beckmann, Jacques S and Boeing, Heiner and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Collins, Francis S and Cupples, L Adrienne and Smith, George Davey and Erdmann, Jeanette and Froguel, Philippe and Gr{\"o}nberg, Henrik and Gyllensten, Ulf and Hall, Per and Hansen, Torben and Harris, Tamara B and Hattersley, Andrew T and Hayes, Richard B and Heinrich, Joachim and Hu, Frank B and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and Kaprio, Jaakko and Karpe, Fredrik and Khaw, Kay-Tee and Kiemeney, Lambertus A and Krude, Heiko and Laakso, Markku and Lawlor, Debbie A and Metspalu, Andres and Munroe, Patricia B and Ouwehand, Willem H and Pedersen, Oluf and Penninx, Brenda W and Peters, Annette and Pramstaller, Peter P and Quertermous, Thomas and Reinehr, Thomas and Rissanen, Aila and Rudan, Igor and Samani, Nilesh J and Schwarz, Peter E H and Shuldiner, Alan R and Spector, Timothy D and Tuomilehto, Jaakko and Uda, Manuela and Uitterlinden, Andre and Valle, Timo T and Wabitsch, Martin and Waeber, G{\'e}rard and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Wright, Alan F and Zillikens, M Carola and Chatterjee, Nilanjan and McCarroll, Steven A and Purcell, Shaun and Schadt, Eric E and Visscher, Peter M and Assimes, Themistocles L and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and van Duijn, Cornelia M and Wichmann, H-Erich and Frayling, Timothy M and Thorsteinsdottir, Unnur and Abecasis, Goncalo R and Barroso, In{\^e}s and Boehnke, Michael and Stefansson, Kari and North, Kari E and McCarthy, Mark I and Hirschhorn, Joel N and Ingelsson, Erik and Loos, Ruth J F} } @article {1094, title = {Body weight dynamics and their association with physical function and mortality in older adults: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Jan}, pages = {63-70}, abstract = {

BACKGROUND: To estimate the associations of weight dynamics with physical functioning and mortality in older adults.

METHODS: Longitudinal cohort study using prospectively collected data on weight, physical function, and health status in four U.S. Communities in the Cardiovascular Health Study. Included were 3,278 participants (2,013 women and 541 African Americans), aged 65 or older at enrollment, who had at least five weight measurements. Weight was measured at annual clinic visits between 1992 and 1999, and summary measures of mean weight, coefficient of variation, average annual weight change, and episodes of loss and gain (cycling) were calculated. Participants were followed from 1999 to 2006 for activities of daily living (ADL) difficulty, incident mobility limitations, and mortality.

RESULTS: Higher mean weight, weight variability, and weight cycling increased the risk of new onset of ADL difficulties and mobility limitations. After adjustment for risk factors, the hazard ratio (95\% confidence interval) for weight cycling for incident ADL impairment was 1.28 (1.12, 1.47), similar to that for several comorbidities in our model, including cancer and diabetes. Lower weight, weight loss, higher variability, and weight cycling were all risk factors for mortality, after adjustment for demographic risk factors, height, self-report health status, and comorbidities.

CONCLUSIONS: Variations in weight are important indicators of future physical limitations and mortality in the elderly and may reflect difficulties in maintaining homeostasis throughout older ages. Monitoring the weight of an older person for fluctuations or episodes of both loss and gain is an important aspect of geriatric care.

}, keywords = {Activities of Daily Living, Age Factors, Aged, 80 and over, Body Weight, Cardiovascular Diseases, Female, Follow-Up Studies, Health Status, Humans, Longevity, Male, Prospective Studies, Risk Factors, Survival Rate, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp050}, author = {Arnold, Alice M and Newman, Anne B and Cushman, Mary and Ding, Jingzhong and Kritchevsky, Stephen} } @article {1168, title = {Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study.}, journal = {J Am Geriatr Soc}, volume = {58}, year = {2010}, month = {2010 Mar}, pages = {421-6}, abstract = {

OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.

DESIGN: Longitudinal cohort study.

SETTING: Pittsburgh, Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5\% women, 16.5\% African American).

MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.

RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95\% confidence interval=1.03-2.05).

CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Dehydroepiandrosterone Sulfate, Female, Humans, Longitudinal Studies, Male, Multivariate Analysis, Regression Analysis, Sex Distribution, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.02724.x}, author = {Sanders, Jason L and Boudreau, Robert M and Cappola, Anne R and Arnold, Alice M and Robbins, John and Cushman, Mary and Newman, Anne B} } @article {1214, title = {Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1208-14}, abstract = {

BACKGROUND: Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated.

METHODS: We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996-1997 and 2005-2006, had serial adiponectin measurements and underwent follow-up through June 2009.

RESULTS: Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95\% confidence interval = 1.36-2.52 per SD >= 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95\% confidence interval = 1.10-1.52 per SD).

CONCLUSIONS: Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group.

}, keywords = {Adiponectin, Age Factors, Aged, Aging, Analysis of Variance, Cardiovascular Diseases, Cause of Death, Chi-Square Distribution, Cohort Studies, Cross-Sectional Studies, Female, Health Status, Humans, Linear Models, Male, Physical Fitness, Proportional Hazards Models, Risk Factors, Sex Factors, Time Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glq122}, author = {Kizer, Jorge R and Arnold, Alice M and Strotmeyer, Elsa S and Ives, Diane G and Cushman, Mary and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Hirsch, Calvin H and Newman, Anne B} } @article {1234, title = {Hundreds of variants clustered in genomic loci and biological pathways affect human height.}, journal = {Nature}, volume = {467}, year = {2010}, month = {2010 Oct 14}, pages = {832-8}, abstract = {

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10\% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16\% of phenotypic variation (approximately 20\% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

}, keywords = {Body Height, Chromosomes, Human, Pair 3, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Metabolic Networks and Pathways, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide}, issn = {1476-4687}, doi = {10.1038/nature09410}, author = {Lango Allen, Hana and Estrada, Karol and Lettre, Guillaume and Berndt, Sonja I and Weedon, Michael N and Rivadeneira, Fernando and Willer, Cristen J and Jackson, Anne U and Vedantam, Sailaja and Raychaudhuri, Soumya and Ferreira, Teresa and Wood, Andrew R and Weyant, Robert J and Segr{\`e}, Ayellet V and Speliotes, Elizabeth K and Wheeler, Eleanor and Soranzo, Nicole and Park, Ju-Hyun and Yang, Jian and Gudbjartsson, Daniel and Heard-Costa, Nancy L and Randall, Joshua C and Qi, Lu and Vernon Smith, Albert and M{\"a}gi, Reedik and Pastinen, Tomi and Liang, Liming and Heid, Iris M and Luan, Jian{\textquoteright}an and Thorleifsson, Gudmar and Winkler, Thomas W and Goddard, Michael E and Sin Lo, Ken and Palmer, Cameron and Workalemahu, Tsegaselassie and Aulchenko, Yurii S and Johansson, Asa and Zillikens, M Carola and Feitosa, Mary F and Esko, T{\~o}nu and Johnson, Toby and Ketkar, Shamika and Kraft, Peter and Mangino, Massimo and Prokopenko, Inga and Absher, Devin and Albrecht, Eva and Ernst, Florian and Glazer, Nicole L and Hayward, Caroline and Hottenga, Jouke-Jan and Jacobs, Kevin B and Knowles, Joshua W and Kutalik, Zolt{\'a}n and Monda, Keri L and Polasek, Ozren and Preuss, Michael and Rayner, Nigel W and Robertson, Neil R and Steinthorsdottir, Valgerdur and Tyrer, Jonathan P and Voight, Benjamin F and Wiklund, Fredrik and Xu, Jianfeng and Zhao, Jing Hua and Nyholt, Dale R and Pellikka, Niina and Perola, Markus and Perry, John R B and Surakka, Ida and Tammesoo, Mari-Liis and Altmaier, Elizabeth L and Amin, Najaf and Aspelund, Thor and Bhangale, Tushar and Boucher, Gabrielle and Chasman, Daniel I and Chen, Constance and Coin, Lachlan and Cooper, Matthew N and Dixon, Anna L and Gibson, Quince and Grundberg, Elin and Hao, Ke and Juhani Junttila, M and Kaplan, Lee M and Kettunen, Johannes and K{\"o}nig, Inke R and Kwan, Tony and Lawrence, Robert W and Levinson, Douglas F and Lorentzon, Mattias and McKnight, Barbara and Morris, Andrew P and M{\"u}ller, Martina and Suh Ngwa, Julius and Purcell, Shaun and Rafelt, Suzanne and Salem, Rany M and Salvi, Erika and Sanna, Serena and Shi, Jianxin and Sovio, Ulla and Thompson, John R and Turchin, Michael C and Vandenput, Liesbeth and Verlaan, Dominique J and Vitart, Veronique and White, Charles C and Ziegler, Andreas and Almgren, Peter and Balmforth, Anthony J and Campbell, Harry and Citterio, Lorena and De Grandi, Alessandro and Dominiczak, Anna and Duan, Jubao and Elliott, Paul and Elosua, Roberto and Eriksson, Johan G and Freimer, Nelson B and Geus, Eco J C and Glorioso, Nicola and Haiqing, Shen and Hartikainen, Anna-Liisa and Havulinna, Aki S and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Illig, Thomas and Jula, Antti and Kajantie, Eero and Kilpel{\"a}inen, Tuomas O and Koiranen, Markku and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Laitinen, Jaana and Liu, Jianjun and Lokki, Marja-Liisa and Marusic, Ana and Maschio, Andrea and Meitinger, Thomas and Mulas, Antonella and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Petersmann, Astrid and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Pouta, Anneli and Ridderstr{\r a}le, Martin and Rotter, Jerome I and Sambrook, Jennifer G and Sanders, Alan R and Schmidt, Carsten Oliver and Sinisalo, Juha and Smit, Jan H and Stringham, Heather M and Bragi Walters, G and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Zagato, Laura and Zgaga, Lina and Zitting, Paavo and Alavere, Helene and Farrall, Martin and McArdle, Wendy L and Nelis, Mari and Peters, Marjolein J and Ripatti, Samuli and van Meurs, Joyce B J and Aben, Katja K and Ardlie, Kristin G and Beckmann, Jacques S and Beilby, John P and Bergman, Richard N and Bergmann, Sven and Collins, Francis S and Cusi, Daniele and den Heijer, Martin and Eiriksdottir, Gudny and Gejman, Pablo V and Hall, Alistair S and Hamsten, Anders and Huikuri, Heikki V and Iribarren, Carlos and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kathiresan, Sekar and Kiemeney, Lambertus and Kocher, Thomas and Launer, Lenore J and Lehtim{\"a}ki, Terho and Melander, Olle and Mosley, Tom H and Musk, Arthur W and Nieminen, Markku S and O{\textquoteright}Donnell, Christopher J and Ohlsson, Claes and Oostra, Ben and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Rioux, John D and Rissanen, Aila and Rivolta, Carlo and Schunkert, Heribert and Shuldiner, Alan R and Siscovick, David S and Stumvoll, Michael and T{\"o}njes, Anke and Tuomilehto, Jaakko and van Ommen, Gert-Jan and Viikari, Jorma and Heath, Andrew C and Martin, Nicholas G and Montgomery, Grant W and Province, Michael A and Kayser, Manfred and Arnold, Alice M and Atwood, Larry D and Boerwinkle, Eric and Chanock, Stephen J and Deloukas, Panos and Gieger, Christian and Gr{\"o}nberg, Henrik and Hall, Per and Hattersley, Andrew T and Hengstenberg, Christian and Hoffman, Wolfgang and Lathrop, G Mark and Salomaa, Veikko and Schreiber, Stefan and Uda, Manuela and Waterworth, Dawn and Wright, Alan F and Assimes, Themistocles L and Barroso, In{\^e}s and Hofman, Albert and Mohlke, Karen L and Boomsma, Dorret I and Caulfield, Mark J and Cupples, L Adrienne and Erdmann, Jeanette and Fox, Caroline S and Gudnason, Vilmundur and Gyllensten, Ulf and Harris, Tamara B and Hayes, Richard B and Jarvelin, Marjo-Riitta and Mooser, Vincent and Munroe, Patricia B and Ouwehand, Willem H and Penninx, Brenda W and Pramstaller, Peter P and Quertermous, Thomas and Rudan, Igor and Samani, Nilesh J and Spector, Timothy D and V{\"o}lzke, Henry and Watkins, Hugh and Wilson, James F and Groop, Leif C and Haritunians, Talin and Hu, Frank B and Kaplan, Robert C and Metspalu, Andres and North, Kari E and Schlessinger, David and Wareham, Nicholas J and Hunter, David J and O{\textquoteright}Connell, Jeffrey R and Strachan, David P and Wichmann, H-Erich and Borecki, Ingrid B and van Duijn, Cornelia M and Schadt, Eric E and Thorsteinsdottir, Unnur and Peltonen, Leena and Uitterlinden, Andr{\'e} G and Visscher, Peter M and Chatterjee, Nilanjan and Loos, Ruth J F and Boehnke, Michael and McCarthy, Mark I and Ingelsson, Erik and Lindgren, Cecilia M and Abecasis, Goncalo R and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N} } @article {1185, title = {Long-term retention of older adults in the Cardiovascular Health Study: implications for studies of the oldest old.}, journal = {J Am Geriatr Soc}, volume = {58}, year = {2010}, month = {2010 Apr}, pages = {696-701}, abstract = {

OBJECTIVES: To describe retention according to age and visit type (clinic, home, telephone) and to determine characteristics associated with visit types for a longitudinal epidemiological study in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. clinical sites.

PARTICIPANTS: Five thousand eight hundred eighty-eight Cardiovascular Health Study (CHS) participants aged 65 to 100 at 1989/90 or 1992/93 enrollment (58.6\% female; 15.7\% black). CHS participants were contacted every 6 months, with annual assessments through 1999 and in 2005/06 for the All Stars Study visit of the CHS cohort (aged 77-102; 66.5\% female; 16.6\% black).

MEASUREMENTS: All annual contacts through 1999 (n=43,772) and for the 2005/06 visit (n=1,942).

RESULTS: CHS had 43,772 total participant contacts from 1989 to 1999: 34,582 clinic visits (79.0\%), 2,238 refusals (5.1\%), 4,401 telephone visits (10.1\%), 1,811 home visits (4.1\%), and 740 other types (1.7\%). In 2005/06, the All Stars participants of the CHS cohort had 36.6\% clinic, 22.3\% home, and 41.1\% telephone visits. Compared with participants aged 65 to 69, odds ratios of not attending a CHS clinic visit were 1.82 (95\% confidence interval (CI)=1.54-2.13), 2.94 (95\% CI=2.45-3.57), 4.55 (95\% CI=3.70-5.56), and 9.09 (95\% CI=7.69-11.11) for those aged 70 to 74, 75 to 79, 80 to 84, and 85 and older, respectively, in sex-adjusted regression. In multivariable regression, participants with a 2005/06 clinic visit were younger, more likely to be male and in good health, and had had better cognitive and physical function 7 years earlier than participants with other visit types. Participants with home, telephone, and missing visits were similar on characteristics measured 7 years earlier.

