@article {709, title = {Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Nov 11}, pages = {2333-41}, abstract = {

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.

OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.

METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.

RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3\%) were identified as frail, 2147 (45.3\%) as intermediate, and 2289 (48.3\%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.

CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

}, keywords = {Aged, Aged, 80 and over, Blood Coagulation Disorders, Cardiovascular Diseases, Cohort Studies, Diabetes Complications, Diabetes Mellitus, Female, Frail Elderly, Geriatric Assessment, Humans, Inflammation, Longitudinal Studies, Male}, issn = {0003-9926}, doi = {10.1001/archinte.162.20.2333}, author = {Walston, Jeremy and McBurnie, Mary Ann and Newman, Anne and Tracy, Russell P and Kop, Willem J and Hirsch, Calvin H and Gottdiener, John and Fried, Linda 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 {905, title = {The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study.}, journal = {J Am Coll Cardiol}, volume = {48}, year = {2006}, month = {2006 Jul 18}, pages = {305-11}, abstract = {

OBJECTIVES: We investigated the association between alcohol consumption and incident congestive heart failure (CHF) both overall and after adjusting for incident myocardial infarction (MI).

BACKGROUND: Moderate alcohol consumption has been associated with lower risk of CHF and MI.

METHODS: The Cardiovascular Health study, a prospective cohort study of cardiovascular disease risk factors and outcomes, followed 5,888 subjects > or =65 years old for 7 to 10 years. Cox models were used to estimate the adjusted risk of CHF by reported alcohol consumption.

RESULTS: There were 5,595 subjects at baseline at risk for incident CHF with alcohol data and 1,056 events during follow-up. Compared with abstainers, the adjusted risk of CHF was lower among subjects who reported consuming 1 to 6 drinks per week (hazard ratio [HR] 0.82, 95\% confidence interval [CI] 0.67 to 1.00, p = 0.05) and 7 to 13 drinks per week (HR 0.66, 95\% CI 0.47 to 0.91, p = 0.01). Time-dependent adjustment for incident MI altered only slightly the association between moderate alcohol consumption and CHF (for 1 to 6 drinks per week, HR 0.84, 95\% CI 0.65 to 1.04; for 7 to 13 drinks per week, HR 0.69, 95\% CI 0.49 to 0.99). Baseline former drinkers had a higher risk of CHF than abstainers (HR 1.51, p < 0.01), but those who quit during the study did not have a higher risk (HR 0.83, 95\% CI 0.66 to 1.03).

CONCLUSIONS: Moderate alcohol use is associated with a lower risk of incident CHF among older adults, even after accounting for incident MI and other factors.

}, keywords = {Aged, Alcohol Drinking, Chi-Square Distribution, Comorbidity, Female, Heart Failure, Humans, Life Style, Male, Multicenter Studies as Topic, Myocardial Infarction, Proportional Hazards Models, Risk Factors, Smoking}, issn = {1558-3597}, doi = {10.1016/j.jacc.2006.02.066}, author = {Bryson, Chris L and Mukamal, Kenneth J and Mittleman, Murray A and Fried, Linda P and Hirsch, Calvin H and Kitzman, Dalane W and Siscovick, David S} } @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 {936, title = {Inflammation biomarkers and near-term death in older men.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Mar 15}, pages = {684-95}, abstract = {

Associations of C-reactive protein (CRP) and fibrinogen with death may weaken over time. Combining both markers may improve prediction of death in older adults. In 5,828 Cardiovascular Health Study participants (United States, 1989-2000), 383 deaths (183 cardiovascular disease (CVD)) in years 1-3 (early) and 914 deaths (396 CVD) in years 4-8 (late) occurred. For men, when comparing highest to lowest quartiles, hazard ratios for early death were 4.1 (95\% confidence interval (CI): 2.7, 6.3) for CRP and 4.1 (95\% CI: 2.7, 6.4) for fibrinogen in models adjusted for CVD risk. For early CVD death, hazard ratios were 4.3 (95\% CI: 2.2, 8.4) and 3.4 (95\% CI: 1.8, 6.3), respectively. When comparing men in the highest quartiles of both biomarkers with those in the lowest, hazard ratios were 9.6 (95\% CI: 4.3, 21.1) for early death and 13.5 (95\% CI: 3.2, 56.5) for early CVD death. Associations were weaker for late deaths. For women, CRP (hazard ratio = 2.3, 95\% CI: 1.4, 3.9), but not fibrinogen (hazard ratio = 1.3, 95\% CI: 0.8, 2.2), was associated with early death. Results were similar for CVD death. Neither was associated with late deaths. CRP and fibrinogen were more strongly associated with death in older men than women and more strongly associated with early than late death. Combining both markers may identify older men at greatest risk of near-term death.