CONCLUSION: Offering home, telephone, and proxy visits are essential to optimizing follow-up of aging cohorts. Home visits increased in-person retention from 36.5\% to 58.8\% and diversified the cohort with respect to age, health, and physical functioning.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Ambulatory Care Facilities, Analysis of Variance, Cardiovascular Diseases, Chi-Square Distribution, Epidemiologic Studies, Female, Geriatric Assessment, House Calls, Humans, Logistic Models, Longitudinal Studies, Male, Multivariate Analysis, Patient Dropouts, Patient Selection, Research Subjects, Telephone, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.02770.x}, author = {Strotmeyer, Elsa S and Arnold, Alice M and Boudreau, Robert M and Ives, Diane G and Cushman, Mary and Robbins, John A and Harris, Tamara B and Newman, Anne B} } @article {1236, title = {Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Nov}, pages = {949-60}, abstract = {

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 {\texttimes} 10$^{-}$$^{9}$ to P = 1.8 {\texttimes} 10$^{-}$$^{4}$$^{0}$) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 {\texttimes} 10$^{-}${\textthreesuperior} to P = 1.2 {\texttimes} 10$^{-}${\textonesuperior}{\textthreesuperior}). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

}, keywords = {Adipose Tissue, Age Factors, Chromosome Mapping, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Sex Characteristics, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.685}, author = {Heid, Iris M and Jackson, Anne U and Randall, Joshua C and Winkler, Thomas W and Qi, Lu and Steinthorsdottir, Valgerdur and Thorleifsson, Gudmar and Zillikens, M Carola and Speliotes, Elizabeth K and M{\"a}gi, Reedik and Workalemahu, Tsegaselassie and White, Charles C and Bouatia-Naji, Nabila and Harris, Tamara B and Berndt, Sonja I and Ingelsson, Erik and Willer, Cristen J and Weedon, Michael N and Luan, Jian{\textquoteright}an and Vedantam, Sailaja and Esko, T{\~o}nu and Kilpel{\"a}inen, Tuomas O and Kutalik, Zolt{\'a}n and Li, Shengxu and Monda, Keri L and Dixon, Anna L and Holmes, Christopher C and Kaplan, Lee M and Liang, Liming and Min, Josine L and Moffatt, Miriam F and Molony, Cliona and Nicholson, George and Schadt, Eric E and Zondervan, Krina T and Feitosa, Mary F and Ferreira, Teresa and Lango Allen, Hana and Weyant, Robert J and Wheeler, Eleanor and Wood, Andrew R and Estrada, Karol and Goddard, Michael E and Lettre, Guillaume and Mangino, Massimo and Nyholt, Dale R and Purcell, Shaun and Smith, Albert Vernon and Visscher, Peter M and Yang, Jian and McCarroll, Steven A and Nemesh, James and Voight, Benjamin F and Absher, Devin and Amin, Najaf and Aspelund, Thor and Coin, Lachlan and Glazer, Nicole L and Hayward, Caroline and Heard-Costa, Nancy L and Hottenga, Jouke-Jan and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kapur, Karen and Ketkar, Shamika and Knowles, Joshua W and Kraft, Peter and Kraja, Aldi T and Lamina, Claudia and Leitzmann, Michael F and McKnight, Barbara and Morris, Andrew P and Ong, Ken K and Perry, John R B and Peters, Marjolein J and Polasek, Ozren and Prokopenko, Inga and Rayner, Nigel W and Ripatti, Samuli and Rivadeneira, Fernando and Robertson, Neil R and Sanna, Serena and Sovio, Ulla and Surakka, Ida and Teumer, Alexander and van Wingerden, Sophie and Vitart, Veronique and Zhao, Jing Hua and Cavalcanti-Proen{\c c}a, Christine and Chines, Peter S and Fisher, Eva and Kulzer, Jennifer R and Lecoeur, C{\'e}cile and Narisu, Narisu and Sandholt, Camilla and Scott, Laura J and Silander, Kaisa and Stark, Klaus and Tammesoo, Mari-Liis and Teslovich, Tanya M and Timpson, Nicholas John and Watanabe, Richard M and Welch, Ryan and Chasman, Daniel I and Cooper, Matthew N and Jansson, John-Olov and Kettunen, Johannes and Lawrence, Robert W and Pellikka, Niina and Perola, Markus and Vandenput, Liesbeth and Alavere, Helene and Almgren, Peter and Atwood, Larry D and Bennett, Amanda J and Biffar, Reiner and Bonnycastle, Lori L and Bornstein, Stefan R and Buchanan, Thomas A and Campbell, Harry and Day, Ian N M and Dei, Mariano and D{\"o}rr, Marcus and Elliott, Paul and Erdos, Michael R and Eriksson, Johan G and Freimer, Nelson B and Fu, Mao and Gaget, Stefan and Geus, Eco J C and Gjesing, Anette P and Grallert, Harald and Gr{\"a}ssler, J{\"u}rgen and Groves, Christopher J and Guiducci, Candace and Hartikainen, Anna-Liisa and Hassanali, Neelam and Havulinna, Aki S and Herzig, Karl-Heinz and Hicks, Andrew A and Hui, Jennie and Igl, Wilmar and Jousilahti, Pekka and Jula, Antti and Kajantie, Eero and Kinnunen, Leena and Kolcic, Ivana and Koskinen, Seppo and Kovacs, Peter and Kroemer, Heyo K and Krzelj, Vjekoslav and Kuusisto, Johanna and Kvaloy, Kirsti and Laitinen, Jaana and Lantieri, Olivier and Lathrop, G Mark and Lokki, Marja-Liisa and Luben, Robert N and Ludwig, Barbara and McArdle, Wendy L and McCarthy, Anne and Morken, Mario A and Nelis, Mari and Neville, Matt J and Par{\'e}, Guillaume and Parker, Alex N and Peden, John F and Pichler, Irene and Pietil{\"a}inen, Kirsi H and Platou, Carl G P and Pouta, Anneli and Ridderstr{\r a}le, Martin and Samani, Nilesh J and Saramies, Jouko and Sinisalo, Juha and Smit, Jan H and Strawbridge, Rona J and Stringham, Heather M and Swift, Amy J and Teder-Laving, Maris and Thomson, Brian and Usala, Gianluca and van Meurs, Joyce B J and van Ommen, Gert-Jan and Vatin, Vincent and Volpato, Claudia B and Wallaschofski, Henri and Walters, G Bragi and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Witte, Daniel R and Zgaga, Lina and Zitting, Paavo and Beilby, John P and James, Alan L and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Nieminen, Markku S and Ohlsson, Claes and Palmer, Lyle J and Raitakari, Olli and Ridker, Paul M and Stumvoll, Michael and T{\"o}njes, Anke and Viikari, Jorma and Balkau, Beverley and Ben-Shlomo, Yoav and Bergman, Richard N and Boeing, Heiner and Smith, George Davey and Ebrahim, Shah and Froguel, Philippe and Hansen, Torben and Hengstenberg, Christian and Hveem, Kristian and Isomaa, Bo and J{\o}rgensen, Torben and Karpe, Fredrik and Khaw, Kay-Tee and Laakso, Markku and Lawlor, Debbie A and Marre, Michel and Meitinger, Thomas and Metspalu, Andres and Midthjell, Kristian and Pedersen, Oluf and Salomaa, Veikko and Schwarz, Peter E H and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Valle, Timo T and Wareham, Nicholas J and Arnold, Alice M and Beckmann, Jacques S and Bergmann, Sven and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Collins, Francis S and Eiriksdottir, Gudny and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Hattersley, Andrew T and Hofman, Albert and Hu, Frank B and Illig, Thomas and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Kao, W H Linda and Kaprio, Jaakko and Launer, Lenore J and Munroe, Patricia B and Oostra, Ben and Penninx, Brenda W and Pramstaller, Peter P and Psaty, Bruce M and Quertermous, Thomas and Rissanen, Aila and Rudan, Igor and Shuldiner, Alan R and Soranzo, Nicole and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Uda, Manuela and Uitterlinden, Andre and V{\"o}lzke, Henry and Vollenweider, Peter and Wilson, James F and Witteman, Jacqueline C and Wright, Alan F and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Frayling, Timothy M and Groop, Leif C and Haritunians, Talin and Hunter, David J and Kaplan, Robert C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Peltonen, Leena and Schlessinger, David and Strachan, David P and Hirschhorn, Joel N and Assimes, Themistocles L and Wichmann, H-Erich and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Stefansson, Kari and Cupples, L Adrienne and Loos, Ruth J F and Barroso, In{\^e}s and McCarthy, Mark I and Fox, Caroline S and Mohlke, Karen L and Lindgren, Cecilia M} } @article {1179, title = {A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 May}, pages = {478-87}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Cohort Studies, Confidence Intervals, Female, Genome-Wide Association Study, Genotype, Humans, Longevity, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1758-535X}, doi = {10.1093/gerona/glq028}, author = {Newman, Anne B and Walter, Stefan and Lunetta, Kathryn L and Garcia, Melissa E and Slagboom, P Eline and Christensen, Kaare and Arnold, Alice M and Aspelund, Thor and Aulchenko, Yurii S and Benjamin, Emelia J and Christiansen, Lene and D{\textquoteright}Agostino, Ralph B and Fitzpatrick, Annette L and Franceschini, Nora and Glazer, Nicole L and Gudnason, Vilmundur and Hofman, Albert and Kaplan, Robert and Karasik, David and Kelly-Hayes, Margaret and Kiel, Douglas P and Launer, Lenore J and Marciante, Kristin D and Massaro, Joseph M and Miljkovic, Iva and Nalls, Michael A and Hernandez, Dena and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome and Seshadri, Sudha and Smith, Albert V and Taylor, Kent D and Tiemeier, Henning and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vaupel, James W and Walston, Jeremy and Westendorp, Rudi G J and Harris, Tamara B and Lumley, Thomas and van Duijn, Cornelia M and Murabito, Joanne M} } @article {1301, title = {Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Jun 26}, pages = {753-60}, abstract = {

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between \~{}2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 {\texttimes} 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 {\texttimes} 10(-11)) and one near SPRY2 (P = 3 {\texttimes} 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

}, keywords = {Adiponectin, Adiposity, Alleles, Body Fat Distribution, Body Mass Index, Body Weight, Female, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Meta-Analysis as Topic, Metabolome, Obesity, Polymorphism, Single Nucleotide, Subcutaneous Fat}, issn = {1546-1718}, doi = {10.1038/ng.866}, author = {Kilpel{\"a}inen, Tuomas O and Zillikens, M Carola and Stan{\v c}{\'a}kov{\'a}, Alena and Finucane, Francis M and Ried, Janina S and Langenberg, Claudia and Zhang, Weihua and Beckmann, Jacques S and Luan, Jian{\textquoteright}an and Vandenput, Liesbeth and Styrkarsdottir, Unnur and Zhou, Yanhua and Smith, Albert Vernon and Zhao, Jing-Hua and Amin, Najaf and Vedantam, Sailaja and Shin, So-Youn and Haritunians, Talin and Fu, Mao and Feitosa, Mary F and Kumari, Meena and Halldorsson, Bjarni V and Tikkanen, Emmi and Mangino, Massimo and Hayward, Caroline and Song, Ci and Arnold, Alice M and Aulchenko, Yurii S and Oostra, Ben A and Campbell, Harry and Cupples, L Adrienne and Davis, Kathryn E and D{\"o}ring, Angela and Eiriksdottir, Gudny and Estrada, Karol and Fern{\'a}ndez-Real, Jos{\'e} Manuel and Garcia, Melissa and Gieger, Christian and Glazer, Nicole L and Guiducci, Candace and Hofman, Albert and Humphries, Steve E and Isomaa, Bo and Jacobs, Leonie C and Jula, Antti and Karasik, David and Karlsson, Magnus K and Khaw, Kay-Tee and Kim, Lauren J and Kivimaki, Mika and Klopp, Norman and Kuhnel, Brigitte and Kuusisto, Johanna and Liu, Yongmei and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and McKnight, Barbara and Mellstr{\"o}m, Dan and Mitchell, Braxton D and Mooser, Vincent and Moreno, Jos{\'e} Maria and M{\"a}nnist{\"o}, Satu and O{\textquoteright}Connell, Jeffery R and Pascoe, Laura and Peltonen, Leena and Peral, Bel{\'e}n and Perola, Markus and Psaty, Bruce M and Salomaa, Veikko and Savage, David B and Semple, Robert K and Skaric-Juric, Tatjana and Sigurdsson, Gunnar and Song, Kijoung S and Spector, Timothy D and Syv{\"a}nen, Ann-Christine and Talmud, Philippa J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Vidal-Puig, Antonio and Wild, Sarah H and Wright, Alan F and Clegg, Deborah J and Schadt, Eric and Wilson, James F and Rudan, Igor and Ripatti, Samuli and Borecki, Ingrid B and Shuldiner, Alan R and Ingelsson, Erik and Jansson, John-Olov and Kaplan, Robert C and Gudnason, Vilmundur and Harris, Tamara B and Groop, Leif and Kiel, Douglas P and Rivadeneira, Fernando and Walker, Mark and Barroso, In{\^e}s and Vollenweider, Peter and Waeber, G{\'e}rard and Chambers, John C and Kooner, Jaspal S and Soranzo, Nicole and Hirschhorn, Joel N and Stefansson, Kari and Wichmann, H-Erich and Ohlsson, Claes and O{\textquoteright}Rahilly, Stephen and Wareham, Nicholas J and Speliotes, Elizabeth K and Fox, Caroline S and Laakso, Markku and Loos, Ruth J F} } @article {1296, title = {Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Oct}, pages = {1100-7}, abstract = {

BACKGROUND: Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined.

METHODS: We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2-9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176).

RESULTS: Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95\% CI] = 0.72 [0.52-0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61-3.44] per SD for levels >=20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78-4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20-2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67-3.67]) (p = .55), as compared with smaller changes for both.

CONCLUSION: Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin-outcome associations reported previously.

}, keywords = {Adiponectin, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Chi-Square Distribution, Enzyme-Linked Immunosorbent Assay, Female, Humans, Inflammation, Interleukin-6, Male, Mortality, Predictive Value of Tests, Risk Factors, Sensitivity and Specificity, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glr098}, author = {Kizer, Jorge R and Arnold, Alice M and Jenny, Nancy S and Cushman, Mary and Strotmeyer, Elsa S and Ives, Diane G and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Hirsch, Calvin H and Newman, Anne B} } @article {1293, title = {Predictors of thyroid hormone initiation in older adults: results from the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Jul}, pages = {809-14}, abstract = {

BACKGROUND: Despite widespread use, there are no data on initiation of thyroid hormone use in older people. We report the prevalence of thyroid hormone use and predictors of thyroid hormone initiation in a population of older men and women.

METHODS: Thyroid hormone medication data were collected annually from 1989 to 2006 in community-dwelling individuals aged 65 years and older enrolled in the Cardiovascular Health Study (N = 5,888). Associations of age, sex, race, body mass index, education, and coronary heart disease with initiation were evaluated using discrete-time survival analysis.

RESULTS: In 1989-1990, 8.9\% (95\% confidence interval 8.1\%-9.7\%) of participants were taking a thyroid hormone preparation, increasing to 20.0\% (95\% confidence interval 8.2\%-21.8\%) over 16 years. The average initiation rate was 1\% per year. The initiation rate was nonlinear with age, and those aged 85 years and older initiated thyroid hormone more than twice as frequently as those aged 65-69 years (hazard ratio = 2.34; 95\% confidence interval 1.43-3.85). White women were more likely to initiate thyroid hormone than any other race and sex group. Higher body mass index was independently associated with higher risk for initiation (p = .002) as was greater education (p = .02) and prevalent coronary heart disease (p = .03).

CONCLUSIONS: Thyroid hormone use is common in older people. The indications and benefits of thyroid hormone use in older individuals with the highest rate of thyroid hormone initiation-the oldest old, overweight and obese individuals, and those with coronary heart disease-should be investigated.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Hypothyroidism, Incidence, Male, Prevalence, Prognosis, Retrospective Studies, Risk Factors, Sex Factors, Thyroid Hormones, Thyroxine, Time Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glr063}, author = {Somwaru, Lily L and Arnold, Alice M and Cappola, Anne R} } @article {1310, title = {Progression of magnetic resonance imaging-defined brain vascular disease predicts vascular events in elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Oct}, pages = {2970-2}, abstract = {

BACKGROUND AND PURPOSE: To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly.

METHODS: The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans≈5 years apart and have been followed for ≈9 years since the follow-up scan for incident vascular events.

RESULTS: Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95\% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95\% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95\% confidence interval, 1.28-2.24), and cardiovascular death (hazard ratio, 1.97; 95\% confidence interval, 1.24-3.14).

CONCLUSIONS: Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown.

}, keywords = {Aged, Brain, Disease Progression, Female, Follow-Up Studies, Heart Failure, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Predictive Value of Tests, Prognosis, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.622977}, author = {Longstreth, W T and Arnold, Alice M and Kuller, Lewis H and Bernick, Charles and Lefkowitz, David S and Beauchamp, Norman J and Manolio, Teri A} } @article {1352, title = {Serum 25-hydroxyvitamin D and physical function in older adults: the Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {59}, year = {2011}, month = {2011 Oct}, pages = {1793-801}, abstract = {

OBJECTIVES: To examine the association between 25-hydroxyvitamin D (25(OH)D) and physical function in adults of advanced age.

DESIGN: Cross-sectional and longitudinal analysis of physical function over 3~years of follow-up in the Cardiovascular Health Study All Stars.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Community-dwelling adults aged 77 to 100 (N~=~988).

MEASUREMENTS: Serum 25-hydroxyvitamin D 25(OH)D), Short Physical Performance Battery (SPPB), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living (ADLs) disability were assessed at baseline and every 6~months over 3~years of follow-up.

RESULTS: Almost one-third (30.8\%) of participants were deficient in 25(OH)D (<20~ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53~(0.24)) than in those with sufficient 25(OH)D (>=30~ng/mL) (7.15~(0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P~=~.006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7~(0.6)~kg vs 26.0~(0.6)~kg, P~=~.02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR~=~1.44, 95\% confidence interval (CI))~=~0.96-2.14) and ADL disability (OR~=~1.51, 95\% CI~=~1.01-2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3~years of follow-up (hazard ratio~=~1.56, 95\% CI~=~1.06-2.30).

CONCLUSION: Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community-dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Female, Follow-Up Studies, Geriatric Assessment, Health Surveys, Humans, Male, Mobility Limitation, Muscle Strength, Physical Fitness, Proportional Hazards Models, Reference Values, United States, Vitamin D, Vitamin D Deficiency}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2011.03601.x}, author = {Houston, Denise K and Tooze, Janet A and Davis, Cralen C and Chaves, Paulo H M and Hirsch, Calvin H and Robbins, John A and Arnold, Alice M and Newman, Anne B and Kritchevsky, Stephen B} } @article {1300, title = {Subclinical vascular disease burden and risk for death and cardiovascular events in older community dwellers.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Sep}, pages = {986-93}, abstract = {

BACKGROUND: Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk. Methods and Results. In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M {\textpm} SD 74.3 years {\textpm} 5.1, 63\% women, 17\% African Americans) had noninvasive vascular assessments in 1992-1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle-arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0-6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95\% confidence interval 0.8-1.6) to 4.7 (3.4-6.9) and, for mortality, from 1.5 (1.0-2.3) to 5.0 (3.3-7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification.

CONCLUSIONS: Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cost of Illness, Female, Humans, Male, Risk, Vascular Diseases}, issn = {1758-535X}, doi = {10.1093/gerona/glr069}, author = {Inzitari, Marco and Arnold, Alice M and Patel, Kushang V and Mercer, Laina D and Karlamangla, Arun and Ding, Jingzhong and Psaty, Bruce M and Williamson, Jeff D and Kuller, Lewis H and Newman, Anne B} } @article {1553, title = {Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Dec 18}, pages = {2951-61}, abstract = {

BACKGROUND: Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk).

METHODS AND RESULTS: In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95\% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95\% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality.

CONCLUSIONS: Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Female, Health Surveys, Humans, Male, Molecular Weight}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.135202}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Mantzoros, Christos S and deFilippi, Christopher R and Newman, Anne B and Djouss{\'e}, Luc} } @article {1374, title = {Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {1970-6}, abstract = {

BACKGROUND: The association between changes in IGF-I and IGF binding protein (IGFBP) levels and mortality in older adults is unknown.

STUDY DESIGN: Participants were 997 persons 77 to 100 yr old enrolled in the Cardiovascular Health Study All Stars Study. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were assessed at two study examinations (1996-1997 and 2005-2006). Mortality was assessed between 2006 and 2010.

RESULTS: Cumulative mortality (CM) was similar among individuals who had at least 10\% decreases over time in IGF-I levels (CM = 29.6\%), individuals who had at least 10\% increases over time in IGF-I levels (CM = 24.7\%), and individuals who had IGF-I levels remaining within {\textpm}10\% over time (CM = 23.5\%). Adjusted for age, sex, race, diabetes, body mass index, creatinine, albumin, and C-reactive protein, decreasing IGF-I level had no significant association with overall cancer mortality or noncancer mortality. Levels of IGFBP-1 increased markedly over time by 38\% (median). Individuals with the largest increases in IGFBP-1 level over time had significantly increased risk of mortality. The adjusted hazard ratio per sd of IGFBP-1 change was 1.40 for overall cancer mortality (95\% confidence interval = 1.10, 1.77; P = 0.01) and 1.14 for noncancer mortality (95\% confidence interval = 1.02, 1.27; P = 0.02). Changes in IGFBP-3 levels were not significantly associated with mortality.

CONCLUSION: Among older adults, decreasing IGF-I level over time does not predict subsequent all-cause mortality, whereas increasing IGFBP-1 predicts increased risk of mortality.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Longitudinal Studies, Male, Mortality, Predictive Value of Tests, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2011-2967}, author = {Kaplan, Robert C and B{\r u}zkov{\'a}, Petra and Cappola, Anne R and Strickler, Howard D and McGinn, Aileen P and Mercer, Laina D and Arnold, Alice M and Pollak, Michael N and Newman, Anne B} } @article {1328, title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Apr}, pages = {409-16}, abstract = {

BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).

METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4\% male, 86.8\% white, and 13.2\% black).

RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35\%.

CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cardiovascular Diseases, Carotid Intima-Media Thickness, Chronic Disease, Cystatin C, European Continental Ancestry Group, Female, Humans, Leukocytes, Lung, Male, Middle Aged, Telomere Homeostasis}, issn = {1758-535X}, doi = {10.1093/gerona/glr173}, author = {Sanders, Jason L and Fitzpatrick, Annette L and Boudreau, Robert M and Arnold, Alice M and Aviv, Abraham and Kimura, Masayuki and Fried, Linda F and Harris, Tamara B and Newman, Anne B} } @article {1404, title = {Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {3944-50}, abstract = {

CONTEXT: Data on thyroid function in the oldest old are sparse, and existing studies show conflicting evidence on the relationship between thyroid function and mortality in this age group.

OBJECTIVE: We describe longitudinal changes in thyroid function in a cohort of elderly individuals and determine the relationship between thyroid function and mortality.

DESIGN, SETTING, AND PARTICIPANTS: Eight hundred forty-three participants in the Cardiovascular Health Study All Stars Study who were not taking thyroid medications and had thyroid function testing in 2005-2006 (mean age 85 yr).

MAIN OUTCOME MEASURE: Thyroid-stimulating hormone (TSH), free T(4) (FT4), total T(3), and thyroid peroxidase antibody status were measured in 1992-1993 and 2005-2006. Deaths were ascertained through February 2011.

RESULTS: There was a statistically significant 13\% increase in TSH, 1.7\% increase in FT4, and 13\% decrease in total T(3) over the 13-yr period. Two hundred eighty-seven deaths occurred over a median follow-up of 5.1 yr. There was no association between subclinical hypothyroidism[hazard ratio (HR) 0.97, 95\% confidence interval (CI) 0.66-1.43], TSH level (HR per milliunits per liter 0.94, 95\% CI 0.88-1.01), or persistent thyroid peroxidase antibody positivity (HR 1.09, 95\% CI 0.62-1.92), and death. However, FT4 was positively associated with death (HR per nanograms per deciliter 2.57, 95\% CI 1.32-5.02).

CONCLUSIONS: TSH increased over time in these older individuals. This elevation was not associated with increased or decreased mortality, although higher FT4 levels were associated with death. These findings raise concern for treatment of mild elevations of TSH in advanced age. Further studies are needed to determine the potential benefit of treating age-related changes in thyroid function.

}, keywords = {Aged, 80 and over, Female, Humans, Longitudinal Studies, Male, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1945-7197}, doi = {10.1210/jc.2012-2481}, author = {Waring, Avantika C and Arnold, Alice M and Newman, Anne B and B{\r u}zkov{\'a}, Petra and Hirsch, Calvin and Cappola, Anne R} } @article {1366, title = {Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Sep}, pages = {970-6}, abstract = {

BACKGROUND: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.

METHODS: We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006.

RESULTS: In 2005-2006, median age was 84.9 years, 63\% were women and 17\% non-white; 21\% had at least a doubling in CRP over time and 23\% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95\% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95\% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality.

CONCLUSIONS: Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.

}, keywords = {Aged, Aged, 80 and over, Aging, C-Reactive Protein, Cardiovascular Diseases, Cognition, Cohort Studies, Cross-Sectional Studies, Female, Humans, Inflammation, Inflammation Mediators, Interleukin-6, Longitudinal Studies, Male, Risk Factors, Vermont}, issn = {1758-535X}, doi = {10.1093/gerona/glr261}, author = {Jenny, Nancy S and French, Benjamin and Arnold, Alice M and Strotmeyer, Elsa S and Cushman, Mary and Chaves, Paulo H M and Ding, Jingzhong and Fried, Linda P and Kritchevsky, Stephen B and Rifkin, Dena E and Sarnak, Mark J and Newman, Anne B} } @article {1360, title = {Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jan 22}, pages = {260-8}, abstract = {

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 {\texttimes} 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

}, keywords = {Age Factors, DNA Helicases, DNA Polymerase gamma, DNA Primase, DNA Repair, DNA Repair Enzymes, DNA-Directed DNA Polymerase, European Continental Ancestry Group, Exodeoxyribonucleases, Female, Genetic Loci, Genome-Wide Association Study, Humans, Immunity, Menopause, Polymorphism, Single Nucleotide, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.1051}, author = {Stolk, Lisette and Perry, John R B and Chasman, Daniel I and He, Chunyan and Mangino, Massimo and Sulem, Patrick and Barbalic, Maja and Broer, Linda and Byrne, Enda M and Ernst, Florian and Esko, T{\~o}nu and Franceschini, Nora and Gudbjartsson, Daniel F and Hottenga, Jouke-Jan and Kraft, Peter and McArdle, Patrick F and Porcu, Eleonora and Shin, So-Youn and Smith, Albert V and van Wingerden, Sophie and Zhai, Guangju and Zhuang, Wei V and Albrecht, Eva and Alizadeh, Behrooz Z and Aspelund, Thor and Bandinelli, Stefania and Lauc, Lovorka Barac and Beckmann, Jacques S and Boban, Mladen and Boerwinkle, Eric and Broekmans, Frank J and Burri, Andrea and Campbell, Harry and Chanock, Stephen J and Chen, Constance and Cornelis, Marilyn C and Corre, Tanguy and Coviello, Andrea D and D{\textquoteright}Adamo, Pio and Davies, Gail and de Faire, Ulf and de Geus, Eco J C and Deary, Ian J and Dedoussis, George V Z and Deloukas, Panagiotis and Ebrahim, Shah and Eiriksdottir, Gudny and Emilsson, Valur and Eriksson, Johan G and Fauser, Bart C J M and Ferreli, Liana and Ferrucci, Luigi and Fischer, Krista and Folsom, Aaron R and Garcia, Melissa E and Gasparini, Paolo and Gieger, Christian and Glazer, Nicole and Grobbee, Diederick E and Hall, Per and Haller, Toomas and Hankinson, Susan E and Hass, Merli and Hayward, Caroline and Heath, Andrew C and Hofman, Albert and Ingelsson, Erik and Janssens, A Cecile J W and Johnson, Andrew D and Karasik, David and Kardia, Sharon L R and Keyzer, Jules and Kiel, Douglas P and Kolcic, Ivana and Kutalik, Zolt{\'a}n and Lahti, Jari and Lai, Sandra and Laisk, Triin and Laven, Joop S E and Lawlor, Debbie A and Liu, Jianjun and Lopez, Lorna M and Louwers, Yvonne V and Magnusson, Patrik K E and Marongiu, Mara and Martin, Nicholas G and Klaric, Irena Martinovic and Masciullo, Corrado and McKnight, Barbara and Medland, Sarah E and Melzer, David and Mooser, Vincent and Navarro, Pau and Newman, Anne B and Nyholt, Dale R and Onland-Moret, N Charlotte and Palotie, Aarno and Par{\'e}, Guillaume and Parker, Alex N and Pedersen, Nancy L and Peeters, Petra H M and Pistis, Giorgio and Plump, Andrew S and Polasek, Ozren and Pop, Victor J M and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Rehnberg, Emil and Rotter, Jerome I and Rudan, Igor and Sala, Cinzia and Salumets, Andres and Scuteri, Angelo and Singleton, Andrew and Smith, Jennifer A and Snieder, Harold and Soranzo, Nicole and Stacey, Simon N and Starr, John M and Stathopoulou, Maria G and Stirrups, Kathleen and Stolk, Ronald P and Styrkarsdottir, Unnur and Sun, Yan V and Tenesa, Albert and Thorand, Barbara and Toniolo, Daniela and Tryggvadottir, Laufey and Tsui, Kim and Ulivi, Sheila and van Dam, Rob M and van der Schouw, Yvonne T and van Gils, Carla H and van Nierop, Peter and Vink, Jacqueline M and Visscher, Peter M and Voorhuis, Marlies and Waeber, G{\'e}rard and Wallaschofski, Henri and Wichmann, H Erich and Widen, Elisabeth and Wijnands-van Gent, Colette J M and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wright, Alan F and Yerges-Armstrong, Laura M and Zemunik, Tatijana and Zgaga, Lina and Zillikens, M Carola and Zygmunt, Marek and Arnold, Alice M and Boomsma, Dorret I and Buring, Julie E and Crisponi, Laura and Demerath, Ellen W and Gudnason, Vilmundur and Harris, Tamara B and Hu, Frank B and Hunter, David J and Launer, Lenore J and Metspalu, Andres and Montgomery, Grant W and Oostra, Ben A and Ridker, Paul M and Sanna, Serena and Schlessinger, David and Spector, Tim D and Stefansson, Kari and Streeten, Elizabeth A and Thorsteinsdottir, Unnur and Uda, Manuela and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Murray, Anna and Murabito, Joanne M and Visser, Jenny A and Lunetta, Kathryn L} } @article {1373, title = {The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Jun}, pages = {1962-9}, abstract = {

CONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time.

OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex.

DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication.

MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex.

RESULTS: Persistence of subclinical hypothyroidism was 56\% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10\% with TSH 7-9.9 mU/liter and 7\% with TSH >=10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15\% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions.

CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Autoantibodies, Cardiovascular Diseases, Cohort Studies, Disease Progression, Female, Humans, Hypothyroidism, Iodide Peroxidase, Logistic Models, Longitudinal Studies, Male, Prevalence, Risk Factors, Seroepidemiologic Studies, Severity of Illness Index, Sex Distribution, Thyrotropin}, issn = {1945-7197}, doi = {10.1210/jc.2011-3047}, author = {Somwaru, Lily L and Rariy, Chevon M and Arnold, Alice M and Cappola, Anne R} } @article {1401, title = {Persistence and remission of musculoskeletal pain in community-dwelling older adults: results from the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {60}, year = {2012}, month = {2012 Aug}, pages = {1393-400}, abstract = {

OBJECTIVES: To characterize longitudinal patterns of musculoskeletal pain in a community sample of older adults over a 6-year period and to identify factors associated with persistence of pain.

DESIGN: Secondary analysis of the Cardiovascular Health Study.

SETTING: Community-based cohort drawn from four U.S. counties.

PARTICIPANTS: Five thousand ninety-three men and women aged 65 and older.

MEASUREMENTS: Over a 6-year period, pain was assessed each year using a single question about the presence of pain in any bones or joints during the last year. If affirmative, participants were queried about pain in seven locations (hands, shoulders, neck, back, hips, knees, feet). Participants were categorized according to the percentage of time that pain was present and according to the intermittent or chronic pattern of pain. Factors associated with persistent pain during five remaining years of the study were identified.

RESULTS: Over 6 years, 32\% of participants reported pain for three or more consecutive years, and 32\% reported pain intermittently. Of those who reported pain the first year, 54\% were pain free at least once during the follow-up period. Most of the pain at specific body locations was intermittent. Factors associated with remission of pain over 5 years included older age, male sex, better self-rated health, not being obese, taking fewer medications, and having fewer depressive symptoms. Approximately half of those with pain reported fewer pain locations the following year.

CONCLUSION: Musculoskeletal pain in older adults, despite high prevalence, is often intermittent. The findings refute the notion that pain is an inevitable, unremitting, or progressive consequence of aging.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Humans, Male, Musculoskeletal Pain, Remission Induction, Residence Characteristics}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2012.04082.x}, author = {Thielke, Stephen M and Whitson, Heather and Diehr, Paula and O{\textquoteright}Hare, Ann and Kearney, Patricia M and Chaudhry, Sarwat I and Zakai, Neil A and Kim, Dae and Sekaran, Nishant and Sale, Joanna E M and Arnold, Alice M and Chaves, Paulo and Newman, Anne} } @article {1356, title = {Total and high-molecular-weight adiponectin and risk of incident diabetes in older people.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Feb}, pages = {415-23}, abstract = {

OBJECTIVE: To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.

RESEARCH DESIGN AND METHODS: Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.

RESULTS: Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95\% CI 0.39-0.63]) and HMW adiponectin (0.42 [0.32-0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.

CONCLUSIONS: In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.

}, keywords = {Adiponectin, Aged, Diabetes Mellitus, Female, Humans, Male, Risk Factors}, issn = {1935-5548}, doi = {10.2337/dc11-1519}, author = {Kizer, Jorge R and Arnold, Alice M and Benkeser, David and Ix, Joachim H and Djouss{\'e}, Luc and Zieman, Susan J and Barzilay, Joshua I and Tracy, Russell P and Mantzoros, Christos S and Siscovick, David S and Mukamal, Kenneth J} } @article {6002, title = {Atrial fibrillation and cognitive decline: a longitudinal cohort study.}, journal = {Neurology}, volume = {81}, year = {2013}, month = {2013 Jul 09}, pages = {119-25}, abstract = {

OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.

METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.

RESULTS: Analyses included 5,150 participants, of whom 552 (10.7\%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95\% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95\% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95\% CI: -5.3, -2.5).

CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Luria-Nebraska Neuropsychological Battery, Male, Predictive Value of Tests}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31829a33d1}, author = {Thacker, Evan L and McKnight, Barbara and Psaty, Bruce M and Longstreth, W T and Sitlani, Colleen M and Dublin, Sascha and Arnold, Alice M and Fitzpatrick, Annette L and Gottesman, Rebecca F and Heckbert, Susan R} } @article {1409, title = {Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study.}, journal = {Am J Hematol}, volume = {88}, year = {2013}, month = {2013 Jan}, pages = {5-9}, abstract = {

While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. We evaluated the determinants and consequences of hemoglobin decline in 3,758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly >=65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: (1) per each 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/dL and 9\% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95\% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95\% CI 1.04, 1.18 per 1 g/dL decrease) predicted subsequent mortality in men and women. Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Anemia, Diabetes Complications, Female, Follow-Up Studies, Hemoglobins, Humans, Kidney Diseases, Male, Prospective Studies, Quality of Life, Risk Factors, Sex Factors, Survival Rate, Time Factors, World Health Organization}, issn = {1096-8652}, doi = {10.1002/ajh.23336}, author = {Zakai, Neil A and French, Benjamin and Arnold, Alice M and Newman, Anne B and Fried, Linda F and Robbins, John and Chaves, Paulo and Cushman, Mary} } @article {1551, title = {Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Feb}, pages = {533-40}, abstract = {

CONTEXT: Use of a single set of thyroid function tests to define subclinical hypothyroidism may lead to misclassification over time and could influence findings from longitudinal studies.

OBJECTIVE: We assessed the risks of coronary heart disease (CHD), heart failure (HF), and cardiovascular (CV) death in older adults with persistent subclinical hypothyroidism.

DESIGN, SETTING, AND PARTICIPANTS: The study included 679 subclinically hypothyroid and 4184 euthyroid U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study and not taking thyroid preparations.

MAIN OUTCOME MEASURE: We measured the 10-yr risk of incident CHD, HF, and CV death from persistent subclinical hypothyroidism, overall and stratified by degree of TSH elevation (4.5-6.9, 7.0-9.9, and 10.0-19.9 mU/liter).

RESULTS: There was no association between persistent subclinical hypothyroidism and incident CHD [hazard ratio (HR), 1.12; 95\% confidence interval (CI), 0.93-1.36], HF (HR, 1.05; 95\% CI, 0.97-1.27), or CV death (HR, 1.07; 95\% CI, 0.87-1.31) in adjusted analyses in which subclinical hypothyroidism was modeled as a time-varying exposure using up to four serial thyroid function tests. When subclinical hypothyroidism was stratified by degree of TSH elevation, no significant associations were found in any stratum. Findings were similar in fixed exposure analyses in which only participants with testing 2 yr apart were considered, with no association between persistent or transient subclinical hypothyroidism and incident CHD, HF, or CV death.

CONCLUSIONS: Our data do not support increased risk of CHD, HF, or CV death in older adults with persistent subclinical hypothyroidism.

}, keywords = {Aged, Aged, 80 and over, Coronary Disease, Female, Heart Failure, Humans, Hypothyroidism, Incidence, Longitudinal Studies, Male, Risk, Thyroid Function Tests}, issn = {1945-7197}, doi = {10.1210/jc.2012-2180}, author = {Hyland, Kristen A and Arnold, Alice M and Lee, Jennifer S and Cappola, Anne R} } @article {5853, title = {Results differ by applying distinctive multiple imputation approaches on the longitudinal cardiovascular health study data.}, journal = {Exp Aging Res}, volume = {39}, year = {2013}, month = {2013}, pages = {27-43}, abstract = {

UNLABELLED: BACKGROUND/STUDY CONTEXT: The objective of this study was to examine sequential and simultaneous approaches to multiple imputation of missing data in a longitudinal data set where losses due to death were common.

METHODS: Comparison of results from analyses and simulations of time to incident difficulty of activities of daily living (ADL) in the Cardiovascular Health Study when missing data were imputed simultaneously or sequentially.

RESULTS: Results differed with imputation methods. The largest proportional differences in 12 risk factor parameter estimates were heart failure by 106\%, social support by 33\%, and arthritis by 27\%.

CONCLUSION: Decedents{\textquoteright} final characteristics were influential on future imputations of those with missing values.

}, keywords = {Activities of Daily Living, Aged, Arthritis, Cardiac Rehabilitation, Cardiovascular Diseases, Data Interpretation, Statistical, Female, Humans, Longitudinal Studies, Male, Outcome Assessment (Health Care), Regression Analysis, Social Support}, issn = {1096-4657}, doi = {10.1080/0361073X.2013.741968}, author = {Ning, Yuming and McAvay, Gail and Chaudhry, Sarwat I and Arnold, Alice M and Allore, Heather G} } @article {6139, title = {Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Jan}, pages = {255-63}, abstract = {

CONTEXT: Adiponectin is atheroprotective in the laboratory, but prospective studies have shown opposite associations with cardiovascular disease (CVD) in healthy middle-aged populations (protective) and older cohorts (adverse). Whether this relates to different proportions of high-molecular-weight (HMW) adiponectin is unknown.

OBJECTIVE: The aim of the study was to test the hypothesis that total adiponectin is directly associated, but HMW adiponectin is inversely related, with CVD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: We evaluated 3290 participants free of prevalent CVD in a longitudinal cohort study of U.S. adults aged 65 yr and older.

MAIN OUTCOME MEASURES: We measured incident CVD (n = 1291), comprising coronary heart disease and ischemic stroke.

RESULTS: Total and HMW adiponectin were tightly correlated (r = 0.94). Cubic splines adjusted for potential confounders revealed that the associations of total and HMW adiponectin with CVD were U-shaped, with inflection points of 20 and 10 mg/liter, respectively. After controlling for potential confounding, levels of total and HMW adiponectin below these cutpoints tended to be inversely associated with incident CVD, driven by their significant or near-significant relations with coronary heart disease [hazard ratio (HR), 0.85 per sd increase; 95\% confidence interval (CI), 0.75-96; and HR, 0.87; 95\% CI, 0.75-1.01, respectively]. These associations were abrogated by additional inclusion of putative metabolic intermediates. Above these cutpoints, however, both total and HMW adiponectin were significantly directly associated with CVD after adjustment for confounders and, particularly, mediators (HR, 1.20 per sd increase; 95\% CI, 1.06-1.35; and HR, 1.12; 95\% CI, 1.02-1.24, respectively).

CONCLUSION: In community-living elders, total and HMW adiponectin showed similar U-shaped relationships with CVD. The inverse relation in the lower range, but not the direct association at the higher end, disappeared after inclusion of putative intermediates, suggesting that high levels may reflect adverse processes separate from adiponectin{\textquoteright}s beneficial glycometabolic properties.

}, keywords = {Adiponectin, Adult, Aged, Aged, 80 and over, Brain Ischemia, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Male, Molecular Weight, Residence Characteristics, Risk Factors, Stroke}, issn = {1945-7197}, doi = {10.1210/jc.2012-2103}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Djouss{\'e}, Luc and Zieman, Susan J and Mukamal, Kenneth J and Tracy, Russell P and Mantzoros, Christos S and Siscovick, David S and Gottdiener, John S and Ix, Joachim H} } @article {6576, title = {Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults.}, journal = {Atherosclerosis}, volume = {235}, year = {2014}, month = {2014 Jul}, pages = {116-21}, abstract = {

BACKGROUND: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.

METHODS: To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.

RESULTS: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95\% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.

CONCLUSIONS: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML{\textquoteright}s value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.

}, keywords = {Aged, Albumins, Antihypertensive Agents, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Creatinine, Female, Glomerular Filtration Rate, Glycation End Products, Advanced, Humans, Immunoassay, Incidence, Lysine, Male, Oxidative Stress, Proportional Hazards Models, Stroke, Treatment Outcome}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2014.04.013}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Ix, Joachim H and Mukamal, Kenneth J and Djouss{\'e}, Luc and Tracy, Russell P and Siscovick, David S and Psaty, Bruce M and Zieman, Susan J} } @article {6000, title = {Do changes in circulating biomarkers track with each other and with functional changes in older adults?}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {174-81}, abstract = {

BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.

METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.

RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).

CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Aging, Biomarkers, Cholesterol, Cognition, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Gait, Hand Strength, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Interleukin-6, Male, Neuropsychological Tests, Psychomotor Performance, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt088}, author = {Sanders, Jason L and Ding, Victoria and Arnold, Alice M and Kaplan, Robert C and Cappola, Anne R and Kizer, Jorge R and Boudreau, Robert M and Cushman, Mary and Newman, Anne B} } @article {6552, title = {Meta-analysis of loci associated with age at natural menopause in African-American women.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 15}, pages = {3327-42}, abstract = {

Age at menopause marks the end of a woman{\textquoteright}s reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

}, keywords = {African Americans, Age Factors, Chromosomes, Human, European Continental Ancestry Group, Female, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Menopause, United States}, issn = {1460-2083}, doi = {10.1093/hmg/ddu041}, author = {Chen, Christina T L and Liu, Ching-Ti and Chen, Gary K and Andrews, Jeanette S and Arnold, Alice M and Dreyfus, Jill and Franceschini, Nora and Garcia, Melissa E and Kerr, Kathleen F and Li, Guo and Lohman, Kurt K and Musani, Solomon K and Nalls, Michael A and Raffel, Leslie J and Smith, Jennifer and Ambrosone, Christine B and Bandera, Elisa V and Bernstein, Leslie and Britton, Angela and Brzyski, Robert G and Cappola, Anne and Carlson, Christopher S and Couper, David and Deming, Sandra L and Goodarzi, Mark O and Heiss, Gerardo and John, Esther M and Lu, Xiaoning and Le Marchand, Lo{\"\i}c and Marciante, Kristin and McKnight, Barbara and Millikan, Robert and Nock, Nora L and Olshan, Andrew F and Press, Michael F and Vaiyda, Dhananjay and Woods, Nancy F and Taylor, Herman A and Zhao, Wei and Zheng, Wei and Evans, Michele K and Harris, Tamara B and Henderson, Brian E and Kardia, Sharon L R and Kooperberg, Charles and Liu, Yongmei and Mosley, Thomas H and Psaty, Bruce and Wellons, Melissa and Windham, Beverly G and Zonderman, Alan B and Cupples, L Adrienne and Demerath, Ellen W and Haiman, Christopher and Murabito, Joanne M and Rajkovic, Aleksandar} } @article {6591, title = {Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Oct 28}, pages = {5068}, abstract = {

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

}, keywords = {Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6068}, author = {Postmus, Iris and Trompet, Stella and Deshmukh, Harshal A and Barnes, Michael R and Li, Xiaohui and Warren, Helen R and Chasman, Daniel I and Zhou, Kaixin and Arsenault, Benoit J and Donnelly, Louise A and Wiggins, Kerri L and Avery, Christy L and Griffin, Paula and Feng, QiPing and Taylor, Kent D and Li, Guo and Evans, Daniel S and Smith, Albert V and de Keyser, Catherine E and Johnson, Andrew D and de Craen, Anton J M and Stott, David J and Buckley, Brendan M and Ford, Ian and Westendorp, Rudi G J and Slagboom, P Eline and Sattar, Naveed and Munroe, Patricia B and Sever, Peter and Poulter, Neil and Stanton, Alice and Shields, Denis C and O{\textquoteright}Brien, Eoin and Shaw-Hawkins, Sue and Chen, Y-D Ida and Nickerson, Deborah A and Smith, Joshua D and Dub{\'e}, Marie Pierre and Boekholdt, S Matthijs and Hovingh, G Kees and Kastelein, John J P and McKeigue, Paul M and Betteridge, John and Neil, Andrew and Durrington, Paul N and Doney, Alex and Carr, Fiona and Morris, Andrew and McCarthy, Mark I and Groop, Leif and Ahlqvist, Emma and Bis, Joshua C and Rice, Kenneth and Smith, Nicholas L and Lumley, Thomas and Whitsel, Eric A and St{\"u}rmer, Til and Boerwinkle, Eric and Ngwa, Julius S and O{\textquoteright}Donnell, Christopher J and Vasan, Ramachandran S and Wei, Wei-Qi and Wilke, Russell A and Liu, Ching-Ti and Sun, Fangui and Guo, Xiuqing and Heckbert, Susan R and Post, Wendy and Sotoodehnia, Nona and Arnold, Alice M and Stafford, Jeanette M and Ding, Jingzhong and Herrington, David M and Kritchevsky, Stephen B and Eiriksdottir, Gudny and Launer, Leonore J and Harris, Tamara B and Chu, Audrey Y and Giulianini, Franco and MacFadyen, Jean G and Barratt, Bryan J and Nyberg, Fredrik and Stricker, Bruno H and Uitterlinden, Andr{\'e} G and Hofman, Albert and Rivadeneira, Fernando and Emilsson, Valur and Franco, Oscar H and Ridker, Paul M and Gudnason, Vilmundur and Liu, Yongmei and Denny, Joshua C and Ballantyne, Christie M and Rotter, Jerome I and Adrienne Cupples, L and Psaty, Bruce M and Palmer, Colin N A and Tardif, Jean-Claude and Colhoun, Helen M and Hitman, Graham and Krauss, Ronald M and Wouter Jukema, J and Caulfield, Mark J} } @article {6137, title = {Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults >=65 years of age (from the Cardiovascular Health study).}, journal = {Am J Cardiol}, volume = {113}, year = {2014}, month = {2014 Jan 15}, pages = {328-34}, abstract = {

Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine{\textquoteright}s association with new-onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged >=65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95\% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95\% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.