}, keywords = {Age Distribution, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Diabetes Complications, Epidemiologic Studies, Female, Fibrinogen, Follow-Up Studies, Humans, Hypercholesterolemia, Hypertension, Inflammation, Male, Middle Aged, Obesity, Population Surveillance, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Risk Factors, Sex Distribution, Smoking, Time Factors, United States}, issn = {0002-9262}, doi = {10.1093/aje/kwk057}, author = {Jenny, Nancy Swords and Yanez, N David and Psaty, Bruce M and Kuller, Lewis H and Hirsch, Calvin H and Tracy, Russell P} } @article {955, title = {Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {167}, year = {2007}, month = {2007 Apr 09}, pages = {635-41}, abstract = {

BACKGROUND: Our research group has previously shown that the geriatric syndrome of frailty is associated with features of the metabolic syndrome (MetS) on cross-sectional analysis.

METHODS: To test whether MetS and its physiologic determinants-insulin resistance as measured by homeostasis model assessment score (IR-HOMA), increased inflammation and coagulation factor levels, and elevated blood pressure-are associated with incident frailty, we studied a subcohort of participants from the Cardiovascular Health Study observed from 1989/1990 through 1998/1999: 3141 community-dwelling adults, aged 69 to 74 years, without frailty and illnesses that increase inflammation markers or mimic frailty. The association of baseline MetS, IR-HOMA, levels of inflammation and coagulation factors, and systolic blood pressure (SBP) with time to onset of frailty was adjusted for demographic and psychosocial factors and incident events. Our main outcome measure was incident frailty.

RESULTS: Metabolic syndrome was not significantly associated with incident frailty (hazard ratio, 1.16 (95\% confidence interval [CI], 0.85-1.57). On the other hand, IR-HOMA and C-reactive protein levels were associated with incident frailty: for every standard deviation increment the hazard ratio for frailty was 1.15 (95\% CI, 1.02-1.31) and 1.16 (95\% CI, 1.02-1.32), respectively. The white blood cell count and factor VIIIc levels had a borderline association. Elevated systolic blood pressure had no association. Similar trends were found for incident prefrailty, a condition that precedes frailty.

CONCLUSIONS: Two physiologic components of MetS- IR-HOMA and inflammation-are associated with incident frailty. Based on these results, IR-HOMA can be considered part of a larger process that leads to generalized decline.

}, keywords = {Aged, Aged, 80 and over, Female, Frail Elderly, Geriatrics, Humans, Inflammation, Insulin Resistance, Male, Metabolic Syndrome, Prospective Studies}, issn = {0003-9926}, doi = {10.1001/archinte.167.7.635}, author = {Barzilay, Joshua I and Blaum, Caroline and Moore, Tisha and Xue, Qian Li and Hirsch, Calvin H and Walston, Jeremy D and Fried, Linda P} } @article {1049, title = {Association between lower digit symbol substitution test score and slower gait and greater risk of mortality and of developing incident disability in well-functioning older adults.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Sep}, pages = {1618-25}, abstract = {

OBJECTIVES: To determine whether, in well-functioning older adults, a lower score on the Digit Symbol Substitution Test (DSST) and slower gait are associated with greater risk of mortality and of developing incident disability independent of other risk factors, including brain structural abnormalities (white matter hyperintensities, brain infarcts, ventricular enlargement) and whether the combination of varying levels of DSST score and gait speed are associated with a greater risk of mortality and disability than low DSST or slow gait alone.

DESIGN: Observational cohort study.

SETTING: Community.

PARTICIPANTS: Three thousand one hundred fifty-six (43\% men, 29\% black, mean age 70.4) participants in the Cardiovascular Health Study (CHS), free from stroke and physical disability and with a modified Mini-Mental State Examination (3MS) score of 80 or higher.

MEASUREMENTS: Total mortality and incident disability (self-report of any difficulty performing one or more of the six activities of daily living) ascertained over a median follow-up time of 8.4 years.