}, keywords = {Adiponectin, Age of Onset, Aged, Biomarkers, Cross-Sectional Studies, Echocardiography, Doppler, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Prognosis, Prospective Studies, Recurrence, Severity of Illness Index, United States, Ventricular Function, Left}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2013.09.027}, author = {Karas, Maria G and Benkeser, David and Arnold, Alice M and Bartz, Traci M and Djouss{\'e}, Luc and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Mantzoros, Christos S and Gottdiener, John S and deFilippi, Christopher R and Kizer, Jorge R} } @article {6243, title = {Serum carboxymethyl-lysine, disability, and frailty in older persons: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Jun}, pages = {710-6}, abstract = {

BACKGROUND: Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.

METHODS: In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 {\textpm} 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.

RESULTS: Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95\% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95\% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.

CONCLUSIONS: Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML{\textquoteright}s value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Aging, Biomarkers, Cardiac Rehabilitation, Cardiovascular Diseases, Disabled Persons, Female, Follow-Up Studies, Frail Elderly, Health Status, Humans, Incidence, Lysine, Male, Prevalence, Prognosis, Retrospective Studies, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt155}, author = {Whitson, Heather E and Arnold, Alice M and Yee, Laura M and Mukamal, Kenneth J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Siscovick, David and Tracy, Russell P and Thielke, Stephen M and Hirsch, Calvin and Newman, Anne B and Zieman, Susan} } @article {6213, title = {Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Apr}, pages = {1220-6}, abstract = {

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.

OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.

METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals >=65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.

RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.

CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

}, keywords = {Aged, Aged, 80 and over, Asymptomatic Diseases, Body Composition, Body Mass Index, Cohort Studies, Female, Humans, Hypothyroidism, Male, Thyroid Gland, Weight Loss}, issn = {1945-7197}, doi = {10.1210/jc.2013-3591}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Tracy, Russell P and Cappola, Anne R} } @article {6401, title = {Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Aug}, pages = {2657-64}, abstract = {

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.

OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.

METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.

RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95\% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95\% CI 0.52-1.21 for two time points] or men (HR 1.27, 95\% CI 0.82-1.95 for a single and HR 1.09, 95\% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95\% CI 0.55-2.25 in women and HR 1.78, 95\% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.

CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

}, keywords = {Absorptiometry, Photon, Aged, Aged, 80 and over, Asymptomatic Diseases, Bone Density, Cardiovascular System, Cohort Studies, Cross-Sectional Studies, Female, Hip Fractures, Humans, Male, Osteoporotic Fractures, Risk Factors, Sex Factors, Thyroid Diseases}, issn = {1945-7197}, doi = {10.1210/jc.2014-1051}, author = {Garin, Margaret C and Arnold, Alice M and Lee, Jennifer S and Robbins, John and Cappola, Anne R} } @article {6589, title = {Subclinical vascular disease burden and longer survival.}, journal = {J Am Geriatr Soc}, volume = {62}, year = {2014}, month = {2014 Sep}, pages = {1692-8}, abstract = {

OBJECTIVES: To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.

DESIGN: Cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals born between June 30, 1918, and June 30, 1921 (N~=~2,082; aged 70-75 at baseline (1992-93)).

MEASUREMENTS: A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.

RESULTS: A 1-point lower SVD score was associated with 1.22 greater odds (95\% confidence interval~=~1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.

CONCLUSION: A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.

}, keywords = {Aged, Aged, 80 and over, C-Reactive Protein, Carotid Intima-Media Thickness, Cohort Studies, Cystatin C, Depression, Diabetes Mellitus, Electrocardiography, Female, Humans, Inflammation, Kidney Diseases, Male, Smoking, Survival Analysis, United States, Vascular Diseases}, issn = {1532-5415}, doi = {10.1111/jgs.13018}, author = {Odden, Michelle C and Yee, Laura M and Arnold, Alice M and Sanders, Jason L and Hirsch, Calvin and DeFilippi, Christopher and Kizer, Jorge R and Inzitari, Marco and Newman, Anne B} } @article {6277, title = {Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study.}, journal = {Clin Endocrinol (Oxf)}, volume = {81}, year = {2014}, month = {2014 Nov}, pages = {746-53}, abstract = {

OBJECTIVE: Ischaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men.

DESIGN: Cohort study.

PARTICIPANTS: 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.

MEASUREMENTS: Adjudicated ischaemic stroke.

RESULTS: Among 1032 men (mean age 76, range 66-97), followed for a median of 10~years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P~=~0{\textperiodcentered}006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75~ng/dl, with greater risk of stroke at DHT levels above 75~ng/dl or below 50~ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 0{\textperiodcentered}77 (95\% CI, 0{\textperiodcentered}61, 0{\textperiodcentered}98) per standard deviation in analyses adjusted for stroke risk factors.

CONCLUSIONS: Dihydrotestosterone 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 whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

}, keywords = {Aged, Aged, 80 and over, Brain Ischemia, Cardiovascular Physiological Phenomena, Dihydrotestosterone, Health, Humans, Incidence, Longitudinal Studies, Male, Stroke, Testosterone}, issn = {1365-2265}, doi = {10.1111/cen.12452}, author = {Shores, Molly M and Arnold, Alice M and Biggs, Mary L and Longstreth, W T and Smith, Nicholas L and Kizer, Jorge R and Cappola, Anne R and Hirsch, Calvin H and Marck, Brett T and Matsumoto, Alvin M} } @article {6278, title = {Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study.}, journal = {J Clin Endocrinol Metab}, volume = {99}, year = {2014}, month = {2014 Jun}, pages = {2061-8}, abstract = {

CONTEXT: Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this.

OBJECTIVE: The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality.

DESIGN: In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection.

MAIN OUTCOME: The main outcomes were incident CVD and all-cause mortality.

RESULTS: Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both).

CONCLUSIONS: In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Dihydrotestosterone, Humans, Incidence, Longitudinal Studies, Male, Mortality, Residence Characteristics, Risk Factors, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2013-3576}, author = {Shores, Molly M and Biggs, Mary L and Arnold, Alice M and Smith, Nicholas L and Longstreth, W T and Kizer, Jorge R and Hirsch, Calvin H and Cappola, Anne R and Matsumoto, Alvin M} } @article {6703, title = {Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Aug}, pages = {1003-8}, abstract = {

BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems.

METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts.

RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest.

CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.

}, keywords = {Aging, Apolipoproteins E, Forkhead Transcription Factors, Genetic Linkage, Genome-Wide Association Study, Humans, Longevity, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1758-535X}, doi = {10.1093/gerona/glv006}, author = {Minster, Ryan L and Sanders, Jason L and Singh, Jatinder and Kammerer, Candace M and Barmada, M Michael and Matteini, Amy M and Zhang, Qunyuan and Wojczynski, Mary K and Daw, E Warwick and Brody, Jennifer A and Arnold, Alice M and Lunetta, Kathryn L and Murabito, Joanne M and Christensen, Kaare and Perls, Thomas T and Province, Michael A and Newman, Anne B} } @article {6550, title = {GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Jan}, pages = {110-8}, abstract = {

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15\% to 25\%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age >=90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 {\texttimes} 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 {\texttimes} 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85{\texttimes}10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages >=90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

}, keywords = {Aged, Aged, 80 and over, Apolipoproteins E, Cell Adhesion Molecules, Cohort Studies, Female, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome-Wide Association Study, Humans, Longevity, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Kainic Acid}, issn = {1758-535X}, doi = {10.1093/gerona/glu166}, author = {Broer, Linda and Buchman, Aron S and Deelen, Joris and Evans, Daniel S and Faul, Jessica D and Lunetta, Kathryn L and Sebastiani, Paola and Smith, Jennifer A and Smith, Albert V and Tanaka, Toshiko and Yu, Lei and Arnold, Alice M and Aspelund, Thor and Benjamin, Emelia J and De Jager, Philip L and Eirkisdottir, Gudny and Evans, Denis A and Garcia, Melissa E and Hofman, Albert and Kaplan, Robert C and Kardia, Sharon L R and Kiel, Douglas P and Oostra, Ben A and Orwoll, Eric S and Parimi, Neeta and Psaty, Bruce M and Rivadeneira, Fernando and Rotter, Jerome I and Seshadri, Sudha and Singleton, Andrew and Tiemeier, Henning and Uitterlinden, Andr{\'e} G and Zhao, Wei and Bandinelli, Stefania and Bennett, David A and Ferrucci, Luigi and Gudnason, Vilmundur and Harris, Tamara B and Karasik, David and Launer, Lenore J and Perls, Thomas T and Slagboom, P Eline and Tranah, Gregory J and Weir, David R and Newman, Anne B and van Duijn, Cornelia M and Murabito, Joanne M} } @article {6596, title = {Multisystem physiologic impairments and changes in gait speed of older adults.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Mar}, pages = {319-24}, abstract = {

BACKGROUND: Slowed gait is an important health indicator in older adults but a single identifiable cause is often lacking. We assessed whether a summary index measuring impairments across multiple physiologic systems was associated with slowed gait in older individuals.

METHODS: Data from the Cardiovascular Health Study (n = 3,010) were used to assess associations between baseline physiologic index (measuring vasculature, brain, kidneys, lungs, and glucose metabolism; range 0-10 with 0-2 points/system and lower score indicating higher function) and annual gait speed (m/s) over 6 years. Participants with complete data on the physiologic index and at least two gait speed measures were included. Mean gait speed and 95\% confidence intervals (CI) by category of index were calculated using mixed effects models.

RESULTS: Those with scores of three or higher on the index had significantly slower gait speed at baseline compared to those with scores of 0-2 (7-10: mean speed = 0.83 m/s, 95\% CI: 0.80, 0.84; 0-2: mean speed = 1.01 m/s, 95\% CI: 0.99, 1.03). Those with higher indices also had faster decline in gait speed compared to those with lower scores after adjustment for demographic and health characteristics (7-10: change in speed = -0.020 m/s/year, 95\% CI: -0.024, -0.016; 0-2: change in speed= -0.010 m/s/year, 95\% CI: -0.014, -0.006).

CONCLUSIONS: Greater impairment across five organ systems was associated with slower gait speed and greater declines in gait speed over 6 years. Impairments accumulated over multiple physiologic systems may make older adults more vulnerable to slow gait speed.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Brain, Cardiovascular Physiological Phenomena, Cohort Studies, Female, Gait, Geriatric Assessment, Glucose, Health Status Indicators, Humans, Kidney, Lung, Male, Sensitivity and Specificity, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glu176}, author = {Rosso, Andrea L and Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Carlson, Michelle C and Rosano, Caterina and Kritchevsky, Stephen B and Newman, Anne B} } @article {6934, title = {Sex, Race, and Age Differences in Observed Years of Life, Healthy Life, and Able Life among Older Adults in The Cardiovascular Health Study.}, journal = {J Pers Med}, volume = {5}, year = {2015}, month = {2015}, pages = {440-51}, abstract = {

OBJECTIVE: Longevity fails to account for health and functional status during aging. We sought to quantify differences in years of total life, years of healthy life, and years of able life among groups defined by age, sex, and race.

DESIGN: Primary analysis of a cohort study.

SETTING: 18 years of annual evaluations in four U.S. communities.

PARTICIPANTS: 5888 men and women aged 65 and older.

MEASUREMENTS: Years of life were calculated as the time from enrollment to death or 18 years. Years of total, healthy, and able life were determined from self-report during annual or semi-annual contacts. Cumulative years were summed across each of the age and sex groups.

RESULTS: White women had the best outcomes for all three measures, followed by white men, non-white women, and non-white men. For example, at the mean age of 73, a white female participant could expect 12.9 years of life, 8.9 of healthy life and 9.5 of able life, while a non-white female could expect 12.6, 7.0, and 8.0 years, respectively. A white male could expect 11.2, 8.1, and 8.9 years of life, healthy life, and able life, and a non-white male 10.3, 6.2, and 7.9 years. Regardless of starting age, individuals of the same race and sex groups spent similar amounts (not proportions) of time in an unhealthy or unable state.

CONCLUSION: Gender had a greater effect on longevity than did race, but race had a greater effect on years spent healthy or able. The mean number of years spent in an unable or sick state was surprisingly independent of the lifespan.

}, issn = {2075-4426}, doi = {10.3390/jpm5040440}, author = {Thielke, Stephen M and Diehr, Paula H and Yee, Laura M and Arnold, Alice M and Qui{\~n}ones, Ana R and Whitson, Heather E and Jacob, Mini E and Newman, Anne B} } @article {6551, title = {Thyroid function in the euthyroid range and adverse outcomes in older adults.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Mar}, pages = {1088-96}, abstract = {

CONTEXT: The appropriateness of current reference ranges for thyroid function testing in older adults has been questioned.

OBJECTIVE: This study aimed to determine the relationship between thyroid function tests within the euthyroid range and adverse outcomes in older adults not taking thyroid medication.

DESIGN, SETTING, AND PARTICIPANTS: US community-dwelling adults years of older (n = 2843) enrolled onto the Cardiovascular Health Study with TSH, free T4 (FT4), and total T3 concentrations in the euthyroid range.

MAIN OUTCOME MEASURES: Incidence of atrial fibrillation, coronary heart disease, heart failure, hip fracture, dementia, and all-cause death were measured.

RESULTS: No departures from linearity were detected. Higher TSH was negatively associated (P = .03) and higher FT4 was positively associated (P = .007) with mortality. Higher FT4 was associated with atrial fibrillation (P < .001) and heart failure (P = .004). Compared with the first quartile, individuals with TSH in the fourth quartile had a 9.6 per 1000 person-year lower incidence of dementia (P < .05) and those with FT4 in the fourth quartile had higher incidences of atrial fibrillation, coronary heart disease, heart failure, and mortality (11.0, 8.0, 7.8, and 14.3 per 1000 person-years, respectively, all P < .05). Total T3 was not associated with any outcome.

CONCLUSIONS: Higher TSH and lower FT4 concentrations within the euthyroid range are associated with lower risk of multiple adverse events in older people, including mortality. This suggests tolerance for lower thyroid hormone levels in this age group. Clinical trials are needed to evaluate the risk-benefit profile of new thresholds for initiating treatment and optimal target concentrations for thyroid hormone replacement in older people.