RESULTS: By the end of follow-up, 704 participants had died and 1,096 had incident disability. In Cox proportional hazards models adjusted for age, sex, race, education, cardiovascular disease, and brain magnetic resonance imaging abnormalities, lower DSST score and slower gait remained significantly associated with greater risk of mortality and of incident disability. Mortality rates were higher in those who had both low DSST score (<27 points) and slow gait (speed <1.0 m/s) than in those who had only low DSST score, only slow gait, or neither (rates per 1,000 person years (p-y): 61.2, 42.8, 20.8, and 16.3, respectively). A similar risk gradient was observed for incident disability (82.0, 57.9, 47.9, and 36.0/1,000 p-y, respectively).

CONCLUSION: In well-functioning older adults, low DSST score and slow gait, alone or in combination, could be risk factors for mortality and for developing disability, independent of other risk factors, including measures of brain integrity.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Analysis of Variance, Atrophy, Brain, Brain Diseases, Cause of Death, Cohort Studies, Disability Evaluation, Discrimination Learning, Female, Gait, Humans, Male, Memory, Short-Term, Mobility Limitation, Neuropsychological Tests, Pattern Recognition, Visual, Psychometrics, Psychomotor Performance, Risk Factors}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.01856.x}, author = {Rosano, Caterina and Newman, Anne B and Katz, Ronit and Hirsch, Calvin H and Kuller, Lewis H} } @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 {1219, title = {Physical activity and years of healthy life in older adults: results from the cardiovascular health study.}, journal = {J Aging Phys Act}, volume = {18}, year = {2010}, month = {2010 Jul}, pages = {313-34}, abstract = {

Little is known about how many years of life and disability-free years seniors can gain through exercise. Using data from the Cardiovascular Health Study, the authors estimated the extra years of life and self-reported healthy life (over 11 years) and years without impairment in activities of daily living (over 6 years) associated with quintiles of physical activity (PA) in older adults from different age groups. They estimated PA from the Minnesota Leisure Time Activities Questionnaire. Multivariable linear regression adjusted for health-related covariates. The relative gains in survival and years of healthy life (YHL) generally were proportionate to the amount of PA, greater among those 75+, and higher in men. Compared with being sedentary, the most active men 75+ had 1.49 more YHL (95\% CI: 0.79, 2.19), and the most active women 75+ had 1.06 more YHL (95\% CI: 0.44, 1.68). Seniors over age 74 experience the largest relative gains in survival and healthy life from physical activity.

}, keywords = {Activities of Daily Living, Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Exercise, Female, Health Behavior, Health Status, Humans, Leisure Activities, Life Style, Male, Quality-Adjusted Life Years, Sex Factors}, issn = {1063-8652}, author = {Hirsch, Calvin H and Diehr, Paula and Newman, Anne B and Gerrior, Shirley A and Pratt, Charlotte and Lebowitz, Michael D and Jackson, Sharon A} } @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 {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 {6167, title = {Impact of inflammatory biomarkers on relation of high density lipoprotein-cholesterol with incident coronary heart disease: cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {231}, year = {2013}, month = {2013 Dec}, pages = {246-51}, abstract = {

BACKGROUND: Inflammatory factors and low HDL-C relate to CHD risk, but whether inflammation attenuates any protective association of high HDL-C is unknown.

OBJECTIVE: Investigate inflammatory markers{\textquoteright} individual and collective impact on the association of HDL-C with incident coronary heart disease (CHD).

METHODS: In 3888 older adults without known cardiovascular disease (CVD), we examined if the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and lipoprotein-associated phospholipase A2 (Lp-PLA$_{2}$) modify the relation of HDL-C with CHD. HDL-C, CRP, IL-6, and Lp-PLA$_{2}$ values were grouped as using gender-specific tertiles. Also, an inflammation index of z-score sums for CRP, IL-6, and Lp-PLA$_{2}$ was categorized into tertiles. We calculated CHD incidence for each HDL-C/inflammation group and performed Cox regression, adjusted for standard CVD risk factors and triglycerides to examine the relationship of combined HDL-C-inflammation groups with incident events.

RESULTS: CHD incidence (per 1000 person years) was higher for higher levels of CRP, IL-6, and the index, and lower for higher levels of HDL-C. Compared to high HDL-C/low-inflammation categories (referent), adjusted HRs for incident CHD were increased for those with high HDL-C and high CRP (HR = 1.50, p < 0.01) or highest IL-6 tertile (HR = 1.40, p < 0.05), but not with highest Lp-PLA$_{2}$ tertile. Higher CHD incidence was similarly seen for those with intermediate or low HDL-C accompanied by high CRP, high IL-6, or a high inflammatory index.

CONCLUSION: The protective relation of high HDL-C for incident CHD appears to be attenuated by greater inflammation.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Inflammation, Interleukin-6, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.08.036}, author = {Tehrani, David M and Gardin, Julius M and Yanez, David and Hirsch, Calvin H and Lloyd-Jones, Donald M and Stein, Phyllis K and Wong, Nathan D} } @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 {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 {7648, title = {Predicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults.}, journal = {Gerontol Geriatr Med}, volume = {1}, year = {2015}, month = {2015 Jan-Dec}, pages = {2333721415605989}, abstract = {

To create personalized estimates of future health and ability status for older adults.Data came from the Cardiovascular Health Study (CHS), a large longitudinal study. Outcomes included years of life, years of healthy life (based on self-rated health), years of able life (based on activities of daily living), and years of healthy and able life. We developed regression estimates using the demographic and health characteristics that best predicted the four outcomes. Internal and external validity were assessed.A prediction equation based on 11 variables accounted for about 40\% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. The resulting CHS Healthy Life Calculator (CHSHLC) is available at http://healthylifecalculator.org.CHSHLC provides a well-documented estimate of future years of healthy and able life for older adults, who may use it in planning for the future.

}, issn = {2333-7214}, doi = {10.1177/2333721415605989}, author = {Diehr, Paula and Diehr, Michael and Arnold, Alice and Yee, Laura M and Odden, Michelle C and Hirsch, Calvin H and Thielke, Stephen and Psaty, Bruce M and Johnson, W Craig and Kizer Md, Jorge R and Newman, Anne} } @article {7117, title = {Cardiovascular Disease, Mortality Risk, and Healthcare Costs by Lipoprotein(a) Levels According to Low-density Lipoprotein Cholesterol Levels in Older High-risk Adults.}, journal = {Clin Cardiol}, volume = {39}, year = {2016}, month = {2016 Jul}, pages = {413-20}, abstract = {

BACKGROUND: The value of lipoprotein(a) (Lp[a]) for predicting cardiovascular disease (CVD) across low-density lipoprotein cholesterol (LDL-C) is uncertain.

HYPOTHESIS: In older high-risk adults, higher LDL and Lp(a) combined would be associated with higher CVD risk and more healthcare costs.

METHODS: We included 3251 high-risk subjects (prior CVD, diabetes, or 10-year Framingham CVD risk >20\%) age >=65 years from the Cardiovascular Health Study and examined the relation of Lp(a) tertiles with incident CVD, coronary heart disease (CHD), and all-cause mortality within LDL-C strata (spanning <70 mg/dL to >=160 mg/dL). We also examined 1-year all-cause and CVD healthcare costs from Medicare claims.

RESULTS: Over a 22.5-year follow-up, higher Lp(a) levels predicted CVD and total mortality (both standardized hazard ratio [HR]: 1.06, P < 0.01), whereas higher LDL-C levels predicted higher CHD (standardized HR: 1.09, P < 0.01) but lower total mortality (standardized HR: 0.94, P < 0.001). Adjusted HRs in the highest (vs lowest) tertile of Lp(a) level were 1.95 (P = 0.06) for CVD events and 2.68 (P = 0.03) for CHD events when LDL-C was <70 mg/dL. One-year all-cause healthcare costs were increased for Lp(a) ($771 per SD of 56 {\textmu}g/mL [P = 0.03], $1976 for Lp(a) 25-64 {\textmu}g/mL vs <25 {\textmu}g/mL [P = 0.02], and $1648 for Lp(a) >=65 {\textmu}g/mL vs <25 {\textmu}g/mL [P = 0.054]) but not LDL-C.

CONCLUSIONS: In older high-risk adults, increased Lp(a) levels were associated with higher CVD risk, especially in those with LDL-C <70 mg/dL, and with higher healthcare costs.