}, keywords = {Aged, Aged, 80 and over, Aging, Atrial Fibrillation, Cause of Death, Coronary Disease, Dementia, Female, Heart Failure, Hip Fractures, Humans, Incidence, Male, Prognosis, Reference Values, Survival Analysis, Thyroid Function Tests, Thyroid Gland}, issn = {1945-7197}, doi = {10.1210/jc.2014-3586}, author = {Cappola, Anne R and Arnold, Alice M and Wulczyn, Kendra and Carlson, Michelle and Robbins, John and Psaty, Bruce M} } @article {6707, title = {Years of able life in older persons--the role of cardiovascular imaging and biomarkers: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {4}, year = {2015}, month = {2015 Apr}, abstract = {

BACKGROUND: As the U.S. population grows older, there is greater need to examine physical independence. Previous studies have assessed risk factors in relation to either disability or mortality, but an outcome that combines both is still needed.

METHODS AND RESULTS: The Cardiovascular Health Study is a population-based, prospective study where participants underwent baseline echocardiogram, measurement of carotid intima-media thickness (IMT), and various biomarkers, then followed for up to 18 years. Years of able life (YAL) constituted the number of years the participant was able to perform all activities of daily living. Linear regression was used to model the relationship between selected measures and outcomes, adjusted for confounding variables. Among 4902 participants, mean age was 72.6 {\textpm} 5.4 years, median YAL for males was 8.8 (interquartile range [IQR], 4.3 to 13.8) and 10.3 (IQR, 5.8 to 15.8) for females. Reductions in YAL in the fully adjusted model for females and males, respectively, were: -1.34 (95\% confidence interval [CI], -2.18, -0.49) and -1.41 (95\% CI, -2.03, -0.8) for abnormal left ventricular (LV) ejection fraction, -0.5 (95\% CI, -0.78, -0.22) and -0.62 (95\% CI, -0.87, -0.36) per SD increase in LV mass, -0.5 (95\% CI, -0.7, -0.29) and -0.79 (95\% CI, -0.99, -0.58) for IMT, -0.5 (95\% CI, -0.64, -0.37) and -0.79 (95\% CI, -0.94, -0.65) for N-terminal pro-brain natriuretic peptide, -1.08 (95\% CI, -1.34, -0.83) and -0.73 (95\% CI, -0.97, -0.5) for high-sensitivity troponin-T, and -0.26 (95\% CI, -0.42, -0.09) and -0.23 (95\% CI, -0.41, -0.05) for procollagen-III N-terminal propeptide. Most tested variables remained significant even after adjusting for incident cardiovascular (CV) disease.

CONCLUSIONS: In this population-based cohort, variables obtained by CV imaging and biomarkers of inflammation, coagulation, atherosclerosis, myocardial injury and stress, and cardiac collagen turnover were associated with YAL, an important outcome that integrates physical ability and longevity in older persons.

}, keywords = {Activities of Daily Living, Aged, Biomarkers, Cardiovascular Diseases, Carotid Intima-Media Thickness, Echocardiography, Female, Humans, Independent Living, Male, Natriuretic Peptide, Brain, Peptide Fragments, Procollagen, Prospective Studies, Stroke Volume, Troponin I}, issn = {2047-9980}, doi = {10.1161/JAHA.114.001745}, author = {Alshawabkeh, Laith I and Yee, Laura M and Gardin, Julius M and Gottdiener, John S and Odden, Michelle C and Bartz, Traci M and Arnold, Alice M and Mukamal, Kenneth J and Wallace, Robert B} } @article {7247, title = {Can a Healthy Lifestyle Compress the Disabled Period in Older Adults?}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Oct}, pages = {1952-1961}, abstract = {

OBJECTIVES: To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life.

DESIGN: Community-based cohort study of older adults followed from 1989 to 2015.

SETTING: Four U.S. communities.

PARTICIPANTS: Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 {\textpm} 5.5, 57\% female, 15.2\% minority) who were not wheelchair dependent and were able to give informed consent at baseline.

MEASUREMENTS: Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL\%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period.

RESULTS: The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95\% confidence interval (CI) = 5.4-9.2) lower YAL/YoL\% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7\% (95\% CI = 1.6-5.9) lower YAL/YoL\% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95\% CI = 0.3-0.8) higher YAL/YoL\%.

CONCLUSION: The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.

}, issn = {1532-5415}, doi = {10.1111/jgs.14314}, author = {Jacob, Mini E and Yee, Laura M and Diehr, Paula H and Arnold, Alice M and Thielke, Stephen M and Chaves, Paulo H M and Gobbo, Liana Del and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {7133, title = {Effects of Disease Burden and Functional Adaptation on Morbidity and Mortality on Older Adults.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Jun}, pages = {1242-9}, abstract = {

OBJECTIVES: To ascertain whether older adults with extensive disease but relative vigor (adapters) shorten the period at the end of life in which they live with morbidity (compress morbidity).

DESIGN: Prospective, community-based cohort study in four U.S. cities.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older.

MEASUREMENTS: Participants were categorized into three groups according to extent of disease (assessed noninvasively), vigor, and frailty (expected agers (n~=~3,528, extent of disease similar to vigor and frailty-reference group), adapters (n~=~882, higher disease but vigorous), and prematurely frail (n~=~855, lower disease but frail)) and compared according to years of able life (YAL), years of self-reported healthy life (YHL), and mortality using multivariable regression and survival analysis.

RESULTS: After adjustment, adapters had 0.97 (95\% confidence interval (CI)~=~0.60-1.33) more YAL and 0.54 (95\% CI~=~0.19-0.90) more YHL than expected agers, and those who were prematurely frail had -0.99 (95\% CI~=~-1.36 to -0.62) fewer YAL and -0.53 (95\% CI~=~-0.89 to -0.17) fewer YHL than expected agers. Adapters had 0.9 more and prematurely frail had 1.5 fewer years of total life than expected agers (P~<~.001). Adapters spent 55\% of their remaining life able and healthy, those who were prematurely frail spent 37\%, and of expected agers spent 47\% (P~<~.001).

CONCLUSION: Despite similar levels of disease burden, older adults who were more vigorous appeared to compress morbidity and live longer. Older adults with higher frailty lengthened morbidity and had greater mortality. Adaptive factors may compress morbidity and decrease mortality.

}, issn = {1532-5415}, doi = {10.1111/jgs.14163}, author = {Sanders, Jason L and Arnold, Alice M and Hirsch, Calvin H and Thielke, Stephen M and Kim, Dae and Mukamal, Kenneth J and Kizer, Jorge R and Ix, Joachim H and Kaplan, Robert C and Kritchevsky, Stephen B and Newman, Anne B} } @article {7142, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {792-800}, abstract = {

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27~581 individuals of European descent over 65~years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β~=~0.47, SE~=~0.08, P-value~=~5.20~{\texttimes}~10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Matteini, Amy M and Tanaka, Toshiko and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and Eicher, John D and Johnson, Andrew D and Arnold, Alice M and Callisaya, Michele L and Davies, Gail and Evans, Daniel S and Holtfreter, Birte and Lohman, Kurt and Lunetta, Kathryn L and Mangino, Massimo and Smith, Albert V and Smith, Jennifer A and Teumer, Alexander and Yu, Lei and Arking, Dan E and Buchman, Aron S and Chibinik, Lori B and De Jager, Philip L and Evans, Denis A and Faul, Jessica D and Garcia, Melissa E and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and Liewald, David C and Liu, Yongmei and Lopez, Lorna and Rivadeneira, Fernando and Rotter, Jerome I and Siggeirsdottir, Kristin and Starr, John M and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Weir, David R and Yaffe, Kristine and Zhao, Wei and Zhuang, Wei Vivian and Zmuda, Joseph M and Bennett, David A and Cummings, Steven R and Deary, Ian J and Ferrucci, Luigi and Harris, Tamara B and Kardia, Sharon L R and Kocher, Thomas and Kritchevsky, Stephen B and Psaty, Bruce M and Seshadri, Sudha and Spector, Timothy D and Srikanth, Velandai K and Windham, B Gwen and Zillikens, M Carola and Newman, Anne B and Walston, Jeremy D and Kiel, Douglas P and Murabito, Joanne M} } @article {6996, title = {Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {36}, year = {2016}, month = {2016 Apr}, pages = {750-6}, abstract = {

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI).

APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged >=65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of >=0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95\% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95\% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95\% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95\% confidence interval 1.09, 1.50).

CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Age Factors, Aged, Aging, Ankle Brachial Index, Biomarkers, Chi-Square Distribution, Female, Humans, Incidence, Inflammation Mediators, Logistic Models, Male, Odds Ratio, Peripheral Arterial Disease, Prognosis, Proportional Hazards Models, Risk Assessment, Risk Factors, Time Factors, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.115.306647}, author = {Garg, Parveen K and Arnold, Alice M and Hinckley Stukovsky, Karen D and Koro, Carol and Jenny, Nancy S and Mukamal, Kenneth J and Criqui, Michael H and Furberg, Curt D and Newman, Anne B and Cushman, Mary} } @article {7358, title = {Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Dec}, pages = {835-845}, abstract = {

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1{\texttimes}10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5{\texttimes}10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103966}, author = {Postmus, Iris and Warren, Helen R and Trompet, Stella and Arsenault, Benoit J and Avery, Christy L and Bis, Joshua C and Chasman, Daniel I and de Keyser, Catherine E and Deshmukh, Harshal A and Evans, Daniel S and Feng, QiPing and Li, Xiaohui and Smit, Roelof A J and Smith, Albert V and Sun, Fangui and Taylor, Kent D and Arnold, Alice M and Barnes, Michael R and Barratt, Bryan J and Betteridge, John and Boekholdt, S Matthijs and Boerwinkle, Eric and Buckley, Brendan M and Chen, Y-D Ida and de Craen, Anton J M and Cummings, Steven R and Denny, Joshua C and Dub{\'e}, Marie Pierre and Durrington, Paul N and Eiriksdottir, Gudny and Ford, Ian and Guo, Xiuqing and Harris, Tamara B and Heckbert, Susan R and Hofman, Albert and Hovingh, G Kees and Kastelein, John J P and Launer, Leonore J and Liu, Ching-Ti and Liu, Yongmei and Lumley, Thomas and McKeigue, Paul M and Munroe, Patricia B and Neil, Andrew and Nickerson, Deborah A and Nyberg, Fredrik and O{\textquoteright}Brien, Eoin and O{\textquoteright}Donnell, Christopher J and Post, Wendy and Poulter, Neil and Vasan, Ramachandran S and Rice, Kenneth and Rich, Stephen S and Rivadeneira, Fernando and Sattar, Naveed and Sever, Peter and Shaw-Hawkins, Sue and Shields, Denis C and Slagboom, P Eline and Smith, Nicholas L and Smith, Joshua D and Sotoodehnia, Nona and Stanton, Alice and Stott, David J and Stricker, Bruno H and St{\"u}rmer, Til and Uitterlinden, Andr{\'e} G and Wei, Wei-Qi and Westendorp, Rudi G J and Whitsel, Eric A and Wiggins, Kerri L and Wilke, Russell A and Ballantyne, Christie M and Colhoun, Helen M and Cupples, L Adrienne and Franco, Oscar H and Gudnason, Vilmundur and Hitman, Graham and Palmer, Colin N A and Psaty, Bruce M and Ridker, Paul M and Stafford, Jeanette M and Stein, Charles M and Tardif, Jean-Claude and Caulfield, Mark J and Jukema, J Wouter and Rotter, Jerome I and Krauss, Ronald M} } @article {7001, title = {Mortality After Bereavement: The Role of Cardiovascular Disease and Depression.}, journal = {Psychosom Med}, volume = {78}, year = {2016}, month = {2016 Jul-Aug}, pages = {697-703}, abstract = {

OBJECTIVES: Late-life bereavement is associated with an increased risk of mortality. This study assesses the associations among bereavement, cardiovascular disease (CVD), and depressive symptoms on mortality in older men and women.

METHODS: We examined data from the Cardiovascular Health Study, a prospective population-based cohort study of older adults. We compared mortality in those who became bereaved from 1989 to 1999 (n = 593) to an age- and sex-matched sample of individuals who remained married (n = 593). Cox regression was used to examine the association between bereavement and 3-year all-cause mortality and whether or not the association differed by sex, presence of CVD, or postbereavement depressive symptoms.

RESULTS: One hundred ninety-nine (16.8\%) individuals died. There was no association of bereavement with mortality (hazard ratio [HR] = 0.98 [0.74-1.30]). However, there were significant interaction effects of bereavement with participant sex (p < .001) and CVD (p = .010). Bereavement decreased the risk of mortality in women (HR = 0.67 [0.46-0.97]) and increased the risk of mortality in men (HR = 1.77 [1.14-2.75]). Within sex, the association of bereavement with mortality differed according to CVD status. The reduced risk of mortality associated with bereavement in women was only observed in women with CVD, and the increased risk in men was only observed in men without CVD. High levels of depressive symptoms attenuated the relation between bereavement and mortality in men without CVD.

CONCLUSIONS: The relation between bereavement and mortality was different in men and women and varied by CVD status. Bereavement decreased mortality in women with CVD and increased mortality in men without CVD.

}, issn = {1534-7796}, doi = {10.1097/PSY.0000000000000317}, author = {Stahl, Sarah T and Arnold, Alice M and Chen, Jia-Yuh and Anderson, Stewart and Schulz, Richard} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {7128, title = {Trajectories of function and biomarkers with age: the CHS All Stars Study.}, journal = {Int J Epidemiol}, year = {2016}, month = {2016 Jun 6}, abstract = {

BACKGROUND: Multimorbidity is a major driver of physical and cognitive impairment, but rates of decline are also related to ageing. We sought to determine trajectories of decline in a large cohort by disease status, and examined their correspondence with biomarkers of ageing processes including growth hormone, sex steroid, inflammation, visceral adiposity and kidney function pathways.

METHODS: We have followed the 5888 participants in the Cardiovascular Health Study (CHS) for healthy ageing and longevity since 1989-90. Gait speed, grip strength, modified mini-mental status examination (3MSE) and the digit symbol substitution test (DSST) were assessed annually to 1998-99 and again in 2005-06. Insulin-like growth hormone (IGF-1), dehydroepiandrosterone sulphate (DHEAS), interleukin-6 (IL-6), adiponectin and cystatin-C were assessed 3-5 times from stored samples. Health status was updated annually and dichotomized as healthy vs not healthy. Trajectories for each function measure and biomarker were estimated using generalized estimating equations as a function of age and health status using standardized values.

RESULTS: Trajectories of functional decline showed strong age acceleration late in life in healthy older men and women as well as in chronically ill older adults. Adiponectin, IL-6 and cystatin-C tracked with functional decline in all domains; cystatin-C was consistently associated with functional declines independent of other biomarkers. DHEAS was independently associated with grip strength and IL-6 with grip strength and gait speed trajectories.

CONCLUSIONS: Functional decline in late life appears to mark a fundamental ageing process in that it occurred and was accelerated in late life regardless of health status. Cystatin C was most consistently associated with these functional declines.

}, issn = {1464-3685}, doi = {10.1093/ije/dyw092}, author = {Newman, Anne B and Sanders, Jason L and Kizer, Jorge R and Boudreau, Robert M and Odden, Michelle C and Zeki Al Hazzouri, Adina and Arnold, Alice M} } @article {7567, title = {Age, Race and Gender Factors in Incident Disability.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2017}, month = {2017 Oct 13}, abstract = {

Background: Incident disability rates enable the comparison of risk across populations. Understanding these by age, sex and race is important for planning for the care of older adults and targeting prevention.

Methods: We calculated incident disability rates among older adults in the Cardiovascular Health Study, a study of 5,888 older adults aged >= 65 years over 6 years of follow-up. Disability was defined in 2 ways: 1) self-report of disability (severe difficulty or inability) in any of 6 ADLs, and 2) mobility difficulty (any difficulty walking half a mile or climbing 10 steps). Incident disability rates were calculated as events per 100 person years for age, gender and race groups.

Results: The incidence of ADL disability, and mobility difficulty were 2.7 (2.5-2.8), and 9.8 (9.4 -10.3) events per 100 person years. Women, older participants and blacks had higher rates in both domains.

Conclusion: Incidence rates are considerably different based on the domain examined as well as age, race and gender composition of the population. Prevention efforts should focus on high risk populations and attempt to ameliorate factors that increase risk in these groups.

}, issn = {1758-535X}, doi = {10.1093/gerona/glx194}, author = {Jacob, Mini E and Marron, Megan M and Boudreau, Robert and Odden, Michelle C and Arnold, Alice M and Newman, Anne B} } @article {7502, title = {Comparing methods to address bias in observational data: statin use and cardiovascular events in a US cohort.}, journal = {Int J Epidemiol}, year = {2017}, month = {2017 Sep 08}, abstract = {

Background: The theoretical conditions under which causal estimates can be derived from observational data are challenging to achieve in the real world. Applied examples can help elucidate the practical limitations of methods to estimate randomized-controlled trial effects from observational data.

Methods: We used six methods with varying design and analytic features to compare the 5-year risk of incident myocardial infarction among statin users and non-users, and used non-cardiovascular mortality as a negative control outcome. Design features included restriction to a statin-eligible population and new users only; analytic features included multivariable adjustment and propensity score matching.

Results: We used data from 5294 participants in the Cardiovascular Health Study from 1989 to 2004. For non-cardiovascular mortality, most methods produced protective estimates with confidence intervals that crossed the null. The hazard ratio (HR) was 0.92, 95\% confidence interval: 0.58, 1.46 using propensity score matching among eligible new users. For myocardial infarction, all estimates were strongly protective; the propensity score-matched analysis among eligible new users resulted in a HR of 0.55 (0.29, 1.05)-a much stronger association than observed in randomized controlled trials.

Conclusions: In designs that compare active treatment with non-treated participants to evaluate effectiveness, methods to address bias in observational data may be limited in real-world settings by residual bias.

}, issn = {1464-3685}, doi = {10.1093/ije/dyx179}, author = {Kaiser, Paulina and Arnold, Alice M and Benkeser, David and Zeki Al Hazzouri, Adina and Hirsch, Calvin H and Psaty, Bruce M and Odden, Michelle C} } @article {7340, title = {The complex genetics of gait speed: genome-wide meta-analysis approach.}, journal = {Aging (Albany NY)}, volume = {9}, year = {2017}, month = {2017 Jan 10}, pages = {209-246}, abstract = {

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

}, issn = {1945-4589}, doi = {10.18632/aging.101151}, author = {Ben-Avraham, Dan and Karasik, David and Verghese, Joe and Lunetta, Kathryn L and Smith, Jennifer A and Eicher, John D and Vered, Rotem and Deelen, Joris and Arnold, Alice M and Buchman, Aron S and Tanaka, Toshiko and Faul, Jessica D and Nethander, Maria and Fornage, Myriam and Adams, Hieab H and Matteini, Amy M and Callisaya, Michele L and Smith, Albert V and Yu, Lei and De Jager, Philip L and Evans, Denis A and Gudnason, Vilmundur and Hofman, Albert and Pattie, Alison and Corley, Janie and Launer, Lenore J and Knopman, Davis S and Parimi, Neeta and Turner, Stephen T and Bandinelli, Stefania and Beekman, Marian and Gutman, Danielle and Sharvit, Lital and Mooijaart, Simon P and Liewald, David C and Houwing-Duistermaat, Jeanine J and Ohlsson, Claes and Moed, Matthijs and Verlinden, Vincent J and Mellstr{\"o}m, Dan and van der Geest, Jos N and Karlsson, Magnus and Hernandez, Dena and McWhirter, Rebekah and Liu, Yongmei and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and Weir, David R and Zhao, Wei and Starr, John M and Johnson, Andrew D and Ikram, M Arfan and Bennett, David A and Cummings, Steven R and Deary, Ian J and Harris, Tamara B and Kardia, Sharon L R and Mosley, Thomas H and Srikanth, Velandai K and Windham, Beverly G and Newman, Ann B and Walston, Jeremy D and Davies, Gail and Evans, Daniel S and Slagboom, Eline P and Ferrucci, Luigi and Kiel, Douglas P and Murabito, Joanne M and Atzmon, Gil} } @article {7328, title = {Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies.We examined the association of fetuin-A levels with \~{} 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (p < 0.05x10-8) SNPs near the AHSG locus, the top SNP was rs4917 (p = 1.27x10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/L (\~{}13\%) lower fetuin-A level. This variant alone explained 14\% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx091}, author = {Jensen, Majken K and Jensen, Richard A and Mukamal, Kenneth J and Guo, Xiuqing and Yao, Jie and Sun, Qi and Cornelis, Marilyn and Liu, Yongmei and Chen, Ming-Huei and Kizer, Jorge R and Djouss{\'e}, Luc and Siscovick, David S and Psaty, Bruce M and Zmuda, Joseph M and Rotter, Jerome I and Garcia, Melissa and Harris, Tamara and Chen, Ida and Goodarzi, Mark O and Nalls, Michael A and Keller, Margaux and Arnold, Alice M and Newman, Anne and Hoogeeven, Ron C and Rexrode, Kathryn M and Rimm, Eric B and Hu, Frank B and Vasan, Ramachandran S and Katz, Ronit and Pankow, James S and Ix, Joachim H} } @article {7493, title = {Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults.}, journal = {Stroke}, volume = {48}, year = {2017}, month = {2017 Jul}, pages = {1818-1826}, abstract = {

BACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.

METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (>=5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).

RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.

CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Brain Ischemia, Cohort Studies, Female, Follow-Up Studies, Frail Elderly, Humans, Male, Recovery of Function, Risk Factors, Stroke, Survival Rate}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.117.016726}, author = {Winovich, Divya Thekkethala and Longstreth, William T and Arnold, Alice M and Varadhan, Ravi and Zeki Al Hazzouri, Adina and Cushman, Mary and Newman, Anne B and Odden, Michelle C} } @article {7355, title = {Health and Functional Status of Adults Aged 90 Years in the United States.}, journal = {JAMA Intern Med}, volume = {177}, year = {2017}, month = {2017 May 01}, pages = {732-734}, issn = {2168-6114}, doi = {10.1001/jamainternmed.2017.0242}, author = {Odden, Michelle C and Koh, William Jen Hoe and Arnold, Alice M and Psaty, Bruce M and Newman, Anne B} } @article {7671, title = {Association of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2018}, month = {2018 Apr 12}, abstract = {

Background: A goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers strongly and independently associated with mortality and which statistically attenuate chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it to a validated Physiologic Index (PI) in older adults.

Methods: The indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor (IGF)-1, IGF binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N=2197) and validation (N=1124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.

Results: In separate age-adjusted models, the hazard ratio (HR) for mortality per point of the BI was 1.30 (95\% CI 1.25, 1.34) and the BI attenuated age by 25\%. The HR for the PI was 1.28 (1.24, 1.33) (29\% age attenuation). In the same model, the HR for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5\%. Associations persisted after further adjustment.

Conclusions: The BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.

}, issn = {1758-535X}, doi = {10.1093/gerona/gly075}, author = {Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Kizer, Jorge R and Kaplan, Robert C and Cappola, Anne R and Cushman, Mary and Jacob, Mini E and Kritchevsky, Stephen B and Newman, Anne B} } @article {7680, title = {Long-Term Cognitive Decline After Newly Diagnosed Heart Failure: Longitudinal Analysis in the CHS (Cardiovascular Health Study).}, journal = {Circ Heart Fail}, volume = {11}, year = {2018}, month = {2018 Mar}, pages = {e004476}, abstract = {

BACKGROUND: Heart failure (HF) is associated with cognitive impairment. However, we know little about the time course of cognitive change after HF diagnosis, the importance of comorbid atrial fibrillation, or the role of ejection fraction. We sought to determine the associations of incident HF with rates of cognitive decline and whether these differed by atrial fibrillation status or reduced versus preserved ejection fraction.

METHODS AND RESULTS: Participants were 4864 men and women aged >=65 years without a history of HF and free of clinical stroke in the CHS (Cardiovascular Health Study)-a community-based prospective cohort study in the United States, with cognition assessed annually from 1989/1990 through 1998/1999. We identified 496 participants with incident HF by review of hospital discharge summaries and Medicare claims data, with adjudication according to standard criteria. Global cognitive ability was measured by the Modified Mini-Mental State Examination. In adjusted models, 5-year decline in model-predicted mean Modified Mini-Mental State Examination score was 10.2 points (95\% confidence interval, 8.6-11.8) after incident HF diagnosed at 80 years of age, compared with a mean 5-year decline of 5.8 points (95\% confidence interval, 5.3-6.2) from 80 to 85 years of age without HF. The association was stronger at older ages than at younger ages, did not vary significantly in the presence versus absence of atrial fibrillation (=0.084), and did not vary significantly by reduced versus preserved ejection fraction (=0.734).

CONCLUSIONS: Decline in global cognitive ability tends to be faster after HF diagnosis than without HF. Clinical and public health implications of this finding warrant further attention.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.117.004476}, author = {Hammond, Christa A and Blades, Natalie J and Chaudhry, Sarwat I and Dodson, John A and Longstreth, W T and Heckbert, Susan R and Psaty, Bruce M and Arnold, Alice M and Dublin, Sascha and Sitlani, Colleen M and Gardin, Julius M and Thielke, Stephen M and Nanna, Michael G and Gottesman, Rebecca F and Newman, Anne B and Thacker, Evan L} } @article {8539, title = {Metabolic Clusters and Outcomes in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {66}, year = {2018}, month = {2018 02}, pages = {289-296}, abstract = {

BACKGROUND/OBJECTIVES: Few studies have the requisite phenotypic information to define metabolic patterns that may inform our understanding of the pathophysiology and consequences of diabetes in older adults. We sought to characterize clusters of older adults on the basis of shared metabolic features.

DESIGN: Population-based prospective cohort study.

SETTING: Four U.S. Cardiovascular Health Study field centers.

PARTICIPANTS: Individuals aged 65 and older taking no glucose-lowering agents (N~=~2,231).

MEASUREMENTS: K-means cluster analysis of 11 metabolic parameters (fasting and postload serum glucose and plasma insulin, fasting C-peptide, body mass index, C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), albuminuria, carboxymethyl lysine (an advanced glycation end-product), procollagen III N-terminal propeptide (a fibrotic marker)) and their associations with incident cardiovascular disease, diabetes, disability, and mortality over 8 to 14.5~years of follow-up and with measures of subclinical cardiovascular disease.

RESULTS: A 6-cluster solution provided robust differentiation into distinct, identifiable clusters. Cluster A (n~=~739) had the lowest glucose and insulin and highest eGFR and the lowest rates of all outcomes. Cluster B (n~=~419) had high glucose and insulin and intermediate rates of most outcomes. Cluster C (n~=~118) had the highest insulin. Cluster D (n~=~129) had the highest glucose with much lower insulin. Cluster E (n~=~314) had the lowest eGFR and highest albuminuria. Cluster F (n~=~512) had the highest CRP. Rates of CVD, mortality, and subclinical atherosclerosis were highest in clusters C, D, and E and were similar to rates in participants with treated diabetes. Incidence of disability was highest in Cluster C.

CONCLUSION: Clustering according to metabolic parameters identifies distinct phenotypes that are strongly associated with clinical and functional outcomes, even at advanced age.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Incidence, Insulin, Longitudinal Studies, Male, Prospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/jgs.15205}, author = {Mukamal, Kenneth J and Siscovick, David S and de Boer, Ian H and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Tracy, Russell P and Boyko, Edward J and Kahn, Steven E and Arnold, Alice M} } @article {7922, title = {Trajectories of Nonagenarian Health: Gender, Age, and Period Effects.}, journal = {Am J Epidemiol}, year = {2018}, month = {2018 Nov 08}, abstract = {

The US population aged 90 years and older is growing rapidly and there are limited data on their health. The Cardiovascular Health Study is a prospective study of black and white adults >=65 years recruited in two waves (1989-90 and 1992-93) from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. We created a synthetic cohort of the 1,889 participants who had reached age 90 at baseline or during follow-up through July 16th, 2015. Participants entered the cohort at 90 years and we evaluated their changes in health after age 90 (median [IQR] follow-up: 3 [1.3-5] years). Measures of health included cardiovascular events, cognitive function, depressive symptoms, prescription medications, self-rated health, and measures of functional status. The mortality rate was high: 19.0 (95\% CI: 17.8, 20.3) per 100 person-years in women and 20.9 (95\% CI: 19.2, 22.8) in men. Cognitive function and all measures of functional status declined with age; these changes were similar by gender. When we isolated period effects, we found that medications use increased over time. These estimates can help inform future research and health care systems to meet the needs of this growing population.

}, issn = {1476-6256}, doi = {10.1093/aje/kwy241}, author = {Odden, Michelle C and Koh, William Jen Hoe and Arnold, Alice M and Rawlings, Andreea M and Psaty, Bruce M and Newman, Anne B} } @article {8285, title = {The association of prediagnosis social support with survival after heart failure in the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {42}, year = {2020}, month = {2020 Feb}, pages = {73-77}, abstract = {

PURPOSE: Although social support has been shown to be associated with survival among persons with cardiovascular disease, little research has focused on whether social support, measured before the onset of heart failure, can enhance survival after diagnosis. The objective of this study was to assess the association between prediagnosis social support and postdiagnosis survival among older adults with heart failure.

METHODS: We obtained the data from the Cardiovascular Health Study, which included noninstitutionalized adults aged 65 years or older from four sites in the United States with primary enrollment in 1989-1990. We used two measures of social support, the Lubben Social Network Scale and the Interpersonal Support Evaluation List. The analytic data set included 529 participants with a social support measure within two years before diagnosis of heart failure.

RESULTS: After adjustment for demographic covariates, cardiovascular risk factors, and general health status, mortality rates were lower among participants in the highest tertile of social network scores (HR 0.74, 95\% CI: 0.59, 0.93) and the middle tertile (HR 0.73 [0.58, 0.90]), compared with the lowest tertile. Results with interpersonal support were null.

CONCLUSIONS: These findings suggest that prediagnosis structural social support may modestly buffer heart failure patients from mortality.

}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2019.12.013}, author = {Kaiser, Paulina and Allen, Norrina and Delaney, Joseph A C and Hirsch, Calvin H and Carnethon, Mercedes and Arnold, Alice M and Odden, Michelle C} } @article {8401, title = {Patterns of Cardiovascular Risk Factors in Old Age and Survival and Health Status at 90.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2020}, month = {2020 Apr 08}, abstract = {

BACKGROUND: The population age 90 years and older is the fastest growing segment of the U.S. population. Only recently is it possible to study the factors that portend survival to this age.

METHODS: Among participants of the Cardiovascular Health Study, we studied the association of repeated measures of cardiovascular risk factors measured over 15-23 years of follow-up and not only survival to 90 years of age, but also healthy aging outcomes among the population who reached age 90. We included participants aged 67-75 years at baseline (n = 3,613/5,888) to control for birth cohort effects, and followed participants until death or age 90 (median follow-up = 14.7 years).