}, issn = {1932-8737}, doi = {10.1002/clc.22546}, author = {Zhao, Yanglu and Delaney, Joseph A and Quek, Ruben G W and Gardin, Julius M and Hirsch, Calvin H and Gandra, Shravanthi R and Wong, Nathan D} } @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 {7002, title = {Incident Atrial Fibrillation and Disability-Free Survival in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Apr}, pages = {838-43}, abstract = {

OBJECTIVES: To assess the associations between incident atrial fibrillation (AF) and disability-free survival and risk of disability.

DESIGN: Prospective cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older and enrolled in fee-for-service Medicare followed between 1991 and 2009 (MN = 4,046). Individuals with prevalent AF, activity of daily living (ADL) disability, or a history of stroke or heart failure at baseline were excluded.

MEASUREMENTS: Incident AF was identified according to annual study electrocardiogram, hospital discharge diagnosis, or Medicare claims. Disability-free survival was defined as survival free of ADL disability (any difficulty or inability in bathing, dressing, eating, using the toilet, walking around the home, or getting out of a bed or chair). ADLs were assessed at annual study visits or in a telephone interview. Association between incident AF and disability-free survival or risk of disability was estimated using Cox proportional hazards models.

RESULTS: Over an average of 7.0 years of follow-up, 660 individuals (16.3\%) developed incident AF, and 3,112 (77\%) became disabled or died. Incident AF was associated with shorter disability-free survival (hazard ratio (HR) for death or ADL disability = 1.71, 95\% confidence interval (CI) = 1.55-1.90) and a higher risk of ADL disability (HR = 1.36, 95\% CI = 1.18-1.58) than in individuals with no history of AF. This association persisted after adjustment for interim stroke and heart failure.

CONCLUSION: These results suggest that AF is a risk factor for shorter functional longevity in older adults, independent of other risk factors and comorbid conditions.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Atrial Fibrillation, Disability Evaluation, Electrocardiography, Female, Geriatric Assessment, Humans, Incidence, Longevity, Longitudinal Studies, Male, Medicare, Prevalence, Prospective Studies, Survival Rate, United States}, issn = {1532-5415}, doi = {10.1111/jgs.14037}, author = {Wallace, Erin R and Siscovick, David S and Sitlani, Colleen M and Dublin, Sascha and Mitchell, Pamela H and Odden, Michelle C and Hirsch, Calvin H and Thielke, Stephen and Heckbert, Susan R} } @article {7244, title = {Risk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study.}, journal = {Cerebrovasc Dis Extra}, volume = {6}, year = {2016}, month = {2016 Nov 16}, pages = {129-139}, abstract = {

BACKGROUND: Population-based risk factors for carotid artery revascularization are not known. We investigated the association between demographic and clinical characteristics and incident carotid artery revascularization in a cohort of older adults.

METHODS: Among Cardiovascular Health Study participants, a population-based cohort of 5,888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), 5,107 participants without a prior history of carotid endarterectomy (CEA) or cerebrovascular disease had a carotid ultrasound at baseline and were included in these analyses. Cox proportional hazards multivariable analysis was used to determine independent risk factors for incident carotid artery revascularization.

RESULTS: Over a mean follow-up of 13.5 years, 141 participants underwent carotid artery revascularization, 97\% were CEA. Baseline degree of stenosis and incident ischemic cerebral events occurring during follow-up were the strongest predictors of incident revascularization. After adjustment for these, factors independently associated with an increased risk of incident revascularization were: hypertension (HR 1.53; 95\% CI: 1.05-2.23), peripheral arterial disease (HR 2.57; 95\% CI: 1.34-4.93), and low-density lipoprotein cholesterol (HR 1.23 per standard deviation [SD] increment [35.4 mg/dL]; 95\% CI: 1.04-1.46). Factors independently associated with a lower risk of incident revascularization were: female gender (HR 0.51; 95\% CI: 0.34-0.77) and older age (HR 0.69 per SD increment [5.5 years]; 95\% CI: 0.56-0.86).

CONCLUSIONS: Even after accounting for carotid stenosis and incident cerebral ischemic events, carotid revascularization is related to age, gender, and cardiovascular risk factors. Further study of these demographic disparities and the role of risk factor control is warranted.

}, issn = {1664-5456}, doi = {10.1159/000452426}, author = {Garg, Parveen K and Koh, Willam J H and Delaney, Joseph A and Halm, Ethan A and Hirsch, Calvin H and Longstreth, William T and Mukamal, Kenneth J and Kucharska-Newton, Anna and Polak, Joseph F and Curtis, Lesley} } @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 {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 {8108, title = {Trends in Blood Pressure and High-Sensitivity Cardiac Troponin-T with Cardiovascular Disease: The Cardiovascular Health Study.}, journal = {Am J Hypertens}, year = {2019}, month = {2019 Jun 21}, abstract = {

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) is individually associated with incident hypertension (HTN) and cardiovascular disease (CVD) events. We hypothesize that the increases in hs-cTnT with increases in blood pressure will be related to higher incidence of CVD.

METHODS: The Cardiovascular Health Study is a longitudinal cohort of older adults. Those with hs-cTnT data and CVD risk factors at baseline and follow-up (2-3 years later) were stratified based on systolic blood pressure (SBP) (optimal: <120 mmHg, intermediate: 120-139 mmHg, elevated: >=140 mmHg) and hs-cTnT (undetectable: <5 ng/L, detectable: 5-13 ng/L, elevated: >=14 ng/L) categories. SBP and hs-cTnT were classified as increased or decreased if they changed categories between exams, and stable if they did not. Cox regression evaluated incident CVD events over an average 9 year follow-up.

RESULTS: Among 2219 adults, 510 (23.0 \%) had decreased hs-cTnT, 1,279 (57.6 \%) had stable hs-cTnT, and 430 (19.4 \%) had increased hs-cTnT. Those with increased hs-cTnT had a higher CVD risk with stable SBP (HR: 1.28 [1.04-1.57], p=0.02) or decreased SBP (HR: 1.57 [1.08-2.28], p=0.02) compared to those within the same SBP group but a stable hs-cTnT. In those with lower SBP at follow-up, there was an inverse relation between DBP and risk of CVD events in those with increased hs-cTnT (HR: 0.44 per 10 mmHg increase, p<0.01).

CONCLUSION: An increase in hs-cTnT over time is associated with a higher risk of CVD even when the blood pressure is stable or decreases over time.

}, issn = {1941-7225}, doi = {10.1093/ajh/hpz102}, author = {Tehrani, David M and Fan, Wenjun and Nambi, Vijay and Gardin, Julius and Hirsch, Calvin H and Amsterdam, Ezra and deFilippi, Christopher R and Polonsky, Tamar and Wong, Nathan D} } @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 {8707, title = {Associations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.}, journal = {J Am Heart Assoc}, volume = {10}, year = {2021}, month = {2021 Mar 16}, pages = {e019135}, abstract = {

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n-6 and n-3], and fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996-1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow-up of 11.7~years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95\% CI, 0.59-0.98; =0.0328) and dihomo-γ-linolenic acid (20:3n-6) was positively associated with CHD mortality (HR, 1.34; 95\% CI, 1.02-1.76; =0.0351). Elaidic acid (18:1n-7) was positively associated with incident nonfatal MI (HR, 1.46; 95\% CI, 1.01-2.12; =0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo-γ-linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.

}, issn = {2047-9980}, doi = {10.1161/JAHA.120.019135}, author = {Huang, Neil K and B{\r u}zkov{\'a}, Petra and Matthan, Nirupa R and Djouss{\'e}, Luc and Hirsch, Calvin H and Kizer, Jorge R and Longstreth, W T and Mukamal, Kenneth J and Lichtenstein, Alice H} } @article {8834, title = {Cardiovascular damage phenotypes and all-cause and CVD mortality in older adults.}, journal = {Ann Epidemiol}, volume = {63}, year = {2021}, month = {2021 Jul 30}, pages = {35-40}, abstract = {

PURPOSE: The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults.

METHODS: Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality.

RESULTS: The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59\%), cardio-renal (11\%), cardiac (15\%), multisystem morbidity (6\%), and inflammatory (9\%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95\% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95\% CI: 3.95, 6.06).