RESULTS: Higher systolic blood pressure was associated with a lower likelihood of survival to age 90, although this association was attenuated at older ages (p-value for interaction <.001) and crossed the null for measurements taken in participants{\textquoteright} 80{\textquoteright}s. Higher levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) were associated with greater longevity. Among the survivors to age 90, those with worse cardiovascular profile (high blood pressure, LDL cholesterol, glucose, and BMI; low HDL cholesterol) had lower likelihood of remaining free of cardiovascular disease, cognitive impairment, and disability.

CONCLUSION: In summary, we observed paradoxical associations between some cardiovascular risk factors and survival to old age; whereas, among those who survive to very old age, these risk factors were associated with higher risk of adverse health outcomes.

}, issn = {1758-535X}, doi = {10.1093/gerona/glaa043}, author = {Odden, Michelle C and Rawlings, Andreea M and Arnold, Alice M and Cushman, Mary and Biggs, Mary L and Psaty, Bruce M and Newman, Anne B} } @article {8399, title = {Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {75}, year = {2020}, month = {2020 Jul 13}, pages = {1523-1529}, abstract = {

BACKGROUND: The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation.

METHODS: We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined.

RESULTS: The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95\% CI: -0. 37, -0.03; p = .02), compared to no change in men (β = 0.07; 95\% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4.

CONCLUSIONS: We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

}, issn = {1758-535X}, doi = {10.1093/gerona/glz217}, author = {Miller, Lindsay M and Jenny, Nancy S and Rawlings, Andreea M and Arnold, Alice M and Fitzpatrick, Annette L and Lopez, Oscar L and Odden, Michelle C} } @article {9008, title = {Association of Retail Environment and Neighborhood Socioeconomic Status with Mortality among Community-dwelling Older Adults in the US: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2021}, month = {2021 Oct 20}, abstract = {

BACKGROUND: Few studies have examined the association of neighborhood environment and mortality among community-dwelling older populations. Geographic Information Systems (GIS)-based measures of neighborhood physical environment may provide new insights on the health effects of the social and built environment.

METHODS: We studied 4,379 community-dwelling older adults in the US aged >=65 years from the Cardiovascular Health Study. Principal component analysis was used to identify neighborhood components from 48 variables assessing facilities and establishments, demographic composition, socio-economic status, and economic prosperity. We used a Cox model to evaluate the association of neighborhood components with five-year mortality. Age, sex, race, education, income, marital status, body mass index, smoking status, disability, coronary heart disease, and diabetes were included as covariates. We also examined the interactions between neighborhood components and sex and race (Black vs. white or other).

RESULTS: We identified five neighborhood components, representing facilities and resources, immigrant communities, community-level economic deprivation, resident-level socio-economic status and residents{\textquoteright} age. Communities{\textquoteright} economic deprivation and residents{\textquoteright} socio-economic status were significantly associated with five-year mortality. We did not find interactions between sex or race and any of the five neighborhood components. The results were similar in a sensitivity analysis where we used ten-year mortality as the outcome.

CONCLUSIONS: We found that communities{\textquoteright} economic status but not facilities in communities was associated with mortality among older adults. These findings revealed the importance and benefits living in a socio-economically advantaged neighborhood could have on health among older residents with different demographic backgrounds.

}, issn = {1758-535X}, doi = {10.1093/gerona/glab319}, author = {Zhang, Kehan and Lovasi, Gina S and Odden, Michelle C and Michael, Yvonne L and Newman, Anne B and Arnold, Alice M and Kim, Dae Hyun and Wu, Chenkai} } @article {8835, title = {Genetic insights into biological mechanisms governing human ovarian ageing.}, journal = {Nature}, volume = {596}, year = {2021}, month = {2021 Aug}, pages = {393-397}, abstract = {

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1\% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03779-7}, author = {Ruth, Katherine S and Day, Felix R and Hussain, Jazib and Mart{\'\i}nez-Marchal, Ana and Aiken, Catherine E and Azad, Ajuna and Thompson, Deborah J and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B and Sulem, Patrick and Walters, Robin G and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W and Aguilera, Paula and Ferrer-Roda, M{\`o}nica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R H J and Ahearn, Thomas U and Alizadeh, Behrooz Z and Naderi, Elnaz and Andrulis, Irene L and Arnold, Alice M and Aronson, Kristan J and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M and Beaumont, Robin N and Becher, Heiko and Beckmann, Matthias W and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Bojesen, Stig E and Bolla, Manjeet K and Boomsma, Dorret I and Bowker, Nicholas and Brody, Jennifer A and Broer, Linda and Buring, Julie E and Campbell, Archie and Campbell, Harry and Castelao, Jose E and Catamo, Eulalia and Chanock, Stephen J and Chenevix-Trench, Georgia and Ciullo, Marina and Corre, Tanguy and Couch, Fergus J and Cox, Angela and Crisponi, Laura and Cross, Simon S and Cucca, Francesco and Czene, Kamila and Smith, George Davey and de Geus, Eco J C N and de Mutsert, Ren{\'e}e and De Vivo, Immaculata and Demerath, Ellen W and Dennis, Joe and Dunning, Alison M and Dwek, Miriam and Eriksson, Mikael and Esko, T{\~o}nu and Fasching, Peter A and Faul, Jessica D and Ferrucci, Luigi and Franceschini, Nora and Frayling, Timothy M and Gago-Dominguez, Manuela and Mezzavilla, Massimo and Garc{\'\i}a-Closas, Montserrat and Gieger, Christian and Giles, Graham G and Grallert, Harald and Gudbjartsson, Daniel F and Gudnason, Vilmundur and Gu{\'e}nel, Pascal and Haiman, Christopher A and H{\r a}kansson, Niclas and Hall, Per and Hayward, Caroline and He, Chunyan and He, Wei and Heiss, Gerardo and H{\o}ffding, Miya K and Hopper, John L and Hottenga, Jouke J and Hu, Frank and Hunter, David and Ikram, Mohammad A and Jackson, Rebecca D and Joaquim, Micaella D R and John, Esther M and Joshi, Peter K and Karasik, David and Kardia, Sharon L R and Kartsonaki, Christiana and Karlsson, Robert and Kitahara, Cari M and Kolcic, Ivana and Kooperberg, Charles and Kraft, Peter and Kurian, Allison W and Kutalik, Zolt{\'a}n and La Bianca, Martina and Lachance, Genevieve and Langenberg, Claudia and Launer, Lenore J and Laven, Joop S E and Lawlor, Deborah A and Le Marchand, Lo{\"\i}c and Li, Jingmei and Lindblom, Annika and Lindstr{\"o}m, Sara and Lindstrom, Tricia and Linet, Martha and Liu, Yongmei and Liu, Simin and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Magnusson, Patrik K E and Mangino, Massimo and Mannermaa, Arto and Marco, Brumat and Marten, Jonathan and Martin, Nicholas G and Mbarek, Hamdi and McKnight, Barbara and Medland, Sarah E and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Metspalu, Andres and Milani, Lili and Milne, Roger L and Montgomery, Grant W and Mook-Kanamori, Dennis O and Mulas, Antonella and Mulligan, Anna M and Murray, Alison and Nalls, Mike A and Newman, Anne and Noordam, Raymond and Nutile, Teresa and Nyholt, Dale R and Olshan, Andrew F and Olsson, H{\r a}kan and Painter, Jodie N and Patel, Alpa V and Pedersen, Nancy L and Perjakova, Natalia and Peters, Annette and Peters, Ulrike and Pharoah, Paul D P and Polasek, Ozren and Porcu, Eleonora and Psaty, Bruce M and Rahman, Iffat and Rennert, Gad and Rennert, Hedy S and Ridker, Paul M and Ring, Susan M and Robino, Antonietta and Rose, Lynda M and Rosendaal, Frits R and Rossouw, Jacques and Rudan, Igor and Rueedi, Rico and Ruggiero, Daniela and Sala, Cinzia F and Saloustros, Emmanouil and Sandler, Dale P and Sanna, Serena and Sawyer, Elinor J and Sarnowski, Chloe and Schlessinger, David and Schmidt, Marjanka K and Schoemaker, Minouk J and Schraut, Katharina E and Scott, Christopher and Shekari, Saleh and Shrikhande, Amruta and Smith, Albert V and Smith, Blair H and Smith, Jennifer A and Sorice, Rossella and Southey, Melissa C and Spector, Tim D and Spinelli, John J and Stampfer, Meir and St{\"o}ckl, Doris and van Meurs, Joyce B J and Strauch, Konstantin and Styrkarsdottir, Unnur and Swerdlow, Anthony J and Tanaka, Toshiko and Teras, Lauren R and Teumer, Alexander and {\TH}orsteinsdottir, Unnur and Timpson, Nicholas J and Toniolo, Daniela and Traglia, Michela and Troester, Melissa A and Truong, Th{\'e}r{\`e}se and Tyrrell, Jessica and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Vachon, Celine M and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and V{\"o}lzke, Henry and Wang, Qin and Wareham, Nicholas J and Weinberg, Clarice R and Weir, David R and Wilcox, Amber N and van Dijk, Ko Willems and Willemsen, Gonneke and Wilson, James F and Wolffenbuttel, Bruce H R and Wolk, Alicja and Wood, Andrew R and Zhao, Wei and Zygmunt, Marek and Chen, Zhengming and Li, Liming and Franke, Lude and Burgess, Stephen and Deelen, Patrick and Pers, Tune H and Gr{\o}ndahl, Marie Louise and Andersen, Claus Yding and Pujol, Anna and Lopez-Contreras, Andres J and Daniel, Jeremy A and Stefansson, Kari and Chang-Claude, Jenny and van der Schouw, Yvonne T and Lunetta, Kathryn L and Chasman, Daniel I and Easton, Douglas F and Visser, Jenny A and Ozanne, Susan E and Namekawa, Satoshi H and Solc, Petr and Murabito, Joanne M and Ong, Ken K and Hoffmann, Eva R and Murray, Anna and Roig, Ignasi and Perry, John R B} } @article {8840, title = {Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2021}, month = {2021 Jul 31}, abstract = {

BACKGROUND: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial (RCT) effects from observational data.

METHODS: We used observational data from 5,580 participants enrolled in the Cardiovascular Health Study from 1989/90 to 1999/2000. We conceptualized the cohort as an overlapping sequence of non-randomized trials. We compared multiple selection (eligible population, prevalent users, new-users) and analytic approaches (multivariable adjustment, inverse probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State (3MS) examination.

RESULTS: When comparing prevalent users to non-users (N=2,772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95\% CI:0.05;0.63). Compared to prevalent user design, estimates from new user designs (e.g. comparing eligible statin initiators to non-initiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N=454), annual 3MS change comparing statin initiators to non-initiators was -0.21 points/year (95\% CI:-0.81;0.39).

CONCLUSIONS: The association of statin use and cognitive decline is attenuated towards the null when using rigorous analytical approaches that more closely mimic RCTs. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.

}, issn = {1758-535X}, doi = {10.1093/gerona/glab220}, author = {Zeki Al Hazzouri, Adina and Jawadekar, Neal and Grasset, Leslie and Kaiser, Paulina and Kezios, Katrina and Calonico, Sebastian and Glymour, M Maria and Hirsch, Calvin and Arnold, Alice M and Varadhan, Ravi and Opoodden, Michelle C} } @article {9170, title = {Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 08 02}, pages = {e024012}, abstract = {

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95\% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.

}, keywords = {Atherosclerosis, Cardiovascular Diseases, Cohort Studies, Glycation End Products, Advanced, Humans, Middle Aged, Risk Factors}, issn = {2047-9980}, doi = {10.1161/JAHA.121.024012}, author = {Lamprea-Montealegre, Julio A and Arnold, Alice M and McClelland, Robyn L and Mukamal, Kenneth J and Djouss{\'e}, Luc and Biggs, Mary L and Siscovick, David S and Tracy, Russell P and Beisswenger, Paul J and Psaty, Bruce M and Ix, Joachim H and Kizer, Jorge R} } @article {9438, title = {Association of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Jul 19}, abstract = {

BACKGROUND: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration.

METHODS: A Biomarker Index (BI) was constructed in the Cardiovascular Health Study (N=3197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up.

RESULTS: The hazard ratio (HR, 95\% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95\% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7\% and 22.0\% in women and men, respectively.

CONCLUSIONS: BI was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad172}, author = {Zhang, Xiao and Sanders, Jason L and Boudreau, Robert M and Arnold, Alice M and Justice, Jamie N and Espeland, Mark A and Kuchel, George A and Barzilai, Nir and Kuller, Lewis H and Lopez, Oscar L and Kritchevsky, Stephen B and Newman, Anne B} } @article {9317, title = {Social networks, social support, and life expectancy in older adults: the Cardiovascular Health Study.}, journal = {Arch Gerontol Geriatr}, volume = {111}, year = {2023}, month = {2023 Mar 03}, pages = {104981}, abstract = {

BACKGROUND: Social support and social networks have long been postulated to impact health outcomes but their impact on life expectancy and disability in older adults remains poorly quantified.

METHODS: As part of the Cardiovascular Health Study, we followed 5,749 adults aged 65 years and older from 4 US field centers for 25 years. We assessed the Lubben social network score [range 0-50] and a social support score [range 0-24] derived from the Interpersonal Support Evaluation List (ISEL-12) in two consecutive years starting at study recruitment. We used remaining years of life (YOL) from study enrollment to death to approximate life expectancy. We defined years of active life (YAL) as the number of study years in which participants lived without any difficulties in activities of daily living. We used compression of disability to reflect the proportion of life lived able (YAL/YOL). We used linear regression to adjust for socio-demographics and comorbidity.

RESULTS: The mean (standard deviation [SD]) scores were 32.3~{\textpm}~6.8 points for social network score and 8.3~{\textpm}~2.4 points for social support score. For every 1-SD increase in social network score, adjusted participant life expectancy was 0.40 years higher (95\% CI 0.22-0.58; p<0.0001) and disability-free life expectancy 0.35 years higher (95\% CI 0.18-0.53; p<0.0001). The association with life expectancy was modified by participant age (p<0.001), but it remained significant even among participants aged >=75 years (3 months per SD; 95\% CI 0.1-6 months, p~=~0.04). Further adjustment for frailty did not attenuate the estimates. The social support scale was not significantly associated with YOL or YAL after adjustment for social network score, and neither measure was associated with compression of disability.

DISCUSSION: In older adults, higher social network scores are significantly associated with longer life expectancy and disability-free life expectancy.

}, issn = {1872-6976}, doi = {10.1016/j.archger.2023.104981}, author = {Bhatia, Roma and Hirsch, Calvin and Arnold, Alice M and Newman, Anne B and Mukamal, Kenneth J} } @article {9640, title = {Plasma proteomic signature of human longevity.}, journal = {Aging Cell}, year = {2024}, month = {2024 Mar 05}, pages = {e14136}, abstract = {

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

}, issn = {1474-9726}, doi = {10.1111/acel.14136}, author = {Liu, Xiaojuan and Axelsson, Gisli Thor and Newman, Anne B and Psaty, Bruce M and Boudreau, Robert M and Wu, Chenkai and Arnold, Alice M and Aspelund, Thor and Austin, Thomas R and Gardin, Julius M and Siggeirsdottir, Kristin and Tracy, Russell P and Gerszten, Robert E and Launer, Lenore J and Jennings, Lori L and Gudnason, Vilmundur and Sanders, Jason L and Odden, Michelle C} }