CONCLUSIONS: Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2021.07.012}, author = {Miller, Lindsay M and Wu, Chenkai and Hirsch, Calvin H and Lopez, Oscar L and Cushman, Mary and Odden, Michelle C} } @article {9043, title = {Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 01 04}, pages = {e023707}, abstract = {

Background Aging is associated with central fat redistribution and skeletal muscle decline, yet the relationships of tissue compartments with heart failure (HF) remain incompletely characterized. We assessed the contribution of body composition to incident HF in elders. Methods and Results Participants from 2 older cohorts who completed dual-energy X-ray absorptiometry (DEXA) and, in one cohort, computed tomography were included. We evaluated associations with incident HF for DEXA principal components (PCs) and total lean, appendicular lean, total fat and trunk fat mass; and for computed tomography measures of abdominal visceral and subcutaneous fat, thigh muscle, intermuscular fat area and thigh muscle density. DEXA analysis included 3621, and computed tomography analysis 2332 participants. During median follow-up of 11.8~years, 927 participants developed HF. DEXA principal components showed no relationship with HF. After adjustment for height, weight, and cardiovascular risk factors, total lean mass was near significantly associated with higher HF (hazard ratio [HR], 1.25 per SD [1.00-1.56]), whereas total fat mass and thigh muscle density were significantly related to lower HF (HR, 0.82 [0.68-0.99] and HR, 0.87 [0.78-0.97], respectively). Patterns were similar for HF subtypes. The relationships with HF for total lean and fat mass were attenuated after adjusting for intercurrent atrial fibrillation or excluding high natriuretic peptide levels. Conclusions Total lean mass was positively associated, while total fat mass and thigh muscle density were inversely associated, with incident HF. These findings highlight the limitations of DEXA for assessment of HF risk in elders and support the preeminence of computed tomography-measured skeletal muscle quality over mass as a determinant of HF incidence.

}, keywords = {Absorptiometry, Photon, Aged, Aging, Body Composition, Body Mass Index, Heart Failure, Humans, Muscle, Skeletal, Prospective Studies}, issn = {2047-9980}, doi = {10.1161/JAHA.121.023707}, author = {Zhang, Lili and Bartz, Traci M and Santanasto, Adam and Djouss{\'e}, Luc and Mukamal, Kenneth J and Forman, Daniel E and Hirsch, Calvin H and Newman, Anne B and Gottdiener, John S and Kizer, Jorge R} } @article {9256, title = {Circulating Androgen Concentrations and Risk of Incident Heart Failure in Older Men: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 Nov}, pages = {e026953}, abstract = {

Background Circulating androgen concentrations in men decline with age and have been linked to diabetes and atherosclerotic cardiovascular disease (ASCVD). A similar relationship has been reported for low total testosterone and incident heart failure (HF) but remains unstudied for free testosterone or the more potent androgen dihydrotestosterone (DHT). We hypothesized that total/free testosterone are inversely related, sex hormone-binding globulin is positively related, and total/free DHT bear a U-shaped relationship with incident HF. Methods and Results In a sample of men from the CHS (Cardiovascular Health Study) without atherosclerotic cardiovascular disease or HF, serum testosterone and DHT concentrations were measured by liquid chromatography-tandem mass spectrometry, and sex hormone-binding globulin by immunoassay. Free testosterone or DHT was calculated from total testosterone or total DHT, sex hormone-binding globulin, and albumin. We used Cox regression to estimate relative risks of HF after adjustment for potential confounders. In 1061 men (aged 76{\textpm}5 years) followed for a median of 9.6 years, there were 368 HF events. After adjustment, lower calculated free testosterone was significantly associated with higher risk of HF (hazard ratio [HR], 1.14 [95\% CI, 1.01-1.28]). Risk estimates for total testosterone (HR, 1.12 [95\% CI, 0.99-1.26]), total DHT (HR, 1.10 [95\% CI, 0.97-1.24]), calculated free dihydrotestosterone (HR, 1.09 [95\% CI, 0.97-1.23]), and sex hormone-binding globulin (HR, 1.07 [95\% CI, 0.95-1.21]) were directionally similar but not statistically significant. Conclusions Calculated free testosterone was inversely associated with incident HF, suggesting a contribution of testosterone deficiency to HF incidence among older men. Additional research is necessary to determine whether testosterone replacement therapy might be an effective strategy to lower HF risk in older men.

}, keywords = {Aged, Androgens, Cardiovascular Diseases, Dihydrotestosterone, Estradiol, Heart Failure, Humans, Male, Sex Hormone-Binding Globulin, Testosterone}, issn = {2047-9980}, doi = {10.1161/JAHA.122.026953}, author = {Njoroge, Joyce N and Tressel, William and Biggs, Mary L and Matsumoto, Alvin M and Smith, Nicholas L and Rosenberg, Emily and Hirsch, Calvin H and Gottdiener, John S and Mukamal, Kenneth J and Kizer, Jorge R} }